Folotyn (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 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.

14 CLINICAL STUDIES

Peripheral T-cell Lymphoma (PTCL)

The safety and efficacy of FOLOTYN was evaluated 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 evaluable for efficacy. Evaluable 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 evaluated 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 evaluable 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)
Evaluable Patients (N=109)
N (%) 95% CI Median Duration of Response Range of Duration of Response
Overall Response
CR+CRu+PR 29 (27) 19, 36 287 days(9.4 months) 1-503 days
CR/CRu 9 (8)
PR 20 (18)
Responses ≥ 14 weeks
CR+CRu+PR 13 (12) 7, 20 Not Reached 98-503 days
CR/CRu 7 (6)
PR 6 (6)

CR = Complete Response, CRu = Complete Response unconfirmed, PR = Partial Response

The initial response assessment was scheduled at the end of cycle 1. Of the responders, 66% responded within cycle 1. The median time to first response was 45 days (range 37-349 days).

15 REFERENCES

1.
Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165.
2.
OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/o tm/otm_vi/otm_vi_2.html
3.
American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
4.
Polovich, M., White, J. M., & Kelleher, L. O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

16 HOW SUPPLIED/STORAGE AND HANDLING

FOLOTYN is available in single-dose clear glass vials containing pralatrexate at a concentration of 20 mg/mL as a preservative-free, sterile, clear yellow solution individually packaged for intravenous use in the following presentations:

NDC 48818-001-01: 20 mg of pralatrexate in 1 mL solution in a vial (20 mg / 1 mL)NDC 48818-001-02: 40 mg of pralatrexate in 2 mL solution in a vial (40 mg / 2 mL)

Vials must be stored refrigerated at 2-8°C (36-46°F) (see USP Controlled Cold Temperature) in original carton to protect from light.

Handle and dispose of FOLOTYN according to guidelines issued for cytotoxic drugs, including the use of gloves and other protective clothing to prevent skin contact [see References (15) ].

Each vial of FOLOTYN is intended for single use only. Any unused drug remaining after injection must be discarded.

17 PATIENT COUNSELING INFORMATION

See FDA-approved labeling (Patient Information).

Patients should be instructed to read the Patient Information carefully.

17.1 Need for Folic Acid and Vitamin B12

Advise patients treated with FOLOTYN to take folic acid and vitamin B12 as a prophylactic measure to reduce the risk of possible side effects [see Dosage and Administration (2.1) ].

17.2 Low Blood Cell Counts

Inform patients of the risk of low blood cell counts and to immediately contact their physician should any signs of infection develop, including fever. Inform patients to contact their physician if bleeding or symptoms of anemia occur.

17.3 Mucositis

Inform patients of the signs and symptoms of mucositis. Instruct patients on ways to reduce the risk of its development, and on ways to maintain nutrition and control discomfort from mucositis if it occurs.

17.4 Fatal Dermatologic Reactions

Advise patients about the risks for and the signs and symptoms of dermatologic reactions. Instruct patients to immediately notify their physician if any skin reactions occur [see Warnings and Precautions (5.3) ].

17.5 Tumor Lysis Syndrome

Inform patients about the risk of and the signs and symptoms of tumor lysis syndrome. Patients should be instructed to notify their physician if they experience these symptoms [see Warnings and Precautions (5.4) ].

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