ALBERT

Description: Introduction: Despite availability of several BCR-ABL1 TKIs for treatment of CML, some patients (pts) fail ≥3 TKIs and/or have co-morbidities that limit use of 2nd generation TKIs (2GTKI: Nilotinib, Dasatinib and Ponatinib). K0706 is a novel third generation TKI effective against wild-type and mutated BCR-ABL1 isoforms with significantly less off-target activity compared to existing TKIs. We report Phase I results of K0706 in pts who were resistant and/or intolerant to ≥3 prior TKIs or who had co-morbidities precluding the use of 2GTKI (NCT02629692). Methods: This was a multicentre, open-label, dose-escalation and expansion study of K0706 to evaluate the safety and anti-leukemic activity of K0706, and determine the MTD. Patients with CML or Ph+ ALL resistant and/or intolerant to ≥3 prior TKIs received escalating doses of K0706 capsules (single daily dose) in 28 day cycles. Treatment continued until unacceptable toxicity, disease progression, consent withdrawal or death. Results: At data cut-off of 30 June 2019, 35pts (19 male) have been treated with K0706 at doses of 12mg (n=1), 24mg (n=1), 48mg (n=6), 66mg (n=7), 90mg (n=3), 126mg (n=5), 174mg (n=5), 204mg (n=4), and 240mg (n=3); median age 61.6 (range 23.5-85.6) years; median time from diagnosis 10.13 (range 0.7-22.9) years. Diagnoses included 27 chronic phase [CP], 3 accelerated phase [AP], 4 blast phase [BP] CML and 1 Ph+ ALL. Eleven and 19pts received ≥3 prior TKIs and ≥4 prior TKIs respectively (intolerant, n=11; resistant and intolerant, n=24). 13pts had BCR-ABL mutations detectable at study entry (F317L, n=2; E255V/K, n=2; T315I, n=2; 1pt each had: Y253H, Y253F, V299L, Q252H and G250E respectively; 1pt each had 2BCR-ABL mutations: E255V, F317L and F359V, E255V respectively). At a median follow-up of 6.9 months (range 0.5-26 months), 68.6% of pts remained on K0706 and 31.5% completed ≥12 months of therapy. 11pts (31.4%) discontinued [10 due to disease progression (with 2 deaths) and 1 with a possibly related AE of CNS bleed confounded by disease progression]. The most common K0706-related AEs included transient mild to moderate gastrointestinal disturbances (18.5%), general disorders [i.e.: myalgia, fatigue, asthenia] (15.7%), neutropenia (12%) and thrombocytopenia (10%). At 240mg, 2 of 3pts had dose-limiting toxicities (DLTs) of ≥25% of doses missed in Cycle 1 because of toxicity (dyspnoea (1x grade 2, 1x grade 3) and non-cardiac chest pain (1x grade 2) DLTs were reversible and pts resolved at 174 mg without recurrence. Of 27 CML CP pts, 7pts achieved a complete cytogenetic remission (CCyR) and 4 maintained CCyR. 1pt achieved partial CyR (PCyR), 1pt had disease progression in Cycle 1 and 5pts are yet to complete post baseline assessments. Of the 12 CML CP cytogenetic responders, 11 remain on treatment [mean duration 6.9 (range 2.9 -26) months in major cytogenetic response (MCyR) while 1pt had disease progression at 9.5 months]. Cytogenetic responses were observed in 2 of 11 CML-CP pts with mutations [CCyR in 1 of 2 pts with F317L and in 1pt with G250E]. Pts with T315I mutations had disease progression in Cycle 1. Following this, protocol was amended to enrol subjects with T315I mutations only when target plasma concentrations required preclinically to inhibit T315I clone are achieved. Five of 27 pts achieved major molecular response (MMR), 2 pts in MR 4.5. Of 8 pts with CML AP (n=3), BP (n=4) or Ph+ ALL (n=1), 4 achieved confirmed MaHR; 2 entered the study in MaHR; 3 had MCyR [2 had CCyR and 1 had PCyR] and 2 had disease progression. 1pt in CML BP had a confirmed MaHR for 12 months. 