A PHASE I STUDY OF DS-3201B IN SUBJECTS WITH ACUTE MYELOGENOUS LEUKEMIA (AML) OR ACUTE LYMPHOCYTIC LEUKEMIA (ALL)

There are 2 parts in this study: Part 1 (dose escalation) and Part 2 (dose expansion). The goal of Part 1 of this clinical research study is to find the highest tolerable dose of DS-3201b that can be given to patients with acute myelogenous leukemia (AML) or acute lymphocytic leukemia (ALL). The goal of Part 2 of this study is to learn if the dose of DS-3201b found in Part 1 can help to control AML or ALL. The safety of DS-3201b will be studied in both parts.

Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic

Treatment Agent: DS-3201

Treatment Location: Both at MDACC & and Other Sites

Sponsor: Daiichi Sankyo, Inc

Primary Objectives Part 1 (Dose Escalation) The primary objectives of Part 1 are as follows: 1. To assess the safety and tolerability of DS-3201b in subjects with relapsed/refractory AML or ALL. 2. To determine the Recommended dose of expansion (RDE) of DS-3201b in subjects with relapsed/refractory AML or ALL. Part 2 (Dose Expansion) The primary objective of Part 2 is as follows: 1. To confirm the safety and tolerability of DS-3201b at the RDE in subjects with relapsed/refractory AML and ALL. Secondary Objectives Part 1 (Dose Escalation) The secondary objective of Part 1 is as follows: 1. To assess the plasma pharmacokinetics (PK) of DS-3201b. Part 2 (Dose Expansion) The secondary objective of Part 2 is as follows: 1. To assess overall response rate (ORR) in subjects with relapsed/refractory AML and ALL using the revised International Working Group (IWG) response criteria^9 and NCCN response criteria, respectively, duration of response (DOR), and OS. Exploratory Objectives Part 1 (Dose Escalation) The exploratory objectives of Part 1 are as follows: 1. To assess the pharmacodynamics (PDy) of DS-3201b, such as hypomethylation status and quantitation of leukemic stem cells, in pre- and post-dose bone marrow aspirates. 2. To evaluate response to DS-3201b per revised IWG response criteria^9 in subjects with relapsed/refractory AML or NCCN response criteria in subjects with relapsed/refractory ALL. Part 2 (Dose Expansion) The exploratory objectives of Part 2 are as follows: 1. To evaluate the relationship between response rate in relapsed/refractory AML and ALL and cytogenetic and molecular-based biomarkers studied in pre-treatment bone marrow biopsies and/or blood samples. 2. To assess the PK and PDy of DS-3201b. 3. To compare complete remission (CR) duration between that observed with DS-3201b treatment and that observed from the most recent therapeutic regimen.

IRB Review and Approval Date: 03/29/2017

Recruitment Status: Open

Projected Accrual: 61

1) Subjects with AML diagnosed according to WHO 2008 criteria and ALL that have failed any prior induction therapy regimen or have relapsed after prior therapy. • Subjects with acute promyelocytic leukemia (APL) must be resistant and/or intolerant to both trans-retinoic acid (ATRA) and arsenic trioxide based-therapies to be considered for inclusion.
2) Age >/= 18 years old.
3) Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
4) Has adequate renal function, defined as: • Creatinine clearance >/= 60 mL/min, as calculated using the modified Cockcroft-Gault equation or Modification of Diet in Renal Disease (MDRD) formula (see Section 16.4) OR serum creatinine </= 1.5 × upper limit of normal (ULN).
5) Has adequate hepatic function, defined as: • AST/ALT </= 3 × ULN (</= 5.0 × ULN if due to leukemic involvement), and • Total bilirubin </= 2.0 times the upper limit of normal (ULN) (or </= 3.0 × ULN if deemed to be elevated due to Gilbert’s disease or leukemia), and • International normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) </= 1.5 × ULN.
6) The interval from prior treatment with cytotoxic agents or noncytotoxic /hypomethylating /investigational /biologic agents to time of initiation of DS-3201b administration will be at least 14 days after the final dose.
7) Subject should be able to provide written informed consent, comply with protocol visits and procedures, be able to take oral medication, and not have any active infection or comorbidity that would interfere with therapy.
8) Women of childbearing potential and their partner must agree to use an adequate method of contraception during the study and until 3 months after the last treatment. Males and their partner must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 3 months after the last treatment.
9) Is willing to provide bone marrow biopsies and comply with evaluations as requested by protocol.
10) Has a life expectancy of at least 3 months.

1) Presence of central nervous system (CNS) involvement of leukemia or a history of CNS leukemia.
2) Has a second concurrent active primary malignancy such as solid tumor or lymphoma under active treatment.
3) Refractory nausea and vomiting, malabsorption, biliary shunt, significant bowel resection, graft-versus-host disease (GVHD) significantly affecting gut motility or absorption, or any other condition that would preclude adequate absorption of DS-3201b in the opinion of the treating physician and/or PI.
4) Has an uncontrolled infection requiring intravenous antibiotics, antivirals, or antifungals, known human immunodeficiency virus infection, or active hepatitis B or C infection. Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines is acceptable.
5) Has a concomitant medical condition that would increase the risk of toxicity, in the opinion of the Investigator or Sponsor.
6) Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE v4, Grade </= 1 or baseline. Subjects with chronic Grade 2 toxicities may be eligible per the discretion of the Investigator and Sponsor (eg, Grade 2 chemotherapy-induced neuropathy).
7) Receipt of hematopoietic stem cell transplantation (HSCT) within 60 days of the first dose of DS-3201b is an exclusion criterion.
8) Is receiving concomitant treatment with a strong inhibitor or inducer of CYP3A4/5 within 7 days of first receipt of DS-3201b.
9) Consumption of herbs/fruits that may have an influence on PK of DS-3201b such as St. Johns wort, star fruit, Seville orange or Seville orange-containing foods and beverages, grapefruit or grapefruit-containing food or beverages from 14 days prior to the start of the study and throughout the entire study.
10) Had major surgery within 4 weeks before study drug treatment.
11) Prolongation of corrected QT interval by Fridericia’s method (QTcF) at rest, where the mean QTcF interval is > 450 milliseconds (ms) based on triplicate electrocardiograms (ECGs), history of additional risk factors for TdP (eg, heart failure, hypokalemia, family history of Long QT Syndrome), or use of concomitant medications that prolong the QT/QTc interval.
12) Pregnant or breastfeeding.
13) Substance abuse or medical, psychological, or social conditions that, in the opinion of the Investigator, may interfere with the subject’s participation in the clinical study or evaluation of the clinical study results.
14) Prior treatment with enhancer of zeste homolog (EZH) inhibitors.

713-794-4392

Phone Number: 1-877-MDA-6789

clinicaltrials.gov NCT No: NCT03110354