Date: 2016-12-06
Type of information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results at the 58th American Society of Hematology (ASH) Annual Meeting
Company: Mateon Therapeutics (USA - CA)
Product: OXi4503 (combretastatin A1-diphosphate or CA1P)
Action
mechanism: vascular disrupting agent/mitotic inhibitor/tubulin binder. The diphosphate prodrug of the stilbenoid combretastatin A1, originally isolated from the plant Combretum caffrum, with vascular-disrupting and antineoplastic activities. Upon administration, combretastatin A1 diphosphate (CA1P) is dephosphorylated to the active metabolite combretastatin A1 (CA1), which promotes rapid microtubule depolymerization; endothelial cell mitotic arrest and apoptosis, destruction of the tumor vasculature, disruption of tumor blood flow and tumor cell necrosis may ensue. In addition, orthoquinone intermediates, metabolized from combretastatin A1 by oxidative enzymes found to be elevated levels in some tumor types, may bind to tumor cell thiol-specific antioxidant proteins and DNA, and stimulate oxidative stress by enhancing superoxide/hydrogen peroxide production. CA1 binds to tubulin at the same site as colchicine but with higher affinity.
Disease: acute myeloid leukemia (AML), myelodysplastic syndrome (MDS)
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details: Phase 1 will investigate maximum tolerated dose of OXi4503 as a single agent and in combination with intermediate-dose cytarabine in subjects with relapsed/refractory AML or MDS. Phase 2 will investigate overall response rate of OXi4503 in combination with intermediate-dose cytarabine in 1) subjects with MDS after failure of 1 prior hypomethylating agent (Arm A) and 2) subjects with relapsed and refractory AML after treatment failure of up to 1 prior chemotherapy regimen (Arm B). (NCT02576301)
Latest
news: * On December 6, 2016, Mateon Therapeutics announced the poster presentation of data from its on-going phase 1b OX1222 study of OXi4503 in combination with cytarabine in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). OX1222 is a dose-ranging study of OXi4503 combined with cytarabine in relapsed/refractory AML and MDS. The poster presented at the 58th Annual Meeting of the American Society of Hematology (ASH) describes results from the initial two cohorts of OX1222, which represent the lowest doses of OXi4503 in the study. * On October 13, 2015, a Phase 1-2 trial sponsored by Mateon Therapeutics was published on the NIH website ClinicalTrials.gov for OXi4503 and is currently recruiting participants.
The first cohort enrolled 6 patients at a dose of 3.75 mg/m2 of OXi4503 in combination with an intermediate dose (1g/m2/day x 5 days) of cytarabine. The second cohort enrolled 4 patients at a dose of 4.68 mg/m2 of OXi4503 in combination with the same intermediate dose of cytarabine. Patients enrolled into OX1222 were treatment-resistant, end-stage AML/MDS patients who had on average four prior therapy failures before entering the study.
In total 2 of 10 (20%) patients achieved a complete remission (CR) on treatment and currently remain in CR without further treatment - one at 6 months and the other at 3 months. One patient of six (17%) responded in the 3.75 mg/m2 dose cohort, and one patient of four (25%) responded in the 4.68 mg/m2 dose cohort. The study is currently enrolling patients in the third cohort at 6.25 mg/m2 of OXi4503.
OXi4503 was generally well tolerated in the first two cohorts of the study. The adverse event profile remains similar to that seen in the monotherapy Phase 1b portion of the trial, with coagulopathies and hematological adverse events the most significant events. The most common drug-related SAEs were anemia (30%), neutropenia (30%), D-dimer increase (20%), thrombocytopenia (20%), and AST increase (20%). One patient in the 3.75 mg/m2 cohort experienced a dose-limiting toxicity of hypofibrinogenemia with no clinical evidence of bleeding, which resolved with treatment.
The poster presentation was entitled "A Phase 1b (OX1222) Dose-Finding Study of OXi4503 Combined with Cytarabine in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome" and was presented by Justin M. Watts , MD, Assistant Professor of Clinical Medicine at the University of Miami .
