Tamibarotene + Venetoclax/Azacitidine for Acute Myeloid Leukemia

No longer recruiting at 30 trial locations

Overseen By Galina Craig

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Syros Pharmaceuticals

Must not be taking: Hypomethylating agents, Chemotherapy

Disqualifiers: APL, CNS involvement, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment option for individuals with acute myeloid leukemia (AML) who have a specific genetic marker called RARA. The study combines a new drug, tamibarotene, with two existing medications, venetoclax and azacitidine, which are already used for AML patients unable to tolerate standard chemotherapy. The goal is to determine if this combination is more effective for patients with the RARA genetic marker. Suitable candidates for this trial have newly diagnosed AML, have not received prior treatment, and test positive for RARA. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to benefit from a potentially more effective therapy.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it does mention that you should not have had prior treatment with certain drugs for AML, except for hydroxyurea.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of tamibarotene, venetoclax, and azacitidine is generally well-tolerated by patients with acute myeloid leukemia (AML). Studies have found that this drug combination does not reduce bone marrow activity more than azacitidine alone.

In related trials, patients taking tamibarotene with venetoclax and azacitidine did not experience unexpected side effects, suggesting the treatment is relatively safe. However, like any treatment, side effects can occur. Additionally, the FDA has given this combination a fast track designation for certain AML cases, indicating a promising safety profile.

Overall, current data supports the safety of this treatment combination for AML patients who are not suitable for standard chemotherapy. Discuss potential side effects with the study staff before joining any clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of tamibarotene with venetoclax and azacitidine for treating Acute Myeloid Leukemia (AML) because it introduces a unique approach by targeting RARA-positive patients. Unlike standard treatments that rely on broad chemotherapy, tamibarotene specifically activates retinoic acid receptors, which can be overexpressed in certain leukemia cells, potentially leading to more targeted and effective treatment with fewer side effects. Additionally, the use of venetoclax, known for its ability to target and inhibit the BCL-2 protein, enhances the regimen by promoting cancer cell death, while azacitidine modifies the DNA of cancer cells to reduce their growth. Together, this triplet combination aims to improve patient outcomes by utilizing these distinct mechanisms of action.

What evidence suggests that this trial's treatments could be effective for AML?

Research has shown that the combination of tamibarotene, venetoclax, and azacitidine, which participants in this trial may receive, may effectively treat acute myeloid leukemia (AML) with a specific genetic makeup. In studies, 61% of patients unable to undergo standard chemotherapy experienced a complete or nearly complete response with this treatment. Another study found that 80% of these patients responded positively overall. Tamibarotene targets a gene called RARA, which is overactive in about 30% of AML cases. This targeted approach might explain the treatment's effectiveness. The combination is generally well-tolerated, with manageable side effects. ^{2 6 7 8 9}

Who Is on the Research Team?

Michael Kelly Executive Medical Director, MD

Principal Investigator

Syros Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed AML who can't start standard chemo due to age, health, or other issues. They must have a certain gene abnormality (RARA-positive) and not have had previous treatments for their leukemia except hydroxyurea.

Inclusion Criteria

I have a new AML diagnosis, haven't been treated, and can't handle strong chemotherapy.

My blood test before treatment showed I am RARA-positive.

Exclusion Criteria

I have not had specific treatments for AML, MDS, or other blood cancers before starting this trial, except for hydroxyurea.

I have acute promyelocytic leukemia (APL).

My acute myeloid leukemia has spread to my brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Part 1: Safety and Dose Evaluation

Evaluation of safety, tolerability, and pharmacokinetics of tamibarotene/venetoclax/azacitidine combination to determine appropriate dosing

28 days per cycle

Multiple visits per cycle

Part 2: Randomized Treatment

Participants are randomized to receive either tamibarotene/venetoclax/azacitidine or venetoclax/azacitidine to compare clinical activity

28 days per cycle, up to 3 years

Multiple visits per cycle

Part 3: Treatment for Progressive Disease

Tamibarotene is added to the regimen for participants experiencing progressive disease, relapse, or treatment failure

28 days per cycle, up to 3 years

Multiple visits per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Tamibarotene
• Venetoclax

Trial Overview The study tests Tamibarotene combined with Venetoclax and Azacitidine in patients with acute myeloid leukemia (AML). It targets those whose cancer has the RARA gene overexpression and are unsuitable for standard chemotherapy.

How Is the Trial Designed?

Group I: Part 3: Tamibarotene/Venetoclax/Azacitidine Experimental Treatment 3 Interventions

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.

Group II: Part 2: Tamibarotene/Venetoclax/Azacitidine Experimental Treatment 3 Interventions

Participants will receive the tamibarotene/venetoclax/azacitidine triplet combination at the dose and regimen selected in Part 1.

Group III: Part 1: Tamibarotene/Venetoclax/Azacitidine Experimental Treatment 3 Interventions

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.

Group IV: Part 2: Venetoclax/Azacitidine Active Control 2 Interventions

Participants will receive the venetoclax/azacitidine combination at the dose and regimen selected in Part 1.

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Syros Pharmaceuticals

Lead Sponsor

Trials

6

Recruited

1,000+

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04905407

NCT04905407 | Tamibarotene Plus Venetoclax/Azacitidine ... This study consists of 3 parts. In Part 1, the safety, tolerability, and pharmacokinetic (PK) evaluation of tamibarotene/venetoclax/azacitidine combination will ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.TPS7065

Tamibarotene in combination with venetoclax and ... Tamibarotene plus aza has been generally well tolerated, with no increase in myelosuppression compared to single agent aza.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265024011868

AML-347 SELECT-AML-1: Phase 2 Randomized Trial of ... Tami-ven-aza demonstrated high CR/CRi rate and rapid onset of response in AML with RARA overexpression as a biomarker target.

4. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/3333/492725/Initial-Results-from-SELECT-AML-1-a-Phase-2-Study

Initial Results from SELECT-AML-1, a Phase 2 Study of ... In patients with newly diagnosed (ND) AML ineligible for standard induction chemotherapy, tamibarotene/azacitidine led to a CR/CRi rate of 61% ...

5. aml-hub.com aml-hub.com/medical-information/tamibarotene-ven-aza-combination-in-patients-with-aml-interim-results-from-the-select-aml-1-phase-ii-trial

Tamibarotene + Ven + Aza combination in patients with AML ORR was 80% and 73%, respectively. In the prespecified efficacy futility analysis, CR/CRi was achieved in 65% of patients receiving tamibarotene ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04905407

NCT04905407 | Tamibarotene Plus Venetoclax/Azacitidine ... This study consists of 3 parts. In Part 1, the safety, tolerability, and pharmacokinetic (PK) evaluation of tamibarotene/venetoclax/azacitidine combination will ...

7. clinical-lymphoma-myeloma-leukemia.com clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(24)01186-8/pdf

AML-347 SELECT-AML-1: Phase 2 Randomized. Trial of Tamibarotene in Combination. With Venetoclax and Azacitidine in Adult Patients With Previously.

8. targetedonc.com targetedonc.com/view/select-aml-1-trial-of-tamibarotene-combo-in-aml-discontinues-enrollment

SELECT-AML-1 Trial of Tamibarotene Combo in AML ... Among the first 40 patients enrolled in the study, those given tamibarotene plus venetoclax and azacitidine (n = 20) experienced a complete ...

9. onclive.com onclive.com/view/fda-grants-fast-track-designation-to-tamibarotene-azacitidine-venetoclax-for-rara-overexpressed-aml

FDA Grants Fast Track Designation to Tamibarotene ... Tamibarotene plus azacitidine and venetoclax has received FDA fast track designation for newly diagnosed, unfit, RARA-overexpressed AML.