ALLG AMLM26 Phase 1B/2 Study Investigating Novel Therapies to Target Early Relapse and Clonal Evolution As Pre-Emptive Therapy in AML (INTERCEPT): A Multi-Arm, Precision-Based, Recursive, Platform Trial

Background Clinical trials investigating novel therapies in relapsed/refractory acute myeloid leukemia (AML) are challenged by rapid disease progression, severe cytopenias and a high frequency of infectious complications, limiting the capacity of such trials to determine efficacy and hematologic tolerance for new drugs and combinations. Guidelines for monitoring measurable residual disease (MRD) and defining MRD relapse have been established (Heuser, Blood 2021), with MRD relapse known to precede clinical relapse by 3-4 months (Ivey, NEJM 2016). A prospective pilot study utilizing low-dose cytarabine (LDAC) plus venetoclax (VEN) for patients with MRD relapse or oligoblastic relapse (5-15% marrow blasts) demonstrated a high response rate and durable outcomes (Tiong, ASH 2021). To extend this concept to include a broader range of targeted drug combinations directed against MRD relapse, we developed the Australasian Leukaemia and Lymphoma Group (ALLG) AMLM26 INTERCEPT study, a multi-domain, multi-arm, platform trial enabling proof-of-concept (POC) efficacy and tolerability to be obtained for multiple therapies in parallel in the setting of MRD relapse.

Study Design and Methods Figure 1 summarizes the trial schema. The INTERCEPT trial (ANZCTR: ACTRN12621000439842), due activation in August 2022, is sponsored by the ALLG and conducted in partnership with the ALLG sites and the MD Anderson Cancer Center, U.S. The trial incorporates 2 phases, an MRD Monitoring Phase, and a Treatment Phase. Patients in first or second remission consent to a Master Protocol linked to a coordinated MRD monitoring framework to track FLT3-ITD, RUNX1::RUNX1T1, CBFB::MYH11, NPM1, KMT2A::X and aberrant myeloid immunophenotype. In patients in whom pre-leukemic clonal hematopoiesis is excluded by reduction of variant frequency in remission to <2.5%, IDH1 and IDH2 are also tracked. For molecular markers, MRD relapse is defined according to ELN recommendations (a log₁₀ increase in serial MRD confirmed by repeat testing on concordant tissue). Flow cytometric detected disease for the INTERCEPT study is defined as an aberrant MRD phenotype ≥0.1% confirmed on repeat testing. MRD relapse is confirmed by a central laboratory and eligibility adjudicated by a blinded MRD reference committee.

For the Treatment Phase, a clinical Trial Management Committee (TMC) will apply a pre-determined set of clinical decision rules to direct allocation of patients to the most applicable treatment "domain", based on review of prior therapy, baseline molecular profile and MRD relapse characteristics. For example, a patient with rising FLT3-ITD MRD meeting relapse criteria may be allocated to treatment with gilteritinib + VEN, rising IDH1 mutation to ivosidenib + VEN, rising KMT2A::X to SNDX-5613, rising NPM1 to LDAC + VEN or alternatively, to SNDX-5613. Where no specific targeted treatment is available, patients will be randomly allocated to non-targeted therapies, if more than one applicable arm exists, to arms including sabatolimab, sabatolimab + azacitidine, ASTX727 + VEN or LDAC + VEN. Future treatment options can be seamlessly incorporated in the INTERCEPT framework by amendment of the Master Protocol and addition of new Therapy-Specific Protocol Appendices (TSPAs). Each TSPA outlines specific eligibility criteria, dose schedules, study conduct and the statistical plan for each treatment arm. Patients may also be allocated to a morphologic relapse stratum, if MRD relapse was not captured by MRD surveillance. This will enable comparison of treatment tolerance and response at MRD vs morphologic relapse. If progression occurs with one treatment arm (including MRD relapse), the protocol allows the same patient to be transitioned to an alternative treatment arm if eligibility criteria are met.

The primary objective is to determine if novel treatment options can produce an MRD response rate of ≥40% as determined by a Bayesian Proof of Concept design in each domain. The primary endpoint is MRD response (≥1 log₁₀ reduction in molecular MRD or flow MRD<0.1%) within 100 days of the first dose of study drug. MRD responses will be determined centrally. Key secondary endpoints will be nadir MRD response, MRD clearance rate, median time to and duration of MRD response, relapse-free survival, overall survival and quality of life measures. Exploratory objectives will include analysis of drug resistance mechanisms and correlates of response.

Wei:Servier: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Walter and Eliza Hall Institute of Medical Research: Current Employment, Other: receives milestone and royalty payments related to venetoclax; Astellas: Consultancy. Reynolds:Novartis: Current equity holder in publicly-traded company; Abbvie: Research Funding; Alcon: Current equity holder in publicly-traded company. Tiong:Servier: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Speakers Bureau. Blombery:AstraZeneca: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; Servier: Honoraria. Anstee:Walter and Eliza Hall Institute: Patents & Royalties: Dr Anstee is an employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to Venetoclax. Koldej:CRISPR Therapeutics: Research Funding. Ritchie:BMS: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Honoraria; Amgen: Honoraria, Research Funding. Ross:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Keros: Consultancy; Celgene: Research Funding; BMS: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Bajel:Abbvie: Honoraria; Amgen: Honoraria, Speakers Bureau; Astellas: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Takeda: Honoraria. Grove:Australian advisory boards as below: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: chairperson at local Abbvie Education Event for which my institution received hororaria., Speakers Bureau; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees. Marlton:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roberts:The Walter and Eliza Hall Institute: Other: AWR is an employee of WEHI which received milestone and royalty payments related to venetoclax, and is eligible for financial benefits associated with these payments.; AbbVie: Patents & Royalties: I am an inventor on a patent assigned to AbbVie related to venetoclax. Please note that I am not remunerated for this, nor eligible for financial benefit.. Pemmaraju:stemline: Consultancy; abbvie: Consultancy; immunogen: Consultancy; mustangbio: Research Funding; incyte: Consultancy; novartis: Research Funding; pacylex: Consultancy, Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; cellularity: Research Funding. Loghavi:Amgen: Research Funding; PeerView: Honoraria; Abbvie: Consultancy, Current equity holder in publicly-traded company; QualWorld: Consultancy; GLG: Consultancy; Astellas: Research Funding. Konopleva:Reata Pharmaceuticals, Novartis and Eli Lilly: Patents & Royalties; AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, Astra Zeneca; Rafael Pharmaceutical; Sanofi, Forty-Seven: Research Funding; Stocks, Reata Pharmaceuticals: Current equity holder in publicly-traded company; AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, Kisoji; Janssen: Consultancy; Forty-Seven; F. Hoffman LaRoche: Honoraria; Stemline Therapeutics, F. Hoffman La-Roche; Janssen: Membership on an entity's Board of Directors or advisory committees. Daver:Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. DiNardo:ImmuneOnc: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Bluebird Bio: Honoraria; Jazz: Honoraria; LOXO: Research Funding; Novartis: Honoraria; Gilead: Honoraria; Astellas: Honoraria; Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; GenMab: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Astex: Research Funding; Cleave: Research Funding; Forma: Research Funding.