ALBERT

Description: Introduction: The BEAM conditioning regimen (carmustine [BCNU], etoposide, cytarabine, melphalan) is widely used as the high dose chemotherapy given to patients with non-Hodgkin (NHL) or Hodgkin lymphoma (HL) who are undergoing autologous stem cell transplant (ASCT). The lyophilized formulation of melphalan (Alkeran) commonly included in the BEAM regimen has several limitation based on its marginal solubility and the requirement to reconstitute it in propylene glycol (PG), which itself is associated with toxicities. PG-free melphalan (Evomela) overcomes these limitations by using the solubilizing agent Captisol, an inactive excipient used in 6 FDA-approved parenteral drug formulations, to improve the stability of the reconstituted melphalan. PG-free melphalan is stable for 8-10 hours after reconstitution, it can be refrigerated (unlike Alkeran), and it avoids the potential toxicities of PG. PG-free melphalan has demonstrated bioequivalence to Alkeran, and it was safe and effective when used as the conditioning regimen for multiple myeloma patients undergoing ASCT. This Phase II study investigated the safety and efficacy of high-dose PG-free melphalan when included in the BEAM regimen. Methods: Adult patients with NHL or HL who were eligible for ASCT and gave informed consent were prospectively enrolled after collection of an adequate peripheral blood stem cell product. Carmustine, etoposide, and cytarabine were given at standard doses on Day -6 thru Day -3. PG-free melphalan, 140 mg/m2, was diluted with normal saline to a concentration of ≤ 0.45 mg/ml and infused over 30 minutes on Day -2. Autologous stem cells were infused on Day 0. Supportive care was per institutional standards. The primary endpoint was toxicity, and patients were followed post-transplant for toxicity, engraftment, and disease response. Results: Forty-five patients were enrolled from April 2014 thru June 2015 (mean age 52, range 18-73; 31 males/14 females; 32 NHL [15 diffuse large B-cell, 8 mantle cell, 9 other]/13 HL). Response prior to transplant was complete remission (CR, n=21), partial remission (PR, n=22), or progressive disease (PD, n=2). All patients completed BEAM with PG-free melphalan and stem cell infusion (median 5.1 CD34+ cells/kg), and 40 patients had sufficient follow-up for toxicity and engraftment assessments. The most common Grade 3-4 non-hematologic toxicities were neutropenic fever, (n= 26, 67%), infections (n=16, 41%), and electrolyte abnormalities (hypokalemia and hypophosphatemia in 8 and 23 patients, respectively). Twenty-four patients (60%) had oral mucositis, which was mostly Grade 2 (21 with Grade 2; 3 with Grade 3). Moderate or severe gastrointestinal toxicities were uncommon; 5 patients (12.5%) had Grade 3 diarrhea and 3 (7.5%) had Grade 3 nausea/vomiting. There were no treatment-related deaths. Thirty-nine patients (98%) had neutrophil and platelet engraftment at mean 10 and 21 days, respectively. One patient did not have platelet engraftment by Day +100. Among 36 patients who had response assessment at 60-100 days post-ASCT, 29 (81%) were in CR, 2 in PR, and 6 had PD. There have been three deaths, at 6-12 months post ASCT, all due to progressive disease. Conclusions: PG-free melphalan can be used in place of the standard, lyophilized formulation of melphalan in the BEAM regimen for lymphoma patients undergoing ASCT. It was shown to have a safety profile that compares favorably with Alkeran, and it avoids potential PG-associated toxicities. Of note, Grade 3-4 mucositis, diarrhea, and nausea/vomiting each occurred in fewer than 15% of patients, the engraftment rate was high (98%), and response rates were consistent with expectations. Disclosures No relevant conflicts of interest to declare.

