Tamibarotene Plus Venetoclax/Azacitidine in Participants With Newly Diagnosed AML

Study Overview
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Brief Summary
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Tamibarotene is being studied as a treatment for participants with a type of leukemia called acute myeloid leukemia, or AML for short. Tamibarotene is being studied as a treatment for participants with AML whose cancer has a specific genetic abnormality characterized by the overexpression of the retinoic acid receptor alpha (RARA) gene. This genetic profile is found in about 3 of every 10 people with AML. During the trial, tamibarotene will be given with 2 other drugs that are already used together to treat people who have AML and who cannot start treatment with standard chemotherapy.

Detailed Description
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This study consists of 3 parts. In Part 1, the safety, tolerability, and pharmacokinetic (PK) evaluation of tamibarotene/venetoclax/azacitidine combination will inform the appropriate tamibarotene dose to be combined with the standard of care (SOC) venetoclax/azacitidine in Part 2 and Part 3. In Part 2, participants will be randomized 1:1 to receive either tamibarotene/venetoclax/azacitidine or venetoclax/azacitidine to compare the clinical activity of the 2 combinations. In Part 3, tamibarotene will be added to the venetoclax/azacytidine regimen of a subset of Part 2 participants who experience progressive disease, relapse after initial complete remission (CR) or CR with incomplete blood count recovery (CRi) response, or treatment failure.

Official Title
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Tamibarotene in Combination With Venetoclax and Azacitidine in Previously Untreated Adult Patients Selected for RARA-positive AML Who Are Ineligible for Standard Induction Therapy

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Tamibarotene
* Drug: Venetoclax
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Note: all inclusion/exclusion criteria should be met prior to the first dose of venetoclax/azacitidine on Cycle 1 Day 1 with the exception of the RARA-biomarker test result referenced in inclusion criterion 2, which should be positive by Cycle 1 Day 8 to continue treatment on study. Inclusion Criteria: All participants must have obtained a blood sample for RARA biomarker investigational assay testing prior to starting treatment on Cycle 1 Day 1. The results of the investigational biomarker assay for all participants must be confirmed as RARA-positive by Cycle 1 Day 8 to enroll (Part 1) or to be randomized (Part 2) in the study. Participants must have newly diagnosed, previously untreated non-acute promyelocytic leukemia (APL) AML with a bone marrow or peripheral blood blast count ≥20% and must be unlikely to tolerate standard intensive chemotherapy at the time of Cycle 1 Day 1 Visit due to age, performance status, or comorbidities based on at least one of the following criteria: age ≥75 years old, or age <75 years old, with at least one of the following: Eastern Cooperative Oncology Group (ECOG) performance status of 3 cardiac history of congestive heart failure (CHF) or documented ejection fraction (EF) ≤50% pulmonary disease with diffusing capacity of the lungs for carbon monoxide (DLCO) ≤65% or forced expiratory volume in one second (FEV1) ≤65% creatinine clearance ≥30 milliliters (mL)/minute (min) to <45 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation hepatic impairment with total bilirubin >1.5 to ≤3.0 * upper limit of normal (ULN) any other comorbidity that the investigator judges to be incompatible with intensive chemotherapy, and reviewed and approved by the sponsor. Exclusion Criteria: Participants have APL. Participants have known active central nervous system involvement with AML. Prior treatment (before Cycle 1 Day 1) for the diagnosis of AML, myelodysplastic syndromes (MDS), or antecedent hematologic malignancy with any hypomethylating agent, venetoclax, chemotherapy, or hematopoietic stem cell transplantation (HSCT), with the exception of prior treatment with hydroxyurea.

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Tamibarotene/Venetoclax/Azacitidine<br>Participants will receive the tamibarotene/venetoclax/azacitidine triplet combination as follows: Azacitidine (intravenously or subcutaneously) at 75 milligrams (mg)/square meter (m^2) once daily, on Days 1 through 7 of each 28-day therapy cycle (per VIDAZA USPI). Alternative dosing of azacitidine (Days 1 through 5, 8, and 9) will be permitted throughout the study. Venetoclax (orally) daily on Days 1 through 28 per standard of care. Standard of care daily dosing is 100 mg on Day 1, 200 mg on Day 2, and 400 mg on Day 3 and beyond. Tamibarotene 6 mg twice daily (BID) orally, on Days 8 through 28 of each 28-day therapy cycle. Tamibarotene will only be administered to participants who have been confirmed as RARA-positive. | Drug: Tamibarotene<br>* Tamibarotene tablets will be administered per dose and schedule specified in the arm.<br>Drug: Venetoclax<br>* Venetoclax tablets will be administered per dose and schedule specified in the arm.<br>* Other names: Venclexta;Drug: Azacitidine<br>* Azacitidine injection will be administered per dose and schedule specified in the arm.<br>* Other names: Vidaza;|
| Experimental: Part 2: Tamibarotene/Venetoclax/Azacitidine<br>Participants will receive the tamibarotene/venetoclax/azacitidine triplet combination at the dose and regimen selected in Part 1. | Drug: Tamibarotene<br>* Tamibarotene tablets will be administered per dose and schedule specified in the arm.<br>Drug: Venetoclax<br>* Venetoclax tablets will be administered per dose and schedule specified in the arm.<br>* Other names: Venclexta;Drug: Azacitidine<br>* Azacitidine injection will be administered per dose and schedule specified in the arm.<br>* Other names: Vidaza;|
| Active Comparator: Part 2: Venetoclax/Azacitidine<br>Participants will receive the venetoclax/azacitidine combination at the dose and regimen selected in Part 1. | Drug: Venetoclax<br>* Venetoclax tablets will be administered per dose and schedule specified in the arm.<br>* Other names: Venclexta;Drug: Azacitidine<br>* Azacitidine injection will be administered per dose and schedule specified in the arm.<br>* Other names: Vidaza;|
| Experimental: Part 3: Tamibarotene/Venetoclax/Azacitidine<br>Part 2 participants treated with venetoclax/azacitidine who experience progressive disease, relapse after initial CR or CRi response, or treatment failure may begin subsequent treatment in Part 3, where tamibarotene will be added to their regimen. | Drug: Tamibarotene<br>* Tamibarotene tablets will be administered per dose and schedule specified in the arm.<br>Drug: Venetoclax<br>* Venetoclax tablets will be administered per dose and schedule specified in the arm.<br>* Other names: Venclexta;Drug: Azacitidine<br>* Azacitidine injection will be administered per dose and schedule specified in the arm.<br>* Other names: Vidaza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants With Adverse Events |  | up to 3 years | 
| Part 2: CR/CRi Rate | CR/CRi rate is estimated by the proportion of participants who achieve CR/CRi (as determined by the investigator). | up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Overall Response Rate (ORR) | Overall response assessment is comprised of CR, CRi, CR with partial hematologic recovery (CRh), morphologically leukemia-free state (MLFS), or partial remission (PR) (as determined by the investigator). ORR is estimated by the proportion of participants who achieve overall response. | up to 3 years | 
| Part 1: Plasma Concentration of Tamibarotene |  | Day 8 and 22 of Cycle 1, Day 15 of Cycles 2 and 3 (cycle length = 28 days) | 
| Part 2: Number of Participants With Adverse Events |  | up to 3 years | 
| Part 2: CR Rate | CR rate is estimated by the proportion of participants who achieve CR (as determined by the investigator). | up to 3 years | 
| Part 2: CR/CRh Rate | CR/CRh rate is estimated by the proportion of participants who achieve CR/CRh (as determined by the investigator). | up to 3 years | 
| Part 2: Duration of CR | Duration of CR is defined as duration from the date of first documented evidence of CR to the date of relapse of disease (as determined by the investigator), or death due to any cause, whichever occurs first. | up to 3 years | 
| Part 2: Duration of CR/CRi | Duration of CR/CRi is defined as duration from the date of first documented evidence of CR/CRi to the date of relapse of disease (as determined by the investigator), or death due to any cause, whichever occurs first. | up to 3 years | 
| Part 2: Duration of CR/CRh | Duration of CR/CRh is defined as duration from the date of first documented evidence of CR/CRh to the date of relapse of disease (as determined by the investigator), or death due to any cause, whichever occurs first. | up to 3 years | 
| Part 2: Time to CR | Time to CR is defined as the duration from the date of Cycle 1 Day 1 Visit to the date of the first documented evidence of CR as determined by the investigator. | up to 3 years | 
| Part 2: Time to CR/CRi | Time to CR/CRi is defined as the duration from the date of Cycle 1 Day 1 Visit to the date of the first documented evidence of CR/CRi as determined by the investigator. | up to 3 years | 
| Part 2: Time to CR/CRh | Time to CR/CRh is defined as the duration from the date of Cycle 1 Day 1 Visit to the date of the first documented evidence of CR/CRh as determined by the investigator. | up to 3 years | 
| Part 2: ORR | Overall response assessment is comprised of CR, CRi, CRh, MLFS, or PR (as determined by the investigator). ORR is estimated by the proportion of participants who achieve overall response. | up to 3 years |