Gemcitabine and Pemetrexed Disodium in Treating Patients With Advanced Mycosis Fungoides or Sézary Syndrome

Intervention Details:

Drug: gemcitabine hydrochloride

Gemcitabine has shown clinical activity in patients with advanced CTCL with a low toxicity profile 15, 16. It was investigated at 2 centers in a phase II trial at a dosage of 1200 mg/m2 (using traditional 3-weekly dosing every 28 days over 30 minutes) in 44 patients with clinical stage IIB-IV MF/SS 15. Twelve percent of patients achieved CR and 26% of patients achieved PR, with a median duration of 15 months and 10 months, respectively. Gemcitabine at a similar dose schedule was also evaluated in 32 patients with untreated MF, peripheral T-cell lymphoma, unclassified (PTCLU), and SS 16. The overall response rate was 75% with CR in 22% and PR in 53% of patients. The reported median duration was 10 months.

Drug: pemetrexed disodium

This agent has shown activity in a wide variety of solid tumors, including non-small cell lung, mesothelioma, breast, bladder, head and neck, and colon cancers 19, 20. Preclinical studies have shown cytotoxic synergy in various tumor cells when pemetrexed was combined with gemcitabine 21, 22. This provided a rationale for studying the drugs in combination. Phase I studies have shown antitumor activity in pre-treated and advanced solid tumors without increased toxicity 23-25. No pharmacokinetic interaction between the 2 drugs was observed. Clinical benefit response as well as survival data suggest a possible advantage over conventional gemcitabine monotherapy.

Detailed Description:

Objectives:

Primary

• Determine the safety and tolerability of gemcitabine hydrochloride and pemetrexed disodium in patients with advanced mycosis fungoides or Sézary syndrome. (Phase I)
• Determine the maximum tolerated dose of gemcitabine hydrochloride when administered with pemetrexed disodium in these patients. (Phase I)
• Evaluate tumor response (cutaneous and extracutaneous manifestations) in patients treated with this regimen. (Phase II)
• Evaluate synergistic toxic effects associated with this treatment regimen in these patients. (Phase II)

Secondary

• Assess response duration in patients treated with this regimen. (Phase II)
• Assess time to response in patients treated with this regimen. (Phase II)
• Assess time to progression in patients treated with this regimen. (Phase II)

Outline: This is a phase I, dose-escalation study of gemcitabine hydrochloride followed by a phase II study.

• Phase I: Patients receive pemetrexed disodium IV over 10 minutes and gemcitabine hydrochloride IV on days 1 and 15. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of gemcitabine hydrochloride until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which ≥ 2 of 6 patients experience dose-limiting toxicity. The recommended phase II dose is defined as the dose one level below the MTD.

• Phase II: Patients receive pemetrexed disodium and gemcitabine hydrochloride at the recommended phase II dose as in phase I. Treatment continues for ≥ 2 courses in the absence of unacceptable toxicity or disease progression or for 2 courses past maximum response.

After completion of study treatment, patients are followed every 3 months for up to 1 year.

Projected Accrual: A total of 38 patients will be accrued for this study.

Eligibility Criteria

Disease Characteristics:

• Histologically confirmed* mycosis fungoides or Sézary syndrome:
  • Stage IB-IVB disease
  • NOTE: *Pathology report must read diagnostic or consistent with mycosis fungoides/Sézary syndrome
• Failed ≥ 1 prior systemic treatment
• Measurable disease:
  • At least 1 indicator lesion must be designated prior to study entry

Patient Characteristics:

• ECOG performance status 0-2
• Life expectancy ≥ 6 months
• Creatinine ≤ 2.0 mg/dL
• Creatinine clearance ≥ 45 mL/min
• Bilirubin ≤ 2.2 mg/dL
• AST and ALT ≤ 2 times upper limit of normal
• WBC ≥ 3,000/mm³
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• No acute infection requiring systemic treatment
• No history of severe hypersensitivity reaction to the study drugs or to any other ingredient used in their formulation
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

Prior Concurrent Therapy:

• See Disease Characteristics
• At least 4 weeks since prior topical therapy, systemic chemotherapy, or biological therapy
• No acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs) for 2 days before and for 2 days after pemetrexed disodium infusion (5 days before and for 2 days after pemetrexed disodium infusion for patients taking NSAIDs with a long half-life [e.g., naproxen, refocoxib, or celecoxib])
• No concurrent topical agents except emollients
• No other concurrent topical or systemic anticancer therapies
• No other concurrent investigational agents