Background: Pralatrexate (PDX) is a novel targeted antifolate that is designed to accumulate preferentially in cancer cells. Pralatrexate has demonstrated activity at a range of doses in patients (pts) with relapsed/refractory T-cell lymphoma. The maximum tolerated dose (MTD) in a trial of pts with aggressive lymphomas was 30 mg/m2 weekly for 6 of 7 weeks. In that Phase 1 study, responses were seen in pts with cutaneous T-cell lymphoma (CTCL). To further explore this activity, we designed PDX-010, a multi-center, open-label, Phase 1 study of pralatrexate with vitamin B12 and folic acid in pts with relapsed/refractory CTCL. As CTCL is often a more indolent disease than peripheral T-cell lymphoma and treatment paradigms use maintenance approaches, we sought to identify the least toxic dose and schedule with activity for this distinct pt population through a dose de-escalation scheme.

Methods: Eligible pts were required to have mycosis fungoides (MF), Sézary syndrome (SS), or cutaneous anaplastic large cell lymphoma (ALCL), and progression of disease (PD) after ≥ 1 systemic therapy. The dosing scheme employed 2 schedules: a 3 out of 4 week schedule and a 2 out of 3 week schedule. Doses are reduced in sequential cohorts based on toxicity. Optimal dose and schedule is defined as evidence of anti-tumor activity without Grade (Gr) 4 hematological toxicity, Gr 3–4 infection, or febrile neutropenia. Responses in skin are investigator-assessed using the modified severity weighted assessment tool (mSWAT).

Results: From August 2007 to August 2008, 23 pts have enrolled, 17 of whom are evaluable for safety and response. The 17 evaluable pts, 15 with MF, 1 with SS, and 1 with ALCL, were enrolled into 4 cohorts: 30 mg/m2 3 of 4 weeks (n=2), 20 mg/m2 3 of 4 weeks (n=3), 20 mg/m2 2 of 3 weeks (n=7), and 15 mg/m2 3 of 4 weeks (n=5). These pts were heavily pretreated with a median of 6 prior regimens (range 1–25), and a median of 3.5 prior systemic regimens (range 1–9). Dose-limiting toxicities (DLTs) to date have included Gr 2 acute renal failure (1), Gr 3 joint stiffness/muscle weakness (1), and Gr 2–3 stomatitis/mucositis (4). The most common treatment-related AEs include mucositis (10 patients [59%]), nausea (8 patients [47%]), and fatigue (7 patients [41%]). Treatment-related SAEs occurred in 3 pts:

  1. stomatitis (Gr 2) at pralatrexate 20 mg/m2 2 of 3 weeks;

  2. chills (Gr 1) and exfoliative dermatitis (Gr 2) at pralatrexate 20 mg/m2 2 of 3 weeks; and

  3. hypoalbuminemia (Gr 3) and tumor lysis syndrome (Gr 3) at pralatrexate 20 mg/m2 3 of 4 weeks.

To date of the 17 evaluable pts, 9 have achieved a response (53%), including partial response (PR) in 7 pts, and complete response (CR) in 2 pts (1 progressed rapidly off treatment). In addition, 6 pts had SD. Eight of the responding pts had MF, and the pt with ALCL had a CR. Seven of the 17 pts remain on treatment, including 3 pts who have been on treatment for 8, 8, and 9 months, respectively.

Conclusion: In this preliminary report, pralatrexate shows marked clinical activity in the treatment of CTCL at much lower doses than those used for aggressive lymphomas. Responses have been observed in pts who had previously received up to 8 prior treatment regimens. This study is ongoing to identify a dose and schedule of pralatrexate that can result in maintained responses with minimal toxicity for pts with CTCL.

Disclosures: Horwitz:ALLOS Therapeutics: Research Funding. Duvic:ALLOS Therapeutics: Consultancy, Research Funding. Kim:ALLOS Therapeutics: Research Funding. Zain:ALLOS Therapeutics: Research Funding. Lechowicz:ALLOS Therapeutics: Consultancy, Research Funding. Chance:ALLOS Therapeutics: Employment. Koutsoukos:ALLOS Therapeutics: Employment. Cagnoni:ALLOS Therapeutics: Employment. Saunders:ALLOS Therapeutics: Employment. O’Connor:ALLOS Therapeutics: Consultancy, Research Funding. Off Label Use: Pralatrexate is not an FDA approved drug. It use in CTCL, the nature of this trial, will be discussed.

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