Clinical Trials Register

Summary
EudraCT Number:	2021-003596-34
Sponsor's Protocol Code Number:	CHDM201K12201
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2022-03-15
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2021-003596-34

A.3

Full title of the trial

A phase Ib/II, open label study of siremadlin monotherapy and in combination with donor lymphocyte infusion as a treatment for patients with acute myeloid leukemia post-allogeneic stem cell transplantation who are in complete remission but at high risk for relapse.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study of efficacy and safety of siremadlin alone and in combination with donor lymphocyte infusion (DLI) in adults with acute myeloid leukemia (AML) who have received allogeneic stem cell transplant (allo-SCT) but are at high risk for relapse.

A.4.1

Sponsor's protocol code number

CHDM201K12201

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Pharma AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma GmbH
B.5.2	Functional name of contact point	Medizinischer Infoservice (MCC)
B.5.3	Address:
B.5.3.1	Street Address	Roonstrasse 25
B.5.3.2	Town/ city	Nürnberg
B.5.3.3	Post code	90429
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49 911 273-12100
B.5.5	Fax number	+49 911 27312160
B.5.6	E-mail	infoservice.novartis@novartis.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	siremadlin
D.3.2	Product code	HDM201
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SIREMADLIN
D.3.9.2	Current sponsor code	HDM201
D.3.9.3	Other descriptive name	HDM201
D.3.9.4	EV Substance Code	SUB198077
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Siremadlin
D.3.2	Product code	HDM201
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SIREMADLIN
D.3.9.2	Current sponsor code	HDM201
D.3.9.3	Other descriptive name	HDM201
D.3.9.4	EV Substance Code	SUB198077
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute Myeloid Leukemia

E.1.1.1

Medical condition in easily understood language

Acute Myeloid Leukemia

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10000886
E.1.2	Term	Acute myeloid leukemia
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Safety Primary Objectives:
• To determine the dose and schedule of siremadlin monotherapy that is tolerable without unacceptable toxicities (recommended dose for the treatment strategy Part 2), measured by incidence of dose-limiting toxicities (DLTs) in Part 1.
• To determine the dose and schedule of siremadlin in combination with DLI that is tolerable without unacceptable toxicities (recommended dose for combination), measured by time to DLT in Part 2.
Efficacy Primary Objectives:
• To evaluate the preliminary efficacy of study treatment strategy (siremadlin monotherapy, as priming and/or maintenance with or without siremadlin in combination with DLI) on prevention of hematologic relapse, measured by the proportion of participants who are alive and maintained CR or CRi with no evidence of hematologic relapse over at least 6 months after start of study treatment strategy (Part 2).

