A Phase I Study of ZN-d5 in Chinese Subjects With Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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A phase I dose-escalation, open-label, multicenter study to assess the safety, tolerability, clinical activity, and pharmacokinetics (PK) of ZN-d5 in Chinese subjects with non-Hodgkin lymphoma (NHL).

Detailed Description
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For the Phase I dose escalation study of ZN-d5, it is planned that after the starting dose, subsequent dose assignments will be made by means of a model-assisted design, until the MTD or RP2D is determined in the Chinese population.

Official Title
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A Phase I Dose Escalation Study of ZN-d5 Monotherapy in Chinese Subjects With Non-Hodgkin Lymphoma

Conditions
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Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: ZN-d5


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: NHL, relapsed from or refractory to at least 2 prior lines of systemic therapy (excluding radiotherapy and surgery); subjects must have failed or not be candidates for available standard therapy expected to provide clinical benefit. Female subjects of childbearing potential must have a negative serum pregnancy test and agree to use contraception while on study. Eastern Cooperative Oncology Group performance status ≤ 1. Adequate blood and other organ function, defined by the following criteria: Neutrophil count (ANC) ≥ 1.0 × 109/L. Platelet count ≥ 75 × 109/L at least 3 days after platelet transfusion (≥ 50 × 109/L permitted if the bone marrow is > 50% lymphoma cells). Hemoglobin ≥ 8.0 g/dL. Coagulation parameters ≤ 1.5 × upper limit of normal (ULN). Liver enzymes ≤ 3 × ULN and total bilirubin ≤ 1.5 × ULN. Creatinine clearance ≥ 60 mL/min. Exclusion Criteria: Received any of the following prior to start of ZN-d5 treatment: Systemic administration of antineoplastic agents (including investigational agents) within the shorter of 28 days or 5 half-lives. Major surgery within 28 days. Radiotherapy within 14 days. Autologous or allogeneic stem cell transplantation within 60 days, or receiving immunosuppression for active graft-versus-host disease. Use of strong CYP3A4 inhibitors, P-gp inhibitors or QT prolonging agents within 5 half-lives, or potent or moderate CYP3A4 inducers within 14 days. Ongoing and clinically significant non-hematologic toxicity related to prior antineoplastic therapy. Presence of major cardiovascular system diseases (including QTcF > 480 msec). Positive serology for human immunodeficiency virus, hepatitis B, or hepatitis C unless no detectable hepatitis B or C viral load. Unable to take oral drugs or presence of severe gastrointestinal abnormalities. Active and uncontrolled clinically significant infection. Other active systemic malignancy or other severe, unstable, or poorly controlled acute or chronic medical conditions. Prior treatment with venetoclax or other BCL-2 inhibitors. Primary or secondary CNS lymphoma. Presence of post-transplant lymphoproliferative disease, Burkitt's lymphoma, Burkitt-like lymphoma, T lymphoblastic lymphoma and T lymphoblastic acute leukemia.

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: 100mg(on empty)<br> | Drug: ZN-d5<br>* BION design<br>|
| Experimental: 200mg(on empty)<br> | Drug: ZN-d5<br>* BION design<br>|
| Experimental: 400mg(on empty)<br> | Drug: ZN-d5<br>* BION design<br>|
| Experimental: 600mg(on empty)<br> | Drug: ZN-d5<br>* BION design<br>|
| Experimental: 600mg（with a meal）<br> | Drug: ZN-d5<br>* BION design<br>|
| Experimental: 800mg(with a meal)<br> | Drug: ZN-d5<br>* BION design<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety monitoring | Incidence and severity of adverse events (AEs), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 | until 30 days after the last dose of study drug | 
| DLT | Dose-limiting toxicities (DLTs) observed in DLT evaluable subjects | at the end of Cycle 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effacy Evaluation | Efficacy as defined by the 2014 Lugano response criteria | up to 24 months | 
| Maximum Plasma Concentration [Cmax] | Plasma PK parameters of ZN-d5 | up to 24 months |