Management of Mucositis with the Use of Leucovorin As Adjunct to Pralatrexate in Treatment of Peripheral T-Cell Lymphomas (PTCL) — Results from a Prospective Multicenter Phase 2 Clinical Trial

Background: A frequent complication of Pralatrexate therapy is development of oral mucositis. In a recent pivotal trial of pralatrexate (PROPEL, O'Connor et al. J Clin Onc 2011) the incidence of ≥ Grade 2 mucositis was 52%, occurring primarily in the first treatment cycle. Mucositis often leads to dose reduction or omission and possibly, diminished efficacy of pralatrexate in relapsed/refractory (R/R) PTCL. Leucovorin (d,l-folinic acid) is an approved rescue therapy for high-dose methotrexate (MTX) therapy, mitigating gastrointestinal lining, and bone marrow cell toxicity and has been used adjunctively with pralatrexate to manage mucositis. The objective of this prospective Phase 2, single-arm study was to evaluate the effect of leucovorin on the incidence of pralatrexate-induced mucositis in patients with R/R PTCL, including primary cutaneous T-cell lymphomas.

Methods: Eligible patients had diagnosis of PTCL, including CTCL, confirmed by local hematopathologist or dermatopathologist and were deemed appropriate for pralatrexate therapy by investigator. Study treatment consisted of two cycles of Pralatrexate, (6 weekly doses (30 mg/m²) followed by 1 week of rest per cycle, currently approved label). All patients received vitamin B12 and folic acid supplementation; oral leucovorin, 25 mg TID was self-administered for 2 consecutive days (a total of 6 doses) beginning 24 hours after each dose of Pralatrexate. Patients underwent in-clinic oral mucositis assessment at baseline and at each visit prior to pralatrexate administration by healthcare professional. Patients also completed a daily oral mucositis questionnaire (OMDQ) from Day 1 of Cycle 1 to the end of treatment visit. Mucositis was assessed by the investigator and recorded as an AE along with grade and causality. Toxicities were assessed using Common Terminology Criteria (CTCAE V4.03). Responses were assessed by the investigator per revised Response Criteria for Malignant Lymphoma (Cheson 2007) and Modified SWAT Criteria for CTCL.The primary endpoint was the incidence of Grade 2 or higher oral mucositis in Cycle 1. Secondary endpoints included the incidence of ≥ Grade 3 mucositis, and overall response rate.

Results: A total of 30 patients have been enrolled as of time of data analysis. The majority of patients were male, white, with the median age of 63 yrs (range, 31-85). To date (5 July 2018) 11 patients have completed the study treatment, 12 patients discontinued (1 AE, 9 PD, 1 death, and 1 withdrawal) and 7 patients remain in the trial. All 30 subjects reached the assessment of the primary endpoint. The primary endpoint of the study has been met. Twenty (67%) patients have reported TEAEs, of which 11 (37%) have been ≥Grade 3 AEs. Overall toxicity profile was consistent with previously reported in the PROPEL trial. Most common Pralatrexate-related AEs were fatigue in 6 (20%) patients and diarrhea that occurred in 4 (13%) patients. SAEs occurred in 9 patients (only pyrexia in >1 pt; N=2), none were treatment-related. The rate of ≥2 mucositis was 4% (95% C.I. = 0, 20%). No Grade 3 or higher mucositis occurred; Grade 1 mucositis was observed in 4 patients. Assessment of treatment response rate (secondary endpoint) is ongoing and will be reported at the meeting.

Conclusions: Overall safety profile of the study treatment was consistent with pivotal trial of Pralatrexate in R/R PTCL. Leucovorin as adjunctive treatment resulted in a significant reduction in rates of both ≥Grade 2, and ≥Grade 3 mucositis and should be considered in patients treated with Pralatrexate.