The US Food and Drug Administration (FDA) has placed a partial clinical hold on a phase 1b/2 study of OXi4503, a vascular disrupting agent.
In this trial (NCT02576301), researchers are evaluating OXi4503, alone and in combination with cytarabine, in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
The partial clinical hold applies to the 12.2 mg/m2 dose of OXi4503.
The FDA is allowing the continued treatment and enrollment of patients using a dose of 9.76 mg/m2.
The agency said additional data on patients receiving OXi4503 at 9.76 mg/m2 must be evaluated before dosing at 12.2 mg/m2 can be resumed.
The partial clinical hold is a result of 2 potential dose-limiting toxicities (DLTs) observed at the 12.2 mg/m2 dose level.
One DLT was hypotension, which occurred shortly after initial treatment with OXi4503. The other DLT was acute hypoxic respiratory failure, which occurred approximately 2 weeks after receiving OXi4503 and cytarabine.
Both events were deemed “possibly related” to OXi4503, and both patients recovered following treatment.
The study protocol generally defines a DLT as any grade 3 serious adverse event where a relationship to OXi4503 cannot be ruled out.
“Although it is disappointing that we are not currently continuing with the higher dose of OXi4503, we look forward to gathering more safety and efficacy data at the previous dose level, where we observed 2 complete remissions in the 4 patients that we treated,” said William D. Schwieterman, MD, chief executive officer of Mateon Therapeutics, Inc., the company developing OXi4503.
According to Mateon Therapeutics, OXi4503 has a dual mechanism of action that disrupts the shape of tumor bone marrow endothelial cells through reversible binding to tubulin at the colchicine binding site, downregulating intercellular adhesion molecules.
This alters the endothelial cell shape, releasing quiescent adherent tumor cells from bone marrow endothelial cells and activating the cell cycle, which makes the tumor cells vulnerable to chemotherapy.
OXi4503 also kills tumor cells directly via myeloperoxidase activation of an orthoquinone cytotoxic mediator.
In preclinical research, OXi4503 demonstrated activity against AML, both when given alone and in combination with bevacizumab. These results were published in Blood in 2010.
In a phase 1 trial (NCT01085656), researchers evaluated OXi4503 in patients with relapsed or refractory AML or MDS. The goals were to determine the safety profile, maximum tolerated dose, and biologic activity of OXi4503.
The researchers said OXi4503 demonstrated preliminary evidence of disease response in heavily pre-treated, refractory AML and advanced MDS.
The maximum tolerated dose of OXi4503 was not identified, but adverse events attributable to the drug included hypertension, bone pain, fever, anemia, thrombocytopenia, and coagulopathies.
Results from this study were presented at the 2013 ASH Annual Meeting.
In 2015, Mateon Therapeutics initiated the phase 1b/2 study of OXi4503 (NCT02576301) that is now on partial clinical hold.
The phase 1 portion of this study was designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent OXi4503 in patients with relapsed/refractory AML and MDS.
The phase 1 portion was also intended to determine the safety, pharmacokinetics, and pharmacodynamics of OXi4503 plus intermediate-dose cytarabine.
The goal of the phase 2 portion is to assess the preliminary efficacy of OXi4503 and cytarabine in patients with AML and MDS.