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Clinical Trial Results:
A Phase I/II, Multicenter, Open-Label, Multi-Arm Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Activity of Idasanutlin in Combination With Either Chemotherapy or Venetoclax in the Treatment of Pediatric and Young Adult Patients With Relapsed/Refractory Acute Leukemias or Solid Tumors

Summary
EudraCT number	2018-004579-11
Trial protocol	GB FR ES NL
Global end of trial date	06 May 2024

Results information
Results version number	v1
This version publication date	20 Nov 2024
First version publication date	20 Nov 2024
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

GO40871

ISRCTN number

US NCT number

NCT04029688

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4058

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001489-PIP01-13

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

06 May 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

06 May 2024

Was the trial ended prematurely?

Yes

Main objective of the trial

This study aims to evaluate the safety, tolerability, and pharmacokinetics (PK) of idasanutlin as a single agent and the safety, tolerability, PK, and preliminary efficacy of idasanutlin in combination with either chemotherapy or venetoclax in children and young adults with acute leukemias or solid tumors that are recurrent or refractory to standard therapy.

Protection of trial subjects

All study subjects were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Jan 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 1

Country: Number of subjects enrolled

Spain: 11

Country: Number of subjects enrolled

France: 5

Country: Number of subjects enrolled

United Kingdom: 13

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

United States: 7

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants with relapsed/refractory solid tumors took part in the study across 12 investigative sites in 6 countries (United States, Spain, United Kingdom, France, Canada, and Netherlands) from January 27, 2020 to May 6, 2024.

Screening details

Study had 3 parts. Part 1a: Idasanutlin dose escalation in pediatric participants with solid tumors. Part 1b: Combination safety run-in, Part 2: Early efficacy & Part 3: Expansion in participants with neuroblastoma/acute leukemia. Leukemia cohorts in Part 1b & all cohorts in Parts 2 & 3 weren't initiated due to early study termination by sponsor.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part 1a: Idasanutlin 2 milligrams/kilograms (mg/kg)

Arm description

Participants with solid tumors received idasanutlin 2 mg/kg orally once daily (QD) on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Idasanutlin

Investigational medicinal product code

RG7388; RO5503781-020

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Idasanutlin 2 mg/kg administered orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Part 1a: Idasanutlin 3 mg/kg

Arm description

Participants with solid tumors received idasanutlin 3 mg/kg orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Idasanutlin

Investigational medicinal product code

RG7388; RO5503781-020

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Idasanutlin 3 mg/kg administered orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Part 1a: Idasanutlin 4.5 mg/kg

Arm description

Participants with solid tumors received idasanutlin 4.5 mg/kg orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Idasanutlin

Investigational medicinal product code

RG7388; RO5503781-020

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Idasanutlin 4.5 mg/kg administered orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Part 1a: Idasanutlin 6.4 mg/kg

Arm description

Participants with solid tumors received idasanutlin 6.4 mg/kg orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Idasanutlin

Investigational medicinal product code

RG7388; RO5503781-020

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Idasanutlin 6.4 mg/kg administered orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Part 1a: Idasanutlin 8 mg/kg

Arm description

Participants with solid tumors received idasanutlin 8 mg/kg orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Idasanutlin

Investigational medicinal product code

RG7388; RO5503781-020

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Idasanutlin 8 mg/kg administered orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy

Arm description

Participants with neuroblastoma received idasanutlin 2.8 mg/kg orally in combination with cyclophosphamide 200 milligrams per square meter (mg/m^2) and topotecan 0.6 mg/m^2 as an IV infusion QD on Days 1-5 of each 28-day cycle. Treatment was administered until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Idasanutlin

Investigational medicinal product code

RG7388; RO5503781-020

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Idasanutlin 2.8 mg/kg administered orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Investigational medicinal product name

Topotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Topotecan 0.6 mg/m^2 was administered as an IV infusion until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 200 mg/m^2 was administered as an IV infusion until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy

Arm description

Participants with neuroblastoma received idasanutlin, 3.6 mg/kg orally, in combination with cyclophosphamide 250 mg/m^2 as and topotecan 0.75 mg/m^2 as an IV infusion QD on Days 1-5 of each 28-day cycle. Treatment was administered until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Idasanutlin

Investigational medicinal product code

RG7388; RO5503781-020

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Idasanutlin 3.6 mg/kg administered orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Investigational medicinal product name

Topotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Topotecan 0.75 mg/m^2 was administered as an IV infusion until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 250 mg/m^2 was administered as an IV infusion until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax

Arm description

Participants with neuroblastoma (first 3) received idasanutlin, 3.6 mg/kg orally QD on Days 1-5, in combination with venetoclax 400 milligrams (mg) adult dose equivalent (adjusted by body weight) on Days 1-28 of each 28-day cycle. After the first three participants were treated, the schedule was modified as idasanutlin, 3.6 mg/kg orally QD on Days 1-5 and venetoclax 400 mg (adult dose equivalent) on Days 1-14 of a each 28-day cycle for the next 3 participants enrolled in this arm. Treatment was administered until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

GDC-0199/ABT-0199

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax 400 milligrams (mg) adult dose equivalent (adjusted by body weight) was administered on Days 1-28 or on Days 1-14 of each 28-day cycle.

Investigational medicinal product name

Idasanutlin

Investigational medicinal product code

RG7388; RO5503781-020

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Idasanutlin 3.6 mg/kg administered orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Number of subjects in period 1	Part 1a: Idasanutlin 2 milligrams/kilograms (mg/kg)	Part 1a: Idasanutlin 3 mg/kg	Part 1a: Idasanutlin 4.5 mg/kg	Part 1a: Idasanutlin 6.4 mg/kg	Part 1a: Idasanutlin 8 mg/kg	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Started	8	3	6	3	6	3	3	6
Completed	0	0	0	0	0	0	0	0
Not completed	8	3	6	3	6	3	3	6
Consent withdrawn by subject	-	-	-	1	-	-	-	-
Death	8	3	6	2	5	-	2	3
Study Terminated by Sponsor	-	-	-	-	1	3	1	3

Baseline characteristics

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Reporting group title

Part 1a: Idasanutlin 2 milligrams/kilograms (mg/kg)

Reporting group description

Reporting group title

Part 1a: Idasanutlin 3 mg/kg

Reporting group description

Reporting group title

Part 1a: Idasanutlin 4.5 mg/kg

Reporting group description

Reporting group title

Part 1a: Idasanutlin 6.4 mg/kg

Reporting group description

Reporting group title

Part 1a: Idasanutlin 8 mg/kg

Reporting group description

Reporting group title

Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy

Reporting group description

Reporting group title

Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy

Reporting group description

Reporting group title

Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax

Reporting group description

Reporting group values	Part 1a: Idasanutlin 2 milligrams/kilograms (mg/kg)	Part 1a: Idasanutlin 3 mg/kg	Part 1a: Idasanutlin 4.5 mg/kg	Part 1a: Idasanutlin 6.4 mg/kg	Part 1a: Idasanutlin 8 mg/kg	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax	Total
Number of subjects	8	3	6	3	6	3	3	6	38
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	7.6 ( 5.0 )	11.3 ( 3.2 )	7.3 ( 3.9 )	15.0 ( 1.7 )	11.5 ( 5.0 )	15.0 ( 11.4 )	5.3 ( 1.2 )	8.0 ( 3.8 )	-
Sex: Female, Male
Units: participants
Female	5	1	2	1	3	1	1	2	16
Male	3	2	4	2	3	2	2	4	22
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0	0
Asian	0	0	0	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0	0
Black or African American	1	0	1	0	0	0	1	0	3
White	4	2	2	3	3	3	1	3	21
More than one race	0	0	0	0	0	0	0	0	0
Unknown or Not Reported	3	1	3	0	3	0	1	3	14
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	2	1	1	0	0	0	1	1	6
Not Hispanic or Latino	3	1	2	3	4	3	2	2	20
Unknown or Not Reported	3	1	3	0	2	0	0	3	12

End points

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Reporting group title

Part 1a: Idasanutlin 2 milligrams/kilograms (mg/kg)

Reporting group description

Reporting group title

Part 1a: Idasanutlin 3 mg/kg

Reporting group description

Reporting group title

Part 1a: Idasanutlin 4.5 mg/kg

Reporting group description

Reporting group title

Part 1a: Idasanutlin 6.4 mg/kg

Reporting group description

Reporting group title

Part 1a: Idasanutlin 8 mg/kg

Reporting group description

Reporting group title

Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy

Reporting group description

Reporting group title

Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy

Reporting group description

Reporting group title

Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax

Reporting group description

Subject analysis set title

Part 1a: Idasanutlin 3.8 mg/kg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received idasanutlin 3.8 mg/kg orally QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Subject analysis set title

Part 2 (Neuroblastoma)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with neuroblastoma were planned to be enrolled in various cohorts in Part 2. Participants with neuroblastoma were to receive idasanutlin in combination with cyclophosphamide 250 mg/m^2 and topotecan 0.75 mg/m^2 on Days 1-5 of each 28-day cycle or venetoclax 400 mg.

