Initial Results of PX-171-004, An Open-Label, Single-Arm, Phase II Study of Carfilzomib (CFZ) in Patients with Relapsed Myeloma (MM)
Authors: Vij Ravi , Wang Michael , Orlowski Robert , Stewart A. Keith , Jagannath Sundar , Kukreti Vishal , Taylor Jessica , Fuhrman Diana , Cruickshank Scott , Schwartz Richard , Kunkel Lori , Siegel David ,   The Multiple Myeloma Research Consortium (MMRC)
Published: October 2019

Abstract
Background: (CFZ) is a novel proteasome inhibitor of the epoxyketone class that exhibits a high level of selectivity for the proteasome and has been shown in a phase 1 study to result in greater than 80% proteasome inhibition on a QDx2 consecutive day schedule. We piloted this agent in MM patients with relapsed disease after one to three prior therapies.
Methods: PX-171-004 is an open-label, multicenter study. Pts are stratified into bortezomib (BTZ) naïve, BTZ responsive (> 6 month response) or BTZ non-responsive(< 6 months response) cohorts. Pts received CFZ 20 mg/m2 IV Days 1, 2, 8, 9, 15 and 16 every 28 days, for up to 12 cycles. Dexamethasone 4 mg po was administered prior to each dose in cycle 1. Responses were evaluated by the International Uniform Response Criteria for Multiple Myeloma.
Results: 31 patients were enrolled, including 45% BTZ naïve, 45% BTZ responsive, and 10% BTZ non-responsive. 29 pts initiated therapy, completed at least one cycle of CFZ, had measurable M-protein and were evaluable for response. The mean number of prior therapies (excluding transplant) was 2.4;65% received prior thalidomide(THAL), 36% prior lenalidomide (LEN) and 87% prior stem cell transplant (SCT).To date, pts received a median of 4 cycles (range 1–8) of CFZ. 19 pts started at least 4 cycles, and 17 remain on therapy. In the evaluable BTZ naïve population (n=13), the overall response rate (ORR) was 54%, including 1 complete response (CR), 2 very good partial responses (VGPR), and 4 partial responses (PR). There were 4 additional pts with stable disease (SD). In 1 pt with insufficient data to evaluate response, due to tumor lysis syndrome (TLS) onset after 2 CFZ doses, an M-protein drop was noted that suggested a PR. Time to response was rapid, frequently occurring in the 1st cycle. There have been no progressions in this subset. With a median follow-up of 109 days, the time-to-progression(TTP) has not yet been reached, and all responders remain in remission. In 16 evaluable BTZ prior treated pts, 3 pts (19%) achieved PR, 1 (6%) pt achieved a minimal response (MR, as defined by EBMT criteria), and 9 pts had SD. The median TTP is 169 days for this subset. CFZ was generally well tolerated. The most common non-hematologic adverse events (AEs) were fatigue (61%), nausea (58%), vomiting (36%), and insomnia (32%). Worsening of hematologic parameters: neutropenia (32%), anemia (29%), and thrombocytopenia (23%) were primarily Grade 1/2; Grade 3/4 occurred in 10% or less of pts. Reports of peripheral neuropathy (PN) were uncommon. Increased creatinine, both drug and non-drug related, was seen in 5 pts (16%), but treatment was discontinued in only 1 pt due to a renal adverse event. Possible tumor lysis was reported in 2 BTZ naïve patients and resulted in early drug discontinuation in 1 pt, as described above; the 2nd event was fatal.
Conclusions: The preliminary results of this trial indicate that CFZ has substantial activity as a single agent in relapsed MM patients, with an ORR of >50% in BTZ naïve patients, indicating better activity in this pt population. CFZ was generally well tolerated, and toxicities were manageable. TLS, which was observed in 2 pts, may be a reflection of the robust drug activity of CFZ. As observed in prior studies with CFZ, reports of PN were uncommon. These observations support further evaluation of CFZ as a promising new agent in MM. Enrollment in this study is ongoing, and additional studies of CFZ in combination with other chemotherapy agents in MM pts are underway.