CALGB 59901: Results of a Phase II Study of 506U78 in CTCL and PTCL.

T-cell lymphoma comprises approximately 10% to 15% of all lymphomas seen in the Western hemisphere and may be broadly categorized into 2 main groups: the various histologies of peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Overall, PTCL patients (pts) are believed to have a worse prognosis than pts with B-cell lymphoma. Except for the favorable subset of ALK-1-positive anaplastic large cell lymphoma, most PTCL are incurable with standard therapy. Salvage chemotherapy is often ineffective in relapsed PTCL or in pts with advanced CTCL no longer responding to agents that modulate T-cell function (e.g. retinoids, interferons, antibodies). New agents are needed for these pts. 506U78 is a pro-drug of ara-G, a deoxyguanosine analogue. Ara-G itself is difficult to synthesize and poorly water soluble. 506U78 is 10 X more water soluble than ara-G and is rapidly demethoxylated in blood to ara-G, which has been shown to be toxic to T-cells at even micromolar concentrations. Based on positive preliminary data with 506U78 in pediatric pts with recurrent/refractory precursor T-lymphoblastic lymphoma or leukemia (PTLL), we activated CALGB protocol 59901, a Phase II study of 506U78 in pts with systemically untreated CTCL or refractory/relapsed PTCL. Objectives were to determine response rate, remission duration, and safety associated with 506U78 given at 1.5 g/m²/day on Days 1, 3, and 5 as an IV infusion q 21 days for a minimum of 2 cycles and/or to continue for 2 cycles after CR (up to max of 8 cycles). Eligibility included: diagnosis of PTCL or CTCL; measurable disease; no CNS lymphoma; no history of seizure disorder or significant (>grade 1) neurologic dysfunction; age <70; PS 0–2; adequate renal and hepatic function; CTCL pts were originally not permitted to have received systemic chemo, but the protocol was amended on 2/15/02 to allow therapy with one prior course of single-agent chemotherapy in an attempt to increase accrual. Nineteen pts were enrolled between 5-15-00 and 3-15-04: 11 CTCL and 8 PTCL pts. Five of 11 CTCL pts had received no prior therapy and 7 of 7 evaluable PTCL pts had received prior chemo and 2 prior BMT. Adverse event (AE) data are available for 18 pts. Grade 3 or 4 AEs were documented in 50% and 28% of pts, respectively. Thirty-three percent of pts experienced Grade 3 or 4 neurologic toxicities which included: ataxia, vertigo, peripheral neuropathy, confusion, and/or depressed consciousness. There were 2 treatment-related deaths, 1 due to infection and 1 due to CNS hemorrhage (both in pts with CTCL). There were 2 PRs to therapy, one each in the PTCL and CTCL groups, with disease progression at 3m and 5.5m, respectively. The overall response rate is 10.5% (1.3% – 33.1%; 95% CI). Fifteen of 19 pts have died. Median EFS was 1.2m (1.0, 1.6 m; 95% CI) and median OS was 3 months (1.4, 9.8m; 95% CI). Due to lack of efficacy and excessive toxicity the protocol was closed on 3/15/04. In contrast to the favorable results seen in pediatric pts with recurrent PTLL, our data demonstrate that 506U78 has low efficacy, is unacceptably toxic and is not recommended as monotherapy in adult pts with CTCL and PTCL.