Subject analysis set title

Part 3: Expansion (Neuroblastoma)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Potential expansion of idasanutlin combination cohorts for participants with TP53 WT neuroblastoma from Parts 1b and 2, meeting the pre-defined efficacy criteria were planned to be initiated in Part 3.

Subject analysis set title

Part 1 (ALL)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with ALL were planned to be enrolled in various cohorts in Part 1 to receive idasanutlin in combination with venetoclax 400 mg.

Subject analysis set title

Part 2 (ALL)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with ALL were planned to be enrolled in Part 2 to receive idasanutlin plus venetoclax 600 mg on Days 1-5 of each 28-day cycle.

Subject analysis set title

Part 3: Expansion (ALL)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Potential expansion of idasanutlin combination cohorts for participants with TP35 WT ALL from Parts 1b and 2 meeting the pre-defined efficacy criteria were planned to be initiated in Part 3.

Subject analysis set title

Part 1 (Leukemia)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) were planned to be enrolled in various cohorts in Part 1. Participants with AML and ALL were to receive idasanutlin in combination venetoclax 400 mg. Participants with AML were to receive idasanutlin plus fludarabine 30 mg/m^2 and high dose cytarabine 2000 mg/m^2 (FLA) on Days 1-5 of each 28-day cycle.

Subject analysis set title

Part 2 (Leukemia)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with AML or ALL were planned to be enrolled in various cohorts in Part 2. Participants with AML were to receive idasanutlin plus fludarabine 30 mg/m^2 and high dose cytarabine 2000 mg/m^2 (FLA) on Days 1-5 of each 28-day cycle . Participants with ALL were to receive idasanutlin plus venetoclax 600 mg on Days 1-5 of each 28-day cycle.

Subject analysis set title

Part 3: Expansion (Leukemia)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Potential expansion of idasanutlin combination cohorts for participants with TP35 WT AML or ALL from Parts 1b and 2 meeting the pre-defined efficacy criteria were planned to be initiated in Part 3.

Primary: Part 1a and 1b: Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5.0)

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End point title

Part 1a and 1b: Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5.0) ^[1]

End point description

AE=untoward medical occurrence in participant administered a pharmaceutical product & regardless of causal relationship with the treatment. AE=unfavorable & unintended sign, symptom/disease temporally associated with use of investigational product, whether or not considered related to it. AEs were graded per NCI CTCAE v5.0. Grade 1=Mild; asymptomatic/mild; clinical/diagnostic observations; intervention not indicated; Grade 2=Moderate; minimal, local/non-invasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL); Grade 3=Severe/medically significant, but not immediately life-threatening; hospitalization/prolongation of hospitalization indicated; disabling; limiting self-care ADL; Grade 4=Life-threatening consequences/urgent intervention indicated; Grade 5=Death related to AE. Safety evaluable (SE) population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not.

End point type

Primary

End point timeframe

From screening up to 30 days after study treatment discontinuation (approximately 7 months)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistics was planned for this endpoint.

End point values	Part 1a: Idasanutlin 2 milligrams/kilograms (mg/kg)	Part 1a: Idasanutlin 3 mg/kg	Part 1a: Idasanutlin 4.5 mg/kg	Part 1a: Idasanutlin 6.4 mg/kg	Part 1a: Idasanutlin 8 mg/kg	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Number of subjects analysed	8	3	6	3	6	3	3	6
Units: participants
AEs, Any Grade	8	3	6	3	6	3	3	6
AEs, Grade 1	1	0	0	0	0	0	0	0
AEs, Grade 2	0	0	0	0	0	0	0	1
AEs, Grade 3	2	1	3	2	1	0	0	3
AEs, Grade 4	5	2	3	1	5	3	3	1
AEs, Grade 5	0	0	0	0	0	0	0	1

No statistical analyses for this end point

Primary: Parts 1a and 1b: Number of Participants With Dose-Limiting Toxicities (DLTs)

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End point title

Parts 1a and 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) ^[2]

End point description

DLTs were assessed for single agent idasanutlin & idasanutlin plus chemotherapy or venetoclax. DLT=AE during DLT assessment window & assessed by investigator as related/possibly related to idasanutlin. AE=untoward medical occurrence in participant administered a pharmaceutical product regardless of causal relationship with the treatment. Following events were considered DLTs: treatment-related death; elevation of serum hepatic transaminase; severe liver injury, in absence of cholestasis/other causes of hyperbilirubinemia; non-hematologic toxicity Grade ≥3; nausea, vomiting/diarrhea if Grade 3 severity lasts >than 24 hrs after initiation of supportive care measures, if Grade 4/higher; hematologic toxicity; event resulting in a dose delay beyond Day 42. DLT-evaluable population=included all participants enrolled in Part 1 who either completed at least 80% of prescribed idasanutlin dose & DLT observation window in Cycle 1 OR experienced a DLT in Cycle 1 of dose-escalation phase.

End point type

Primary

End point timeframe

Cycle 1 (one cycle is 28 days)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistics was planned for this endpoint.

End point values	Part 1a: Idasanutlin 2 milligrams/kilograms (mg/kg)	Part 1a: Idasanutlin 3 mg/kg	Part 1a: Idasanutlin 4.5 mg/kg	Part 1a: Idasanutlin 6.4 mg/kg	Part 1a: Idasanutlin 8 mg/kg	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Number of subjects analysed	8	3	6	3	6	3	3	6
Units: participants	0	0	1	0	4	1	2	0

No statistical analyses for this end point

Primary: Part 1b: Objective Response Rate (ORR) in Participants With TP53 Wild Type (WT) Neuroblastoma Assessed According to International Neuroblastoma Response Criteria (INRC)

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End point title

Part 1b: Objective Response Rate (ORR) in Participants With TP53 Wild Type (WT) Neuroblastoma Assessed According to International Neuroblastoma Response Criteria (INRC) ^[3] ^[4]

End point description

ORR=percentage of participants with complete response (CR)/partial response (PR) at any time during study treatment, on 2 consecutive occasions ≥4 weeks apart, as determined by investigator per INRC. Primary tumor: CR= <10 millimeters(mm) residual soft tissue (ST) at primary site (PS) & complete resolution of meta-iodobenzylguanidine (MIBG)/fluorodeoxyglucose-positron emission tomography (FDG-PET) uptake at PS. PR= ≥30% decrease in longest diameter (LD) of PS & MIBG/FDG-PET uptake at PS stable, improved/resolved. ST & bone metastases: CR=resolution of all disease sites; PR=≥30% decrease in sum of non-primary target lesions, with no new lesions/≥50% reduction in MIBG score/in number of FDG-PET–avid bone lesions; Bone marrow: CR=no tumor infiltration on reassessment. Participants in SE population with TP53 WT tumor per central testing were analyzed for this endpoint. SE population=participants who received any amount of study treatment, whether prematurely withdrawn from study/not.

End point type

Primary

End point timeframe

From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistics was planned for this endpoint.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1b only.

End point values	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Number of subjects analysed	2	3	4
Units: percentage of participants
number (confidence interval 95%)	0 (0.0 to 84.19)	33.3 (0.84 to 90.37)	0 (0.0 to 60.24)

No statistical analyses for this end point

Primary: Parts 2 and 3: ORR in Participants With TP53 WT Neuroblastoma Assessed According to INRC

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End point title

Parts 2 and 3: ORR in Participants With TP53 WT Neuroblastoma Assessed According to INRC ^[5]

End point description

ORR was defined as the percentage of participants with CR or PR at any time during study treatment, on 2 consecutive occasions ≥ 4 weeks apart, as determined by the investigator per INRC. Primary tumor: CR = <10 mm residual soft tissue at primary site and complete resolution of MIBG or FDG-PET uptake at primary site. PR = ≥ 30% decrease in longest diameter of primary site and MIBG or FDG-PET uptake at primary site stable, improved, or resolved. Soft tissue & bone metastases: CR = resolution of all disease sites; PR = ≥30% decrease in sum of non-primary target lesions, with no new lesions or ≥50% reduction in MIBG score or in number of FDG-PET–avid bone lesions; Bone marrow: CR = no tumor infiltration on reassessment. The study was terminated before initiation of Parts 2 and 3 as per sponsor’s decision. Hence no data were collected, and this outcome measure was not assessed or analyzed.

End point type

Primary

End point timeframe

Up to approximately 29 months

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistics was planned for this endpoint.

End point values	Part 2 (Neuroblastoma)	Part 3: Expansion (Neuroblastoma)
Number of subjects analysed	0 ^[6]	0 ^[7]
Units: percentage of participants
number (confidence interval 95%)	( to )	( to )

Notes
[6] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.
[7] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.

No statistical analyses for this end point

Primary: Parts 2 and 3: Minimal Residual Disease (MRD) - Negative Rate in Participants With ALL

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End point title

Parts 2 and 3: Minimal Residual Disease (MRD) - Negative Rate in Participants With ALL ^[8]

End point description

MRD – negative rate was defined as percentage of participants with ALL who have an MRD value < 0.01%, as measured by next-generation sequencing (NGS), within 2 cycles of study treatment. The study was terminated before initiation of Parts 2 and 3 as per sponsor’s decision. Hence no data were collected, and this endpoint was not assessed or analyzed.

