A Study of Venetoclax and AMG 176 in Patients With Relapsed/Refractory Hematologic Malignancies

Study Overview
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Brief Summary
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This dose-escalation study evaluating the safety, pharmacokinetics and preliminary efficacy of venetoclax in combination with AMG 176 in participants with relapsed or refractory acute myeloid leukemia (AML) and participants with Non-Hodgkin's lymphoma (NHL)/diffuse large B-cell lymphoma (DLBCL). This study will include a dose escalation phase to identify the maximum tolerated dose/recommended phase 2 dose (MTD/RPTD) of venetoclax plus AMG 176 as well as a dose expansion phase to confirm safety, explore efficacy, and confirm the suitability of the preliminary RPTD.

Official Title
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Phase 1b Study of Venetoclax and AMG 176 in Patients With Relapsed/Refractory Hematologic Malignancies

Conditions
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Acute Myeloid Leukemia, Non-Hodgkin's Lymphoma, Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Venetoclax
* Drug: AMG 176


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adequate kidney, liver and hematology values as described in the protocol. Diagnosis of relapsed or refractory (R/R) acute myeloid leukemia (AML) or R/R Non-Hodgkin's lymphoma (NHL)/diffuse large B-cell lymphoma (DLBCL) confirmed by the World Health Organization (WHO) criteria, as appropriate. Meets the following disease activity criteria: AML: must have received at least 1 prior therapy for AML and be ineligible for cytotoxic therapy and allogeneic stem cell transplant. NHL/DLBCL: measurable disease with a bidimensional lesion measuring at least 1.5 cm; received at least 1 prior therapy for NHL with no curative treatment option as determined by the investigator and be ineligible for a stem cell transplant. Exclusion Criteria: History of clinically significant medical condition that, in the opinion of the investigator, would adversely affect participation in this study. History of of any malignancy within the last 6 months except for those specified in this protocol and low-grade malignancies not requiring active treatment such as non-melanoma skin cancer, cervical intraepithelial neoplasia, or prostate cancer in situ. Prior allogeneic stem cell transplant or autologous stem cell transplant within 100 days of study drug administration and no signs or symptoms of acute or chronic graft-versus-host disease. Previous enrollment in a randomized trial including either venetoclax or AMG 176. Known active or chronic pancreatitis; severe chronic obstructive pulmonary disease with hypoxemia; central nervous system manifestations of malignancy. Active, uncontrolled infection.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Venetoclax + AMG 176<br>Venetoclax and AMG 176 will be administered in combination. Different combinations of dose levels for venetoclax and AMG 176 will be explored. | Drug: Venetoclax<br>* tablet, oral<br>* Other names: ABT-199;Drug: AMG 176<br>* solution, intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RPTD) for Venetoclax + AMG 176 | The MTD and/or RPTD of venetoclax and of AMG 176 will be determined during the dose escalation phase of the study. | Up to 28 days after first dose of study drug in a dose-escalation phase | 
| Number of Participants With Adverse Events | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. | From first dose of study drug until 30 days or 5 half-lives after discontinuation of study drug administration will be collected (up to approximately 4 years). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Complete Remission Rate (CRc) for Participants with AML | CRc rate is defined as CR + CRi (CR with incomplete blood count recovery). | Up to approximately 2 years from last subject first dose | 
| Objective Response Rate (ORR) for Participants with AML | ORR is defined as the percentage of participants with documented partial response (PR) or better (CR + CRi + partial response [PR]) based on International Working Group (IWG) criteria for AML | Up to approximately 2 years from last subject first dose | 
| ORR for Participants with NHL | ORR is defined as the percentage of participants with documented CR + PR based on Lugano criteria for NHL. | Up to approximately 2 years from last subject first dose | 
| Maximum Plasma Concentration (Cmax) of Venetoclax | Maximum observed plasma concentration (Cmax) of venetoclax. | Up to approximately 28 days after first dose of study drug | 
| Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax | Time to maximum plasma concentration (Tmax) of Venetoclax. | Up to approximately 28 days after first dose of study drug | 
| AUC of Venetoclax | Area under the plasma concentration-time curve (AUC) of venetoclax. | Up to approximately 28 days after first dose of study drug | 
| Maximum Plasma Concentration (Cmax) of AMG 176 | Maximum observed plasma concentration (Cmax) of AMG 176 | Up to approximately 16 days after first dose of study drug | 
| Half-life (t1/2) of AMG 176 | Terminal phase elimination half-life (t1/2) | Approximately 16 days after first dose of study drug | 
| AUC of AMG 176 | Area Under the Plasma Concentration-time Curve (AUC) of AMG 176 | Approximately 16 days after first dose of study drug | 
| Clearance (CL) of AMG 176 | Clearance (CL) is defined the volume of plasma cleared of the drug per unit time. | Approximately 16 days after first dose of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, Non-Hodgkin's Lymphoma, Cancer, Venetoclax, AMG 176, diffuse large B-cell lymphoma (DLBCL)