Enrollment to Discontinue for SELECT-AML-1 Trial of Tamibarotene Triplet in Newly Diagnosed RARA+ AML

Enrollment in the phase 2 SELECT-AML-1 trial (NCT04905407) will discontinue following results from a prespecified interim analysis of the study, which was evaluating the addition of tamibarotene to venetoclax (Venclexta) plus azacitidine in patients with newly diagnosed, RARA-overexpressed acute myeloid leukemia (AML), according to an announcement from Syros Pharmaceuticals.¹

In the prespecified, non-binding futility analysis of the first 40 patients enrolled in the study, patients treated with tamibarotene plus venetoclax and azacitidine (n = 20) experienced a complete response (CR)/CR with incomplete hematologic recovery (CRi) rate of 65% (95% CI, 40.8%-84.6%) compared with 70% (95% CI, 45.7%-88.1%) for patients who received venetoclax plus azacitidine (n = 20).

No new safety signals were reported for tamibarotene when combined with venetoclax and azacitidine.

Previously enrolled patients will be permitted to continue receiving study treatment at investigator discretion. Data from SELECT-AML-1 will be presented at the 12th Annual Society of Hematologic Oncology Meeting in September.

“We are disappointed by this unexpected outcome, especially for people living with AML,” David A. Roth, MD, chief medical officer of Syros Pharmaceuticals, stated in a news release.¹ “In our prior phase 2 clinical trial [NCT02807558], the doublet combination of tamibarotene and azacitidine delivered a 61% CR/CRi rate in [patients with] newly diagnosed AML [or myelodysplastic syndrome (MDS)] with RARA overexpression. This supports our conviction in pursuing a doublet strategy in higher-risk MDS, where we are comparing tamibarotene and azacitidine to azacitidine alone. We remain steadfast in our commitment to delivering tamibarotene for the treatment of higher-risk MDS and look forward to sharing pivotal data from [the phase 3] SELECT-MDS-1 [trial (NCT04797780)] by mid-fourth quarter.”

SELECT-MDS-1 passed a prespecified futility test in the first quarter of 2024, and data anticipated later in 2024 will include CR findings for tamibarotene plus azacitidine vs placebo plus azacitidine in patients with newly diagnosed, RARA-overexpressed, high-risk MDS.^1,2

SELECT-AML-1 was an open-label, randomized, phase 2 study that enrolled patients at least 18 years of age with newly diagnosed AML who had a bone marrow or peripheral blood blast count of at least 20% and were unlikely to tolerate standard intensive chemotherapy at first study treatment due to age, performance status, or comorbidities.³

Specifically, patients needed to be at least 75 years of age, or they needed to be under 75 years of age and meet the at least 1 of the following criteria: an ECOG performance status of 3; a history of congestive heart failure or documented ejection fraction of no more than 50%; pulmonary disease with diffusing capacity of the lungs for carbon monoxide of no more than 65% or forced expiratory volume in one second of no more than 65%; a creatinine clearance of at least 30 mL/min and less than 45 mL/min; hepatic impairment with total bilirubin of more than 1.5 and no more than 3 times the upper limit of normal; or have any other comorbidity that would make them ineligible for intensive chemotherapy in the opinion of the investigator.

Patients were also required to have confirmed RARA overexpression by cycle 1, day 8 in part 1 or at the time of randomization in part 2.

Key exclusion criteria consisted of acute promyelocytic leukemia; known active central nervous system involvement with AML; and prior treatment for AML, MDS, or an antecedent hematologic malignancy with any hypomethylating agent, venetoclax, chemotherapy, or hematopoietic stem cell transplantation. Prior treatment with hydroxyurea was allowed.

In part 1, all patients received tamibarotene at 6 mg twice per day on days 8 to 28 of each 28-day cycle, azacitidine at 75 mg/m2 once per day on days 1 to 7, and venetoclax once per day on days 1 to 28. Venetoclax was given at 100 mg on day 1, 200 mg on day 2, and 400 mg on day 3 and beyond. Notably, azacitidine was allowed to be given on days 1 to 5, then days 8 and 9 of each cycle.

In part 2, patients were randomly assigned to receive tamibarotene plus venetoclax and azacitidine or venetoclax plus azacitidine alone.

The rate of adverse effects served as the primary end point in part 1; CR/CRi rate was the primary end point in part 2. Secondary end points in part 1 included overall response rate (ORR) and pharmacokinetics. Secondary end points in part 2 consisted of CR rate; CR/CR with partial hematologic recovery (CRh) rate; duration of CR, CR/CRi, and CR/CRh; time to CR, CR/CRi, and CR/CRh; ORR; and safety.

References

1. Syros provides update on SELECT-AML-1 phase 2 clinical trial. News release. Syros Pharmaceuticals. August 12, 2024. Accessed August 13, 2024. https://ir.syros.com/press-releases/detail/308/syros-provides-update-on-select-aml-1-phase-2-clinical-trial
2. Tamibarotene plus azacitidine in participants with newly diagnosed RARA-positive higher-risk myelodysplastic syndrome. ClinicalTrials.gov. Updated March 13, 2024. Accessed August 13, 2024. https://clinicaltrials.gov/study/NCT04797780
3. Tamibarotene plus venetoclax/​azacitidine in participants with newly diagnosed AML. ClinicalTrials.gov. Updated July 31, 2024. Accessed August 13, 2024. https://clinicaltrials.gov/study/NCT04905407