Clinical Trials Register

Summary
EudraCT Number:	2016-001860-12
Sponsor's Protocol Code Number:	CMAK683X2101
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:	2016-09-15
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

2016-001860-12

A.3

Full title of the trial

A phase I/II, multicenter, open-label study of MAK683 in adult patients with advanced malignancies

A.3.1

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

A safety and efficacy study of MAK683 in adults patients with advanced solid tumors

A.4.1

Sponsor's protocol code number

CMAK683X2101

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 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.3.2	Product code	MAK683
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	not established yet
D.3.9.2	Current sponsor code	MAK683
D.3.9.3	Other descriptive name	MAK683
D.3.9.4	EV Substance Code	SUB182318
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	2.5
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.3.2	Product code	MAK683
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	not established yet
D.3.9.2	Current sponsor code	MAK683
D.3.9.3	Other descriptive name	MAK683
D.3.9.4	EV Substance Code	SUB182318
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: 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	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	MAK683
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	not established yet
D.3.9.2	Current sponsor code	MAK683
D.3.9.3	Other descriptive name	MAK683
D.3.9.4	EV Substance Code	SUB182318
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.IMP: 4
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	MAK683
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	not established yet
D.3.9.2	Current sponsor code	MAK683
D.3.9.3	Other descriptive name	MAK683
D.3.9.4	EV Substance Code	SUB182318
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	100
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

Advanced malignancies

E.1.1.1

Medical condition in easily understood language

advanced malignancies

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.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10066481
E.1.2	Term	Hematological malignancy
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: To characterize safety and tolerability and determine the MTD and/or RP2D of MAK683
Phase II: To assess the anti-tumor activity of MAK683

E.2.2

Secondary objectives of the trial

Phase I:
•To characterize the anti-tumor activity of MAK683
•To characterize the PK profile of MAK683
•To characterize the pharmacodynamics effect of MAK683
Phase II:
•To characterize the anti-tumor activity of MAK683
•To characterize the safety and tolerability of MAK683
•To characterize the PK profile of MAK683
•To characterize the pharmacodynamics effect of MAK683

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Patients Age ≥ 18 years
2.ECOG performance status 0 to 2
3.Patients have progressed after standard therapy or are intolerant of standard therapy and for whom no standard therapy exists.
4. Measurable disease according to RECIST v1.1 for patients with solid tumors or Cheson criteria for patients with NHL (Cheson et al 2014).
5. Tumor biopsy is mandatory at study entry. Patients must have a site of disease amenable for biopsy and be a candidate for umor biopsy. On-Treatment biopsy is required for patients with solid tumors, unless determined by the Investigator as not
clinically feasible.
6. Histologically or cytologically confirmed diagnosis is required for all indications
- For patients with DLBCL and FL: In Phase II, patients are required to have documentation of EZH2 mutational status.
Patients with relapsed or refractory indolent lymphomas, such as FL, must have signs or symptoms indicating the necessity of therapy such as described in practice guidelines ( e.g. Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria, The British National Lymphoma Investigation (BNLI), Italian Society of Hematology (SIE) guideline, or others
local practice guidelines).
7. For patients with NPC: Patients must have documentation of presence of p16/CDKN2A gene (at least one copy of p16/CDKN2A gene)
8. For patients with ovarian cancer: Patients must have primary tumor with great than 50% clear cell histomorphology.
9. For patients with prostate cancer: Patients must have evidence of castration resistance as evidenced by a confirmed rising PSA (per Prostate Cancer Working Group 2 [PCWG2] criteria) and a castrate^serum testosterone level (i.e. ≤ 50 ng/dL).
10. For patients with sarcoma: Enrollment is limited to epithelioid sarcoma, other types of sarcoma with SWI/SNF alterations may be considered with approval from Novartis.

E.4

Principal exclusion criteria

1.Other malignant disease than the one being treated in this study
2.Severe and/or uncontrolled medical conditions that in the investigator’s opinion could affect the safety of individual or impair the assessment of study result.
3.B-cell lymphoma patients who have received prior allogeneic stem cell transplant
4.Patient have received anti-cancer therapies within defined time frames prior to the first dose of study treatment
5.Symptomatic CNS involvement which are neurologically unstable or requiring increasing doses of steroids to control.
6.Patient having out of range laboratory values defined as:
1)Insufficient bone marrow function at screening:
•Platelets ≤ 50 x 109/L (50,000/mm3)
•Hemoglobin (Hgb) ≤ 90 g/L (9 g/dL)
•Absolute neutrophil count (ANC) ≤ 1.0 x 109/L (1000/mm3)
2)Insufficient hepatic and renal function at screening:
•ALP, ALT, and AST > 3 x ULN (>5 x ULN if subject has liver metastases)
•Total bilirubin ≥2 x ULN
•Serum creatinine > 1.5 x ULN and/or creatinine clearance ≤ 50 mL/min
7.Unable to stop any prohibited medications, including strong CYP3A4 inhibitors or inducers, CYP3A4 or CYP2C8 substrates with a narrow therapeutic index, long acting proton pump inhibitors.
Other protocol-defined exclusion criteria may apply.

E.5 End points

E.5.1

Primary end point(s)

Phase I:
Safety:
1.Incidence of dose limiting toxicities (DLTs) in the first 28 days of treatment
2.Incidence and severity of AEs and SAEs, including changes in laboratory parameters, vital signs and ECGs
Tolerability:
Dose interruptions, reductions and dose intensity
Phase II:
Overall response rate (ORR), based on local assessment per Response Assessment of Hodgkin and Non-Hodgkin Lymphoma (Cheson, 2014), Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and PCWG2

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase I:
Safety:
1. Day 28
2. End of study
Phase II: End of study

E.5.2

Secondary end point(s)

Phase I part:
ORR, Duration of overall response (DOR), Progression-free survival (PFS) and Best Overall Response (BOR)
Plasma concentrations and derived PK parameters of MAK683
Pre-and post-treatment expression of H3K27 trimethylation in blood
Phase II part:
Duration of overall response (DOR), Progression-free survival (PFS) and Best Overall Response (BOR)
Safety: Incidence and severity of AEs and SAEs, including changes in laboratory parameters, vital signs and ECGs
Tolerability: Dose interruptions, reductions and dose intensity.
Plasma concentrations and PK profiles of MAK683
Pre-and post-treatment level expression of H3K27 trimethylation in blood

E.5.2.1

Timepoint(s) of evaluation of this end point

End of study

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

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

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

Hong Kong

Singapore

Canada

China

Germany

Italy

Japan

Korea, Republic of

Netherlands

Spain

United States

France

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 study will end when the treatment period, 30-day safety follow-up and progression disease follow up (if applicable) have completed for all patients or if the study is terminated early.

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:

110

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

170

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

2017-01-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-10-06

P. End of Trial
P.	End of Trial Status	Completed

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