Phase 1 Trial of Vodobatinib, a Novel Oral BCR-ABL1 Tyrosine Kinase Inhibitor (TKI): Activity in CML Chronic Phase Patients Failing TKI Therapies Including Ponatinib
Authors: Cortes Jorge E. , Saikia Tapan , Kim Dong-Wook , Alvarado Yesid , Nicolini Franck E , Khattry Navin , Rathnam Krishnakumar , Apperley Jane , Deininger Michael W. , de Lavallade Hugues , Charbonnier Aude , Granacher Nikki , Gambacorti-Passerini Carlo , Lucchesi Alessandro , Mauro Michael J. , Verhoef Gregor , Vandenberghe Peter , Whiteley Andrew R. , Apte Shashikant , Yao Siu-Long , Kothekar Mudgal , Sreenivasan Jayasree , HV Bimba , Chimote Geetanjali 
Published: February 2021

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.