A Study to Assess Safety and Efficacy of Venetoclax in Combination With Gilteritinib in Participants With Relapsed/Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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A dose-escalation study evaluating the safety, tolerability, pharmacokinetics (PK) and efficacy of venetoclax, in combination with gilteritinib, in participants with relapsed or refractory (R/R) acute myeloid leukemia (AML) who have failed to respond to, and/or have relapsed or progressed after at least 1 prior therapy.

Official Title
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A Multicenter, Open-Label Phase 1b Study to Assess Safety and Efficacy of Venetoclax in Combination With Gilteritinib in Subjects With Relapsed/Refractory Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: Venetoclax
* Drug: Gilteritinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Should have an established, confirmed diagnosis of Acute Myeloid Leukemia (AML) by World Health Organization (2016). Should have failed at least 1 line of prior therapy (defined as failure to respond to therapy, and/or progression during or after therapy). Should have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Should have adequate hematologic, kidney and liver function as described in the protocol. For participants enrolling into the Expansion Cohort only: a documented FMS-like Tyrosine Kinase (FLT3) mutation in bone marrow or peripheral blood, as described in the protocol. Exclusion Criteria: Has a diagnosis of acute promyelocytic leukemia (APL) or BCR-ABL-positive leukemia. Has a history of other malignancies within 2 years prior to study entry, with exceptions as described in the protocol. Has active central nervous system leukemia. Has a history of chronic New York Heart Association (NYHA) class IV heart failure. Has a corrected QT interval of > 450 ms. Has a chronic respiratory disease that requires continuous oxygen use.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Venetoclax + Gilteritinib<br>Different combinations of dose levels for venetoclax in combination with gilteritinib will be administered to determine the recommended phase 2 dose (RPTD). | Drug: Venetoclax<br>* tablet, oral<br>* Other names: GDC-0199;Drug: Gilteritinib<br>* tablet, oral<br>* Other names: ASP-2215;|
| Experimental: Dose Expansion Venetoclax + Gilteritinib<br>Participants will receive venetoclax in combination with gilteritinib at the dose determined in dose escalation portion. | Drug: Venetoclax<br>* tablet, oral<br>* Other names: GDC-0199;Drug: Gilteritinib<br>* tablet, oral<br>* Other names: ASP-2215;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 Dose (RPTD) of Co-administered Study Drugs | The RPTD of co-administered venetoclax and gilteritinib will be determined during the dose escalation phase of the study. RPTD will be determined using available safety and pharmacokinetics data. | Up to approximately 6 months after the last participant is enrolled | 
| Modified Composite Complete Remission (CRc) | Modified CRc rate is defined as the proportion of participants with documented complete response (CR) + CR with partial blood count recovery (CRp) + CR with incomplete blood count recovery (CRi) plus Morphologic Leukemia-Free State (MLFS) based on guidelines adapted from the International Working Group (IWG) for Acute Myeloid Leukemia (AML). | Up to approximately 6 months after the last participant is enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics - Cmax of Venetoclax | Maximum observed plasma concentration (Cmax) of study drug. | Approximately 16 days after first dose of study drug | 
| Pharmacokinetics - Cmax of Gilteritinib | Maximum observed plasma concentration (Cmax) of study drug. | Approximately 16 days after first dose of study drug | 
| Pharmacokinetics - Tmax of Venetoclax | Time to maximum plasma concentration (Tmax) of study drug. | Approximately 16 days after first dose of study drug | 
| Pharmacokinetics - Tmax of Gilteritinib | Time to maximum plasma concentration (Tmax) of study drug. | Approximately 16 days after first dose of study drug | 
| Pharmacokinetics - AUCt of Venetoclax | Area Under the Plasma Concentration-time Curve (AUC) from Time 0 to Time of the Last Measurable Concentration (AUCt) of study drug. | Approximately 16 days after first dose of study drug | 
| Pharmacokinetics - AUCt of Gilteritinib | Area Under the Plasma Concentration-time Curve (AUC) from Time 0 to Time of the Last Measurable Concentration (AUCt) of study drug. | Approximately 16 days after first dose of study drug | 
| Pharmacokinetics - AUC0-24 Post-dose of Study Drug of Venetoclax | Area under the plasma concentration-time curve from 0 to 24 hours (AUC24) post-dose of study drug. | Approximately 16 days after first dose of study drug | 
| Pharmacokinetics - AUC0-24 Post-dose of Study Drug of Gilteritinib | Area under the plasma concentration-time curve from 0 to 24 hours (AUC24) post-dose of study drug. | Approximately 16 days after first dose of study drug | 
| Composite Complete Remission (CRc) Rate | CRc is defined as the proportion of participants with documented CR + CRp + CRi based on guidelines adapted from the International Working Group (IWG) for Acute Myeloid Leukemia (AML). | Up to approximately 6 months after the last participant is enrolled | 
| Duration of Response (DOR) of Modified Composite Complete Remission (CRc) | DOR of modified CRc will be defined as time from the first date achieving modified CRc to disease progression (including morphologic relapse) or death from any cause whichever is earlier. | Up to approximately 6 months after the last participant is enrolled | 
| Complete Remission (CR) + with Partial Hematologic Recovery (CRh) | It is defined as the proportion of participants achieving CR or CRh based on guidelines adapted from the International Working Group (IWG) for Acute Myeloid Leukemia (AML). | Up to approximately 6 months after the last participant is enrolled | 
| Duration of Response (DOR) of Complete Remission (CR) + Complete Remission with Partial Hematologic Recovery (CRh) | DOR of CR + CRh will be defined as time from the first date achieving CR and/or CRh to disease progression (including morphologic relapse) or death from any cause whichever is earlier. | Up to approximately 6 months after the last participant is enrolled | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Acute Myeloid Leukemia (AML), Relapsed or Refractory AML, Pharmacokinetics, venetoclax, gilteritinib