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Tamibarotene Plus Venetoclax/Azacitidine in Participants With Newly Diagnosed AML

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ClinicalTrials.gov Identifier: NCT04905407
Recruitment Status : Recruiting
First Posted : May 27, 2021
Last Update Posted : April 6, 2022
Sponsor:
Information provided by (Responsible Party):
Syros Pharmaceuticals

Study Description
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Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Tamibarotene Drug: Venetoclax Drug: Azacitidine Phase 2

Detailed Description:
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 triplet dose and regimen for Part 2. In Part 2, participants will be randomized 1:1 to receive either tamibarotene/venetoclax/azacitidine or venetoclax/azacitidine to explore comparative 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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 95 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Tamibarotene in Combination With Venetoclax and Azacitidine in Adult Patients With RARA-positive, Previously Untreated AML Who Are Ineligible for Standard Induction Therapy
Actual Study Start Date : August 26, 2021
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Part 1: Tamibarotene/Venetoclax/Azacitidine

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.

 Drug: Tamibarotene
Tamibarotene tablets will be administered per dose and schedule specified in the arm.

Drug: Venetoclax
Venetoclax tablets will be administered per dose and schedule specified in the arm.
Other Name: Venclexta

Drug: Azacitidine
Azacitidine injection will be administered per dose and schedule specified in the arm.
Other Name: Vidaza
Experimental: Part 2: Tamibarotene/Venetoclax/Azacitidine
Participants will receive the tamibarotene/venetoclax/azacitidine triplet combination at the dose and regimen selected in Part 1.
 Drug: Tamibarotene
Tamibarotene tablets will be administered per dose and schedule specified in the arm.

Drug: Venetoclax
Venetoclax tablets will be administered per dose and schedule specified in the arm.
Other Name: Venclexta

Drug: Azacitidine
Azacitidine injection will be administered per dose and schedule specified in the arm.
Other Name: Vidaza
Active Comparator: Part 2: Venetoclax/Azacitidine
Participants will receive the venetoclax/azacitidine combination at the dose and regimen selected in Part 1.
 Drug: Venetoclax
Venetoclax tablets will be administered per dose and schedule specified in the arm.
Other Name: Venclexta

Drug: Azacitidine
Azacitidine injection will be administered per dose and schedule specified in the arm.
Other Name: Vidaza
Experimental: Part 3: Tamibarotene/Venetoclax/Azacitidine
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
Tamibarotene tablets will be administered per dose and schedule specified in the arm.

Drug: Venetoclax
Venetoclax tablets will be administered per dose and schedule specified in the arm.
Other Name: Venclexta

Drug: Azacitidine
Azacitidine injection will be administered per dose and schedule specified in the arm.
Other Name: Vidaza


Outcome Measures
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Primary Outcome Measures :
  1. Part 1: Number of Participants With Adverse Events [ Time Frame: up to 3 years ]
  2. Part 2: CR/CRi Rate [ Time Frame: up to 3 years ]
    CR/CRi rate is defined as proportion of participants who achieve CR/CRi (as determined by the investigator).


Secondary Outcome Measures :
  1. Part 1: Overall Response Rate (ORR) [ Time Frame: up to 3 years ]
    ORR is defined as the proportion of participants who achieve CR, CRi, CR with partial hematologic recovery (CRh), morphologically leukemia-free state (MLFS), or partial remission (PR) (as determined by the investigator).

  2. Part 1: Plasma Concentration of tamibarotene [ Time Frame: Day 8 and 22 of Cycle 1, Day 15 of Cycles 2 and 3 (cycle length = 28 days) ]
  3. Part 2: Number of Participants With Adverse Events [ Time Frame: up to 3 years ]
  4. Part 2: CR Rate [ Time Frame: up to 3 years ]
    CR rate is defined as proportion of participants who achieve CR (as determined by the investigator).

  5. Part 2: CR/CRh Rate [ Time Frame: up to 3 years ]
    CR/CRh rate is defined as proportion of participants who achieve CR/CRh (as determined by the investigator).

  6. Part 2: Duration of CR [ Time Frame: up to 3 years ]
    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.

  7. Part 2: Duration of CR/CRi [ Time Frame: up to 3 years ]
    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.

  8. Part 2: Duration of CR/CRh [ Time Frame: up to 3 years ]
    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.

  9. Part 2: Time to CR [ Time Frame: up to 3 years ]
    Time to CR is defined as the duration from the date of randomization to the date of the first documented evidence of CR as determined by the investigator.

  10. Part 2: Time to CR/CRi [ Time Frame: up to 3 years ]
    Time to CR/CRi is defined as the duration from the date of randomization to the date of the first documented evidence of CR/CRi as determined by the investigator.

  11. Part 2: Time to CR/CRh [ Time Frame: up to 3 years ]
    Time to CR/CRh is defined as the duration from the date of randomization to the date of the first documented evidence of CR/CRh as determined by the investigator.

  12. Part 2: ORR [ Time Frame: up to 3 years ]
    ORR is defined as the proportion of participants who achieve CR, CRi, CRh, MLFS, or PR (as determined by the investigator).


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants must be RARA-positive based on the investigational assay.

  • 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 study entry 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 prior to enrollment.

Exclusion Criteria:

  • Participants have APL.
  • Participants have known active central nervous system involvement with AML.
  • Prior treatment 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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04905407


Contacts
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Contact: Kim Caliri Director, Clinical Operations 617-674-9053 kcaliri@syros.com
Contact: Erica Warlick Medical Director, MD 617-865-2108 ewarlick@syros.com

Locations
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United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Brian Ball, MD    626-218-2405      
Principal Investigator: Brian Ball, MD         
United States, Colorado
University of Colorado Recruiting
Denver, Colorado, United States, 80204
Contact: Olivia Ondracek    720-848-9384    OLIVIA.ONDRACEK@CUANSCHUTZ.EDU   
Principal Investigator: Christine McMahon, MD         
Colorado Blood Cancer Institute Recruiting
Denver, Colorado, United States, 80218
Contact: Sonya Grohowski    720-754-8067      
Principal Investigator: Alizera Eghtedar, MD         
United States, Florida
BRCR Global Recruiting
Plantation, Florida, United States, 33322
Contact: Ines Padron    561-447-0614    ipadron@brcrglobal.com   
Principal Investigator: Jason Tache, DO         
United States, Idaho
Saint Alphonsus Regional Medical Center Recruiting
Boise, Idaho, United States, 83706
Contact: Laura O'Brien    208-367-3481    Laura.OBrien@saintalphonsus.org   
Principal Investigator: Karl Schultheiss, MD         
United States, Missouri
HCA Midwest Research Medical Center Recruiting
Kansas City, Missouri, United States, 64132
Contact: Lauren Wright    816-276-4227      
Principal Investigator: Suman Kambhampati, MD         
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Eytan Stein       SteinE@mskcc.org   
Principal Investigator: Eytan Stein, MD         
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Michelle Velasquez    713-745-9852      
Principal Investigator: Gautam Borthakur, MD         
Sponsors and Collaborators
Syros Pharmaceuticals
Investigators
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Study Director: Michael Kelly Executive Medical Director, MD Syros Pharmaceuticals
More Information
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Responsible Party: Syros Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04905407    
Other Study ID Numbers: SY-1425-202
First Posted: May 27, 2021    Key Record Dates
Last Update Posted: April 6, 2022
Last Verified: March 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Azacitidine
Venetoclax
Antimetabolites, Antineoplastic
Antimetabolites
 Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors