Study of the ZN-d5 and ZN-c3 in Subjects With Acute Myeloid Leukemia (AML)

Study Overview
=================
Brief Summary
-----------------
A Phase 1/2 dose escalation study of BCL-2 Inhibitor ZN-d5 and the Wee1 Inhibitor ZN-c3 in Subjects with Acute Myeloid Leukemia (AML).

Detailed Description
-----------------
This is an open-label multicenter Phase 1/2 dose escalation study, evaluating the safety, tolerability, clinical activity, pharmacokinetics and pharmacodynamics of the novel BCL-2 inhibitor ZN-d5 and Wee1 inhibitor ZN-c3 in subjects with AML.

Official Title
-----------------
A Phase 1/2 Dose Escalation Study of the BCL-2 Inhibitor ZN-d5 and the WEE1 Inhibitor ZN-c3 in Subjects With Acute Myeloid Leukemia

Conditions
-----------------
Acute Myeloid Leukemia (AML)

Intervention / Treatment
-----------------
* Drug: ZN-d5 ZN-c3
* Drug: ZN-c3


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults with AML (including secondary or therapy-related), relapsed from or refractory to one or more prior lines of therapy, which may include venetoclax except in Expansion Cohort A ECOG performance status score ≤2. Projected life expectancy of at least 12 weeks. Estimated glomerular filtration rate ≥60 mL/min Women of childbearing potential must not be pregnant and must use effective birth control during the study and for 6 months after the last dose of study drugs. Men must agree to use a condom when having intercourse during the study and for 3 months after the last dose of study drugs. Exclusion Criteria: Known active CNS involvement Diagnosis of acute promyelocytic leukemia. Peripheral blast count of >25 × 109/L (cytoreduction permitted). Adequate washout from prior therapy including hematopoietic stem cell transplant and recovery from prior treatment-related toxicities to Grade 2 or lower Significant cardiovascular disease Corrected QT interval (QTc) of >480 msec Active hepatitis B or hepatitis C infection Concurrent treatment with strong CYP3A inhibitors or strong or moderate CYP3A inducers

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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acute Myeloid Leukemia<br>Phase 1: Dose Escalation- c3 monotherapy and d5+c3 combination Phase 2: Dose Expansion | Drug: ZN-d5 ZN-c3<br>* Oral agent<br>* Other names: Study Drug;Drug: ZN-c3<br>* Oral agent<br>* Other names: Study Drug;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed dose limiting toxicities | Observed Dose Limiting Toxicities (DLTs) in DLT evaluable subjects. | At the end of Cycle 1 (each cycle is 28 days) | 
| Incidence, severity, and relatedness of adverse events( AEs) |  | Through study completion, typically < 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. To investigate the plasma PK of ZN-c3 when given as monotherapy - Maximum Plasma Concentration | The maximum plasma concentration (Cmax) of ZN-c3 (and its potential metabolites, as applicable) will be determined | Through study completion, typically <12 months | 
| 2. To investigate the plasma PK of ZN-c3 when given as monotherapy - Area under the plasma concentration-time curve from 0 to 24h | Area under the plasma concentration-time curve from 0 to 24h [AUC0-24h] of ZN-c3 (and its potential metabolites, as applicable) will be determined | Through study completion, typically < 12 months | 
| 5. To investigate the plasma PK of ZN-c3 and ZN-d5 when given in combination - Maximum Plasma Concentration | The maximum plasma concentration (Cmax) of ZN-c3 (and its potential metabolites, as applicable) and ZN-d5 (and its potential metabolites, as applicable) will be determined | Through study completion, typically < 12 months | 
| 6. To investigate the plasma PK of ZN-c3 and ZN-d5 when given in combination - Area under the plasma concentration-time curve from 0 to 24h | Area under the plasma concentration-time curve from 0 to 24h [AUC0-24h] of ZN-c3 (and its potential metabolites, as applicable) and ZN-d5 (and its potential metabolites, as applicable) will be determined | Through study completion, typically < 12 months | 
| Rate and duration or remission according to the European LeukemiaNet 2017 criteria |  | Through study completion, typically < 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
BCL-2 Inhibitors, Wee1 Inhibitors, AML