AML-108 SELECT-AML-1 Trial in Progress: A Phase 2 Study of Tamibarotene in Combination With Venetoclax and Azacitidine in Previously Untreated Adult Patients Selected for RARA-Positive AML who are Ineligible for Standard Induction Therapy

Context: RARA-positive AML is a novel, genomically defined subset with an actionable target for treatment with tamibarotene, an oral and selective RARα agonist (McKeown 2017). In a previous trial in RARA-positive newly diagnosed (ND) AML patients ineligible for standard induction therapy, tamibarotene/azacitidine led to a CR/CRi rate of 61% with a rapid onset of response. The combination was generally well tolerated with no increase in myelosuppression compared to azacitidine alone (de Botton 2020). Responses were observed irrespective of mutations or cytogenetic risk. Approximately one-third of ND unfit AML patients do not respond to venetoclax, and nearly all patients eventually relapse (DiNardo 2020). Translational data suggest that RARA positivity, found in approximately 30% of patients in this AML subset (Vigil 2017), enriches for monocytic features reported to be associated with venetoclax resistance (Fiore 2020, Pei 2019). This suggests that the blood-based RARA biomarker selects for patients who may respond to tamibarotene and may be less likely to respond to venetoclax/azacitidine. Objectives: The primary objectives are to characterize the safety of the combination and to compare the CR/CRi rate of tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine; the secondary objectives are to compare the CR rate, CR/CRh rate, duration of response, time to response, and overall survival. Design: A phase 2, open-label, multi-center trial comparing the activity of tamibarotene/venetoclax/azacitidine with that of venetoclax/azacitidine in treatment-naive RARA⁺ unfit AML patients. This 3-part trial includes a safety lead-in, randomized efficacy study, and salvage arm. Following the safety lead-in, patients will be randomized 1:1 to receive tamibarotene/venetoclax/azacitidine or venetoclax/azacitidine. Clinical activity will be characterized by European LeukemiaNet criteria. Response rates and 95% exact binomial confidence intervals will be calculated by treatment group. In the salvage arm, tamibarotene will be added for patients randomized to venetoclax/azacitidine who experience progressive disease, treatment failure, or relapse. Intervention: Patients will be treated with azacitidine at 75 mg/m² IV/SC daily on days 1–7, venetoclax on days 1–28 per VENCLEXTA® (venetoclax) USPI, and tamibarotene 6 mg twice per day by mouth on days 8–28 of each 28-day cycle. SELECT-AML-1 (NCT04905407) opened in July 2021 with ongoing enrollment. Setting: U.S. and France.