Phase I Study of Carfilzomib in Patients (Pts) with Relapsed and Refractory Multiple Myeloma (MM) and Varying Degrees of Renal Insufficiency.

Renal impairment affects 20% of newly diagnosed MM pts and over 50% during the course of their disease. Renal impairment confers shorter survival due to high tumor load and the difficulty in delivering adequate doses of active drugs, such as alkylating agents and immunomodulatory drugs (IMiDs) due to enhanced side effects (Kyle, Mayo Clin 2003). Pts with renal insufficiency have been traditionally excluded from clinical trials. Carfilzomib (CFZ) is a novel peptide epoxyketone proteasome inhibitor designed to have a high level of selectivity for the proteasome. In previous Phase 2 studies, CFZ has demonstrated single agent activity in heavily pretreated MM pts including those with mild renal insufficiency. The primary objective of this study was to evaluate the tolerability and pharmacokinetic properties of CFZ in MM pts with renal insufficiency, including those on dialysis.

In this multicenter study, MM pts who had relapsed after at least two prior therapies were enrolled into 4 cohorts based on renal impairment: normal (CrCl > 80mL/min), mild (CrCl 50–80 mL/min), moderate (CrCl 30–49 mL/min), and severe (CrCl < 30 mL/min) including dialysis pts. The primary and secondary objectives of the study included pharmacokinetics (PK), safety, pharmacodynamics (PDn; proteasome inhibition in blood) and efficacy endpoints: ORR (overall response rate, ≥ PR) CBR (clinical benefit response, ≥ MR), duration of response (DOR) and time to progression (TTP). Pts received CFZ at a dose of 15 mg/m² IV on day (D) 1, 2, 8, 9, 15 and 16 every 28 d for cycle (C) 1, with dose escalation to 20 mg/m² in C2 and 27 mg/m² in C3 and thereafter if tolerated. Pts received 40 mg of dexamethasone (Dex) in cycle 3 if they had less than a partial response (PR). Pts were followed for toxicity and efficacy over the course of the study. EKG changes from baseline including QT/QTc effects were assessed in C1 and C2. PK was measured on C1 D1,15 and C2 D15 and PDn was measured on C1 D1,2,8 and C2 D1.

Nineteen pts received at least 1 dose of CFZ and were evaluable for safety; 18 pts completed at least 1 C of CFZ and were evaluable for response and PK/PDn. All pts had refractory MM and 42% had progressed during their last therapy. The median number of prior therapies was 5 (range 2–10). All pts had received bortezomib and 26% were refractory; all pts received at lease one IMiD (90% thalidomide and 85% lenalidomide). Seventy percent had prior stem cell transplant. To date, pts have received a median of 3 cycles (range 1–7+) of CFZ; 9 pts have completed ≥ 6 cycles. The most common adverse events were fatigue, anemia, back pain and fever. There was no appreciable difference in the safety profile between the 4 cohorts either in frequency of events or in CTC-AE grade. Two deaths from disease progression with 1 complicated by a parainfluenza upper respiratory tract infection occurred while on study. No treatment emergent QT/QTc prolongations were observed during C1 and C2 in any group. Sixteen pts had grade 1 or 2 peripheral neuropathy at study entry and no cases of newly emergent or exacerbations occurred on study. Two pts discontinued drug due to worsening renal failure, one in the mild and one in the moderate cohort; both were related to disease progression. In all cohorts, CFZ was cleared with a t_½ of 30–60 minutes and reached undetectable levels in plasma within 3 hours. There was no accumulation of CFZ after two cycles. Proteasome inhibition measured 1 hr post-dose in whole blood and PBMC ranged from 75–89% at doses of 15–20 mg/m². PK and PDn were similar between the cohorts of pts with varying degrees of renal impairment. The ORR was 16.6% and CBR was 33.3%. Two BTZ-refractory pts achieved PR. An additional 38.9% had stable disease across all groups despite entering the study with progressive disease. Seven of 18 pts received Dex in ≥ C3 with 2 exhibiting an upgraded response (1 PR and 1 MR).

CFZ can be administered to MM pts with substantial renal dysfunction and does not require dose adjustment. CFZ toxicities in this study were manageable and importantly, exacerbation of pre-existing PN or myelosuppression was not observed in these renally impaired MM patients. Responses in relapsed and refractory MM pts with renal insufficiency are encouraging. Further evaluation of CFZ in renally impaired patients is ongoing, including in patients receiving hemodialysis.

Vij:Proteolix, Inc.: Consultancy, Research Funding. Zonder:Celgene: Speakers Bureau; Pfizer: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen: Consultancy; Millennium: Research Funding. Woo:Proteolix, Inc.: Employment. Wang:Proteolix, Inc.: Employment. Lee:Proteolix, Inc.: Employment. Wong:Proteolix, Inc.: Employment. Niesvizky:Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Seattle Genetics, Inc: Research Funding; Proteolix: Research Funding, data monitoring committee.