ALBERT

Beschreibung: Abstract 1674 Poster Board I-700 Background Pralatrexate is a new anti-folate with increased affinity for the reduced folate carrier 1 (RFC-1) and longer intracellular retention in tumor cells due to efficient polyglutamation by folylpolyglutamyl synthetase (FPGS). Pralatrexate and gemcitabine each have activity as monotherapy in patients with relapsed or refractory lymphoma. Preclinical data reported synergy for the combination in NHL cell lines and xenografts that was schedule dependent (pralatrexate followed by gemcitabine) (Clin Cancer Res 2006;12:924-932). We initiated a multi-center Phase 1/2a study (PDX-009; NCT00481871) to evaluate this treatment combination. The primary objective of the Phase 1 portion was to determine the maximum tolerated dose (MTD) and optimal Phase 2 dose and schedule for the combination of pralatrexate and gemcitabine in patients with relapsed or refractory lymphoma. Methods Eligibility criteria included histologically confirmed lymphoma, progressive disease after ≥1 prior treatment and ECOG performance score 0-2. Patients in group A (n=7) received pralatrexate on day 1 and gemcitabine on day 2, once weekly for 3/4 wks. Patients in group B (n=10) also received pralatrexate and gemcitabine on sequential days, but were treated only every 2 wks (q2w). Patients in group C (n=17) received pralatrexate followed 1h later by gemcitabine on the same day q2w. All patients received vitamin B12 and folic acid supplementation. Prior gemcitabine exposure was permitted. Results As of May 2009, 34 patients were treated in Phase 1, including 24 men (71%), and median age was 63 years (range, 19-81). Histology included 13 patients with B-cell lymphoma, 11 with T/NK-cell lymphoma, 7 with Hodgkin's lymphoma, and 3 with “other” lymphoma. Patients had received a median of 3.5 prior regimens (range 1-11). All patients with once-weekly sequential-day dosing (pralatrexate 10-15 mg/m2 and gemcitabine 300-400 mg/m2) in Group A had dose-limiting toxicities (DLTs) of thrombocytopenia and/or neutropenia; therefore accrual to this schedule was halted and subsequent cohorts received pralatrexate with gemcitabine on the q2w schedule (groups B and C). The MTD with the q2w dosing schedule was pralatrexate/gemcitabine 10/400 mg/m2 when given on sequential days (group B) and 15/600 mg/m2 when given on the same day (group C). The DLTs for group B were cellulitis, pulmonary embolus, thrombocytopenia, and febrile neutropenia and the DLTs for Group C were fatigue, hypoxia, mucositis, and thrombocytopenia. Across all groups, the most frequently reported Gr 3-4 pralatrexate-related adverse events were neutropenia (41%), thrombocytopenia (35%), anemia (29%), and leukopenia (12%). Of 33 patients who were evaluable for response, 7 (21%) showed partial response, including patients with Hodgkin's lymphoma (4), diffuse large B-cell lymphoma (1), angioimmunoblastic T-cell lymphoma (1), and composite diffuse large B-cell lymphoma and T-cell lymphoma (1). Responses were seen in patients treated on the same day as well as the sequential day schedules. Conclusion Treatment with pralatrexate and gemcitabine is feasible, with acceptable toxicity, when administered on a q2w schedule. However, the MTD of each drug is 50% greater when given on the same day as compared to treating on sequential days. Preliminary results show activity of the combination of pralatrexate and gemcitabine in lymphoid malignancies with a 21% response rate in this heavily pretreated population. Phase 2 expansions at the MTD will explore both sequential-day dosing (10/400 mg/m2) and same-day dosing (15/600 mg/m2) in a q2w schedule. Disclosures Horwitz: Allos Therapeutics, Inc: Consultancy, Research Funding. Advani:Allos Therapeutics, Inc: Research Funding. Fruchtman:Allos Therapeutics, Inc.: Employment.

Beschreibung: 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) &