End point type

Primary

End point timeframe

Up to Cycle 2 (cycle length=28 days) (approximately 8 weeks)

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistics was planned for this endpoint.

End point values	Part 2 (ALL)	Part 3: Expansion (ALL)
Number of subjects analysed	0 ^[9]	0 ^[10]
Units: percentage of participants
number (confidence interval 95%)	( to )	( to )

Notes
[9] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.
[10] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.

No statistical analyses for this end point

Primary: Parts 2 and 3: Complete Remission Rate (CRR) in Participants With TP53 WT Leukemia Participants

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End point title

Parts 2 and 3: Complete Remission Rate (CRR) in Participants With TP53 WT Leukemia Participants ^[11]

End point description

CRR = percentage of participants with morphologic complete remission (CR), complete remission with incomplete blood count recovery (CRi), or complete remission with incomplete platelet count recovery (CRp) within 2 cycles of study treatment. CR=Bone marrow blasts <5% (AML) & no evidence of circulating blasts (ALL); absence of blasts with Auer rods (AML); absence of extramedullary disease; absolute neutrophil count (ANC) >1.0*10^9/liter (L) [1000/microliter (µL)]; platelet count > 100*10^9/L (100,000/µL); no transfusions for a minimum of 1 week (AML and ALL). CRi= All CR criteria except for ANC <1.0*10^9/L[1000/µL] or insufficient recovery of platelet count <100* 10^9/L [100,000/µL] (AML and ALL). CRp= All CR criteria except for ANC >1.0*10^9/L[1000/µL]) or but with insufficient recovery of platelet (<100* 10^9/L [100,000/µL]) (ALL). Study was terminated before initiation of Parts 2 and 3 as per sponsor’s decision. Hence no data were collected, assessed/analyzed for this endpoint.

End point type

Primary

End point timeframe

Up to Cycle 2 (cycle length=28 days) (approximately 8 weeks)

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistics was planned for this endpoint.

End point values	Part 2 (Leukemia)	Part 3: Expansion (Leukemia)
Number of subjects analysed	0 ^[12]	0 ^[13]
Units: percentage of participants
number (confidence interval 95%)	( to )	( to )

Notes
[12] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.
[13] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.

No statistical analyses for this end point

Secondary: Part 1a: Clinical Benefit Rate (CBR) in Participants with Solid Tumors From SE Population Assessed According to Response Evaluation Criteria Version 1.1 (RECIST v1.1) or INRC

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End point title

Part 1a: Clinical Benefit Rate (CBR) in Participants with Solid Tumors From SE Population Assessed According to Response Evaluation Criteria Version 1.1 (RECIST v1.1) or INRC ^[14]

End point description

CBR was defined as the percentage of participants achieving confirmed CR, PR, or stable disease (SD) on 2 consecutive occasions ≥4 weeks apart during the total study period. Per RECIST, CR was defined as the disappearance of all target lesions. PR = at least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. SD = neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference smallest sum on study. PD = at least a 20% increase in the SOD of target lesions, taking as reference smallest sum on study (nadir), including baseline. Participants who had neuroblastoma were assessed by INRC. CR & PR per INRC were defined as outlined in the description for Part 1b: ORR endpoint. SE population = all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not. Percentages have been rounded off to the nearest decimal point.

End point type

Secondary

End point timeframe

From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1a only.

End point values	Part 1a: Idasanutlin 2 milligrams/kilograms (mg/kg)	Part 1a: Idasanutlin 3 mg/kg	Part 1a: Idasanutlin 4.5 mg/kg	Part 1a: Idasanutlin 6.4 mg/kg	Part 1a: Idasanutlin 8 mg/kg
Number of subjects analysed	8	3	6	3	6
Units: percentage of participants
number (confidence interval 95%)	12.3 (0.32 to 52.65)	33.3 (0.84 to 90.57)	0 (0.0 to 45.93)	66.7 (9.43 to 99.16)	0 (0.0 to 45.93)

No statistical analyses for this end point

Secondary: Part 1b: CBR in Participants with Neuroblastoma From SE Population Assessed According to INRC

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End point title

Part 1b: CBR in Participants with Neuroblastoma From SE Population Assessed According to INRC ^[15]

End point description

CBR=percentage of participants with CR/PR/SD on 2 consecutive occasions ≥4 weeks apart per INRC. Primary tumor: CR=residual ST at PS is <10 mm, with complete resolution of MIBG/FDG-PET uptake; PR= ≥30% decrease in LD of PS, with stable/improved MIBG/FDG-PET uptake; SD=Insufficient shrinkage for PR/increase for PD. PD= >20% increase in LD from smallest sum & min. 5 mm increase in LD. ST & bone metastases: CR=resolution of all disease sites; PR=≥30% decrease in sum of non-primary target lesions with no new lesions/≥50% reduction in MIBG/number of FDG-PET–avid bone lesions; PD=new ST lesions per CT/MRI or MIBG/FDG-PET avid bone site; SD=no sufficient change in non-primary lesions. Bone marrow: CR=no tumor infiltration; PD=new tumor infiltration >5%/infiltration increased >2-fold with >20% tumor infiltration; SD=persistent infiltration at >5% w/o meeting other criteria. SE population=participants who received any amount of study treatment, whether prematurely withdrawn from study or not.

End point type

Secondary

End point timeframe

From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1b only.

End point values	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Number of subjects analysed	3	3	6
Units: percentage of participants
number (confidence interval 95%)	33.3 (0.84 to 90.57)	33.3 (0.84 to 90.57)	0 (0.0 to 45.93)

No statistical analyses for this end point

Secondary: Part 1b: CBR in Participants With TP53 WT Neuroblastoma Assessed According to INRC

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End point title

Part 1b: CBR in Participants With TP53 WT Neuroblastoma Assessed According to INRC ^[16]

End point description

CBR=percentage of participants with CR/PR/SD on 2 consecutive occasions ≥4 weeks apart per INRC. Primary tumor: CR=residual ST at PS is <10 mm, with complete resolution of MIBG/FDG-PET uptake; PR= ≥30% decrease in LD of PS, with stable/improved MIBG/FDG-PET uptake; SD=Insufficient shrinkage for PR/increase for PD. PD= >20% increase in LD from smallest sum & min. 5 mm increase in LD. ST & bone metastases: CR=resolution of all disease sites; PR=≥30% decrease in sum of non-primary target lesions with no new lesions/≥50% reduction in MIBG/number of FDG-PET–avid bone lesions; PD=new ST lesions per CT/MRI or MIBG/FDG-PET avid bone site; SD=no sufficient change in non-primary lesions. Bone marrow: CR=no tumor infiltration; PD=new tumor infiltration >5%/infiltration increased >2-fold with >20% tumor infiltration; SD=persistent infiltration at >5% w/o meeting other criteria. Participants in SE population with TP53 WT tumor as assessed by central testing were analyzed for this endpoint.

End point type

Secondary

End point timeframe

From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1b only.

End point values	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Number of subjects analysed	2	3	6
Units: percentage of participants
number (confidence interval 95%)	50.0 (1.26 to 98.74)	33.3 (0.84 to 90.57)	0 (0.0 to 60.24)

No statistical analyses for this end point

Secondary: Part 1a: Duration of Response (DOR) in Participants with Solid Tumors from SE Population Assessed According to RECIST v1.1 or INRC

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End point title

Part 1a: Duration of Response (DOR) in Participants with Solid Tumors from SE Population Assessed According to RECIST v1.1 or INRC ^[17]

End point description

DOR was defined as the time from the first tumor assessment that supports a participant’s objective response (OR) (CR or PR) to the time of PD or death from any cause (whichever occurs first), as determined by the investigator using RECIST v1.1 for INRC. Per PECIST, CR was defined as disappearance of all target lesions. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference smallest sum on study (nadir), including baseline. Participants who had neuroblastoma were assessed by INRC. CR/PR/PD were defined per INRC as outlined in the description for the Part 1b: CBR endpoint. SE population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not. DOR was only evaluated in participants who achieved an objective response (CR or PR).

End point type

Secondary

End point timeframe

From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1a only.

End point values	Part 1a: Idasanutlin 2 milligrams/kilograms (mg/kg)	Part 1a: Idasanutlin 3 mg/kg	Part 1a: Idasanutlin 4.5 mg/kg	Part 1a: Idasanutlin 6.4 mg/kg	Part 1a: Idasanutlin 8 mg/kg
Number of subjects analysed	0 ^[18]	0 ^[19]	0 ^[20]	0 ^[21]	0 ^[22]
Units: months
median (confidence interval 95%)	( to )	( to )	( to )	( to )	( to )

Notes
[18] - DOR was only evaluated in participants who achieved an OR (CR/PR). No participants achieved CR/PR.
[19] - DOR was only evaluated in participants who achieved an OR (CR/PR). No participants achieved CR/PR.
[20] - DOR was only evaluated in participants who achieved an OR (CR/PR). No participants achieved CR/PR.
[21] - DOR was only evaluated in participants who achieved an OR (CR/PR). No participants achieved CR/PR.
[22] - DOR was only evaluated in participants who achieved an OR (CR/PR). No participants achieved CR/PR.

