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309 An Update of Safety and Efficacy Results from Phase 1 Dose-Escalation and Expansion Study of Vodobatinib, a Novel Oral BCR-ABL1 Tyrosine Kinase Inhibitor (TKI), in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Failing Prior TKI Therapies

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Mechanisms of resistance and expanded therapies
Hematology Disease Topics & Pathways:
Adults, Clinical Trials, Clinical Research, Clinically Relevant, Study Population
Saturday, December 11, 2021: 4:30 PM

Jorge E. Cortes, MD1, Tapan Saikia, MD2, Dong-Wook Kim, M.D., Ph.D.3,4, Yesid Alvarado, MD5, Franck E. Nicolini, MD, PhD6, Krishnakumar Rathnam, MD, DM7*, Navin Khattry, MD, DM8*, Jane F Apperley, FRCP, FRCPath, MB9, Michael W. Deininger, MD, PhD10,11, Hugues de Lavallade, MD, PhD12*, Aude Charbonnier, MD13*, Nikki Granacher, MD14*, Carlo Gambacorti-Passerini, MD15, Alessandro Lucchesi, MD16*, Michael J. Mauro, MD17, Peter Vandenberghe, MD, PhD18, Gregor Verhoef, MD, PhD18*, Andrew R. Whiteley, MD19, Arijit Nag, MD, DM20*, Vivek S Radhakrishnan, MD, DM, MSc20, Shashikant Apte, MD, FRCPA21, Siu-Long Yao, MD22, Sandeep Inamdar, MBBS23*, Jayasree Sreenivasan, MSc23*, Ruchika Irene Dillu, MD23* and Geetanjali Chimote, MD, PhD23*

1Georgia Cancer Center Augusta University, Augusta, GA
2Prince Aly Khan Hospital, Mumbai, India
3Department of Hematology, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of (South)
4Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of (South)
5Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
6Hematology department, Centre Léon Bérard, Lyon, France
7Lake Area,Melur Main Rd, Meenakshi Mission Hospital and Research Centre, Tamil Nadu, India
8BMT unit, Department of Medical oncology, ACTREC., Tata Memorial Centre, Navi Mumbai, India
9Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College, London, United Kingdom
10Division of Hematology and Hematologic Malignancies, University of Wisconsin Milwaukee, Milwaukee, WI
11Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT
12Department of Haematological Medicine, Kings College Hospital, NHS Foundation Trust, London, United Kingdom
13Departement d'Hematologie, Institut Paoli Calmettes, Marseille, France
14Ziekenhuis Netwerk Antwerpen, Antwerp, Belgium
15Dept of Medicine and Surgery, University of Milano Bicocca, Monza, MB, Italy
16Hematology Unit,, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), FC, Italy
17Myeloproliferative Neoplasms Program, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
18Department of Hematology, UZ Leuven, Leuven, Belgium
19Baylor University Medical Center, Dallas, TX
20Clinical Hematology Oncology & HCT, Tata Medical Center, Kolkata, India
21Pune’s Sahyadri Hospital, Maharashtra, India
22Sun Pharmaceutical Industries, Inc., Princeton, NJ
23Sun Pharma Advanced Research Company Ltd, Mumbai, India

Introduction: Vodobatinib is a novel third generation TKI effective against wild-type and mutated BCR-ABL1 (except T315I) with limited off-target activity. We present updated results from the Phase 1 dose-escalation (DEs) and expansion (DEx) study in CML and Ph+ALL patients (pts) failing ≥ 3 prior TKIs (< 3 prior TKIs if approved TKI is not clinically advised or available); patients with T315I are not eligible (NCT02629692).

Methods: This is an open-label, phase 1, multicentre, 3+3 study evaluating maximum tolerated dose (MTD), safety and efficacy of vodobatinib administered once daily in 28 day cycles (dose range: 12 to 240 mg). MTD was established at 204 mg. DEx study enrolled chronic phase CML (CP-CML) patients at 174 mg dose of vodobatinib. Treatment continued until unacceptable toxicity, disease progression, consent withdrawal or death. Adverse events were assessed using NCI-CTCAE v4.03.

Results: As of 15 Jul 2021, 52 pts are enrolled in DEs and DEx cohorts. Forty one of these pts received doses from 12 to 240 mg in the DEs cohort;32 chronic phase (CP-CML), 3 accelerated phase CML (AP-CML), 4 blast phase CML (BP-CML), 2 Ph+ ALL. Eleven CP-CML pts were enrolled in DEx cohort at 174 mg dose. The baseline demographics and disease history are represented in Table 1.

