Phase 1 Trial of K0706, a Novel Oral BCR-ABL1 Tyrosine Kinase Inhibitor (TKI): In Patients with Chronic Myelogenous Leukemia (CML) and Phildelphia Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Failing ≥ 3 Prior TKI Therapies: Initial Safety and Efficacy

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