No statistical analyses for this end point

Secondary: Part 1b: DOR in Participants with Neuroblastoma From SE Population Assessed According to INRC

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End point title

Part 1b: DOR in Participants with Neuroblastoma From SE Population Assessed According to INRC ^[23]

End point description

DOR is the time from first tumor assessment that supports a participant’s OR (CR/PR) to PD/death from any cause per INRC. Primary tumor: CR=residual ST at PS is <10 mm, with complete resolution of MIBG/FDG-PET uptake; PR= ≥30% decrease in LD of PS, with stable/improved MIBG/FDG-PET uptake; PD= >20% increase in LD from smallest sum & min. 5 mm increase in LD. ST & bone metastases: CR=resolution of all disease sites; PR=≥30% decrease in sum of non-primary target lesions with no new lesions/≥50% reduction in MIBG/number of FDG-PET–avid bone lesions; PD=new ST lesions per CT/MRI or MIBG/FDG-PET avid bone site; Bone marrow: CR=no tumor infiltration; PD=new tumor infiltration >5%/infiltration increased >2-fold with >20% tumor infiltration. SE population used. DOR was only evaluated in participants with an OR. 0.9999: Only 1 participant responded, hence the lower limit of the 95%CI is unevaluable. 9999: Only 1 participant responded, hence the upper limit of the 95%CI is unevaluable.

End point type

Secondary

End point timeframe

From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1b only.

End point values	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Number of subjects analysed	0 ^[24]	1	0 ^[25]
Units: months
median (confidence interval 95%)	( to )	4.5 (0.99999 to 99999)	( to )

Notes
[24] - DOR was only evaluated in participants who achieved an OR (CR/PR). No participants achieved CR/PR.
[25] - DOR was only evaluated in participants who achieved an OR (CR/PR). No participants achieved CR/PR.

No statistical analyses for this end point

Secondary: Part 1b: DOR in in Participants with TP53 WT Neuroblastoma Assessed According to INRC

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End point title

Part 1b: DOR in in Participants with TP53 WT Neuroblastoma Assessed According to INRC ^[26]

End point description

DOR=time from initial tumor assessment of OR (CR/PR) to PD/death from any cause. Primary tumor: CR=residual ST at PS is <10 mm, with complete resolution of MIBG/FDG-PET uptake; PR= ≥30% decrease in LD of PS, with stable/improved MIBG/FDG-PET uptake; PD=>20% increase in LD from smallest sum & min. 5 mm increase in LD. ST & bone metastases: CR=resolution of all disease sites; PR=≥30% decrease in sum of non-primary target lesions with no new lesions/≥50% reduction in MIBG/number of FDG-PET–avid bone lesions; PD=new ST lesions per CT/MRI or MIBG/FDG-PET avid bone site; Bone marrow: CR=no tumor infiltration; PD=new tumor infiltration >5%/infiltration increased>2-fold with>20% tumor infiltration. Participants in the SE population with TP53 WT tumor per central testing were analyzed. DOR was evaluated in participants with OR. 0.9999: Only 1 participant responded, so lower limit of the 95%CI is unevaluable. 9999: Only 1 participant responded, so upper limit of the 95%CI is unevaluable.

End point type

Secondary

End point timeframe

From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1b only.

End point values	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Number of subjects analysed	0 ^[27]	1	0 ^[28]
Units: months
median (confidence interval 95%)	( to )	4.5 (0.9999 to 9999)	( to )

Notes
[27] - DOR was only evaluated in participants who achieved an OR (CR/PR). No participants achieved CR/PR.
[28] - DOR was only evaluated in participants who achieved an OR (CR/PR). No participants achieved CR/PR.

No statistical analyses for this end point

Secondary: Part 1a: Progression Free Survival (PFS) in Participants with Solid Tumors From SE Population Assessed According to RECIST v1.1 or INRC

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End point title

Part 1a: Progression Free Survival (PFS) in Participants with Solid Tumors From SE Population Assessed According to RECIST v1.1 or INRC ^[29]

End point description

PFS was defined as the time from initiation of study drug to the first documented occurrence of PD or death from any cause (whichever occurs first), as determined by the investigator using RECIST or INRC. Per RECIST, PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference smallest sum on study (nadir), including baseline. Participants with neuroblastoma were assessed by INRC. PD per INRC: Primary tumor: = >20% increase in LD from smallest sum & minimum 5 mm increase in LD; Soft tissue & bone metastases =new soft tissue lesions per CT/MRI or MIBG/FDG-PET avid bone site; Bone marrow =new tumor infiltration >5% or infiltration increased >2-fold with >20% tumor infiltration. SE population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not. 99999=Upper limit of the 95% CI was not estimable because there was an insufficient number of events.

End point type

Secondary

End point timeframe

From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1a only.

End point values	Part 1a: Idasanutlin 2 milligrams/kilograms (mg/kg)	Part 1a: Idasanutlin 3 mg/kg	Part 1a: Idasanutlin 4.5 mg/kg	Part 1a: Idasanutlin 6.4 mg/kg	Part 1a: Idasanutlin 8 mg/kg
Number of subjects analysed	8	3	6	3	6
Units: months
median (confidence interval 95%)	0.8 (0.7 to 1.3)	0.9 (0.9 to 99999)	0.8 (0.8 to 0.9)	3.5 (2.8 to 99999)	1.9 (0.8 to 99999)

No statistical analyses for this end point

Secondary: Part 1b: PFS in Participants with Neuroblastoma From SE Population Assessed According to INRC

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End point title

Part 1b: PFS in Participants with Neuroblastoma From SE Population Assessed According to INRC ^[30]

End point description

PFS was defined as the time from initiation of study drug to the first documented occurrence of PD or death from any cause (whichever occurs first), as determined by the investigator using INRC for participants with neuroblastoma. Primary tumor: PD= >20% increase in LD from smallest sum & minimum 5 mm increase in LD. Soft tissue & bone metastases: PD=new soft tissue lesions per CT/MRI or MIBG/FDG-PET avid bone site. Bone marrow: PD=new tumor infiltration >5% or infiltration increased >2-fold with >20% tumor infiltration. Safety evaluable population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not. 99999=upper limit of the 95% CI was not estimable because there was an insufficient number of events.

End point type

Secondary

End point timeframe

From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1b only.

End point values	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Number of subjects analysed	3	3	6
Units: months
median (confidence interval 95%)	1.9 (1.8 to 99999)	1.8 (1.6 to 99999)	1.7 (1.0 to 99999)

No statistical analyses for this end point

Secondary: Part 1b: PFS in Participants with TP53 WT Neuroblastoma Assessed According to INRC

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End point title

Part 1b: PFS in Participants with TP53 WT Neuroblastoma Assessed According to INRC ^[31]

End point description

PFS = the time from initiation of study drug to the first documented occurrence of PD or death from any cause (whichever occurs first), as determined by the investigator using INRC for participants with neuroblastoma. Primary tumor: PD= >20% increase in LD from smallest sum & minimum 5 mm increase in LD. Soft tissue & bone metastases: PD=new soft tissue lesions per CT/MRI or MIBG/FDG-PET avid bone site. Bone marrow: PD=new tumor infiltration >5% or infiltration increased >2-fold with >20% tumor infiltration. Participants in the SE population who had TP53 WT tumor as assessed by central testing were analyzed for this outcome measure. SE Population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not. 9999=median & upper limit of the 95% CI was not estimable because there was an insufficient number of events. 99999=upper limit of the 95% CI was not estimable because there was an insufficient number of events.

End point type

Secondary

End point timeframe

From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1b only.

End point values	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Number of subjects analysed	2	3	4
Units: months
median (confidence interval 95%)	9999 (1.8 to 9999)	1.8 (1.6 to 99999)	1.7 (1.5 to 99999)

No statistical analyses for this end point

Secondary: Parts 1a and 1b: Overall Survival (OS) in SE Population

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End point title

Parts 1a and 1b: Overall Survival (OS) in SE Population

End point description

OS was defined as the time from initiation of the study drug to death from any cause. SE population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not. 99999=upper limit of the 95% CI was not estimable because there was an insufficient number of events. 9999=The median, upper and lower limit of the 95% CI was not estimable because there was an insufficient number of events.

