Pralatrexate: Phase 1/2 Study in Japanese Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL)
Authors: Maeda Yoshinobu , Tobinai Kensei , Nagai Hirokazu , Nakane Takahiko , Shimoyama Tatsu , Nakazato Tomonori , Sakai Rika , Ishikawa Takayuki , Izutsu Koji , Ueda Ryuzo 
Published: October 2019

Abstract
Introduction:Pralatrexate (PDX) is a dihydrofolate reductase inhibitor with high affinity for reduced folate carrier 1 and folylpolyglutamate synthetase, resulting in extensive internalization and accumulation in tumor cells. In the previous phase 2 study for relapsed or refractory (R/R) PTCL in western countries, the overall response rate (ORR) was 29% (32 of 109 evaluable patients [pts]), as assessed by an independent central review (O'Connor et al. JCO 2011). We conducted this phase 1/2 study to evaluate the tolerability, safety, efficacy and pharmacokinetics of PDX in Japanese pts with R/R PTCL.
Methods: Eligibility criteria included age ≥20, histologically confirmed PTCL according to the 2008 WHO classification, disease progression after ≥1 prior systemic therapy, ≥1 measurable disease and Eastern Cooperative Oncology Group performance status ≤2. PDX was administered intravenously weekly for 6 weeks in 7-week cycles with concurrent vitamin B12 and folic acid. There were 2 cohorts in phase 1: Cohort 1 was at 30 mg/m2 of the US-approved dose and Cohort 2 would start at 20 mg/m2 if 30 mg/m2 was not tolerated. The primary endpoint was ORR in phase 2 and secondary endpoints included duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Response was evaluated by the independent central imaging review using the International Workshop Criteria (Cheson et al. JCO 1999). Cryotherapy and professional oral care (e.g. dental cleaning and oral hygiene instruction) by dentists before and during PDX treatment were recommended to reduce the severity of mucositis. An educational handbook was offered to all pts to learn symptoms, prevention and self-care of oral mucositis.
Results:A total of 25 pts received ≥1 dose of PDX and were included in the safety analysis (median age 71 years; 68% male; median of 3 prior therapies; 32% refractory to the most recent therapy; 16% low risk, 48% low-intermediate risk, 24% high-intermediate risk and 12% high risk by International Prognostic Index). Of these, 3 pts were enrolled in phase 1 and 22 pts in phase 2. Two pts in phase 2 were excluded from the efficacy analysis due to lack of a confirmed diagnosis of PTCL by the central pathology review.
In phase 1, no dose-limiting toxicity was observed in 3 pts for Cohort 1. In phase 2, using 30 mg/m2 as the recommended dose, the ORR was 45% (9 of 20 evaluable pts in phase 2; 90% CI, 26% to 65%) with 2 complete responses and 7 partial responses achieved in Cycle 1. At the time of data cut-off, median DoR of 9 responders was not reached (range, 1 to 358 days) and 4 responders were still on PDX treatment. The median PFS of all 20 evaluable pts was 150 days (95% CI, 43 to 183). Among 23 evaluable pts for efficacy in phase 1/2, 5 pts had died and median OS was not reached (range, 41 to 570 days) after a median follow-up of 183 days for censored cases. In contrast to the results from the previous phase 2 study in western countries showing the ORR of 8% (1 of 13) in pts with angioimmunoblastic T-cell lymphoma (AITL), the ORR in AITL pts was 44% (4 of 9), which was similar to the ORR in pts with PTCL not otherwise specified (50%; 6 of 12) or pts with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (50%; 1 of 2) in this study.
The plasma PDX concentration peaked immediately after intravenous injection over 3 to 5 minutes and the elimination half-life was about 10 to 20 minutes.
The most common grade (G) 3 or 4 adverse events were lymphopenia (52%; 13 pts), thrombocytopenia (40%; 10 pts), leukopenia (28%; 7 pts), neutropenia (24%; 6 pts), anemia (20%; 5 pts). Mucositis was observed in 21 pts (84%) including G1 (20%; 5 pts), G2 (44%; 11 pts) and G3 (20%; 5 pts). G4 mucositis did not occur in any pts. Median duration of G2 mucositis was 8 days (range, 3 to 15) and that of G3 was 12 days (range, 8 to 17). According to the criteria for dose modification, the dose of PDX was reduced to 20 mg/m2 due to mucositis in 6 pts. One pt discontinued the treatment due to G2 mucositis recurrence after dose reduction. All 25 treated pts received ≥1 time cryotherapy at PDX administration and 20 of them continued it throughout the study. Thirteen pts received ≥1 time dental scaling or dental cleaning.
Conclusion: PDX at 30 mg/m2 weekly for 6 of 7 weeks was effective and well-tolerated in Japanese pts with R/R PTCL. Early oral or dental care potentially ameliorates mucositis and it may be useful for continuing PDX treatment more safely.
This study was sponsored by Mundipharma KK.

Disclosures
Maeda: Mundipharma KK: Research Funding. Tobinai:Ono Pharmaceutical: Research Funding; Takeda: Honoraria, Research Funding; HUYA Bioscience: Honoraria; Daiichi Sankyo Co., Ltd.: Consultancy; Zenyaku Kogyo: Honoraria; SERVIER: Research Funding; GlaxoSmithKline: Research Funding; Kyowa Hakko Kirin: Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Chugai Pharma: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Eisai: Honoraria, Research Funding; Mundipharma KK: Honoraria, Research Funding. Nagai:Mundipharma KK: Research Funding; Takeda: Honoraria, Research Funding; Janssen: Research Funding. Nakane:Mundipharma KK: Research Funding. Shimoyama:Mundipharma KK: Research Funding. Nakazato:Mundipharma KK: Research Funding. Sakai:Mundipharma KK: Research Funding. Ishikawa:Mundipharma KK: Research Funding. Izutsu:Eisai: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria; Takeda Pharmaceutical: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Celgene: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Mundipharma KK: Research Funding. Ueda:Kyowa Hakko Kirin: Research Funding; Mundipharma KK: Consultancy.