E.2.2

Secondary objectives of the trial

• To evaluate the preliminary efficacy of siremadlin monotherapy on prevention of hematologic relapse (Part 1 - siremadlin monotherapy at the recommended dose for Part 2)
• To assess relapse free survival (RFS) (Part 2).
• To assess cumulative incidence of relapse at 1 year and at 2 years after start of study treatment (Part 1 and Part 2).
• To assess overall survival (OS) (Part 2).
• To assess safety and tolerability of siremadlin monotherapy (during dose confirmation, priming and maintenance) and in combination with DLI (Part 1 and Part 2).
• To assess the proportion of participants stopping study treatment due to GvHD or other adverse events (Part 1 and Part 2).
• To assess the incidence of grade III and IV acute graft vs host disease (GvHD), moderate and severe chronic GvHD (Part 1 and Part 2).
• To assess GvHD-free/relapse-free survival (GRFS) (Part 1 and Part 2).
• To characterize the pharmacokinetics of siremadlin in monotherapy and in combination with DLI (Part 1 and Part 2).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent must be obtained prior to participation in the study.
2. Adults ≥ 18 years of age.
3. Participants with AML diagnosis, who underwent one allo-SCT to treat AML and are currently at Day ≥60 but no later than Day 120 (≤ Day 120) post allo-SCT.
4. Pre-allo-SCT - Participants must have any of the following risk factors that put them at high risk for relapse:
• AML in first CR (CR1) prior to allo-SCT with one of the following:
• Adverse risk genetic abnormalities per 2017 ELN risk stratification. patients with TP53 mutant AML at diagnosis are eligible if they meet eligibility criteria.
• Therapy-related AML (t-AML).
• Secondary AML (sAML) [AML secondary to antecedent myelodysplastic syndrome (MDS) or AML secondary to myeloproliferative neoplasm (MPN)].
• AML in second or greater CR (≥CR2) prior to allo-SCT.
5. Allo-SCT must have the following characteristics:
• Unmanipulated/T cell-replete bone marrow or peripheral blood stem cells as a graft source.
• Matched related (family) donor (MFD) or matched unrelated donor (MUD): Human Leukocyte Antigen (HLA) matching of donor and recipient should be at a minimum of 8/8 antigen or allele matched at HLA-A, -B, -C, -DRB1 loci.
• Any conditioning regimen intensity is permitted, the use of anti-thymocyte globulin (ATG) or alemtuzumab or post-transplant cyclophosphamide as a part of conditioning is allowed.
6. Donor lymphocytes are collected, cryopreserved and available for infusion (DLI), or obtaining donor lymphocytes for DLI is feasible (applicable only for the Part 2).
7. Post-allo-SCT, participants must have achieved complete remission (CR) or CR with incomplete count recovery (CRi) with no current evidence of hematologic relapse (bone marrow blasts <5%; no circulating blasts in the blood; no evidence of extramedullary disease).
10. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.
11. Adequate liver function tests (AST and ALT ≤ 3 × ULN, total bilirubin ≤ 1.5 × ULN) and renal function (estimated Glomerular Filtration Rate (eGFR) ≥ 45 mL/min/1.73 m2) (within 14 days prior to start of study treatment).
12. Evidence of adequate engraftment post allo-SCT: ANC ≥ 1.0x109/L, platelet count ≥ 75x109/L, hemoglobin ≥ 8 g/dL (within 14 days prior to start of study treatment).

E.4

Principal exclusion criteria

1. Prior exposure to MDM-inhibitor.
2. Active acute GvHD of any grade (per Harris et al 2016) requiring systemic therapy at time of study treatment initiation.
3. Active chronic GvHD of any grade (per NIH criteria (Jagasia et al 2015) requiring systemic therapy at time of study treatment initiation.
4. Past history of grade III or IV acute GvHD (per Harris et al 2016) and/or past history of moderate or severe chronic GvHD (per NIH criteria (Jagasia et al 2015)). History of lower grades of GvHD is permitted if GvHD resolved to grade 0 for at least 4 weeks prior to start of study treatment.
5. Recipient of allo-SCT from a matched unrelated donor (MUD) with one or more antigen or allele mismatch at HLA-A, -B, -C, -DRB1 locus (HLA matching less than 8/8 antigens).
6. Recipient of allo-SCT from a haploidentical family donor.
7. Recipients of cord blood transplant as a graft source.
8. Human immunodeficiency virus (HIV) infection not controlled by standard therapy and/or with known history of opportunistic infection.
9. Active Hepatitis B (HBV) or Hepatitis C (HCV) infection. Participants whose disease is controlled under antiviral therapy should not be excluded.
10. Prior systemic cancer-directed treatments or investigational modalities ≤ 5 half-lives or 4 weeks prior to starting study, whichever is longer.
11. Prior systemic AML-directed treatments given at any time after allo-SCT (including DLI).
12. History of another primary malignancy that is currently clinically significant or currently requires active intervention. Participants who are receiving adjuvant hormonal therapy for breast, prostate or other cancers such as hormone therapy are eligible.
13. Participants who require the use of herbal preparations/medications St. John’s wort (Hypericum perforatum) within 7 days prior to first dose of study treatment or are expected to use such products during the entire study.
14. Participants who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment.
15. Participants who require treatment with moderate or strong CYP3A inducers within 14 days prior to starting study treatment, or are expected to receive moderate or strong CYP3A4 inducers during the entire study.
16. Use of live vaccines within 30 days prior to first dose of siremadlin.
17. Female participants who are pregnant or breastfeeding.
18. GI disorders that may prevent the intake and absorption of oral siremadlin (eg, diarrhea, uncontrolled nausea and/or vomiting, GI bleeding, etc).
19. Any concurrent severe and/or active uncontrolled bacterial, viral or fungal infection requiring parenteral antibacterial, antiviral or antifungal therapy. Prophylactic antimicrobial use (oral or parenteral) is allowed.
20. Cardiac or cardiac repolarization abnormality, including but not limited to any of the following:
• History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to starting study treatment.
• Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block).
• Baseline QTcF interval > 470 ms.
• Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA Grade III/IV).
21. Other concurrent severe and/or uncontrolled medical conditions or serious organ dysfunction or other co-morbidity that, in the opinion of the investigator, predisposes the participant to high risk of noncompliance with the protocol.