End point type

Secondary

End point timeframe

Up to approximately 29 months

End point values	Part 1a: Idasanutlin 2 milligrams/kilograms (mg/kg)	Part 1a: Idasanutlin 3 mg/kg	Part 1a: Idasanutlin 4.5 mg/kg	Part 1a: Idasanutlin 6.4 mg/kg	Part 1a: Idasanutlin 8 mg/kg	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Number of subjects analysed	8	3	6	3	6	3	3	6
Units: months
median (confidence interval 95%)	5.6 (2.1 to 20.8)	12.5 (1.1 to 99999)	3.6 (2.3 to 9.8)	16.4 (7.2 to 99999)	5.4 (3.4 to 99999)	9999 (9999 to 9999)	3.2 (1.6 to 99999)	99999 (2.9 to 99999)

No statistical analyses for this end point

Secondary: Part 1b: OS in Participants With TP53 WT Neuroblastoma

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End point title

Part 1b: OS in Participants With TP53 WT Neuroblastoma ^[32]

End point description

OS was defined as the time from initiation of the study drug to death from any cause. Participants in the SE population who had TP53 WT tumor as assessed by central testing were analyzed for this outcome measure. SE Population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not. 9999=The median, upper and lower limit of the 95% CI was not estimable because there was an insufficient number of events. 99999=upper limit of the 95% CI was not estimable because there was an insufficient number of events. 999=The median and upper limit of the 95% CI was not estimable because there was an insufficient number of events.

End point type

Secondary

End point timeframe

Up to approximately 29 months

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1b only.

End point values	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Number of subjects analysed	2	3	4
Units: months
median (confidence interval 95%)	9999 (9999 to 9999)	3.2 (1.6 to 99999)	999 (1.5 to 999)

No statistical analyses for this end point

Secondary: Part 1a: ORR Irrespective of TP53 Mutation Status in Participants With Solid Tumor From SE Population According to RECIST v1.1 or INRC

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End point title

Part 1a: ORR Irrespective of TP53 Mutation Status in Participants With Solid Tumor From SE Population According to RECIST v1.1 or INRC ^[33]

End point description

ORR = percentage of participants with CR or PR at any time during study treatment, on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to RECIST or INRC. Per RECIST, CR = disappearance of all target lesions. PR = at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. Participants who had neuroblastoma were assessed by INRC. Per INRC, Primary tumor: CR= <10 mm residual ST at the primary site and complete resolution of MIBG/FDG-PET uptake at PS. PR= ≥30% decrease in LD of PS & MIBG/FDG-PET uptake at PS stable, improved/resolved. ST & bone metastases: CR=resolution of all disease sites; PR=≥30% decrease in sum of non-primary target lesions, with no new lesions/≥50% reduction in MIBG score/in number of FDG-PET–avid bone lesions; Bone marrow: CR=no tumor infiltration on reassessment. SE population = all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not.

End point type

Secondary

End point timeframe

From screening (maximum 28 days) up to Cycle 5 (cycle length=28 days)

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1a only.

End point values	Part 1a: Idasanutlin 2 milligrams/kilograms (mg/kg)	Part 1a: Idasanutlin 3 mg/kg	Part 1a: Idasanutlin 4.5 mg/kg	Part 1a: Idasanutlin 6.4 mg/kg	Part 1a: Idasanutlin 8 mg/kg
Number of subjects analysed	8	3	6	3	6
Units: percentage of participants
number (confidence interval 95%)	0 (0.0 to 36.94)	0 (0.0 to 70.96)	0 (0.0 to 45.93)	0 (0.0 to 70.96)	0 (0.0 to 45.93)

No statistical analyses for this end point

Secondary: Part 1b: ORR Irrespective of TP53 Mutation Status in Participants with Neuroblastoma From SE Population according to INRC

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End point title

Part 1b: ORR Irrespective of TP53 Mutation Status in Participants with Neuroblastoma From SE Population according to INRC ^[34]

End point description

ORR was defined as the percentage of participants with CR or PR at any time during study treatment, on 2 consecutive occasions ≥ 4 weeks apart, as determined by the investigator per INRC. Primary tumor: CR= <10 mm residual soft tissue at primary site and complete resolution of MIBG or FDG-PET uptake at primary site. PR= ≥ 30% decrease in longest diameter of primary site and MIBG or FDG-PET uptake at primary site stable, improved, or resolved. Soft tissue & bone metastases: CR= resolution of all disease sites; PR= ≥30% decrease in sum of non-primary target lesions, with no new lesions or ≥50% reduction in MIBG score or in number of FDG-PET–avid bone lesions; Bone marrow: CR= no tumor infiltration on reassessment. SE population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not.

End point type

Secondary

End point timeframe

From screening (maximum 28 days) up to Cycle 6 (cycle length=28 days)

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1b only.

End point values	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Number of subjects analysed	3	3	6
Units: percentage of participants
number (confidence interval 95%)	33.3 (0.84 to 90.57)	0 (0.0 to 45.93)	0 (0.0 to 45.93)

No statistical analyses for this end point

Secondary: Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy

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End point title

Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy ^[35]

End point description

Pharmacokinetic (PK)-evaluable population included all participants who received at least one dose of study treatment and who have data from at least one post dose sample. One participant assigned to the 6.4 mg/kg dose level received a dose of 3.8 mg/kg due to the maximum absolute dose cap of 300 mg/day in protocol v3 and earlier. Hence this participant has been reported in a separate arm for PK analysis. 99999=Since only 1 participant was analyzed Geometric Coefficient of Variation was not estimable.

End point type

Secondary

End point timeframe

Days 1 and 5 of Cycle 1 (cycle length = 28 days)

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1a only.

End point values	Part 1a: Idasanutlin 2 milligrams/kilograms (mg/kg)	Part 1a: Idasanutlin 3 mg/kg	Part 1a: Idasanutlin 4.5 mg/kg	Part 1a: Idasanutlin 6.4 mg/kg	Part 1a: Idasanutlin 8 mg/kg	Part 1a: Idasanutlin 3.8 mg/kg
Number of subjects analysed	8	3	6	2	6	1
Units: ng/mL(nanograms/millilitres)
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1	1429 ( 36 )	2110 ( 27 )	3174 ( 25 )	4474 ( 90 )	5102 ( 67 )	1560 ( 99999 )
Cycle 1 Day 5	2548 ( 21 )	2784 ( 27 )	4892 ( 53 )	7748 ( 81 )	6298 ( 67 )	2940 ( 99999 )

No statistical analyses for this end point

Secondary: Part 1b: Cmax of Idasanutlin in Combination With Chemotherapy or Venetoclax

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End point title

Part 1b: Cmax of Idasanutlin in Combination With Chemotherapy or Venetoclax ^[36]

End point description

PK-evaluable population included all participants who received at least one dose of study treatment and who have data from at least one post dose sample.

End point type

Secondary

End point timeframe

Days 1 and 5 of Cycle 1 (cycle length = 28 days)

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1b only.

End point values	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Number of subjects analysed	3	3	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1	2834 ( 31 )	1540 ( 11 )	2131 ( 43 )
Cycle 1 Day 5	2393 ( 31 )	2110 ( 72 )	2272 ( 32 )

No statistical analyses for this end point

Secondary: Part 1a: Cmax of Idasanutilin Metabolite M4 following Idasanutilin as a Monotherapy

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End point title

Part 1a: Cmax of Idasanutilin Metabolite M4 following Idasanutilin as a Monotherapy ^[37]

End point description

PK-evaluable population included all participants who received at least one dose of study treatment and who have data from at least one post dose sample. One participant assigned to the 6.4 mg/kg dose level received a dose of 3.8 mg/kg due to the maximum absolute dose cap of 300 mg/day in protocol v3 and earlier. Hence this participant has been reported in a separate arm for PK analysis. 99999=Since only 1 participant was analyzed Geometric Coefficient of Variation was not estimable.

End point type

Secondary

End point timeframe

Days 1 and 5 of Cycle 1 (cycle length = 28 days)

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1b only.

End point values	Part 1a: Idasanutlin 2 milligrams/kilograms (mg/kg)	Part 1a: Idasanutlin 3 mg/kg	Part 1a: Idasanutlin 4.5 mg/kg	Part 1a: Idasanutlin 6.4 mg/kg	Part 1a: Idasanutlin 8 mg/kg	Part 1a: Idasanutlin 3.8 mg/kg
Number of subjects analysed	8	3	6	2	6	1
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1	129 ( 63 )	184 ( 39 )	340 ( 60 )	820 ( 153 )	575 ( 148 )	72 ( 99999 )
Cycle 1 Day 5	436 ( 73 )	419 ( 23 )	542 ( 76 )	1865 ( 197 )	1511 ( 201 )	345 ( 99999 )

No statistical analyses for this end point

Secondary: Part 1b: Cmax of Idasanutlin Metabolite M4 (Idasanutilin in Combination With Chemotherapy or Venetoclax)

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End point title

Part 1b: Cmax of Idasanutlin Metabolite M4 (Idasanutilin in Combination With Chemotherapy or Venetoclax) ^[38]

End point description

PK-evaluable population included all participants who received at least one dose of study treatment and who have data from at least one post-dose sample.

End point type

Secondary

End point timeframe

Days 1 and 5 of Cycle 1 (cycle length = 28 days)

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1b only.

End point values	Part 1b: Idasanutlin (2.8 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Number of subjects analysed	3	3	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1	229 ( 56 )	214 ( 72 )	213 ( 67 )
Cycle 1 Day 5	442 ( 148 )	524 ( 97 )	369 ( 58 )

No statistical analyses for this end point

Secondary: Part 1b: Plasma Concentration of Venetoclax in Combination with Idasanutlin

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End point title

Part 1b: Plasma Concentration of Venetoclax in Combination with Idasanutlin ^[39]

End point description

PK-evaluable population included all participants who received at least one dose of study treatment and who have data from at least one post dose sample. 'n' is the number of participants with data available for analyses at the specified timepoints.

