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

ABSTRACT

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 CPCML 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 include 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.