Clinical Trials Register

Summary
EudraCT Number:	2015-002354-12
Sponsor's Protocol Code Number:	CMBG453X2101
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-12-21
Trial results	View 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

Netherlands - Competent Authority

A.2

EudraCT number

2015-002354-12

A.3

Full title of the trial

A phase I-Ib/II, open-label, multi-center study of the safety and efficacy of MBG453 as single agent and in combination with PDR001 in adult patients with advanced malignancies

A.3.1

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

An interventional study of MBG453 as single agent and in combination with PDR001 in patients with advanced malignancies

A.4.1

Sponsor's protocol code number

CMBG453X2101

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 Services 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 Services 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 Services AG
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Forum 1, Novartis Campus
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4056
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+4161324 1111
B.5.5	Fax number	+4161324 8001
B.5.6	E-mail	clinicaltrial.enquiries@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.3.2	Product code	MBG453
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not established yet
D.3.9.2	Current sponsor code	MBG453
D.3.9.3	Other descriptive name	MBG453
D.3.9.4	EV Substance Code	SUB178459
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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.3.2	Product code	PDR001
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not established yet
D.3.9.2	Current sponsor code	PDR001
D.3.9.3	Other descriptive name	PDR001
D.3.9.4	EV Substance Code	SUB171710
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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: 3
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	Yes
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	decitabine
D.3.2	Product code	L01BC08
D.3.4	Pharmaceutical form	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DECITABINE
D.3.9.1	CAS number	2353-33-5
D.3.9.4	EV Substance Code	SUB06932MIG
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	50
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

Solid tumors

E.1.1.1

Medical condition in easily understood language

Solid tumors

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10065252
E.1.2	Term	Solid tumor
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase I/Ib part
● To characterize the safety and tolerability of MBG453 single agent in ROW and Japanese pateints separately and in combination with PDR001 and to identify recommended doses for future studies
● To characterize safety and tolerability of MBG453 in combination with decitabine and identify recommended dose for future studies.
Phase I-Ib dose ranging part
● To further investigate the safety and tolerability of different doses of MBG453 as single agent or in combination with PDR001
Phase II part
● To estimate anti-tumor activity of MBG453 as single agent and in combination with PDR001 or in combination with decitabine

E.2.2

Secondary objectives of the trial

Ph I-Ib/II part
● preliminary ant-tumor activity of MBG453 as single agent in combination with PDR001 or in combination with decitabine
● pharmacokinetic profile of MBG453 as single agent in combination with PDR001 or in combination with decitabine
● To assess anti-MBG453 and anti-PDR001 antibodies following one or more i.v. infusions of MBG453 as single agent in combination with PDR001 or in combination with decitabine
● potential predictors of efficacy of MBG453 as single agent in combination with PDR001 or in combination with decitabine in tumor sample
● pharmacodynamic effect of MBG453 as single agent in combination with PDR001 or in combination with decitabine in tumor sample
● survival distribution of patients treated with MBG453 as single agent in combination with PDR001 or in combination with decitabine for each disease group
Phase II (combination):
● To make an initial comparison for MBG453 and PDR001 administered in combination on a Q2W and Q4W dosing schedules.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histologically documented advanced or metastatic solid tumors.
2. Phase I-Ib part (including dose ranging part): Patients with advanced/metastatic solid tumors, with measurable or non measurable disease as determined by RECIST v1.1, who have progressed despite standard therapy or are intolerant to standard therapy, or for whom no standard therapy exists.
Prior therapy with PD-1/PDL-1 inhibitors is allowed provided any toxicity attributed to prior PD-1 or PD-L1-directed therapy did not lead to discontinuation of therapy and after discussion between the Investigator and Novartis study medical representative.
3. Phase II part (MBG453 single agent): Patients with advanced/metastatic solid tumors in the indication in which signs of anti-tumor activity (CR, PR or durable SD with tumor shinkrage that does not qualify for PR) were seen during the dose escalation phase I part. Patients must have measurable disease as determined by RECIST v1.1, have progressed despite standard therapy or be intolerant to standard therapy.
4. Phase II part (MBG453 in combination with PDR001): Patients with advanced/metastatic tumors in the below selected indications, with at least one measurable lesion as determined by RECIST v1.1, who have received standard therapy and are intolerant of standard therapy or have progressed following their last prior therapy.:
• Melanoma (anti-PD-1/PD-L1 therapy naïve or pre-treated)
• NSCLC (anti-PD-1/PD-L1 therapy naïve or pre-treated)
• RCC (anti-PD-1/PD-L1 therapy naïve or pre-treated)
5. Must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening/baseline, and during therapy on the study.
6. For MBG453 in combination with decitabine (phase Ib/II): anti-PD-1/PD-L1 therapy naïve SCLC patients who have failed no more than two lines of standard chemotherapy including topotecan.
Other protocol-defined inclusion criteria may apply.