End point type

Secondary

End point timeframe

Cycle 1: Predose on Days 2 and 5, 4 and 6 hours post dose on Days 1 and 5 (1 cycle = 28 days)

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned for Part 1b only.

End point values	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax
Number of subjects analysed	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1, Post dose 4 Hours (n=6)	693 ( 44 )
Cycle 1 Day 1, Post dose 6 Hours (n=5)	669 ( 86 )
Cycle 1 Day 2, Predose (n=6)	202 ( 109 )
Cycle 1 Day 5, Predose (n=6)	221 ( 108 )
Cycle 1 Day 5, Post dose 4 Hours (n=6)	1145 ( 45 )
Cycle 1 Day 5, Post dose 6 Hours (n=6)	968 ( 39 )

No statistical analyses for this end point

Secondary: Parts 1, 2 and 3: Number of Participants with Leukemia Receiving Transplant After Study Treatment

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End point title

Parts 1, 2 and 3: Number of Participants with Leukemia Receiving Transplant After Study Treatment

End point description

The study was terminated before initiation of Parts 2 and 3 as per sponsor’s decision. No participants with leukemia were enrolled in Part 1. Hence no data were collected, and this outcome measure was not assessed or analyzed.

End point type

Secondary

End point timeframe

Up to approximately 29 months

End point values	Part 1 (Leukemia)	Part 2 (Leukemia)	Part 3: Expansion (Leukemia)
Number of subjects analysed	0 ^[40]	0 ^[41]	0 ^[42]
Units: participants

Notes
[40] - No leukemia participants enrolled in Part 1.
[41] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.
[42] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.

No statistical analyses for this end point

Secondary: Parts 1, 2 and 3: Duration of Objective Response in Participants with Leukemia

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End point title

Parts 1, 2 and 3: Duration of Objective Response in Participants with Leukemia

End point description

DOR=time from 1st tumor assessment supporting OR to time of relapse/death from any cause, whichever occurs first. CR=Bone marrow blasts <5%(AML), no evidence of circulating blasts, must be <1%(ALL); absence of blasts with Auer rods(AML); absence of extramedullary disease; ANC>1.0*10^9/L [1000/µL]; platelet count>100*10^9/L (100,000/µL); independence of transfusions for a minimum of 1 week (AML &ALL). CRi=All CR criteria except for ANC <1.0*10^9/L[1000/µL] or insufficient recovery of platelet count <100*10^9/L[100,000/µL] (AML &ALL). CRp=All CR criteria except for ANC >1.0*10^9/L[1000/µL]) or but with insufficient recovery of platelet (<100*10^9/L [100,000/µL])(ALL). Relapse=participants who achieved a CR/CRp/CRi &subsequently developed: Bone marrow blasts ≥5%; reappearance of blasts in blood ≥1%; development of extra-medullary disease. No leukemia participants enrolled in Part 1. Study was terminated before Parts 2&3 initiation due to sponsors decision. Hence, no data were collected.

End point type

Secondary

End point timeframe

Up to approximately 29 months

End point values	Part 1 (Leukemia)	Part 2 (Leukemia)	Part 3: Expansion (Leukemia)
Number of subjects analysed	0 ^[43]	0 ^[44]	0 ^[45]
Units: months
median (confidence interval 95%)	( to )	( to )	( to )

Notes
[43] - No leukemia participants enrolled in Part 1.
[44] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.
[45] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.

No statistical analyses for this end point

Secondary: Parts 1, 2 and 3: Event-Free Survival (EFS) in Participants with Leukemia

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End point title

Parts 1, 2 and 3: Event-Free Survival (EFS) in Participants with Leukemia

End point description

EFS=time from initiation of study drug to first documented occurrence of M3 marrow after Cycle 1, failure to achieve CR/CRp/CRi after Cycle 2, disease progression, relapse after achieving CR/CRp/CRi, or death from any cause, whichever occurs first. CR=Bone marrow blasts <5% (AML), no evidence of circulating blasts, must be <1% (ALL); absence of blasts with Auer rods (AML); absence of extramedullary disease; ANC>1.0*10^9/L [1000/µL]; platelet count>100*10^9/L (100,000/µL); independence of transfusions for a minimum of 1 week (AML & ALL). CRi=All CR criteria except for ANC <1.0*10^9/L[1000/µL] or insufficient recovery of platelet count <100*10^9/L [100,000/µL] (AML & ALL). CRp=All CR criteria except for ANC >1.0*10^9/L[1000/µL]) or but with insufficient recovery of platelet (<100*10^9/L [100,000/µL]) (ALL). Relapse=participants who achieved a CR/CRp/CRi &subsequently developed: Bone marrow blasts ≥5%; reappearance of blasts in blood ≥1%; or development of extra-medullary disease.

End point type

Secondary

End point timeframe

Up to approximately 29 months

End point values	Part 1 (Leukemia)	Part 2 (Leukemia)	Part 3: Expansion (Leukemia)
Number of subjects analysed	0 ^[46]	0 ^[47]	0 ^[48]
Units: months
median (confidence interval 95%)	( to )	( to )	( to )

Notes
[46] - No leukemia participants enrolled in Part 1.
[47] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.
[48] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.

No statistical analyses for this end point

Secondary: Parts 1, 2 and 3: OS in Participants with Leukemia

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End point title

Parts 1, 2 and 3: OS in Participants with Leukemia

End point description

OS was defined as the time from initiation of study drug to death from any cause. The study was terminated before initiation of Parts 2 and 3 as per sponsor’s decision. No participants with leukemia were enrolled in Part 1. Hence no data were collected, and this outcome measure was not assessed or analyzed.

End point type

Secondary

End point timeframe

Up to approximately 29 months

End point values	Part 1 (Leukemia)	Part 2 (Leukemia)	Part 3: Expansion (Leukemia)
Number of subjects analysed	0 ^[49]	0 ^[50]	0 ^[51]
Units: months
median (confidence interval 95%)	( to )	( to )	( to )

Notes
[49] - No leukemia participants enrolled in Part 1.
[50] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.
[51] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.

No statistical analyses for this end point

Secondary: Parts 1, 2 and 3: CRR of Efficacy-evaluable Population Irrespective of TP53 Mutation Status in Participants with Leukemia

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End point title

Parts 1, 2 and 3: CRR of Efficacy-evaluable Population Irrespective of TP53 Mutation Status in Participants with Leukemia

End point description

CRR was defined as the percentage of participants with CR, CRi, or CRp within 2 cycles of study treatment. CR=Bone marrow blasts <5% (AML) & no evidence of circulating blasts (ALL); absence of blasts with Auer rods (AML); absence of extramedullary disease; absolute neutrophil count (ANC) >1.0*10^9/L [1000/µL]; platelet count > 100*10^9/L (100,000/µL); no transfusions for a minimum of 1 week (AML and ALL). CRi= All CR criteria except for ANC <1.0*10^9/L[1000/µL] or insufficient recovery of platelet count <100* 10^9/L [100,000/µL] (AML and ALL). CRp=All CR criteria except for ANC >1.0*10^9/L[1000/µL]) or but with insufficient recovery of platelet (<100* 10^9/L [100,000/µL]) (ALL). The study was terminated before initiation of Parts 2 and 3 as per sponsor’s decision. No participants with leukemia were enrolled in Part 1. Hence no data were collected, and this outcome measure was not assessed or analyzed.

End point type

Secondary

End point timeframe

Up to approximately 29 months

End point values	Part 1 (Leukemia)	Part 2 (Leukemia)	Part 3: Expansion (Leukemia)
Number of subjects analysed	0 ^[52]	0 ^[53]	0 ^[54]
Units: percentage of participants
number (confidence interval 95%)	( to )	( to )	( to )

Notes
[52] - No leukemia participants enrolled in Part 1.
[53] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.
[54] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.

No statistical analyses for this end point

Secondary: Parts 1, 2 and 3: MRD - Negative Rate in Participants With ALL

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End point title

Parts 1, 2 and 3: MRD - Negative Rate in Participants With ALL

End point description

MRD – negative rate was defined as defined as the percentage of participants with AML who are MRD negative within 2 cycles of study treatment. The study was terminated before initiation of Parts 2 and 3 as per sponsor’s decision. No participants with leukemia were enrolled in Part 1. Hence no data were collected, and this outcome measure was not assessed or analyzed.

