Background: Patients with FLT3 mutant AML are found to have many co-occurring mutations including those in the epigenetic pathway (e.g. DNMT3A, TET2, IDH-1, IDH2, WT-1, MLL), RTK-MAP Kinase pathway (PTPN-11, c-kit, RAS), apoptosis pathway (p53), etc. FLT3 resistant clones emerge after treatment with chemotherapy and or IDH1 and IDH2 inhibitors and FLT3 mutations are a known mechanism of resistance to the BCL2 inhibitor venetoclax. Clonal heterogeneity with multiple driver mutations are even more common in relapsed/refractory AML. This necessitates combination therapy with FLT3 inhibitors with inhibitors that are selected based on the mutation profile of each patients. Drugs targeting IDH1, IDH2 and bcl-2 have now been approved in AML permitting clinical trials to be designed that combine FLT3 inhibitors with one or more of these AML agents

Crenolanib is a type I, pan-FLT3 inhibitor with activity against a number of activating FLT3 and KIT mutations. Crenolanib also has a short half-life, does not accumulate and does not cause QT prolongation, that making it possible to combine it with a variety of other TKIs. Phase I study in pediatric population has already demonstrated that crenolanib can be safely combined at full doses with sorafenib (Inaba et al). Crenolanib has also been combined with axitinib in adults with advanced malignancies. Crenolanib has also been combined at full doses with standard salvage chemotherapy and azacitidine.

Aim: Determine the feasibility and efficacy of crenolanib combination regimens in FLT3 mutant AML personalized to patient mutation and prior treatment profiles. This initial exploratory study aims to identify subgroups of patients with specific clinical and genomic features that benefit from combinations with crenolanib to move on to an extension and expansion phased study.

Patient Population: Patients with FLT3 mutations including ITD, Kinase domain mutations including D835, D839E/G, N841I, Gate keeper mutations F691, and other activating point mutations against which crenolanib has shown activity (A680V, D586Y, D600G, E573D/Q, E596G/K, E596G/K, E598D, F594C, F594Y, F612L, L576R, L616R, M664I, M665L, N676K, T582N, V581G, V592A, and Y599C or alone or combination. Patients with KIT D816 or N822 are also eligible. Treatment arms will be chosen based on co-occurring mutations and prior treatments.

Study Design: The proposed study design has 6 arms.

  • Arm 1, crenolanib plus ivosidenib, will be administered to patients with FLT3 and IDH1 mutations who have not had prior ivosidenib treatment.

  • Arm 2, crenolanib plus enasidenib, will be administered to patients with FLT3IDH2 who have not had prior enasidenib treatment.

  • Arm 3, crenolanib plus venetoclax, will be available to patients with IDH1/2 mutations and prior IDH inhibitor treatment, or to patients with TP53 mutations/loss and no prior venetoclax treatment.

  • Arm 4, crenolanib plus venetoclax/azacitidine, will be administered to patients with TP53 mutations/loss who have received prior venetoclax.

  • Arm 5, crenolanib plus salvage hemotherapy (HAM or FLAG-Ida) will be available for patients with other mutations not included in other arms.

  • Arm 6, crenolanib plus Vyxeos will be available for patients who are not eligible for intensive salvage chemotherapy such as older patients or patients with treatment-related or secondary AML.

Correlative assessment: Detailed correlative assessments will be investigated in each arm including Pharmacokinetics, pharmacodynamics, crenolanib free levels, FLT3 ligand and PIA assays to correlate with safety and clinical responses. Biomarkers detection for target inhibition of the novel combinations including FLT3 mutations, BH3 profiling and 2-hydroyglutarate levels will additionally be performed to explore and correlated with outcomes.

Conclusion: This will be the first trial to combine crenolanib with a number of novel targeted agents and will allow us to learn about the tolerability, drug-drug interaction, pharmacokinetics, pharmacodynamics of these agents when given in combination with crenolanib. The trial contemplates expansion cohorts for any of the arms that provides a clinically meaning clinical remission rates. Additional arms can be added to this trial as additional anti-leukemic agents beco5me available.

Disclosures

Daver:ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goldberg:Dava Oncology: Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Pfizer: Research Funding; Celularity: Research Funding; AROG: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. DiNardo:Notable Labs: Membership on an entity's Board of Directors or advisory committees; Calithera: Research Funding; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Jazz: Honoraria; Takeda: Honoraria. Kadia:JAZZ: Honoraria, Research Funding; Astellas: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Incyte: Research Funding; Ascentage: Research Funding; Amgen: Research Funding; Pulmotec: Research Funding; Genentech: Honoraria, Research Funding; Cyclacel: Research Funding; Astra Zeneca: Research Funding; Cellenkos: Research Funding; Celgene: Research Funding. Wang:Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy; Pfizer: Speakers Bureau; Genentech: Consultancy; Stemline: Speakers Bureau. Stone:Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gemoab: Consultancy; Celgene: Consultancy, Other; Daiichi-Sankyo: Consultancy; Agios: Consultancy, Research Funding; Pfizer: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Syros: Consultancy; Trovagene: Consultancy; Stemline: Consultancy; Aztra-Zeneca: Consultancy; Macrogenics: Consultancy; Jazz: Consultancy; Astellas: Consultancy; Arog: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Syndax: Consultancy, Research Funding; Takeda: Other: DSMB; Syntrix: Other: DSMB; Argenix: Other; Biolinerx: Consultancy. Zhang:Arog Pharmaceuticals: Current Employment. Messahel:AROG Pharmaceuticals: Current Employment.

Author notes

*

Asterisk with author names denotes non-ASH members.