A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma

Abstract

Peripheral T-cell lymphomas (PTCL) are a group of rare malignancies characterized by chemotherapy resistance and poor prognosis. Romidepsin and pralatrexate were approved by the US Food and Drug Administration for patients with relapsed/refractory PTCL, exhibiting response rates of 25% and 29% respectively. Based on synergy in preclinical models of PTCL, we initiated a phase 1 study of pralatrexate plus romidepsin in patients with relapsed/refractory lymphoma. This was a single institution dose-escalation study of pralatrexate plus romidepsin designed to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetic profile, and response rates. Patients were treated with pralatrexate (10 to 25 mg/m²) and romidepsin (12 to 14 mg/m²) on 1 of 3 schedules: every week × 3 every 28 days, every week × 2 every 21 days, and every other week every 28 days. Treatment continued until progression, withdrawal of consent, or medical necessity. Twenty-nine patients were enrolled and evaluable for toxicity. Coadministration of pralatrexate and romidepsin was safe, well tolerated, with 3 DLTs across all schedules (grade 3 oral mucositis × 2; grade 4 sepsis × 1). The recommended phase 2 dose was defined as pralatrexate 25 mg/m² and romidepsin 12 mg/m² every other week. Twenty-three patients were evaluable for response. The overall response rate was 57% (13/23) across all patients and 71% (10/14) in PTCL. The phase 1 study of pralatrexate plus romidepsin resulted in a high response rate in patients with previously treated PTCL. A phase 2 study in PTCL will determine the efficacy of the combination. This trial was registered at www.clinicaltrials.gov as #NCT01947140.

Graphical abstract

Figure 1.

Schematic of study design, patient disposition, and thrombocytopenia as a function of schedule dose. (A) Screening and enrollment data for all patients. (B-D) Platelet trend over time. Platelet-retreatment parameter is 50 000/μL. (B) Cohort 1 patients were treated with pralatrexate 10 mg/m² and romidepsin 12 mg/m² on days 1, 8, and 15 every 28 days. (C) Cohorts treated on schedule A received pralatrexate 15 to 20 mg/m² and romidepsin 12 to 14 mg/m² on days 1 and 8 every 21 days. (D) Cohorts treated on schedule B received pralatrexate 15 to 25 mg/m² and romidepsin 12 to 14 mg/m² days 1 and 15 every 28 days. C, cycle; D, day; SCR, screening.

Figure 2.

Summary of response rates across study population for patients treated with romidepsin and pralatrexate. (A) Response rates by disease subtype. (B) Waterfall plot representing the percentage change in tumor growth following treatment depicted by disease subtype. ORR, overall response rate; TCL, T-cell lymphoma.

Figure 3.

PFS and OS as a function of treatment in study population. Curves on the left represent all patients who received study drug (N = 29) and CIs. Curves on the right are subdivided between non–T-cell (n = 11) and T-cell patients (n = 18). (A) Median PFS is 3.7 months for all patients (95% CI, 1.4, 10.8) and 4.4 months for T-cell lymphoma patients (95% CI, 3.5) and for non–T-cell lymphoma is 1.8 months (95% CI, 1.2). (B) Median OS for all patients is 13.8 months (95% CI, 8.8 to not achieved [N/A]); for TCL patients is 12.4 months (95% CI, 8.1) and non–T-cell lymphoma 34 months (95% CI, 9.7). (C) Swimmer’s plot detailing the PFS of all T-cell lymphoma patients enrolled in the study. Start time denotes the first dose of study drugs. Stop time denotes progression of disease (POD), change in treatment (including transplant), or death.

Figure 4.

PK parameters for pralatrexate and romidepsin in the study population. (A-B) Concentration over time for each dose cohort of pralatrexate (A) and romidepsin (B). (C) C_max, T_max, t_1/2, AUC, CI, and V_obs (volume observed) for pralatrexate and romidepsin at each dose cohort.