End point type

Secondary

End point timeframe

Up to approximately 29 months

End point values	Part 1 (ALL)	Part 2 (ALL)	Part 3: Expansion (ALL)
Number of subjects analysed	0 ^[55]	0 ^[56]	0 ^[57]
Units: percentage of participants
number (confidence interval 95%)	( to )	( to )	( to )

Notes
[55] - No leukemia participants enrolled in Part 1.
[56] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.
[57] - Study was terminated before initiation of Parts 2 & 3 per sponsor’s decision.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse Events: From screening up to 30 days after study treatment discontinuation (approximately 7 months) All-cause mortality: From screening up to end of follow up (approximately 29 months)

Adverse event reporting additional description

Safety population included all participants who received any amount of the study treatment, whether prematurely withdrawn from the study or not.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Part 1a: Idasanutlin 2 mg/kg

Reporting group description

Participants with solid tumors received idasanutlin 2 mg/kg QD on Days 1-5 of each 28-day cycle until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Reporting group title

Part 1a: Idasanutlin 3 mg/kg

Reporting group description

Reporting group title

Part 1a: Idasanutlin 4.5 mg/kg

Reporting group description

Reporting group title

Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax

Reporting group description

Participants with neuroblastoma (first 3) received idasanutlin, 3.6 mg/kg orally QD on Days 1-5, in combination with venetoclax 400 mg on Days 1-28 of each 28-day cycle. After the first three participants were treated, the schedule was modified as idasanutlin, 3.6 mg/kg orally QD on Days 1-5 and venetoclax 400 mg on Days 1-14 of a each 28-day cycle for the next 3 participants enrolled in this arm. Treatment was administered until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Reporting group title

Part 1a: Idasanutlin 8 mg/kg

Reporting group description

Reporting group title

Part 1b: Idasanutlin (2.8mg/kg) +Chemotherapy

Reporting group description

Participants with neuroblastoma received idasanutlin 2.8 mg/kg orally in combination with cyclophosphamide 200 mg/m^2 and topotecan 0.6 mg/m^2 as an IV infusion QD on Days 1-5 of each 28-day cycle. Treatment was administered until disease progression, death, unacceptable toxicity, or decision to discontinue, whichever occurred first.

Reporting group title

Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy

Reporting group description

Reporting group title

Part 1a: Idasanutlin 6.4 mg/kg

Reporting group description

Serious adverse events	Part 1a: Idasanutlin 2 mg/kg	Part 1a: Idasanutlin 3 mg/kg	Part 1a: Idasanutlin 4.5 mg/kg	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax	Part 1a: Idasanutlin 8 mg/kg	Part 1b: Idasanutlin (2.8mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1a: Idasanutlin 6.4 mg/kg
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 8 (75.00%)	3 / 3 (100.00%)	4 / 6 (66.67%)	4 / 6 (66.67%)	6 / 6 (100.00%)	2 / 3 (66.67%)	3 / 3 (100.00%)	2 / 3 (66.67%)
number of deaths (all causes)	8	3	6	3	5	0	2	2
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Aspiration
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Lymphocyte count decreased
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femoral neck fracture
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eschar
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Haemorrhage intracranial
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	3 / 8 (37.50%)	2 / 3 (66.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)	3 / 6 (50.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	6 / 6	3 / 3	3 / 3	0 / 0	5 / 5	1 / 1	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematotoxicity
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	2 / 8 (25.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	4 / 4	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphopenia
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	3 / 8 (37.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	7 / 7	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	4 / 8 (50.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	7 / 7	1 / 1	0 / 0	1 / 1	2 / 2	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Hypoacusis
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Nausea
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	3 / 4	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacteraemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Central nervous system infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part 1a: Idasanutlin 2 mg/kg	Part 1a: Idasanutlin 3 mg/kg	Part 1a: Idasanutlin 4.5 mg/kg	Part 1b: Idasanutlin (3.6mg/kg) + Venetoclax	Part 1a: Idasanutlin 8 mg/kg	Part 1b: Idasanutlin (2.8mg/kg) +Chemotherapy	Part 1b: Idasanutlin (3.6 mg/kg) +Chemotherapy	Part 1a: Idasanutlin 6.4 mg/kg
Total subjects affected by non serious adverse events
subjects affected / exposed	8 / 8 (100.00%)	3 / 3 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	3 / 8 (37.50%)	1 / 3 (33.33%)	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	5	1	3	1	0	1	0	1
Asthenia
subjects affected / exposed	2 / 8 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	3	0	0	0	0	0	0	0
Mucosal inflammation
subjects affected / exposed	2 / 8 (25.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	1	0	0	0	0	0	0
Non-cardiac chest pain
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	5	1	0	0	0	0	0
Pain
subjects affected / exposed	1 / 8 (12.50%)	1 / 3 (33.33%)	3 / 6 (50.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	4	0	0	0	0	0
Pyrexia
subjects affected / exposed	3 / 8 (37.50%)	3 / 3 (100.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	3	3	3	1	1	0	0	1
Vascular device occlusion
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Swelling
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	3	0	2	0	0	1	0
Cough
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1	0	1	1	0	2
Rhinorrhoea
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	0	0	1	0
Dyspnoea
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Asthma
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	3	0	0	0	0	0
Hypoxia
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Wheezing
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Tachypnoea
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Agitation
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Confusional state
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Irritability
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Insomnia
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 8 (25.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 3 (66.67%)	2 / 3 (66.67%)	0 / 3 (0.00%)
occurrences all number	2	0	1	0	1	2	6	0
Aspartate aminotransferase increased
subjects affected / exposed	4 / 8 (50.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 3 (66.67%)	2 / 3 (66.67%)	0 / 3 (0.00%)
occurrences all number	4	0	1	2	1	2	6	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Blood bicarbonate increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Blood bilirubin increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 3 (66.67%)	3 / 3 (100.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	2	5	0
Blood chloride decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Platelet count decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Blood uric acid increased
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 3 (100.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	4	1	0
Lymphocyte count decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	5	0
Neutrophil count decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	4	0
Blood creatinine increased
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	2	0	0	0	1	0	1	0
Weight decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0
White blood cell count decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	2	0	3	1
Blood phosphorus decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
SARS-CoV-2 test positive
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	1	0	0	0
Pelvic fracture
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Accidental overdose
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Nervous system disorders
Lethargy
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Seizure
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0
Tremor
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Headache
subjects affected / exposed	2 / 8 (25.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	5	0	2	2	1	0	0	1
Paraesthesia
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Dizziness
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 8 (50.00%)	2 / 3 (66.67%)	3 / 6 (50.00%)	1 / 6 (16.67%)	6 / 6 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	1 / 3 (33.33%)
occurrences all number	5	2	4	1	6	4	9	1
Febrile neutropenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Thrombocytopenia
subjects affected / exposed	2 / 8 (25.00%)	1 / 3 (33.33%)	2 / 6 (33.33%)	2 / 6 (33.33%)	3 / 6 (50.00%)	3 / 3 (100.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)
occurrences all number	2	1	2	2	3	7	2	1
Lymphopenia
subjects affected / exposed	2 / 8 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	2	0	0	0	2	0	1	0
Neutropenia
subjects affected / exposed	2 / 8 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	3 / 3 (100.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)
occurrences all number	2	0	0	3	1	10	3	1
Leukopenia
subjects affected / exposed	3 / 8 (37.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	3 / 3 (100.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	3	0	0	2	0	8	3	0
Lymphadenopathy
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Eye disorders
Eye pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Periorbital oedema
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 8 (37.50%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	5	2	0	0	1	0	1	0
Constipation
subjects affected / exposed	1 / 8 (12.50%)	2 / 3 (66.67%)	2 / 6 (33.33%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	1	4	2	1	1	0	2	0
Diarrhoea
subjects affected / exposed	3 / 8 (37.50%)	1 / 3 (33.33%)	5 / 6 (83.33%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 3 (33.33%)	2 / 3 (66.67%)	3 / 3 (100.00%)
occurrences all number	4	3	7	1	1	1	4	4
Gastritis
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Lip swelling
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Oral pain
subjects affected / exposed	0 / 8 (0.00%)	2 / 3 (66.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	0	1	0	0
Stomatitis
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	0	0	0	0	0	1
Vomiting
subjects affected / exposed	4 / 8 (50.00%)	2 / 3 (66.67%)	4 / 6 (66.67%)	4 / 6 (66.67%)	2 / 6 (33.33%)	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 3 (33.33%)
occurrences all number	7	8	9	7	2	1	7	3
Nausea
subjects affected / exposed	3 / 8 (37.50%)	2 / 3 (66.67%)	4 / 6 (66.67%)	5 / 6 (83.33%)	3 / 6 (50.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	2 / 3 (66.67%)
occurrences all number	4	6	6	6	3	0	5	2
Anal fissure
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Dyspepsia
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Haematochezia
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Mouth swelling
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	1	1	0
Pruritus
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0
Rash
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Skin exfoliation
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Skin hyperpigmentation
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Pain of skin
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Livedo reticularis
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Alopecia
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Purpura
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1
Dysuria
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	2	0	0	1	1	0	0	1
Back pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Groin pain
subjects affected / exposed	2 / 8 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0
Neck pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Pain in extremity
subjects affected / exposed	2 / 8 (25.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	4	0	2	1	0	0	0	0
Myalgia
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Infections and infestations
Bacteraemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Oral candidiasis
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Skin infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1	0	0	0	0	1
Upper respiratory tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Mucosal infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
COVID-19
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Device related infection
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Fungal skin infection
subjects affected / exposed	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Lower respiratory tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Lymphangitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Parainfluenzae virus infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Respiratory tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Paronychia
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 8 (12.50%)	1 / 3 (33.33%)	2 / 6 (33.33%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	1	2	3	2	0	0	1	0
Hyperglycaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Hyperuricaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0
Hypocalcaemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	1	0	2	0
Hypokalaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	4	0
Hyponatraemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)
occurrences all number	1	0	1	0	0	0	2	0
Hypophosphataemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)
occurrences all number	2	0	0	2	1	0	9	0
Hypoalbuminaemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)
occurrences all number	1	0	0	1	0	0	7	0
Hypercalcaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

15 Jun 2020

1. The primary efficacy objective endpoint for leukemia for participants with ALL was clarified. 2. The DLTs definitions were revised. 3. Because no assessments of peripheral blood mononuclear cells were planned, sampling of these for biomarkers assessment was removed. 4. Administration of idasanutlin via nasogastric tube was added for participants receiving idasanutlin tablets dissolved in water. 5. Risks associated with venetoclax were updated.

