ALBERT

Description: Key PointsThe CHAMPION-1 study is the first clinical trial to investigate carfilzomib on a once-weekly dosing schedule with dexamethasone. Once-weekly carfilzomib (30-minute infusion; 20 and 70 mg/m2) with dexamethasone is feasible and effective in relapsed/refractory MM.

Description: Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who previously received POM treatment were ineligible. POM was administered orally on days 1-21 of a 28-day cycle, while DEX (40 mg) and PLD (5mg/m2) were both infused on days 1, 4, 8, and 11. During phase 1 enrollment, three cohorts were enrolled at 2, 3 and 4 mg doses of POM, and DEX and PLD were both administered at fixed doses. Phase 2 enrollment commenced once the MTD was established from the phase 1 portion of the study. Results As of August 1, 2015, 70 pts were screened, 68 were enrolled in the trial (with the pre-planned enrollment goal reached) and had received study drug, and a total of 50 pts were evaluable for safety and efficacy. Among all enrolled pts, 60pts discontinued treatment and 8 remain active. Pts had received a median of 4 prior treatments (range 1-18). Median number of cycles for all pts was 4 (range 1-8), with a median follow-up time of 5.5 months (range 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 57 pts enrolled in phase 2, 53% percent were refractory to LEN and steroids with or without other agents and 31% had previously received PLD. A median of 4 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Fifty-five pts were evaluable for response as 2 pts are active but have not yet had any post-baseline disease assessment. Among all evaluable pts (n=55) enrolled in phase 2, the overall response rate (ORR) was 33% (CR= 5%, VGPR= 5% and PR=23%) and clinical benefit rate (CBR) was 47% with 11 pts (26%) showing stable disease and 5 pts (12%) demonstrating progressive disease. For all evaluable pts enrolled in phase 2, the median follow-up time was 3.6 months (range 0-12 months) and the median PFS was 4.2 months (range 0.3- 29.0+). ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (36% and 51%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (49 pts; 72.0%), lymphopenia (36 pts; 52.9%), leukopenia (33 pts; 48.5%), hyponatremia (27 pts; 39.7%), and hypokalemia (26pts; 38.2%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures No relevant conflicts of interest to declare.

Description: We examined the IgM VH gene subgroup use-distribution in serial blood samples of 37 human immunodeficiency virus (HIV)-infected patients and a group of HIV-seronegative healthy adults. The IgM VH gene repertoires of healthy adults were relatively similar to one another and were stable over time. In contrast, individuals infected with HIV had IgM VH gene repertoires that were significantly more heterogeneous and unstable. Persons at early stages of HIV infection generally had abnormal expression levels of Ig VH3 genes and frequently displayed marked fluctuations in the relative expression levels of this VHgene subgroup over time. In contrast, persons with established acquired immunodeficiency syndrome (AIDS) had a significantly lower incidence of abnormalities in Ig VH3 expression levels, although continued to display abnormalities and instability in the expression levels of the smaller Ig VH gene subgroups. Moreover, the skewing and/or fluctuations in the expressed-IgM VHgene repertoire appeared greatest for persons at earlier stages of HIV infection. These studies show that persons infected with HIV have aberrant and unstable expression of immunoglobulin genes suggestive of a high degree humoral immune dysregulation and ongoing humoral immune responses to HIV-associated antigens and superantigens. © 1998 by The American Society of Hematology.

Description: Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/ progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who have previously received POM treatment were ineligible. In the phase 1 portion, POM was administered at 2, 3 or 4 mg daily in three cohorts on days 1-21 of a 28-day cycle and DEX (40 mg) and PLD (5 mg/m2) were fixed and given intravenously on days 1, 4, 8, and 11. Results As of June 20th, 2014, 48 pts were enrolled in the trial and a total of 47 pts had received study drug. Pts had received a median of 4 prior treatments (range 1-18), with a median of 2 prior IMiD-containing regimens (range, 0-8). Fifty-three percent of the pts had received a prior PLD-containing regimen and 21% had received a prior IMiD and PLD combination treatment. Among all enrolled pts, 40 pts discontinued treatment and seven remain active. Pts completed a median of 3 cycles (range: 1-8), with a median follow-up time of 5.4 months (range: 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 36 pts enrolled in phase 2, 78% percent were refractory to LEN and steroids with or without other agents and 47% had previously received PLD. A median of 2 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Thirty-five pts were evaluable for response as one pt was active but had not yet had any post-baseline disease assessments. Among all pts enrolled in phase 2, the overall response rate (ORR) and clinical benefit rate (CBR) were 29% and 49%, respectively, with 6 pts (17%) showing stable disease and 12 pts (34%) demonstrating progressive disease. For all pts enrolled in phase 2, the median follow-up time was 4.7 months (range 0-12) and the median PFS was 5.3 months. ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (32% and 58%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (21 pts; 44.7%), lymphopenia (10 pts; 21.3%), and hyponatremia (4 pts; 8.5%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Consultancy, Honoraria. Vescio:Celgene: Honoraria.

