A Phase 1/2A Open-Label Study of Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lymphoproliferative Malignancies.
Authors: Horwitz Steven M. , Vose Julie M. , Advani Ranjana , Sankhala Kamalesh , Padmanabhan Swaminathan , Hamlin Paul A. , Chen Andy , Wilroy Shannon , Zain Jasmine M. , Wright Danielle , Weissbrot Hanna , Hohenstein Maribeth , Cagnoni Pablo J , Saunders Michael E , O’Connor Owen A. 
Published: April 2020

Abstract
Background: Pralatrexate (PDX) is a novel targeted antifolate that is designed to accumulate preferentially in cancer cells. Pralatrexate has demonstrated activity in the treatment of non-Hodgkin’s lymphoma (NHL). Single-agent gemcitabine (Gem) has demonstrated promising activity in relapsed Hodgkin’s lymphoma, T-cell lymphoma, and select sub-types of B-cell NHL. Based on pre-clinical data demonstrating a schedule dependent synergy for this combination (pralatrexate + Gem) (Clin Cancer Res2006; 12(3):924–932), a Phase 1/2a, non-randomized, open-label, multi-center trial was designed to assess the potential co-administration of these 2 agents. The primary objective of the study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose when pralatrexate and Gem are administered with vitamin B12 and folic acid supplementation to patients (pts) with relapsed/refractory lymphoma.
Methods: Initially, pts were assigned to a schedule of pralatrexate, followed the next day by Gem, once weekly for 3 of 4 weeks (Treatment group A). When this schedule was poorly tolerated, new cohorts were enrolled in a dose escalating fashion: Treatment group B – pralatrexate (10 mg/m2) followed the next day by Gem (300–400 mg/m2) once every 2 weeks (q 2 weeks); and Treatment group C – pralatrexate (10 mg/m2) followed 1 hour later by Gem (300–400 mg/m2) q 2 weeks. Eligibility criteria include histologically confirmed lymphoma, documented disease progression (PD) after 3 1 prior treatment, and ECOG PS £ 2.
Results: As of August 2008, 20 pts have been treated on this study, including 11 males (55%) and 9 females (45%). Pt histology is as follows: 8 pts [40%] diffuse large B-cell lymphoma [DLBCL]; 1 pt [5%] follicular lymphoma, Hodgkin lymphoma (HL) (5 pts [26%]), T/NK-cell (5 pts [26%]), and composite DLBCL and PTCL (1 pt [5%]). Pts were heavily pre-treated having received a median of 4 prior regimens (range 3–12) with a median of 3 prior systemic regimens (range 2–10). Treatment group A was not well tolerated as evidenced by the incidence of Grade (Gr) 3–4 hematological toxicities. In comparison pts in treatment groups B and C had far fewer adverse events (AEs) with lower severity toxicities.
Across all dose cohorts and treatment groups, the most frequently reported Gr 3–4 AEs considered to be treatment related have been neutropenia (9 pts [45%]) thrombocytopenia (9 pts [45%]), and anemia (8 pts [40%]). Preliminary efficacy data show 6 pts (30%) with partial response (PR): 4 with HL, 1 with DLBCL, and 1 with composite DLBCL and PTCL. PRs occurred on both the sequential dosing schedule (5 pts) and the same-day dosing schedule (1 pt). The HL pts with a PR were heavily pretreated (7, 8, 11, and 12 prior therapies) and all had received previous Gem, 3 of the 4 without response.
Conclusion: The combination of pralatrexate and Gem can be safely administered on a q 2 week schedule. The MTD was established for the sequential day schedule as pralatrexate 10/Gem 300 (mg/m2). Dose escalation continues on the same day schedule. Pralatrexate and Gem administration at a frequency of 3/4 weeks is not feasible in heavily pretreated pts due to hematologic toxicity; however, when administered on a 2 q week schedule, the combination has shown a favorable safety profile. The combination of pralatrexate and Gem has shown encouraging activity in pts with heavily pre-treated, refractory lymphomas and enrollment in the study is ongoing to define the MTD on a same day schedule.
Cohort Number of Pts Dose Pralatrexate/Gem (mg/m2) Schedule #DLTs DLT (Grade) A1 2 15/400 Sequential days, 3/4 weeks 2 Thrombocytopenia (Gr 4); Neutropenia (Gr 3) & Thrombocytopenia (Gr 3) A-1 2 10/400 Sequential days, 3/4 weeks 2 Neutropenia (Gr 3) Thrombocytopenia Gr 3) A-2 3 10/300 Sequential days, 3/4 weeks 2 Thrombocytopenia (Gr 3) Neutropenia (Gr 3) B1 3 10/300 Sequential days, q 2 weeks 0 B2 3 10/400 Sequential days, q 2 weeks 0 B3 2 15/400 Sequential days, q 2 weeks 2 Cellulitis (Gr 3) Pulmonary embolus (Gr 3) C1 3 10/300 Same day, q 2 weeks 0 C2 2 10/400 Same day, q 2 weeks 1 Hypoxia (Gr 3) &