Phase 1 First in Human Study of ZN-d5 as a Single Agent

Study Overview
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Brief Summary
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Phase 1 dose escalation study of ZN-d5 in subjects with relapsed or refractory non-Hodgkin lymphoma (NHL) or acute myeloid leukemia (AML).

Detailed Description
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This is an open-label multicenter Phase 1 dose escalation study evaluating the safety, tolerability, clinical activity, pharmacokinetics and pharmacodynamics of the novel BCL-2 inhibitor ZN-d5 in subjects with (NHL) or (AML) in order to determine the recommended phase 2 dose of ZN-d5.

Official Title
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Phase 1 First in Human Dose-Escalation Study of ZN-d5 as a Single Agent in Subjects With Non-Hodgkin Lymphoma or Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia, Non Hodgkin Lymphoma

Intervention / Treatment
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* Drug: ZN-d5


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: NHL: relapsed or refractory NHL including DLBCL, FL, MZL, MCL, LCL, LPL and PTC Subjects must have received at least 2 prior lines of therapy and have either failed or not be eligible for any available therapies expected to provide clinical benefit and have measurable disease. AML: Primary, secondary, or treatment-related AML, relapsed or refractory to prior therapy, which may include failure of one cycle of induction therapy. White blood cell count < 25 × 109/L. Cytoreduction prior to treatment is acceptable. Subjects may not be pregnant and must agree to use an effective method of contraception. Eastern Cooperative Oncology Group performance status ≤ 2. Estimated life expectancy of at least 12 weeks. Adequate hematologic and organ function, including creatinine clearance ≥ 60 mL/min. Key Exclusion Criteria: Recent interventions including major surgery, radiation therapy, stem cell transplant. Treatment with anti-neoplastic agents with 5 half-lives. Significant unresolved toxicity from prior treatments including active GVHD. Active central nervous system disease. Clinically substantial myocardial impairment. Prior therapy with venetoclax.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZN-d5 Single Agent Dose Escalation - NHL<br>Non-Hodgkin Lymphoma | Drug: ZN-d5<br>* Oral agent; 25 mg or 100 mg formulation<br>* Other names: Study Drug;|
| Experimental: ZN-d5 Single Agent Dose Escalation - AML<br>Acute Myeloid Leukemia | Drug: ZN-d5<br>* Oral agent; 25 mg or 100 mg formulation<br>* Other names: Study Drug;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed Dose Limiting Toxicities | Observed Dose Limiting Toxicities (DLTs) in DLT-evaluable subjects. | Through completion of Cycle 1; 1 to 2 months. | 
| Incidence and severity of AEs, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v 5.0 | Safety profile of ZN-d5. | Through study completion, typically < 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic parameters for ZN-d5 - Cmax | Characterize the Pharmacokinetics of ZN-d5 in subjects with NHL and AML using peak plasma concentration (Cmax). | approximately 6 months | 
| Pharmacokinetic parameters for ZN-d5 - Tmax | Characterize the Pharmacokinetics of ZN-d5 in subjects with NHL and AML using the time to maximum plasma concentration (Tmax). | approximately 6 months | 
| Pharmacokinetic parameters for ZN-d5 - AUC | Characterize the Pharmacokinetics of ZN-d5 in subjects with NHL and AML using area under the plasma concentration versus time curve (AUC). | approximately 6 months | 
| For NHL, evaluate response according to the Lugano 2014 classification | Evaluate response according to the Lugano 2014 classification for NHL subjects. The Lugano Classification is based on a 5-point scale for scoring of metabolically active lesions detected by PET-CT in FDG-avid lymphomas, and lesion size for non-FDG-avid tumors. A complete metabolic response would require a score of 1 or 2 on target and non-target lesions and the spleen for high-risk disease, and a score of 1,2, or 3 for low-risk disease. A partial response, no response, or progression would require a score of 4 or 5 for low-risk disease, and a score of 3, 4, or 5 for high-risk disease. | Through study completion, typically < 12 months | 
| For AML, remission rate based on European LeukemiaNet 2017 criteria | Evaluate remission rate according to the European LeukemiaNet 2017 criteria (Overall Response Rate (ORR) defined as Complete Remission (CR) + CR with incomplete hematologic recovery (CRi) + Morphologic Leukemia-Free State (MLFS) + Partial Remission (PR)) for AML subjects. | Through study completion, typically < 12 months | 
| For AML, duration of remission based on European LeukemiaNet 2017 criteria | Evaluate duration of remission according to the European LeukemiaNet 2017 criteria. | Through study completion, typically < 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BCL-2 Inhibitors, BH3 mimetics