Efficacy: Of the 32 CP-CML pts enrolled in DEs: At baseline, 21 (65%) pts had no cytogenetic response, 4 (12.5%) were in PCyR, 7 (22%) were in CCyR. On vodobatinib therapy, 11(34%) pts achieved CCyR, 3 (9%) achieved PCyR and 7 (22%) maintained baseline CCyR. Baseline major molecular response (MMR) was present in 1 (3%) pt; and 14 pts (44%) achieved MMR on study. Of the remaining 11 pts, 5 (16%) had haematologically stable disease (no CyR and molecular response) and 6 (19%) had disease progression (cytogenetic or hematological) as their best response (Table 2 and 3). Seventeen CP-CML pts had prior ponatinib treatment, of which 11 (65%) had MCyR (4 achieved CCyR, 4 maintained CCyR, 3 achieved PCyR); while 8 (47%) achieved MMR. In the remaining 15 pts ponatinib naïve CP-CML: 10 (66%) had CCyR (7 achieved CCyR, 3 maintained CCyR); with 7 (47%) with MMR (6 achieved, 1 maintained).

Two of the 3, AP-CML pts had baseline hematological response (CHR) with absence of cytogenetic and molecular response. The 3 pts further deepened their responses with 1 pt achieving CCyR with MMR and 2 pts in PCyR. Of the 4 BP-CML pts, 2 achieved CHR and 2 patients had disease progression as their best response; Of the 2 Ph+ ALL pts, 1 pt maintained CCyR and MMR while the other reported disease progression as the best response. Median duration of treatment overall was 23 (0.5–51) months [CP-CML 23 (0.5-51); AP-CML 36 (9-40); BP-CML 3 (0.5-18) and Ph+ ALL 4 (0.7-7.3) months]. Twenty one pts continue in study.

In the DEx cohort, 1 of the 11 CP-CML pts was in PCyR at baseline. No pts had molecular response. Of the 11 patients, 6 (54 %) pts achieved CCyR, 1(10%) pt achieved PCyR. MMR was achieved by 1 pt (10%). Data is maturing for 1 pt. Median duration of treatment is 16 (0.3-19) months and 10 pts continue in study.

Safety: Forty nine of 52 pts reported at least 1 TEAE. Most common any grade TEAEs included thrombocytopenia (33%), cough (19%), anaemia & diarrhoea (17% each).

Thirty one pts (60%) reported Grade 3 and 4 treatment emergent AEs: most common were thrombocytopenia (15%), neutropenia and anaemia (12%), increased amylase and lipase (8% each). Ten (19%) pts reported cardiovascular TEAEs (Grade 1: angina pectoris, palpitations, ventricular extra-systoles, arteriosclerosis, hot flush, hypotension, intermittent claudication; Grade 2: hypertension, hypotension; Grade 3: cardiac failure congestive, hypertension); with a Grade 2 hypertension being vodobatinib related. Nineteen pts (37%) reported SAEs; vodobatinib related SAEs were reported in 3 pts (fatal intracranial haemorrhage (ICH), Grade 2 back pain and Grade 3 amnesia reported in 1 pt each). There were 5 deaths on study: 1 was related to use of vodobatinib (1 ICH, confounded by disease progression to blast phase that included extra- medullary sites) and the remaining unrelated (1 sudden death, 1 disease progression, 1 pneumonia fungal, 1 suspected COVID-19).

Conclusion: Vodobatinib continues to be associated with favourable long term safety and efficacy in heavily pre-treated CML failing ≥ 3 prior TKIs, including ponatinib. Phase 2 study evaluating vodobatinib in pts failing at least 3 prior lines of therapy, including ponatinib, is ongoing.

Disclosures: Cortes: Pfizer: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kim: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; ILYANG: Research Funding; Takeda: Research Funding. Alvarado: MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Sun Pharma: Consultancy, Research Funding; CytomX Therapeutics: Consultancy; Jazz Pharmaceuticals: Research Funding; BerGenBio: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; BMS: Honoraria; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Apperley: Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau. Deininger: Fusion Pharma, Medscape, DisperSol: Consultancy; Novartis: Consultancy, Research Funding; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding. de Lavallade: Bristol Myers Squibb: Research Funding; Incyte: Honoraria, Research Funding; Novartis: Speakers Bureau. Charbonnier: Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gambacorti-Passerini: Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy. Mauro: Novartis: Consultancy, Research Funding; Sun Pharma / SPARC: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; Pfizer: Consultancy. Vandenberghe: Pfizer: Research Funding; Bristol Myers Squibb/Celgene: Consultancy; Miltenyi Biotec: Consultancy; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy; Gilead Sciences: Consultancy, Other: Travel support. Radhakrishnan: Intas Pharmaceuticals: Research Funding; Emcure Pharmaceuticals: Research Funding; Dr Reddy's Laboratories: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen India: Honoraria; Cipla Pharmaceuticals India: Research Funding; Bristol-Myers-Squibb India: Membership on an entity's Board of Directors or advisory committees, Research Funding; Aurigene: Speakers Bureau; AstraZeneca India: Honoraria, Speakers Bureau; NATCO Pharmaceuticals: Research Funding; Novartis India: Membership on an entity's Board of Directors or advisory committees; Roche India: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yao: Sun Pharma: Current Employment. Inamdar: Sun Pharma Advanced Research Company: Current Employment. Sreenivasan: Sun Pharma Advanced Research Company: Current Employment. Dillu: Sun Pharma Advanced Research Company: Current Employment. Chimote: Sun Pharma Advanced Research Company: Current Employment.

*signifies non-member of ASH