19 Mar 2021

1. Initiation of the safety run-in cohorts for the planned combinations in neuroblastoma may occur asynchronously. Thus, the randomization of participants with neuroblastoma in study Part 2 to either chemotherapy or venetoclax was removed. 2. An early efficacy gate was added at the end of the safety run-in (Gate 1b) for the neuroblastoma cohorts, which included participants treated at the recommended Phase II dose (RP2D). 4. A requirement for a minimum of 6 participants treated at the RP2D in neuroblastoma safety run-in was added. 5. The pre-defined maximum dose of idasanutlin was eliminated. 6. The definition of dose-limiting toxicities was revised to accommodate the known and manageable toxicities of the chemotherapy combination agents, as well as to be more consistent with the standards used in other pediatric clinical trials. 7. The inclusion criterion on the ability to swallow tablets or liquid was removed since the administration of idasanutlin via nasogastric tube is possible. 8. Dosing of topotecan and cyclophosphamide based on body weight rather than body surface area for patients weighing less than 12 kg. This is more consistent with standard dosing for this regimen.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 1a and 1b: Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5.0)

Primary: Part 1a and 1b: Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5.0)

Primary: Parts 1a and 1b: Number of Participants With Dose-Limiting Toxicities (DLTs)

Primary: Parts 1a and 1b: Number of Participants With Dose-Limiting Toxicities (DLTs)

Primary: Part 1b: Objective Response Rate (ORR) in Participants With TP53 Wild Type (WT) Neuroblastoma Assessed According to International Neuroblastoma Response Criteria (INRC)

Primary: Part 1b: Objective Response Rate (ORR) in Participants With TP53 Wild Type (WT) Neuroblastoma Assessed According to International Neuroblastoma Response Criteria (INRC)

Primary: Parts 2 and 3: ORR in Participants With TP53 WT Neuroblastoma Assessed According to INRC

Primary: Parts 2 and 3: ORR in Participants With TP53 WT Neuroblastoma Assessed According to INRC

Primary: Parts 2 and 3: Minimal Residual Disease (MRD) - Negative Rate in Participants With ALL

Primary: Parts 2 and 3: Minimal Residual Disease (MRD) - Negative Rate in Participants With ALL

Primary: Parts 2 and 3: Complete Remission Rate (CRR) in Participants With TP53 WT Leukemia Participants

Primary: Parts 2 and 3: Complete Remission Rate (CRR) in Participants With TP53 WT Leukemia Participants

Secondary: Part 1a: Clinical Benefit Rate (CBR) in Participants with Solid Tumors From SE Population Assessed According to Response Evaluation Criteria Version 1.1 (RECIST v1.1) or INRC

Secondary: Part 1a: Clinical Benefit Rate (CBR) in Participants with Solid Tumors From SE Population Assessed According to Response Evaluation Criteria Version 1.1 (RECIST v1.1) or INRC

Secondary: Part 1b: CBR in Participants with Neuroblastoma From SE Population Assessed According to INRC

Secondary: Part 1b: CBR in Participants with Neuroblastoma From SE Population Assessed According to INRC

Secondary: Part 1b: CBR in Participants With TP53 WT Neuroblastoma Assessed According to INRC

Secondary: Part 1b: CBR in Participants With TP53 WT Neuroblastoma Assessed According to INRC

Secondary: Part 1a: Duration of Response (DOR) in Participants with Solid Tumors from SE Population Assessed According to RECIST v1.1 or INRC

Secondary: Part 1a: Duration of Response (DOR) in Participants with Solid Tumors from SE Population Assessed According to RECIST v1.1 or INRC

Secondary: Part 1b: DOR in Participants with Neuroblastoma From SE Population Assessed According to INRC

Secondary: Part 1b: DOR in Participants with Neuroblastoma From SE Population Assessed According to INRC

Secondary: Part 1b: DOR in in Participants with TP53 WT Neuroblastoma Assessed According to INRC

Secondary: Part 1b: DOR in in Participants with TP53 WT Neuroblastoma Assessed According to INRC

Secondary: Part 1a: Progression Free Survival (PFS) in Participants with Solid Tumors From SE Population Assessed According to RECIST v1.1 or INRC

Secondary: Part 1a: Progression Free Survival (PFS) in Participants with Solid Tumors From SE Population Assessed According to RECIST v1.1 or INRC

Secondary: Part 1b: PFS in Participants with Neuroblastoma From SE Population Assessed According to INRC

Secondary: Part 1b: PFS in Participants with Neuroblastoma From SE Population Assessed According to INRC

Secondary: Part 1b: PFS in Participants with TP53 WT Neuroblastoma Assessed According to INRC

Secondary: Part 1b: PFS in Participants with TP53 WT Neuroblastoma Assessed According to INRC

Secondary: Parts 1a and 1b: Overall Survival (OS) in SE Population

Secondary: Parts 1a and 1b: Overall Survival (OS) in SE Population

Secondary: Part 1b: OS in Participants With TP53 WT Neuroblastoma

Secondary: Part 1b: OS in Participants With TP53 WT Neuroblastoma

Secondary: Part 1a: ORR Irrespective of TP53 Mutation Status in Participants With Solid Tumor From SE Population According to RECIST v1.1 or INRC

Secondary: Part 1a: ORR Irrespective of TP53 Mutation Status in Participants With Solid Tumor From SE Population According to RECIST v1.1 or INRC

Secondary: Part 1b: ORR Irrespective of TP53 Mutation Status in Participants with Neuroblastoma From SE Population according to INRC

Secondary: Part 1b: ORR Irrespective of TP53 Mutation Status in Participants with Neuroblastoma From SE Population according to INRC

Secondary: Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy

Secondary: Part 1a: Maximum Plasma Concentration (Cmax) of Idasanutlin as a Monotherapy

Secondary: Part 1b: Cmax of Idasanutlin in Combination With Chemotherapy or Venetoclax

Secondary: Part 1b: Cmax of Idasanutlin in Combination With Chemotherapy or Venetoclax

Secondary: Part 1a: Cmax of Idasanutilin Metabolite M4 following Idasanutilin as a Monotherapy

Secondary: Part 1a: Cmax of Idasanutilin Metabolite M4 following Idasanutilin as a Monotherapy

Secondary: Part 1b: Cmax of Idasanutlin Metabolite M4 (Idasanutilin in Combination With Chemotherapy or Venetoclax)

Secondary: Part 1b: Cmax of Idasanutlin Metabolite M4 (Idasanutilin in Combination With Chemotherapy or Venetoclax)

Secondary: Part 1b: Plasma Concentration of Venetoclax in Combination with Idasanutlin

Secondary: Part 1b: Plasma Concentration of Venetoclax in Combination with Idasanutlin

Secondary: Parts 1, 2 and 3: Number of Participants with Leukemia Receiving Transplant After Study Treatment

Secondary: Parts 1, 2 and 3: Number of Participants with Leukemia Receiving Transplant After Study Treatment

Secondary: Parts 1, 2 and 3: Duration of Objective Response in Participants with Leukemia

Secondary: Parts 1, 2 and 3: Duration of Objective Response in Participants with Leukemia

Secondary: Parts 1, 2 and 3: Event-Free Survival (EFS) in Participants with Leukemia

Secondary: Parts 1, 2 and 3: Event-Free Survival (EFS) in Participants with Leukemia

Secondary: Parts 1, 2 and 3: OS in Participants with Leukemia

Secondary: Parts 1, 2 and 3: OS in Participants with Leukemia

Secondary: Parts 1, 2 and 3: CRR of Efficacy-evaluable Population Irrespective of TP53 Mutation Status in Participants with Leukemia

Secondary: Parts 1, 2 and 3: CRR of Efficacy-evaluable Population Irrespective of TP53 Mutation Status in Participants with Leukemia

Secondary: Parts 1, 2 and 3: MRD - Negative Rate in Participants With ALL

Secondary: Parts 1, 2 and 3: MRD - Negative Rate in Participants With ALL

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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