Safety and Efficacy of MAK683 in Adult Patients With Advanced Malignancies

Study Overview
=================
Brief Summary
-----------------
The purpose of this Phase I/II study is to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) and to evaluate the safety, antitumor activity and pharmacokinetic (PK) profile of MAK683 in patients with advanced malignancies such as Diffuse Large B cell Lymphoma (DLBCL), nasopharyngeal carcinoma (NPC) or other advanced solid tumors for whom no further effective standard treatment is available.

Detailed Description
-----------------
The purpose phase I of this trial is to characterize safety and tolerability and determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of MAK683. The purpose of the phase II of this trial is to evaluate the anti-tumor activity of MAK683. Phase II part will not be opened.

Official Title
-----------------
A Phase I/II, Multicenter, Open-label Study of MAK683 in Adult Patients With Advanced Malignancies

Conditions
-----------------
Diffuse Large B-cell Lymphoma

Intervention / Treatment
-----------------
* Drug: MAK683


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG): 0 to 2 Relapsed or refractory diffuse large B cell lymphoma with measurable disease as determined by Non-Hodgkin's Lymphoma Cheson response criteria (2014) Advanced or recurrent/metastatic solid tumor, including nasopharyngeal carcinoma, castration-resistant prostate cancer, gastric cancer, ovarian clear cell carcinoma and sarcoma, with measurable disease as determined by RECIST 1.1. Exclusion Criteria: Other malignant diseases than the ones being treated in this study 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. B-cell lymphoma patients who have received prior allogeneic stem cell transplant Patient have received anti-cancer therapies within defined time frames prior to the first dose of study treatment Symptomatic central nervous system (CNS) involvement which are neurologically unstable or requiring increasing doses of steroids to control. Patient having out of range laboratory values defined as: 1) Insufficient bone marrow function at screening: Platelets ≤ 50,000/mm3 Hemoglobin (Hgb) ≤ 80 g/L Absolute neutrophil count (ANC) ≤ 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 >1.5 x ULN Serum creatinine > 1.5 x ULN and/or creatinine clearance ≤ 50 mL/min

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I - All<br>advanced stage (relapsed/refractory or recurrent/metastatic) malignancy limited to the following malignancies; DLBCL, nasopharyngeal carcinoma, gastric cancer, ovarian cancer, prostate cancer and sarcoma. | Drug: MAK683<br>* Drug: MAK683<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities (DLTs) | Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) | up to 28 days | 
| Safety and tolerability | Incidence and severity of AEs, SAEs, changes in laboratory values, vital signs and ECGs, dose interruptions and reductions | up to approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) |  | up to 30 months | 
| Duration of overall response (DOR) |  | up to 30 months | 
| Progression-free survival (PFS) |  | up to 30 months | 
| Best Overall Response (BOR) |  | up to 30 months | 
| Peak Plasma Concentration (Cmax) of MAK683 | Pharmacokinetic profile of MAK683 | 30 months | 
| Area Under the Plasma Concentration (AUC) Time Curve of MAK683 | Pharmacokinetic profile of MAK683 | 30 months | 
| Half-Life of MAK683 | Pharmacokinetic profile of MAK683 | 30 months | 
| H3K27 tri methylation level in PBMC | Cycle 1 Day 1,8,15 Cycle 2 Day1 Cycle 3 Day 1 End of treatment (EOT); Disease progression PBMC: peripheral blood mononuclear cell | up to day 15 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
MAK683, DLBCL, EED - Embryonic ectoderm development, EZH2 - Enhancer of zeste homolog 2