Phase I clinical trial of the base excision repair inhibitor methoxyamine in combination with fludarabine for patients with advanced hematologic malignancies.

Purpose: We determined the safety, pharmacokinetics, pharmacodynamics and recommended phase II dose of the base excision repair blocker methoxyamine combined with fludarabine.
Materials and Methods: This was a phase I study with intravenous fludarabine (25 mg/m ² , days 1-5), and methoxyamine (15 mg/m ² -120 mg/m ² , once). A maximum of six cycles were given. Adult patients with relapsed/refractory hematologic malignancies, excluding acute myeloid leukemia, were eligible.
Results: Twenty patients were treated; diagnoses included CLL/SLL ( n = 10), follicular lymphoma ( n = 3), DLBCL ( n = 3), mantle cell lymphoma ( n = 1), anaplastic large cell lymphoma ( n = 1) and plasma cell myeloma ( n = 2). No DLTs were observed and dose escalation reached the maximum planned dose. Hematologic toxicity was frequent; most common grade 3-4 toxicities were lymphopenia (70%), neutropenia (60%), leukopenia (50%) and anemia (40%). Four patients achieved a partial remission and 8 achieved stable disease. The drug combination resulted in increased DNA damage measured with the Comet assay.
Conclusions: Methoxyamine combined with fludarabine was safe and well tolerated. Hematologic toxicity was comparable to single agent fludarabine. Activity appears to correlate with increased levels of DNA damage. Further studies will examine use of this combination of as part conditioning regimens of stem cell transplant and use of methoxyamine as fludarabine dose-sparing agent.
Competing Interests: CONFLICTS OF INTEREST SLG holds patents under Case Western Reserve University for the use of methoxyamine, is compensated for service on the Scientific Advisory Board for Tracon, holds shares, and has a royalty and milestone interest through Case Western Reserve University for Methoxyamine (TRC-102). All other authors have no relevant conflicts of interest to disclose.