In part 1 of this study, patients were enrolled in a traditional 3 + 3 dose-escalation scheme, starting with dose level 1, with dose escalation as shown in supplemental Table 1 . Pralatrexate was administered at 10, 15, 20, 25, or 30 mg/m2 as an IV on days 1 and 8 of a standard 21-day CHOP regimen (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 [maximum, 2 mg] on day 1 and oral prednisone 100 mg on days 1-5).
A DLT was defined as an adverse event (AE) that, because of its type, severity, or relationship to study drug, must be counted toward determining the MTD. For purposes of determining the MTD of pralatrexate (Folotyn; Acrotech Biopharma, East Windsor, NJ) plus CHOP (Fol-CHOP) treatment, AEs that were considered DLTs when they occurred during the first treatment cycle included severe infections (grade 4); grade 4 neutropenia lasting for ≥7 days despite granulocyte colony-stimulating factor administration; any grade 4 thrombocytopenia or any grade thrombocytopenia with clinically significant bleeding (excluding epistaxis); or grade ≥3 study treatment-related nonhematologic toxicity, excluding nausea/vomiting in the absence of appropriate antiemetic therapy that occurred during the first cycle of the Fol-CHOP therapy.
Once the MTD was established in part 1, an expansion cohort (part 2) applying the MTD was included to allow for better characterization of efficacy and safety. (Figure 1 ) Patients were treated with the pralatrexate MTD on days 1 and 8 of each 21-day cycle, administered ∼15 minutes after CHOP. Treatment was repeated every 21 days (1 cycle) for up to 6 cycles.![]()
Patients were instructed to take leucovorin tablets (25 mg) 3 times a day for 2 days beginning 24 hours after each pralatrexate treatment as mucositis prophylaxis.20 The next dose of pralatrexate began at least 72 hours after the last dose of leucovorin administration.
Patients participated in the study for ∼26 weeks, which included a screening period (up to 30 days), up to six 3-week treatment cycles (18 weeks), and an end-of-study visit, which occurred at least 30 days after the last dose of pralatrexate.
A DLT was defined as an adverse event (AE) that, because of its type, severity, or relationship to study drug, must be counted toward determining the MTD. For purposes of determining the MTD of pralatrexate (Folotyn; Acrotech Biopharma, East Windsor, NJ) plus CHOP (Fol-CHOP) treatment, AEs that were considered DLTs when they occurred during the first treatment cycle included severe infections (grade 4); grade 4 neutropenia lasting for ≥7 days despite granulocyte colony-stimulating factor administration; any grade 4 thrombocytopenia or any grade thrombocytopenia with clinically significant bleeding (excluding epistaxis); or grade ≥3 study treatment-related nonhematologic toxicity, excluding nausea/vomiting in the absence of appropriate antiemetic therapy that occurred during the first cycle of the Fol-CHOP therapy.
Once the MTD was established in part 1, an expansion cohort (part 2) applying the MTD was included to allow for better characterization of efficacy and safety. (
Patients were instructed to take leucovorin tablets (25 mg) 3 times a day for 2 days beginning 24 hours after each pralatrexate treatment as mucositis prophylaxis.20 The next dose of pralatrexate began at least 72 hours after the last dose of leucovorin administration.
Patients participated in the study for ∼26 weeks, which included a screening period (up to 30 days), up to six 3-week treatment cycles (18 weeks), and an end-of-study visit, which occurred at least 30 days after the last dose of pralatrexate.