Description: Background: Despite improvements in overall survival (OS) and progression free survival (PFS), the prognosis of patients with relapsed/refractory multiple myeloma (RRMM) remains poor. Carfilzomib (CFZ), a second generation proteasome inhibitor, is active as a single-agent or in combination with lenalidomide and/or dexamethasone (DEX) in RRMM. Pegylated liposomal doxorubicin (PLD) combined with bortezomib has been shown to prolong PFS and OS and is FDA approved as combination therapy in MM. We investigated the combination of CFZ with PLD in RRMM in a Phase I study. Objective: To determine the maximum tolerated dose (MTD) of CFZ combined with PLD. Patient/Methods: Patients with RRMM after ≥ 1 lines of therapy, with measureable disease, and good performance status, organ function and hematological reserve were eligible. Prior CFZ or PLD/doxorubicin exposure was not exclusionary. CFZ was given on days 1, 2, 8, 9, 15 and 16 at escalating doses of 27-56mg/m2 and PLD was given on day 8 in 28 day cycles at a dose of 30mg/m2. All dose levels included a lead-in dose of 20mg/m2 of CFZ on days 1 and 2 of cycle 1. Following 6 cycles of combination therapy, PLD was discontinued and patients were treated with maintenance CFZ (once weekly). Dose escalation was performed using a 3+3 design; MTD was defined as the highest dose level where dose limiting toxicity (DLT) occurred in less than 2 of 6 patients. Disease response was determined using International Myeloma Working Group (IMWG) criteria. Results: 16 patients were enrolled from May 2012-March 2014. Median age was 66 years (range 53-79) and 11 were female. Seven patients were ISS stage 3, 9 were stage 1. 3 patients had 〉 50% plasma cells present on bone marrow aspirate, 8 had 〈 20%. By mSMART criteria, 2 patients were high-risk, 2 were intermediate-risk, and 12 were standard-risk. Most patients were IgG Kappa subtype (12); while 3 patients had Kappa light chain subtype, and 1 had IgG Lambda subtype. Median number of prior therapies was 3 (range 1-12). Median time from diagnosis to start of protocol was 42 months (range 9-236). 100% had prior exposure to lenalidomide; 87.5% had prior exposure to bortezomib; 75% had undergone autologous transplantation; 6% had prior PLD or doxorubicin exposure; and 6% had prior CFZ exposure. No DLTs were observed in any cohort. Two patients were unable to complete the first cycle of treatment due to early progressive disease, and were replaced. Grade 3/4 non-hematologic adverse events were rare, but included: UTIs (3), sepsis (2), pneumonitis (2), dyspnea (2), syncope (1), pleural effusion (1). Grade 3/4 hematologic AEs were limited to: anemia (7), thrombocytopenia (4), neutropenia (5), lymphopenia (4), and hemolysis (2). Most of the neutropenia (60%) and thrombocytopenia (75%) occurred in the 56mg/m2 cohort. The median number of cycles completed was 3.5 (range

Description: Background: We previously reported on a phase I dose escalation trial of CDD [carfilzomib (CFZ), pegylated liposomal doxorubicin (PLD), and dexamethasone (DEX)] (Keller, et, al, ASH 2014 Abstract 4731). The combination was well tolerated and an MTD was not reached despite administering the currently approved single-agent doses. In the maximum dose level tested, the overall response rate (ORR) was 72% (5/7) in a heavily pre-treated population. Based on the promising results of the phase I study we conducted a phase II expansion to further evaluate the efficacy of the regimen. Patient/Methods: Patients with RRMM after ≥ 1 lines of therapy, with measureable disease, and good performance status, organ function and hematological reserve were eligible. Prior CFZ or PLD/doxorubicin exposure was permitted. CFZ was given on days 1, 2, 8, 9, 15 and 16 in 28 day cycles at a dose of 56mg/m2, PLD on day 8 at a dose of 30mg/m2,DEX on days 1, 2, 8, 9, 15 and 16 at a dose of 20mg. Following 6 cycles of combination therapy, PLD was discontinued and patients were treated with maintenance CFZ and DEX (once weekly). Response was assessed per IMWG criteria. Overall response rate (ORR) was defined as partial response (PR) or better, event-free survival as the interval from start of therapy to discontinuation. Results: Twenty-three patients were enrolled from April 2014-Mar 2016. Median age was 63 years (range 27-70) and 52% were male. Ten patients were ISS stage 1, 6 were stage 2, and 7 were stage 3. By mSMART criteria, 1 patient was high risk and 5 were intermediate risk. Ten patients were IgG Kappa subtype; 4 had IgG Lambda subtype, 2 had IgA Kappa subtype, 2 had IgA Lambda subtype, 3 kappa light chain, and 2 lambda light chain. The median number of prior therapies was 2 (range 1-13); median time from diagnosis to start of protocol was 40 months (range 8-200). All had prior exposure to lenalidomide; 91% to bortezomib; 9% to PLD or doxorubicin; 9% to CFZ; 96% had undergone autologous transplantation. The overall response rate was 83% with 48% achieving a complete or very good partial response. The median number of cycles was 11; the median estimated event-free survival was 7.4 months at a median follow-up of 10.6 months. Five patients discontinued due to disease progression, 7 due to toxicity, 1 to proceed to a second transplant, and 10 remain on treatment at time of submission. Individual patient responses are summarized in Table 1. Grade 3/4 non-hematologic toxicity was uncommon but included: infections (11), hypertension (4), RPLS (1), and MI (1). Grade 3/4 hematologic toxicity included: thrombocytopenia (11), anemia (8), neutropenia (7), TTP (1), and hemolysis (1). Conclusion: CDD is well tolerated and efficacious in relapsed or refractory MM. The estimated ORR of the combination is 83% (95% CI 67%-98%) a notable increase compared to standard dose CFZ and DEX. Disclosures Abboud: Gerson and Lehman Group: Consultancy; Baxalta: Honoraria; Takeda: Honoraria; Novartis: Research Funding; Seattle Genetics: Research Funding; Alexion: Honoraria; Cardinal: Honoraria; Teva: Research Funding, Speakers Bureau; Pharmacyclics: Honoraria; Pfizer: Research Funding; Merck: Research Funding. DiPersio:Incyte Corporation: Research Funding. Vij:Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Shire: Consultancy; Jazz: Consultancy; Karyopharma: Consultancy; Novartis: Consultancy.