Oprozomib Shows Promise in Hematologic Malignancies
Atlanta, GA—Promising preliminary results for oprozomib (ONX 0912), an orally available structural analogue of carfilzomib (Kyprolis), were presented at the 2012 American Society of Hematology meeting. Oprozomib is being studied in hematologic malignancies, primarily in patients with multiple myeloma, and in solid tumors.
Phase 1b Trial in Hematologic Malignancies
Lead investigator Michael R. Savona, MD, Director of Leukemia Research, Sarah Cannon Research Institute, Nashville, TN, gave an oral presentation of the first report of a phase 1b dose escalation study of split-dose oprozomib in patients with hematologic malignancies.
Oprozomib is an orally bioavailable structural analogue of carfilzomib that irreversibly and selectively inhibits the proteasome. Studies of oprozomib in patients with solid tumors showed that a twice-daily dose resulted in a higher maximum tolerated dose than once-daily administration, with stable disease as the best response. The trial in hematologic malignancies enrolled heavily pretreated patients, 11 with multiple myeloma and 2 with chronic lymphocytic leukemia (CLL). Escalating doses of oprozomib from 120 mg daily to 210 mg daily in 2 doses 4 to 6 hours apart were administered with antiemetics, and an optional 4 mg of dexamethasone was administered on days 1 to 5 of a 14-day cycle.
The maximum tolerated dose was not reached at the highest dose, and no dose-limiting toxicities were seen.
Adverse events reported for the first 9 evaluable patients included gastrointestinal disturbances, cytopenias (including grade 4 thrombocytopenia), fatigue, pyrexia, hypoalbuminemia, and cognitive disorder. Dose-dependent proteasome inhibition was seen, with more than 80% inhibition at the highest doses tested.
At the time of this report, more than 50% of the patients had received a median of 3 to 4 cycles of treatment at the 2 highest doses. In the 9 patients with multiple myeloma and 1 with CLL who were evaluable for response, partial response was the best response in only 3 patients (ie, 2 with multiple myeloma and 1 with CLL).
Robert Z. Orlowski, MD, PhD, Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, M.D. Anderson Cancer Center, Houston, commented, “Oprozomib is much earlier in the development process [than carfilzomib], but the benefit hopefully will be that it retains activity, and as an oral formulation. Carfilzomib is still intravenous, so it’s a little bit less convenient for patients as an IV [intravenous] as opposed to an oral formulation.”
Dose escalation will continue to the maximum tolerated dose in a phase 2 expansion trial of oprozomib in patients with myeloma or Waldenström’s macroglobulinemia.