1pt in AP with chromosome 3 inversion, had CCyR at 3 months and maintaining for 13 months. Conclusion:K0706 has acceptable safety profile with activity in heavily pre-treated patients who had failed at least ≥3 prior lines of TKIs. The study provides early proof of principle for the effectiveness of K0706 in a setting with few available treatment options. Disclosures Cortes: Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Biopath Holdings: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding. Kim:Novartis: Research Funding; Pfizer: Research Funding; Il-Yang co.: Research Funding; Takeda: Research Funding; BMS: Research Funding. Charbonnier:Pfizer: Consultancy; Novartis: Consultancy; Incyte: Speakers Bureau. Apperley:Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Deininger:Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Ascentage Pharma: Consultancy, Honoraria; Fusion Pharma: Consultancy; TRM: Consultancy; Sangoma: Consultancy; Novartis: Honoraria; Sangamo: Consultancy; Incyte: Honoraria; Adelphi: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Humana: Honoraria. De Lavallade:Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding. Whiteley:Seattle Genetics: Speakers Bureau; Jazz pharmaceuticals: Speakers Bureau. Mauro:Pfizer: Consultancy; Takeda: Consultancy; Novartis Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Lucchesi:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Yao:Sun Pharma Advance Research Company: Employment. Kothekar:Sun Pharma Advance Research Company: Employment. Chimote:Sun Pharma Advance Research Company: Employment.

Description: Introduction: Vodobatinib, a novel 3rd generation (3G) TKI effective against wild-type and mutated BCR-ABL1 with limited off-target activity, was evaluated in a Phase I multicentre dose-escalation study in chronic myeloid leukemia (CML) patients (pts) who failed ≥ 3 TKIs or less (if not eligible for other approved 3G TKIs) (NCT02629692). The activity and safety of vodobatinib was evaluated in ponatinib treated (PT) and ponatinib naïve (PN) chronic phase (CP)-CML subjects in an exploratory analysis. Methods: Multiple escalating doses of vodobatinib (once daily) in 28-day cycles were evaluated in a 3+3 study design. The primary objective was determination of the maximal tolerated dose (MTD) or recommended phase 2 dose (RP2D) along with safety and a secondary objective was to evaluate anti-leukemic activity. Dose escalation involved dose doubling until 2 pts in a cohort experienced Grade 2 toxicity, or 1 pt experienced Grade 3 or 4 toxicity, after which dose escalation was reduced to 40% increments. Treatment continued until unacceptable toxicity, disease progression (PD), consent withdrawal, or death. Results: As of 15 Jul 2020, 31 CP-CML pts received vodobatinib at doses of 12 to 240 mg; 16 pts (9 males) in ponatinib treated (PT) cohort [7 (44%) ponatinib was the immediate prior TKI] and 15 pts (7 males) in the ponatinib naïve (PN) cohort. The baseline demographics and disease history are represented in Table 1. Efficacy: Median duration of treatment was 17.3 (0.6-36) and 14.8 (0.5- 42) months in the Ponatinib treated and naive groups, respectively; 11 pts in the PT group [2 in Deep molecular response (DMR), 3 in MMR; 5 in MCyR (2 in CCyR and 3 in PCyR); 1 in stable disease] and 10 pts in the PN group (2 in DMR, 4 in MMR and 3 in CCyR, 1 in stable disease) are continuing on treatment. Overall efficacy outcomes are included in Tables 2 and 3. Of 16 PT pts, 2 (13%) pts, both with double mutations, had disease progression. Of 15 PN pts, 4 (26%) pts (with baseline mutation of T315I at 48 mg, Y253H at 66 mg, F317L and E255V mutation at 174 mg) progressed. Safety: In ponatinib treated pts, the most commonly reported treatment emergent adverse events (TEAEs), (all grades) included nausea (4, 25%) and diarrhea (3, 25%). Other commonly reported TEAEs included thrombocytopenia (3, 19%), rash (3, 19%), non-cardiac chest pain (3, 19%), increased amylase (3, 19%), and fall (3, 19%). Grade ≥ 3 TEAEs were reported in 10 (63%) pts included 1 pt each with anemia, lymphopenia, fall, skull fracture, spinal fracture, lipase increase, fluid overload, syncope, dyspnea, and hypertension. Vodobatinib related AEs included amylase increase, lipase increase, dyspnea, fluid overload, thrombocytopenia