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

Abstract

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.

Third-line therapy for chronic myeloid leukemia: current status and future directions

“…Vodobatinib (K0706) is another orally bioavailable BCR-ABL1 TKI designed using a structure-guided drug-design platform with significant activity in vitro against most BCR-ABL mutations, but not T315I [ 73 ]. Vodobatinib showed an acceptable safety profile in a phase I study in patients with CML who experienced treatment failure with ≥ 3 TKIs and/or patients with comorbidities that restrict the use of certain TKIs (nilotinib, dasatinib, and ponatinib) [ 74 , 75 ]. At the time of data cutoff, 35 patients received doses ranging from 12 to 240 mg—27 of whom had CML-CP.…”

“…Mild to moderate gastrointestinal AEs were reported in 18.5% of patients. Two patients enrolled had T315I mutations; these patients experienced disease progression in cycle 1 of treatment, leading to a protocol amendment to exclude patients with T315I mutations from this study [ 74 ]. In a recently published exploratory analysis, efficacy, and safety of vodobatinib was assessed in ponatinib-pretreated and -naive patients with CML-CP, with the goal of determining MTD or RP2D.…”

Parkinson's Disease Modification Through Abl Kinase Inhibition: An Opportunity

“…Other AEs included dyspnea and non-cardiac chest pain, both of which returned to normal following dose-reduction. 93 In a 14-day placebo-controlled trial in 46 PD patients, Vodobatinib was reported to be well-tolerated with no serious clinical or laboratory AEs that were considered to be drug-related. Plasma concentrations are reported to have reached levels that were efficacious in PD animal models and CSF measures.…”

Potential Approaches Versus Approved or Developing Chronic Myeloid Leukemia Therapy

“…A phase I/II study (NCT02629692) is ongoing to evaluate the efficacy and safety of K0706 in patients with comorbidities precluding the use of conventional secondgeneration TKIs or after ≥ 3 TKIs failure. The initial phase I results of this study showed disease progression in patients carrying BCR-ABL T315I mutation, therefore the enrolment of patients with this mutation was stopped (67).…”