Schwartz, Richard

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.

Abstract Background: Carfilzomib (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 and refractory disease, who had failed bortezomib (BTZ) and at least one immunomodulatory (IMiD) agent, e.g., thalidomide (THAL) and/or lenalidomide (LEN). Methods: PX-171-003 is an open-label, multicenter study enrolling pts with MM who have relapsed from at least 2 prior therapies and who are refractory; defined as progressing on or within 60 days of last therapy or<25% response to the last therapy. 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. Clinical benefit response (CBR) was defined as complete response (CR) + partial/very good partial response (PR/VGPR) + minimal response (MR, as defined by EBMT criteria). Responses were adjudicated by an independent review committee. Results: 46 pts were enrolled, including 78% with progression on or within 60days of last therapy and 22% with no response to last therapy. 39 pts initiated treatment, completed at least one cycle of CFZ, had measurable M-protein, and were evaluable (eval) for response. The mean number of prior therapies (excluding transplant) was 6.4(range 1 to 18). 100% of pts received prior BTZ, 91% prior THAL, 89% prior LEN, and 83% prior stem cell transplantation (SCT). To date, pts received a median of 3 cycles(range 1–9) of CFZ; 22 started at least 4 cycles. The CBR was 26% (10/39 eval pts), including 5 pts achieving PR, 5 pts achieving MR, and 16 additional patients achieving stable disease (SD). Time to response was rapid, frequently occurring in the 1st cycle. CFZ was generally well tolerated; the most common adverse events (AEs) were fatigue(65%), nausea (37%), upper respiratory infection (37%), and diarrhea (33%). Worsening of hematologic parameters: anemia (65%); thrombocytopenia (46%) and neutropenia(20%) were predominantly Grades 1 and 2. Increased creatinine, both drug and non-drug related, was seen in 15/46 pts (33%), but treatment was discontinued in only 3 patients due to a renal adverse event. Acute renal failure was documented in 4 pts (9%), 2 (4%) of whom also had possible tumor lysis. 78% of pts had Grade 1 or 2 peripheral neuropathy (PN) at baseline. Exacerbation of PN was rare, and there were no study discontinuations or dose reductions due to PN. Conclusions: In the context of this heavily pre-treated MM population, single agent CFZ was able to induce CBR in 26% of MM patients, the majority of whom had failed BTZ, LEN, THAL, and SCT. CFZ was generally well-tolerated, and toxicities were manageable. Importantly, exacerbation of pre-existing PN was rare and did not result in dose reduction or discontinuation of therapy. These observations support further evaluation of CFZ as a promising new agent in MM. Enrollment is proceeding at an escalated dose (based on tolerability) in this trial. Additional studies of CFZ in patients who are less heavily pretreated and in combination with other chemotherapy agents are ongoing.

Abstract Glioblastoma (GBM) is the most common brain cancer. Front-line systemic therapy with temozolomide (TMZ) is often ineffective due to O6-methylguanine-DNA-methyltransferase (MGMT)-mediated resistance and patients with recurrent glioma have limited treatment options and very poor prognosis. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent that readily crosses the blood-brain barrier and has demonstrated activity against GBM in prior NCI-sponsored clinical trials. VAL-083 induces cross-links at N7 of guanine causing double-strand DNA breaks and apoptosis independent of MGMT expression against multiple GBM cell lines and cancer stem cells in vitro. VAL-083 cytotoxic activity also appears to be less dependent on wild type p53 compared to other alkylating agents. The main goal of this clinical trial was to determine an appropriate dose for VAL-083 for advancement to Phase II/III trials as a potential new treatment for refractory GBM. METHOD: Open-label, single-arm Phase I dose-escalation study (3+3 design) of IV treatment with VAL-083 on days 1, 2, 3 of a 21-day cycle, until MTD was reached. In Phase II, additional patients with GBM are treated at the MTD to gather further safety and outcomes data. Patients must have histologically confirmed GBM, previously treated with surgery and radiation and must have failed both TMZ and bevacizumab, unless contraindicated. RESULTS: Phase I has been completed and 40 mg/m2/d confirmed as the MTD. 29 GBM patients were enrolled in Phase I across 9 dose cohorts (1.5 - 50 mg/m2/d). Myelosuppression was mild; no drug-related serious adverse events were reported at doses ?40 mg/m2/d. Dose limiting toxicities (DLT), consisting of thrombocytopenia, were observed at 50 mg/m2/d and at an interim 45 mg/m2/d cohort. Platelet nadir occurred around day 20 and resolved rapidly and spontaneously. Pharmacokinetic analyses show dose-dependent linear systemic exposure with a short 1-2h plasma terminal half-life; average Cmax 781 ng/mL (5.3μM) at 40 mg/m2/d resulting in estimated CNS concentrations within the IC50 range observed for GBM cell-lines in vitro. A 14 patient Phase II expansion cohort was enrolled at 40 mg/m2/d. Safety observations in the Phase II expansion cohort to date are consistent with Phase I: Observed myelosuppression is mild, with the exception of 1 patient previously treated with CCNU who developed grade 4 thrombocytopenia. To date, 20 GBM patients (6 patients in Phase I and 14 patients in Phase II) have been treated with VAL-083 at therapeutic doses of 30 or 40 mg/m2/d. CONCLUSIONS: VAL-083 at 40 mg/m2/d on days 1, 2, 3 of a 21-day cycle exhibits a favorable safety profile and the Phase I part of the study showed a trend toward clinically meaningful improved survival in refractory GBM patients. Updated safety and outcomes data from the Phase II expansion cohort will be presented. ClinicalTrials.gov Identifier NCT01478178. Citation Format: Kent C. Shih, Manish R. Patel, Nicholas Butowski, Gerald S. Falchook, Sani H. Kizilbash, Jeffrey A. Bacha, Dennis M. Brown, Anne Steino, Richard Schwartz, Sarath Kanekal, Lorena M. Lopez, Howard A. Burris. Phase I/II study of VAL-083 in patients with recurrent glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT074.