Ponatinib Safety and Efficacy in Japanese Patients with Philadelphia Positive Leukemia: Update of a Phase 1/2 Study
Authors: Kyo Taiichi , Tojo Arinobu , Yamamoto Kazuhito , Takahashi Naoto , Nakamae Hirohisa , Kobayashi Yukio , Tauchi Tetsuzo , Okamoto Shinichiro , Miyamura Koichi , Iwasaki Hiromi , Hatake Kiyohiko , Matsumura Itaru , Usui Noriko , Yanase Kumiko , Hu Simin , Naoe Tomoki , Ohyashiki Kazuma 
Published: October 2019

Abstract
Background: Ponatinib is a potent pan–BCR-ABL tyrosine kinase inhibitor (TKI), active against native and mutated BCR-ABL, including T315I, and approved by the US FDA for the treatment of adult patients with chronic myeloid leukemia (CML; all phases) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) that is T315I-positive or for whom no other TKI therapy is indicated. This is the first study evaluating the safety and efficacy of ponatinib in Japanese patients.
Methods: This is an ongoing phase 1/2, multi-center, open-label, dose-finding study of ponatinib in Japanese patients with CML who have experienced a failure of dasatinib or nilotinib therapy, or Ph+ ALL who have experienced a failure of prior TKIs because of resistance or intolerance (ClinicalTrials.gov ID: NCT01667133). Following completion of the dose-escalation portion, in which 2 doses of ponatinib (30 mg once daily n=6; 45 mg once daily n=6) were evaluated, 45 mg once daily was selected for further study in phase 2 (n=35) to confirm the anti-leukemic activity of ponatinib. In phase 2, the primary efficacy endpoints were major cytogenetic response (MCyR) for CP-CML and major hematologic response (MaHR) for AP, BP, or Ph+ ALL. Data from the phase 1 portion have been previously presented (Japanese Society of Hematology 2013). Herein we report data as of 3 Feb 2014 from the phase 2 portion.
Results: As of 30 Sep 2013, enrollment was completed with 35 patients; median age was 62 (30-77) years; median time since diagnosis was 2 (0.2-26) years; 80% patients had received ≥2 prior TKIs. Diagnoses at baseline were 17 CP-CML, 2 AP-CML, 4 BP-CML, and 12 Ph+ ALL. Twenty-two (63%) patients were resistant to their last TKI therapy, and 17 (49%) had one or more BCR-ABL mutation at baseline; 14/35 (40%) patients had the T315I mutation. At the time of analysis, 19 (54%) patients remain on therapy (15 CP-CML, 2 AP-CML, 2 BP- CML, and 0 Ph+ ALL). Primary reasons for discontinuation include adverse events (AEs; n=2), lack of efficacy (n=4) and progressive disease (n=7, all Ph+ ALL who died). Median duration of exposure was 174 (3-539) days. Median dose intensity was 38 (11-45) mg/day. To date, 23 (66%) patients had their dose reduced. Ten (59%) CP-CML patients attained the primary efficacy endpoint of MCyR (6 CCyR, 4 MMR). The primary efficacy endpoint of MaHR was achieved by 10 (56%) patients: 2/2 AP-CML, 2/4 BP-CML and 6/12 Ph+ ALL patients. Major molecular response (MMR) was observed in 5 (14%) patients.
Treatment-emergent AEs (TEAEs) were observed in all patients, most common TEAEs (≥30% any grade) were thrombocytopenia (60%), pyrexia (57%), rash (37%), and hypertension (34%). Serious TEAEs were observed in 13 (37%) patients, the most common was pyrexia (n=3). No cases of pancreatitis were observed. Overall, 4 (11%) patients experienced arterial thrombotic events, 3 (9%) patients experienced serious events (1 brain stem infarction, 2 myocardial infarctions) and 1 patient experienced a non-serious event (ECG T wave inversion).
Conclusions: Initial data indicate ponatinib has substantial anti-leukemic activity in these heavily pretreated CML and Ph+ ALL Japanese patients; the primary efficacy endpoint was achieved in >50% patients. Additional follow-up will allow for a more complete assessment of the benefits and risks of ponatinib therapy in Japanese CML and Ph+ ALL patients.

Disclosures
Off Label Use: Ponatinib is a BCR-ABL kinase inhibitor that has been approved by the US FDA for the treatment of adult patients with CML (all phases) or Ph+ ALL that is T315I-positive or for whom no other TKI therapy is indicated.. Tojo:Novartis: Research Funding, Speakers Bureau; BMS: Research Funding. Yamamoto:Novartis: Honoraria, Research Funding, Speakers Bureau, support of manuscript preparation, support of manuscript preparation Other; Pfizer : Research Funding, support of manuscript preparation, support of manuscript preparation Other; ARIAD: Research Funding. Takahashi:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis, BMS, Kyowa Hakko Kirin, Chugai Pharma, Dainippon Sumitomo Pharma, Celgene, Janssen Pharma : Honoraria, Research Funding, Speakers Bureau; Takeda Pharma: Research Funding; Asahikasei Pharma: Honoraria. Kobayashi:ARIAD, Otsuka Pharma, Boehringer Ingelheim : Research Funding. Matsumura:Bristol-Myers Squibb: Honoraria; Novartis: Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Usui:ARIAD: data monitoring committee Other. Yanase:ARIAD: Employment, Equity Ownership. Hu:ARIAD: Employment, Equity Ownership. Naoe:ARIAD: Consultancy. Ohyashiki:ARIAD: Consultancy.