Phase 1 Study Evaluating ZEN003365 in Relapsed/Refractory Lymphoproliferative Malignancies or Relapsed/Refractory AML

Study Overview
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Brief Summary
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The purpose of this study is to determine safety, tolerability, dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of ZEN003365 in patients with relapsed/refractory lymphoproliferative malignancies (LPM) or relapsed/refractory acute myeloid leukemia (AML).

Official Title
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Phase 1 Open-label Dose Escalation and Expansion Study of ZEN003365 in Subjects With Relapsed or Refractory Lymphoproliferative Malignancies or Acute Myeloid Leukemia

Conditions
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Lymphoproliferative Malignancies, Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: ZEN003365


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Dose Escalation and Expansion Stages: ECOG performance status ≤ 1 for LPM patients, ≤ 2 for AML patients Age 18 years or older Adverse events (AEs), except for alopecia, from any previous treatments must have recovered to eligibility levels from prior toxicity Adequate renal, hepatic and coagulation function, as specified per protocol Written informed consent granted prior to any study-specific screening procedures LPM Patients: Histologically confirmed lymphoproliferative malignancy Have received prior protocol-specified disease-dependent prior treatments Have measurable disease Platelets ≥ 75,000/µL (≥50,000/µL if bone marrow involvement), absolute neutrophil count (ANC) ≥ 1,000/ µL, and hemoglobin (Hgb) ≥ 8 g/dL Patients must have been off previous anticancer therapy for at least 3 weeks or 5 half-lives, whichever is longer, and the subject must have recovered to eligibility levels from prior toxicity AML: Refractory or relapsed AML patients, without curative intent, e.g., not a stem cell transplant candidate Any prior chemotherapy must have been completed ≥ 2 weeks, any therapy with biologics must have been completed ≥ 4 weeks prior to day 1 of study treatment, and the participant must have recovered to eligibility levels from prior toxicity Blast count ≤ 10,000/µL prior to initiation of therapy Exclusion Criteria Dose Escalation and Expansion Stages: Prior exposure to a BET inhibitor Prior allogeneic hematopoietic cell transplant Chronic graft versus host disease Known, active fungal, bacterial, and/or viral infection Uncontrolled autoimmune hemolytic anemia or thrombocytopenia Current subdural hematoma CNS or leptomeningeal metastases Requirement for medications or agents known to be sensitive CYP3A4 substrate drugs, CYP3A4 substrate drugs with a narrow therapeutic range or to be strong inhibitors/inducers of CYP3A4 Requirement for immunosuppressive agents Evidence of significant cardiovascular disease or significant screening ECG abnormalities Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient. AML patients: Acute promyelocytic leukemia (APL) Chronic myeloid leukemia (CML) in blast crisis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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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: Dose Escalation Stage - ZEN003365<br>ZEN003365 will be administered orally as a single agent, enrolling LPM patients and AML patients | Drug: ZEN003365<br> <br> |
| Experimental: Dose Expansion Stage - ZEN003365<br>ZEN003365 will be administered orally as a single agent, enrolling LPM patients and AML patients | Drug: ZEN003365<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose escalation stage - The safety of orally administered ZEN003365, assessed by frequency of adverse events, including worsening of medical conditions/diseases |  | From Day 1 Cycle 1 through the last day of treatment with ZEN003365 (12 weeks, average) | 
| Dose escalation stage - To characterize the DLTs of orally administered ZEN003365, using NCI CTCAE v4.03 |  | The first 25 days of at least 12 doses of ZEN003365 | 
| Dose expansion stage - Preliminary evidence of the antitumor activity of orally administered ZEN003365 in selected patients, assessed by objective response, duration of objective response and progression-free survival |  | From Day 1 Cycle 1 through the last day of treatment with ZEN003365 (12 weeks, average) | 
| Dose expansion stage - The safety of orally administered ZEN003365, at the dose chosen based upon the dose escalation stage, assessed by frequency of adverse events, including worsening of medical conditions/diseases |  | From Day 1 Cycle 1 through the last day of treatment with ZEN003365 (12 weeks, average) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose escalation stage - To characterize the pharmacokinetics (PK) of orally administered ZEN003365 in patients, using the following parameters: AUC, Tmax, Cmax, Cmin, pre-dose concentration, and accumulation ratio |  | From Day 1 Cycle 1 through the last day of treatment with ZEN003365 (12 weeks, average) | 
| Dose expansion stage - To characterize the PK of orally administered ZEN003365, at the dose chosen based upon the dose escalation stage, using the following parameters: AUC, Tmax, Cmax, Cmin, pre-dose concentration, and accumulation ratio |  | From Screening Visit through 40 days after the last day of treatment with ZEN003365 (19 weeks, average) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic lymphocytic leukemia, B-prolymphocytic leukemia, Non-Hodgkin's lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, diffuse large B-cell lymphoma, unclassifiable lymphoma, T-cell lymphoma, Richter's syndrome, Waldenström's macroglobulinemia