E.5 End points

E.5.1

Primary end point(s)

Safety:
• Incidence of DLTs with siremadlin monotherapy in dose confirmation [Part 1]
• Time to DLT with siremadlin/DLI in combination phase [Part 2]

Efficacy:
• Proportion of participants who are alive and maintained CR or CRi with no evidence of hematologic relapse over at least 6 months after start of study treatment strategy (siremadlin monotherapy, as priming and/or maintenance, with or without siremadlin in combination with DLI) [Part 2].

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Primary safety endpoint in Part 1 will take place after each dose escalation cohort with required number of participants in dose determining set 1 (DDS1) completes the one-cycle (4 weeks) DLT observation period.
2. Primary safety endpoint in Part 2: Safety assessments will be conducted after each cohort of 3 participants completed the first siremadlin/DLI treatment cycle or experienced a DLT. The final safety assessment will take place after all participants in dose-determining set 2 (DDS2) complete combination phase (Part 2).
3. Primary efficacy endpoint: The primary efficacy analysis will be performed on all participant data at the time all participants who are still receiving study treatment will have completed at least 6 months or discontinued earlier.

E.5.2

Secondary end point(s)

• Participants who are alive and maintained CR or CRi with no evidence of hematologic relapse over at least 6 months after start of siremadlin monotherapy [Part 1 - siremadlin monotherapy at the recommended dose for Part 2].
• Time from start of study treatment to the date of first documented hematologic relapse or death due to any cause, whichever occurs first
• Cumulative incidence of AML relapse at 1 year and at 2 years after start of study treatment
• Time from start of study treatment to the date of death from any cause.
• Incidence and severity of AEs and SAEs, changes in laboratory values and vital signs.
• Proportion of participants with permanent discontinuation of study treatment due to GvHD or other adverse events.
• Incidence of treatment emergent grade III or grade IV aGvHD.
Incidence of treatment emergent moderate to severe cGvHD.
• Time from start of study treatment to the date of first documented occurrence or worsening of treatment emergent grade III or IV aGvHD, cGvHD requiring initiation of systemic immunosuppressive treatment, occurence of disease relapse, or death due to any cause, whichever occurs first.
• Pharmacokinetic parameters (e.g., AUC, Cmax, Tmax) and concentration vs time profiles of siremadlin in monotherapy and in combination with DLI.

E.5.2.1

Timepoint(s) of evaluation of this end point

The secondary endpoints will be evaluated at the primary efficacy analysis and final analysis (at the end of study):
Time point for PK in monotherapy is both primary efficacy analysis and final analysis (end of study), while time point for PK in combination with DLI is final analysis.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Phase Ib/II proof of concept study

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Open label

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Israel

United States

Spain

Germany

Italy

United Kingdom

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

At the end of the study, in alignment with local regulations, treatment continuity will be offered outside this study through an alternative setting to participants who are receiving treatment with siremadlin and in the opinion of investigator are still deriving clinical benefit. Safety will be monitored and reported to Health Authorities as per regulatory requirements.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2023-01-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-05-31

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-10-26

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IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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