and neutropenia. Grade ≥ 3 TEAEs reported in more than one pt included neutropenia (2, 13%) amylase increase (2, 13%) and thrombocytopenia (2, 13%). In PN pts, the most commonly reported TEAEs (all grades) included myalgia (5, 33%) and back pain (4, 27%). Other commonly reported TEAEs were thrombocytopenia (4, 27%), and nasopharyngitis (3, 20%).Grade ≥ 3 TEAEs were reported in 7 (47%) pts (1 pt with anemia, 1 pt with pneumonia, 1 pt with neutropenia, 1 pt with gout, hypokalemia, thrombocytopenia, 1 pt with increased liver and pancreatic enzymes and 1 pt each with dementia and amnesia. Vodobatinib related AEs included alanine aminotransferase increase, blood bilirubin increased, amnesia, neutropenia and thrombocytopenia. No grade ≥ 3 event was reported in more than 1 pt. Overall, three cardiovascular TEAEs were reported, in 2 pts (1 each in PT and PN), all deemed unrelated to vodobatinib. Three pts died on study: 1 due to disease progression in the PT group; 1 due to pneumonia (suspected COVID-19) and 1 due to intracranial hemorrhage in the PN group. The intracranial hemorrhage event (Grade 5 AE) was considered possibly related and was confounded by disease progression to blast phase that included extra-medullary sites. At the highest dose of 240 mg, two dose limiting toxicities were reported. The next lower dose level of 204 mg was established as MTD with a favorable safety profile in heavily pre-treated CP-CML pts. Conclusion: Vodobatinib was evaluated over 9 escalating doses. Comparable and promising efficacy was noted in both PT (50% CCyR) and PN (67% CCyR) groups, meriting further study of vodobatinib as a potential new agent for treatment of previously treated CP-CML. Disclosures Cortes: Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding. Alvarado:BerGenBio ASA: Research Funding; MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; FibroGen: Research Funding; Tolero Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding. Nicolini:Sun Pharma Ltd: Consultancy; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Apperley:Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Deininger:DisperSol: Consultancy; Pfizer: Honoraria, Other, Research Funding; Leukemia & Lymphoma Society: Research Funding; Ariad: Consultancy, Honoraria, Other; Medscape: Consultancy; Novartis: Consultancy, Other, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fusion Pharma: Consultancy; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: part of a study management committee, Research Funding; Incyte: Consultancy, Honoraria, Other, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; SPARC: Research Funding; Gilead Sciences: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other, Research Funding; Galena: Consultancy, Honoraria, Other; Celgene: Research Funding. de Lavallade:Incyte: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Pfizer: Honoraria. Charbonnier:Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartts: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy. Lucchesi:Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Mauro:Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Sun Pharma/SPARC: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding. Whiteley:Novartis: Consultancy; Dova: Consultancy; Jazz: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Epizyme: Current equity holder in publicly-traded company, Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company; Aprea: Current equity holder in publicly-traded company; MorphoSys: Consultancy; Agios: Consultancy, Speakers Bureau; Pfizer: Consultancy; Rigel: Consultancy. Yao:Sun Pharma Industries Incorporated: Current Employment. Kothekar:Sun Pharma Advanced Research Company Limited: Current Employment. Sreenivasan:Sun Pharma Advanced Research Company Limited: Current Employment. HV:Sun Pharma Advanced Research Company Limited: Current Employment. Chimote:Sun Pharma Advanced Research Company Limited: Current Employment.