Urquilla, P. R.

8003 Background: Carfilzomib is a novel, irreversible tetrapeptide proteasome inhibitor derived from the natural product epoxomicin. Carfilzomib was well tolerated in preclinical animal studies when administered on a two-week cycle, QDx5; proteasome inhibition one hour after dosing at the MTD was >80%. Two Phase I dose-escalation studies are ongoing, aimed at determining the safety, tolerability, and biological response to carfilzomib. Methods: Carfilzomib was administered according to two different dose-intensive schedules. In PX-171–001, carfilzomib was administered on a two week cycle, QDx5 with nine days rest; in PX-171–002, carfilzomib was administered on a four week cycle, QDx2 weekly for three weeks with 12 days rest. Eligible patients have multiple myeloma (MM), Non-Hodgkin's Lymphoma (NHL), Hodgkin's Disease (HD), or Waldenström's Macroglobulinemia (WM). Results: Thus far, a total of 54 subjects have been enrolled. Although the maximum tolerated dose (MTD) has not yet been identified on either study, responses seen on both protocols have established 11 and 15 mg/m2 as the minimal effective doses (MEDs) on PX-171–001 and 002, respectively. Of 3 patients with MM or WM treated on the 001 protocol, one MM patient has had a Partial Response (PR) and one WM patient had a Minimal Response (MR). Of 8 patients with MM treated on the 002 protocol, 3 patients have had PRs. 6 additional patients have had Stable Disease lasting longer than 6 months and symptomatic improvement has been seen in patients on both protocols. 11 subjects remain on study with stable disease or better. Proteasome inhibition in whole blood at the highest dose levels exceeded 80% one hour after the first dose. Carfilzomib has been well tolerated at doses at and above the MED thus far. There has been no incidence of painful peripheral neuropathy on either study. No dose-limiting toxicities (DLTs) have occurred on PX-171–001; one DLT (Gr 4 anemia and thrombocytopenia) was observed at 27 mg/m2 on PX-171–002. Conclusions: Thus far, intensive dosing with carfilzomib is well-tolerated at proteasome inhibition levels of more than 80%. Five responses have been observed, and several subjects have achieved long lasting SD and/or symptomatic improvement. No significant financial relationships to disclose.

Abstract INTRODUCTION: PR-171 is a novel, irreversible proteasome inhibitor under investigation for the treatment of hematological malignancies. In preclinical studies, PR-171 was well tolerated in rats and monkeys when given daily × 5 (QDx5), every two weeks. Proteasome inhibition determined in blood and other tissues one hour after dosing at the maximum tolerated dose (MTD) was >80%. Despite the irreversible mechanism of action, the half-life of recovery of proteasome inhibition in tissues was approximately 24 hours. PR-171 was effective in suppression of tumor growth in xenograft studies in mice when administered QDx2 every week for three weeks. Two phase I dose-escalation studies have been initiated, aimed at determining the safety, tolerability, and clinical response to PR-171. METHODS: Two different dose-intensive schedules were employed in these phase I studies. In PX-171-001, PR-171 was administered on a two week cycle, QDx5 with nine days rest, while in PX-171-002, PR-171 was administered on a four week cycle, QDx2 weekly for three weeks with 12 days rest. The objective of these studies was to evaluate the safety and effectiveness of single-agent PR-171 administered according to a modified Fibonacci dose escalation scheme in cohorts of three. Patients with multiple myeloma (MM), non-Hodgkin Lymphoma (NHL), Hodgkin disease, or Waldenstrom’s Macroglobulinemia who received two or more prior treatments were eligible. RESULTS: Both studies were initiated with a dose of 1.2 mg/m2. Thus far, a total of 15 and 23 subjects have been enrolled in PX-171–001 and -002, respectively. PR-171 has been well tolerated at the highest doses thus far, 8.4 and 15 mg/m2, respectively. Proteasome inhibition in whole blood at the highest dose levels exceeded 75%, and in peripheral blood mononuclear cells inhibition exceeded 65%, one hour after the first dose. There have been no dose-limiting toxicities, no adverse events (AEs) considered probably related to study medication, no dose-related increases in the incidence or severity of AEs, and no incidence of painful peripheral neuropathy on either study. Although the MTD has not yet been identified on either study, preliminary evidence of efficacy has been observed with reduction in myeloma paraprotein levels and symptomatic improvement in patients on both protocols. Eleven subjects remain on study with stable disease (SD), which has been observed in MM and NHL patients on both studies, lasting up to eight months. CONCLUSION: PR-171 is well-tolerated in relapsed and refractory MM and NHL patients at proteasome inhibition levels of more than 75%. Several subjects have achieved long-lasting SD, reduction in paraprotein levels or symptomatic improvement. Further data from these ongoing trials will be discussed at the meeting.