E.4

Principal exclusion criteria

1. Presence of symptomatic central nervous system (CNS) metastases.
2. History of severe hypersensitivity reactions to any ingredients of
study drugs and other monoclonal
antibodies (mAbs) and/or their excipients.
3. HBV or HCV positive patients, with active disease or whose hepatitis is
not controlled by therapy are excluded.
HIV positive patients are excluded.
4. Active autoimmune disease or a documented history of autoimmune
disease, including ulcerative colitis and Crohn's disease or any condition
that requires systemic steroids.
5. Systemic steroid therapy or any immunosuppressive therapy (≥
10mg/day prednisone or equivalent).
6. Use of any vaccines against infectious diseases (e.g. varicella,
pneumococcus) within 4 weeks of initiation of study treatment.
7. Pre-treatment with anti-CTLA4 antibodies in combination with any
other antibody or drug specifically targeting T-cell co-stimulation or
checkpoint pathway.
8. Participation in an interventional, investigational non-immunotherapy
study within 2 weeks of the first dose of study treatment.
9. Prior participation in an interventional, investigational cancer vaccine
or immunotherapy study except for an anti-PD-1/PD-L1 study.
Other protocol-defined exclusion criteria may apply.

E.5 End points

E.5.1

Primary end point(s)

Phase I/Ib parts:
• The incidence and severity of AEs and SAEs, including changes in laboratory parameters, vital signs and ECGs
• Dose interruptions, reductions and dose intensity
• The incidence of DLTs during the first cycle of treatment with single agent MBG453
• The incidence of DLTs during the first and second cycle of treatment with MBG453 in combination with PDR001
•The incidence of DLTs during the first and second cycle of treatment with MBG453 in combination with decitabine
Phase I-Ib dose ranging part:
• Incidence and severity of AEs and SAEs, including changes in laboratory parameters, vital signs and ECGs
• Dose interruptions, reductions and dose intensity
Phase II part:
• Overall response rate (ORR) per RECIST v1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase I/Ib parts:
• Up to 150 days after last dose or longer
• During a treatment cycle (28 days)
• End of cycle 1
• End of cycle 1 and end of cycle 2
Phase I-Ib dose ranging part:
• Up to 150 days after last dose or longer
• During a treatment cycle (28 days)
Phase II part:
• Every 8 weeks until week 40, and then every 12 weeks until
progression of disease

For details on the timepoints please refer to the protocol

E.5.2

Secondary end point(s)

Phase I/Ib parts:
• Best Overall Response (BOR), Progression Free Survival (PFS) and
Duration of Response (DOR) per RECIST v1.1; ORR and PFS per irRC
• Serum PK parameters (e.g., AUC, Cmax, Tmax, half-life); Serum
concentration vs. time profiles
• Presence and/or concentration of anti-MBG453 and anti-PDR001
antibodies
• Assess potential associations between expression of PD-L1 and other
immunological markers such as, but not restricted to TIM-3, CD8, FoxP3
and anti-tumor activity
• Tumor Infiltrating Lymphocytes (TIL) counts
• Overall survival (OS)
Phase II part (combination):
• Incidence and severity of AEs and SAEs, including changes in
laboratory parameters, vital signs and ECGs
• Dose interruptions, reductions and dose intensity
• Serum PK parameters (e.g., AUC, Cmax, Tmax, half-life); Serum
concentration vs. time profiles
• ORR, BOR, PFS and DOR per RECIST v1.1; ORR and PFS per irRC

E.5.2.1

Timepoint(s) of evaluation of this end point

Phase I/Ib parts:
• Every 8 weeks until week 40, and then every 12 weeks until
progression of disease
• Cycle 1 and Cycle 3 Days 1,2,8,11 and 15. Cycles 2, 3, 4, 5 and 6 on
Day 1, and end of treatment
• Cycles 1 to 6 on Day 1 and end of treatment
• Screening and after Cycle 3 Day 1
• Screening and after Cycle 3 Day 1
• From time of start treatment until the date of death
Phase II part (combination):
• Up to 150 days after last dose or longer
• During a treatment cycle (28 days)
• Cycle 1 and Cycle 3 Days 1,2,8,11 and 15. Cycles 2, 3, 4, 5 and 6 on Day 1, and end of treatment
• Every 8 weeks until week 40, and then every 12 weeks until
progression of disease

For details on the timepoints please refer to the protocol

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

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

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

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

Yes

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

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.8.2.4

Number of treatment arms in the trial

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

Singapore

Switzerland

Taiwan

Australia

Canada

Korea, Republic of

United States

Germany

Italy

Netherlands

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

The end of the study will be when at least 80% of the patients have completed the survival follow-up period, or discontinued the study for any reason, and all patients have completed treatment as well as the 150 day safety follow-up period, or if the study is terminated early, or another clinical study becomes available that can continue to provide study treatment
in this patient population.

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:

187

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

120

F.4.2.2

In the whole clinical trial

267

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)

None

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

2015-12-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-02-19

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2022-08-30

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