PROPEL: A Multi-Center Phase 2 Open-Label Study of Pralatrexate (PDX) with Vitamin B₁₂ and Folic Acid Supplementation in Patients with Replapsed or Refractory Peripheral T-Cell Lymphoma

Background: Pralatrexate (PDX) is a novel targeted antifolate that is designed to accumulate preferentially in cancer cells. Pralatrexate selectively enters cells expressing RFC-1, a protein that is over expressed on cancer cells compared to normal cells. Once inside cancer cells, pralatrexate is very efficiently polyglutamated, which leads to high intracellular drug retention. The PROPEL trial, a pivotal Phase 2, single-arm, nonrandomized, open-label, multi-center study is the largest prospective study in pts with PTCL. PROPEL was designed to evaluate the safety and efficacy of pts with relapsed or refractory PTCL.

Methods: Pts receive 30 mg/m² of pralatrexate intravenously (IV) weekly for 6 of 7 weeks in addition to vitamin B₁₂ and folic acid supplementation. The primary endpoint is objective response rate (ORR), with secondary endpoints of response duration, progression-free survival (PFS), and overall survival (OS). Eligibility criteria included histologically/cytologically confirmed PTCL, documented disease progression (PD) after □ 1 prior treatment, and Eastern Cooperative Oncology Group performance status (ECOG PS) □ 2. Response was assessed by independent central review using the International Workshop Criteria (IWC). Safety was monitored at 3 preplanned time-points during the study by an external data safety monitoring committee (DSMB).

Results: This study is fully accrued. From Aug 2006 to Apr 2008, 115 pts were enrolled, 107 of whom are considered evaluable per the protocol for response (those who received at least 1 dose of pralatrexate whose diagnosis of PTCL was confirmed by independent review). Interim data are available at this time for the first 65 evaluable pts, which includes 41 males (63%) and 24 females (37%). These pts were heavily pre-treated and had failed a median of 3 prior regimens. Ten (15%) had previously undergone an autologous stem cell transplant. The majority (34, 52%) of pts had PTCL not-otherwise specified (PTCL-NOS), with most others having anaplastic large cell lymphoma (10, 15%; 3 AKL+, 7 ALK−), transformed mycosis fungoides (7, 11%), or angioimmunoblastic T-cell lymphoma (7, 11%). Nineteen of 65 patients responded (29%). See the table below for complete efficacy results per independent central oncology review. Seven pts of the 19 responding pts (37% of responders) had a best response of CR. Four pts had insufficient response data, and response could not be assessed for 9 pts due to discontinuation prior to cycle 1 completion, although these pts are counted in the denominator for the ORR.

Efficacy Results According to Central Review

Of the 19 responders, 17 pts had evaluation by positron emission topography (PET) scan: 8 pts were deemed to have a CR and 9 had a PR. ORR as assessed by study investigators showed that 45% (n=29) of pts experienced either a CR or PR. Of the 65 pts, 14 (22%) received pralatrexate for □ 6 months. The most frequently reported Grade (Gr) 3–4 AEs considered to be related to pralatrexate were thrombocytopenia (20 pts [31%]), mucositis (9 pts [14%]), anemia (8 pts [12%]), and neutropenia (7 pts [11%]).

Conclusion: To our knowledge, this represents the largest prospective study conducted in pts with relapsed or refractory PTCL. The results demonstrate that pralatrexate exhibits substantial activity, including CRs, in pts with heavily pre-treated PTCL. This trial is now fully accrued and study results on the entire population will be presented at the meeting.