SELECT-AML-1 Trial of Tamibarotene Combo in AML Discontinues Enrollment

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The phase 2 SELECT-AML-1 trial (NCT04905407) evaluating tamibarotene plus venetoclax (Venclexta) and azacitidine for the treatment of patients with newly diagnosed, RARA-overexpressed acute myeloid leukemia (AML) plans to discontinue enrollment following results from a prespecified interim, nonbinding futility analysis of the study.¹

Among the first 40 patients enrolled in the study, those given 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%) vs 70% (95% CI, 45.7%-88.1%) for patients treated with venetoclax and azacitidine (n = 20).

Additionally, there were no new safety signals seen in the tamibarotene, venetoclax, and azacitidine arm.

“We are disappointed by this unexpected outcome, especially for people living with AML,” David A. Roth, MD, chief medical officer of Syros Pharmaceuticals, said in a press release. “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.”

Those who were previously enrolled in the SELECT-AML-1 trial are permitted to continue receiving study treatment at investigator discretion.

Findings from the trial are expected to be presented at the 12th Annual Society of Hematologic Oncology Meeting in September. Further, the phase 3 SELECT-MDS-1 study passed a prespecified futility test in the first quarter of 2024. Data from this study plan to be released later in 2024 and will include CR findings for the addition of tamibarotene plus azacitidine vs placebo plus azacitidine in patients with newly diagnosed, RARA-overexpressed, high-risk MDS.^1,2

About the SELECT-AML-1 Trial

The open-label, randomized, phase 2 SELECT-AML-1 trial sought to assess the combination oftamibarotene plus venetoclax and azacitidine vs venetoclax and azacitidine alone in patients aged 18 years or older with newly diagnosed AML who had a bone marrow or peripheral blood blast count of at least 20%. Patients were required to be unlikely to tolerate standard intensive chemotherapy at first study treatment because of their age, performance status, or comorbidities.³

Patients must have been at least 75 years of age to be included in the study. If they were under 75 years of age, they must have met at least 1 of the following criteria: an ECOG performance status of 3; a history of congestive heart failure or documented ejection fraction of 50% or less; 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.

Additionally, patients needed to have confirmed RARA overexpression by day 8 of cycle 1 in part 1 or by the time of randomization in part 2.

All the patients included in part 1 were treated with tamibarotene 6 mg twice per day on days 8 to 28 of each 28-day cycle, along with azacitidine at 75 mg/m2 once per day on days 1 to 7, and venetoclax given once a day on days 1 to 28, including at 100 mg on day 1, 200 mg on day 2, and 400 mg on day 3 and beyond. Azacitidine was allowed to be given on days 1 to 5, then days 8 and 9 of each cycle.

Patients were randomly assigned to receive the addition of tamibarotene to venetoclax and azacitidine or venetoclax plus azacitidine alone in part 2.

For part 1 of the study, the primary end point was the rate of adverse events, and in part 2, it was CR/CRi rate. Secondary end points for part 1 consisted of overall response rate (ORR) and pharmacokinetics. In part 2, the secondary end points were 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://tinyurl.com/mptftt37

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