A Phase 1b Dose-Escalation Study of Split-Dose Oprozomib (ONX0912) in Patients with Hematologic Malignancies

Oprozomib (OPZ, formerly ONX 0912), a structural analog of carfilzomib (CFZ), is an orally bioavailable, next-generation proteasome inhibitor being evaluated in hematologic malignancies and solid tumors. Similar to CFZ, OPZ is a potent, selective, and irreversible proteasome inhibitor. In an earlier dose-escalation study of once-daily (QD) OPZ in patients with advanced refractory solid tumors, the maximum tolerated dose (MTD) was 150 mg QD, leading to exploration of a split-dose schedule with the drug administered twice daily (BID). The present phase 1 study (NCT01416428) is evaluating OPZ administered using the split-dose schedule in patients with hematologic malignancies.

This is an ongoing, phase 1b, open-label, dose-escalation study of OPZ in patients with hematologic malignancies. The primary objectives are to evaluate safety and tolerability and to determine the MTD. Secondary objectives of the study include pharmacokinetic and pharmacodynamic analyses. OPZ is administered PO on days 1–5 of a 14-day cycle using a standard 3 + 3 dose-escalation scheme. Treatment was initiated at 120 mg (60 mg BID), with an interval of 4–6 h between doses, with escalation in 30-mg increments in successive cohorts until MTD is determined. Tumor response is assessed by investigator.

As of June 15, 2012, 9 patients have been enrolled in the study, 3 in each of the 120-mg, 150-mg, and 180-mg dosing cohorts. No dose-limiting toxicities have been observed. Enrollment is ongoing at 210 mg/day. The median age of all patients is 67 years (range 53−81) and prior therapies included a median of 4 chemotherapy regimens (range 2−8). Patients have received a median of 5 cycles of treatment with OPZ, including 4 patients who have received ≥6 cycles. Dose reduction was required by only 1 patient in the 180-mg (90 mg BID) group for Grade 3 diarrhea and abdominal pain. Gastrointestinal (GI) AEs predominantly of Grade 1/2 in severity were the most common, with diarrhea and nausea each occurring in 7 patients, and vomiting occurring in 6 patients. The majority of GI AEs improved or resolved with concomitant medications. Thrombocytopenia was the only Grade 3/4 AE reported in more than 1 patient, occurring in 3 patients (1 at each dose level). Notably, no events of peripheral neuropathy were noted in patients in the first 3 dosing cohorts. AEs led to discontinuation in 2 patients at the 180-mg dose level, and no deaths have been reported. OPZ showed dose-dependent exposure across the 120- to 180-mg dose levels. Patients receiving split dosing had similar total exposure and lower C_max than patients receiving QD dosing of the same total daily dose, although there was high inter-patient variability. Dose-dependent proteasome inhibition was observed in whole blood and increased from the first to the second of the split daily doses. Proteasome inhibition levels were similar to those achieved with single-dose equivalents and were >80% at the 180-mg dose level. Eight of 9 patients are evaluable for efficacy. There was preliminary evidence of anti-tumor activity of ≥SD across all doses, including 1 patient with chronic lymphocytic leukemia who attained a PR after prior exposure to 3 lines of therapy, and 1 PR and 1 MR in patients with multiple myeloma.

Oral OPZ was generally well tolerated using a split-dose schedule in this phase 1 trial in patients with hematologic malignancies. AEs were generally mild and manageable. An MTD has not been reached at cumulative doses up to 180 mg/d (90 mg BID). Dose-dependent proteasome inhibition was observed, with >80% inhibition at the highest dose tested. OPZ also demonstrated encouraging clinical activity across the first 3 dose levels in heavily pretreated patients. Dose escalation will continue until the MTD is reached, with planned phase 2 expansion at the MTD in patients with hematologic malignancies.

Off Label Use: Oprozomib is in Phase 1 clinical trials for hematologic malignancies and is not approved by the FDA for any use. Lee:Onyx Pharmaceuticals: Employment. Wong:Onyx Pharmaceuticals: Employment. Lee:Onyx Pharmaceuticals: Employment. Gillenwater:Onyx Pharmaceuticals: Employment. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau.