AbstractIntroduction: Overall survival for patients with multiple myeloma (MM) has improved, but most patients relapse and eventually succumb to complications of the disease. The development of new therapeutic agents to treat relapsed and relapsed/refractory MM is therefore vital. Proteins of the Ras family are frequently mutated in human cancers, including MM. However, direct, selective, potent inhibitors of mutant Ras proteins are not clinically available. Extensive efforts have been made to identify agents which are "synthetically active" against the activated Ras pathway which may not inhibit the Ras protein itself, but target other molecules selectively important for cells with, but not those without, Ras mutation. PRLX 93936, 3-(2-ethoxyphenyl)-2-[(1-piperazinyl)methyl]-4(3H)-quinazolinone, is an analog of such a "synthetically active" compound against the activated Ras pathway. The compound has demonstrated promising efficacy in preclinical laboratory studies and mouse models of MM with an improvement in survival and 30% suppression in tumor growth at the lowest tested dose. A phase 1, multi-center, open-label, dose escalation trial was conducted to determine the maximum tolerated dose (MTD), assess toxicities, and evaluate response to treatment with monotherapy of PRLX 93936 in patients with relapsed or relapsed/refractory MM.Methods: Patients (Pts) with relapsed or relapsed/refractory MM in whom at least two prior anti-myeloma regimens had failed (including a proteasome inhibitor and/or immunomodulatory drug) were considered. PRLX 93936 as a single agent was given intravenously 3 days/week for 3 weeks followed by a 9 day rest period constituting a 28-day treatment cycle. Sequential cohorts of at least three pts were treated with escalating doses of PRLX 93936 beginning at 10 mg/m2 and increasing the dose in increments of 5mg/m2 until the MTD was established. Pts received a minimum of 2 cycles of treatment at their assigned dose level for evaluation of anti-myeloma activity of PRLX 93936 and could receive up to 8 cycles followed by an option of maintenance therapy. Dexamethasone at a dose of 20 mg provided on each day of PRLX 93936 infusion could be added at the investigator’s discretion after a minimum of 2 cycles or after cycle 1 for patients with progressive disease. Adverse events were assessed according to version 4.0 of the CTC, and response per the International Myeloma Working Group uniform response criteria, incorporating the modified EBMT response criteria, were assessed with each cycle. Correlative studies from peripheral blood and bone marrow were collected.Results: To date, 14 pts (4 women, 10 men) enrolled in the trial and 13 have completed therapy. Mean age was 61 years (range, 48-81). Prior to enrollment, pts had received an average of 5 lines of therapy (median 4, range 2-9) including 6 who received stem cell transplantation (4 autologous, 2 allogeneic). The median time since diagnosis was 5 years (range 2-11.5). Of the 13 pts whom completed treatment, 11 completed at least one full 28 day cycle (range 1-15). This includes 3 pts at the 10mg/m2 dose, 3 pts at the 15mg/m2 dose, 5 pts at the 20 mg/m2 dose, and 2 pts at the 25mg/m2 dose. Of the 13 pts who completed study therapy, 7 experienced at least one serious adverse event (SAE). The most frequently reported SAEs (2 each) included sepsis and cellulitis. Four SAEs were considered related to PRLX 93936 by the investigator (thrombocytopenia, neutropenia, nausea, and vomiting). The MTD was determined to be 20 mg/m2. Dose limiting toxicities that occurred at the next higher level of 25mg/m2 included nausea, vomiting, and neutropenia (both pts) and thrombocytopenia, weakness, elevated AST, and elevated creatinine (1 pt). The best response among 11 evaluable pts was minimal response (MR) in 2 pts (18%). Stable disease (n=4) and progressive disease (n=5) was observed in the remaining pts. Analysis of the impact of dexamethasone is on-going, but no significant additive toxicity has been seen.Conclusions: PRLX 93936, a “synthetically active” compound against the activated Ras pathway, has demonstrated activity as a single agent in relapsed and refractory MM patients with MR in 18% of patients to date. Toxicity has proven manageable and the MTD has been defined at 20 mg/m2. Additional studies, including those involving PRLX 93936 as part of combination therapy and correlative studies to determine those pts most likely to benefit, are warranted.DisclosuresVoorhees: Millennium: The Takeda Oncology Company : Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: PRLX 93936 is a non-FDA approved drug currently in phase 1 development in multiple myeloma. Gasparetto:Millenium: Honoraria; Celgene: Consultancy, Honoraria. Jacobstein:Prolexys Pharmaceuticals, Inc: Employment. Anderson:BMS: Consultancy; Sanofi Aventis: Consultancy; Gilead: Consultancy; Onyx: Consultancy; Millenium: Consultancy; Celgene: Consultancy; Oncopep/Acetylon: Equity Ownership. Mitsiades:Millennium: A Takeda Oncology Company: Consultancy; Celgene: Consultancy; Johnson & Johnson: Research Funding; Amgen: Research Funding. Laubach:Celgene: Research Funding; Novartis: Research Funding; Millennium: A Takeda Oncology Company: Research Funding; Onyx: Research Funding. Richardson:Janssen: Membership on an entity's Board of Directors or advisory committees; Millennium: The Takeda Oncology Co.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.