Delivery of standard therapeutics in formulations which allow increased drug delivery with equivalent or less toxicity may improve outcome. Vincristine is an essential component of ALL therapy. Its cytotoxicity occurs in a time and dose-dependent manner, but the dose needs to be capped at 2 mg to prevent severe neurotoxicity. SV is a form of vincristine encapsulated in sphingomyelin liposomes or “sphingosomes” with an increased circulation half-life of 12 hours compared with 6–12 minutes for free vincristine. In vivo, SV has more anti-tumor activity than free vincristine in mice bearing P388 and L1210 leukemias. A previous study of single agent SV 2.0 mg/m2 given every 2 weeks (without dose capping) was conducted in 16 patients (pts) with relapsed or refractory ALL. Objective responses were observed in 14% (1 complete response [CR], 1 partial response [PR]); 36% had transient reduction in marrow leukemia infiltrate with very minimal toxicity (

Thomas et al., Cancer 106:1641, 2006
). An increase in dose intensity was considered the strategy for future trials. A standard 3 + 3 phase I study of weekly escalating doses of SV (1.5 mg/m2, 1.825 mg/m2, 2 mg/m2, 2.25 mg/m2, 2.4 mg/m2) with pulse dexamethasone (D) 40 mg daily days 1–4 and 11–14 was initiated. Pts with active grade 2 or greater central or peripheral neuropathy (PN) were excluded. Pts were evaluated for dose-limiting toxicities (DLT) after 1 course (defined as 4 weekly doses of SV + D). To date, 36 pts with relapsed/refractory ALL were enrolled. Median age was 34 years (range, 21–62). Median number of prior salvage regimens was 2 (range, 1–3); all pts had prior vincristine. SV was discontinued early for progressive disease (n=5), death due to sepsis (n=3) or other toxicities (n=3). Thus, twenty-five pts (71%) completed 1 full course and were considered evaluable. DLTs were observed at the 2.4 mg/m2 dose level (grade 3 PN, seizure with intracranial hemorrhage, grade 4 hepatotoxicity). The tentative MTD is 2.25 mg/m2 (expansion of cohort ongoing). Expected toxicities included infections related to neutropenia, grade 1–3 constipation, grade 1–2 PN and transient grade 1–3 elevations in hepatic transaminases related to azole antifungal prophylaxis. Six pts (24%) achieved CR (2 at 1.5 mg/m2, 1 at 1.825 mg/m2, 2 at 2.25 mg/m2, 1 at 2.4 mg/m2), 1 a PR (at 2.25 mg/m2), and 3 (12%) hematological improvements (of platelets at 1.825 mg/m2 and 2 mg/m2 or clearance of marrow blasts at 2.25 mg/m2). Five responders proceeded to allogeneic stem cell transplant. In conclusion, SV with pulse dexamethasone demonstrated encouraging activity in relapsed or refractory ALL. Phase II and III studies of SV in ALL are planned.

Topics:
acute lymphocytic leukemia, dexamethasone, vincristine, liposomes, brachial plexus neuritis, toxic effect, leukemia, allogeneic stem cell transplant, azole antifungal, cancer

Disclosures: Drug studied is investigational and not commercially available.; Research funding provided by Inex Pharmaceuticals, Inc.; Participation in Marqibo Advisory Board.

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2006, The American Society of Hematology
2006
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