and organic anion transporter 3 (OAT3) transporter systems.
In vitro, pralatrexate inhibits MRP2 and MRP3 transporter systems ([I]/IC50 > 0.1) at concentrations of pralatrexate that can be reasonably expected clinically. MRP3 is a transporter that may affect the transport of etoposide and teniposide.
In vitro, pralatrexate did not significantly inhibit the P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B1, and OATP1B3 transporter systems at concentrations of pralatrexate that can be reasonably expected clinically.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies have not been performed with pralatrexate.
Mutagenesis
Pralatrexate did not cause mutations in the Ames test or the Chinese hamster ovary cell chromosome aberration assay. Nevertheless, these tests do not reliably predict genotoxicity for this class of compounds. Pralatrexate did not cause mutations in the mouse micronucleus assay.
Impairment of Fertility
No fertility studies have been performed.
Clinical Studies
Peripheral T-cell Lymphoma (PTCL)
The safety and efficacy of Folotyn was eva luated in an open-label, single-arm, multi-center, international trial that enrolled 115 patients with relapsed or refractory PTCL. One hundred and eleven patients were treated with Folotyn at 30 mg/m2 once weekly by IV push over 3-5 minutes for 6 weeks in 7-week cycles until disease progression or unacceptable toxicity. Of the 111 patients treated, 109 patients were eva luable for efficacy. eva luable patients had histologically confirmed PTCL by independent central review using the Revised European American Lymphoma (REAL) World Health Organization (WHO) disease classification, and relapsed or refractory disease after at least one prior treatment.
The primary efficacy endpoint was overall response rate (complete response, complete response unconfirmed, and partial response) as assessed by International Workshop Criteria (IWC). The key secondary efficacy endpoint was duration of response. Response assessments were scheduled at the end of cycle 1 and then every other cycle (every 14 weeks). Duration of response was measured from the first day of documented response to disease progression or death. Response and disease progression were eva luated by independent central review using the IWC.
The median age of treated patients was 59.0 years (range 21-85); 68% were male and 32% were female. Most patients were White (72%) and other racial origins included: Black (13%), Hispanic (8%), Asian (5%), other and unknown (<1% each). Patients had an Eastern Cooperative Oncology Group (ECOG) performance status at study entry of 0 (39%), 1 (44%), or 2 (17%). The median time from initial diagnosis to study entry was 15.6 months (range 0.8 – 322.3).
The median number of prior systemic therapies was 3 (range 1-12). Approximately one-fourth of patients (24%, n = 27) did not have evidence of response to any previous therapy. Approximately two-thirds of patients (63%, n = 70) did not have evidence of response to their most recent prior therapy before entering the study.
In all eva luable patients (n = 109) treated with Folotyn, the response rate, as determined by independent central review by IWC, was 27% (n = 29) (Table 5).
Table 5 Response Analysis per Independent Central Review (IWC) eva luable Patients
(N=109)
N (%) 95% CI Median Duration of Response Range of Duration of Response
Overall Response
Fou |
