An Open-Label, Phase 1 Study Evaluating the Safety and Pharmacokinetics of Pralatrexate in Relapsed/Refractory Advanced Solid Tumors or Advanced Lymphoma/Myeloma Patients with Mild, Moderate, and Severe Renal Impairment

Introduction: Pralatrexate is a folate analogue indicated for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) that is preferentially taken up in cancer cells through the reduced folate carrier. While 34% of pralatrexate is excreted unchanged in the urine following a single, 30 mg/m² dose administered as an IV push, a population PK analysis showed that drug clearance decreased with decreasing creatinine clearance. In addition, methotrexate, also a folate analogue, does need to be dose-reduced for patients with moderate or severe renal impairment. Pralatrexate, however, has not been formally tested in patients with renal impairment, and previous studies excluded patients with severe renal impairment. This study was, therefore, conducted to determine the need for pralatrexate dosing adjustments in patients with renal impairment.

Methods: This was an open label, nonrandomized, Phase 1 study to determine the PK profile of pralatrexate in patients with relapsed/refractory advanced solid tumors or advanced lymphoma/myeloma with renal impairment. Primary objective of the study was to establish dosing recommendation of pralatrexate in renally compromised patients and to determine the pharmacokinetic profile in these patients. Four cohorts (n=6 per cohort) were planned to be enrolled in this study for a total of 24 patients. Patients with normal renal function (eGFR ≥90 mL/min/1.73 m², Cohort A), mild (eGFR= 60 to <90 mL/min/1.73 m², Cohort B) and moderate renal function (eGFR = 30 to < 60 mL/min/1.73 m², Cohort C) were dosed with 30 mg/m² pralatrexate once weekly for 6-weeks in a 7-week cycle. The pralatrexate dose was empirically reduced to 20 mg/m² in patients with severe renal impairment (eGFR = 15 to < 30 mL/min/1.73 m², Cohort D). Plasma and urine samples were collected at pre-specified time points to determine the PK profile. Patients who continued treatment with pralatrexate were then followed for safety and tolerability.

Results: A total of 29 patients (14 male and 13 female) were enrolled in the study with 6 patients in each cohort. There were slightly more male patients (n=14, 52%) than female patients (n=13, 48%) enrolled; fewer males (33%) were in the mild renal impairment group and more males (83%) were in the moderate renal impairment group. The median age was 62.0 years. The majority of patients were White (n=22, 81%); the remaining patients were Black (n=5, 19%). Because of a qualifying toxicity in Cohort C, the starting dose was reduced to 15 mg/m² in Cohort D. The major effect of chronic renal impairment was to decrease renal clearance of the pralatrexate diastereomers, PDX-10a and PDX-10b, but systemic exposure to these diastereomers was not dramatically affected by renal impairment. Mean total exposures of PDX-10a and PDX-10b were comparable across cohorts, including Cohort D. The empiric dose reduction to 15 mg/m² in Cohort D was able to match the average exposures for Cohort A (with normal dose of 30 mg/m²). Although Cohorts B and C had elevated mean exposures and higher inter-patient variability than Cohorts A and D, it appears to be a result of non-renal factors. In summary, total exposures of PDX-10a and PDX-10b after a single IV injection of racemic pralatrexate are not dramatically affected by renal impairment.

There was no apparent difference in either the incidence or types of TEAEs between the four treatment cohorts, and, therefore, the safety of pralatrexate was not affected by differences in renal function. The most common treatment related AEs were stomatitis (n=23, 83%), nausea (n=10, 37%), anemia (n=7, 26%) and fatigue (n=6, 22%).

Conclusion: The pralatrexate exposure in patients with mild or moderate renal impairment is similar to the patients with normal renal function at a dose of 30 mg/m2. For patients with severe renal impairment, a pralatrexate dose of 15 mg/m² is recommended.