Description: Introduction Ruxolitinib (RUX) is an FDA-approved oral, selective inhibitor of Janus kinase (JAK) 1/2 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea or intermediate or high-risk myelofibrosis (MF). Preclinical studies from our laboratory have demonstrated that RUX in combination with the immunomodulatory agent lenalidomide (LEN) and dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Furthermore, MUC1 is responsible for LEN resistance in MM cells, and RUX blocks its expression in multiple myeloma (MM) cells. Thus, RUX may restore sensitivity to LEN. RUX also downregulates PD-L1 and PD-L2 expression on MM cells and reduces tumor stimulatory M2 macrophage polarization in MM bone marrow. Therefore, a phase 1 trial was conducted to determine the safety and efficacy of RUX in combination with LEN and the steroid methylprednisolone (MP) for relapsed/refractory (RR) MM patients who had previously been treated with LEN/steroids and a proteasome inhibitor (PI) and showed progressive disease at study entry. Methods A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with expansion once a MTD was determined. Subjects received RUX twice daily continuously, LEN daily on d1-21 of a 28-d cycle and MP orally every other day. In DL0, patients received RUX 5 mg, LEN 5 mg, and MP 40 mg. In DL+1 and +2, both doses of LEN and MP remained unchanged and RUX was escalated to 10 and 15 mg, respectively. DL+3 escalated LEN to 10 mg with MP unchanged and RUX at 15 mg. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results Thirty-four patients have been enrolled, and 31 were evaluable for response as of July 13, 2018. The median age was 68 years (range, 49-81), and 20 (59%) were male. Patients received a median of 6 prior treatments including lenalidomide and a PI. No DLTs occurred, and DL+3 was expanded (n=25). Among all 31 evaluable patients, the CBR and ORR were 48% and 39%, respectively (1 CR, 9 PR, 2 VGPR, and 3 MR), and 11 and 5 showed SD and PD, respectively. Notably, all 15 patients achieving ≥ MR were refractory to LEN (i.e. progressed while on or within 8 weeks of last dosage). The median PFS for all evaluable patients was 7.4 months. Grade 3/4 adverse events included transient thrombocytopenia (11.1%), anemia (8.8%), neutropenia (6.7%), hypoxia (4.4%) and gastrointestinal bleeding (4.4%). Common serious adverse events included abdominal pain (6.7%), gastrointestinal bleeding (6.7%) and hypoxia (6.7 %). Conclusions This phase 1 trial demonstrates for the first time that a JAK inhibitor, RUX, can overcome refractoriness to LEN and steroids for RRMM patients. This all oral regimen was well tolerated, and reversible Grade 3/4 cytopenias occurred in only a small minority of patients. These promising results are leading to other clinical trials using immunomodulatory agents, steroids and RUX, for treating RRMM patients, and this may represent a new therapeutic approach for these patients. Disclosures Berenson: BMS: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Daiichi: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.

Description: Abstract 1857 Background: Multiple myeloma (MM), the second most common hematologic cancer in the United States, has a 5-year survival rate of 38%. Bendamustine is a unique alkylating agent with multiple actions leading to cancer cell death in several tumor types. In patients with MM, bendamustine, alone and in combination with prednisone, has been shown to be efficacious, with durable responses. Bortezomib is a proteasome inhibitor approved as monotherapy for MM. It has been found to sensitize highly chemoresistant MM cell lines to alkylating agents such as melphalan. Subsequent clinical trials have reported anti-MM activity and acceptable safety for bortezomib plus melphalan for relapsed or refractory MM and for bortezomib, ascorbic acid, and melphalan (BAM) for patients with newly diagnosed MM. The present phase 1/2 study assessed the safety, tolerability, and efficacy of bortezomib plus bendamustine for patients with relapsed or refractory MM. Methods: All patients were ≥18 years old and had biopsy-confirmed MM, measurable by a serum monoclonal immunoglobulin spike ≥1 gm/dL and/or a urine monoclonal spike ≥200 mg/24 hours. Also, all patients received ≥1 prior MM treatment, not including bendamustine, and showed signs or symptoms of progressive disease, either relapsed (progression following stabilization or response) or refractory (progression during or within 6 months after an antimyeloma regimen). Patients were enrolled in successive groups of 3 to 5. The groups received open-label bendamustine administered as a 1-hour intravenous (IV) infusion of 50, 70, or 90 mg/m2 on days 1 and 4 of each 28-day treatment cycle. Each infusion was preceded by bortezomib administered as a 3- to 5-second IV push of 1.0 mg/m2. Bortezomib was also given on days 8 and 11. Enrollment at each dose level was permitted only if the first 3 patients at the previous level received 1 cycle without unacceptable dose-limiting toxicity (DLT). If not, an additional 3 patients would be treated at the previous level (for a maximum 6 at each level). The maximum tolerated dose was defined as the highest dose at which

Description: Background Thalidomide and its immunomodulatory drug (IMiD) derivatives such as lenalidomide (LEN) have shown great promise as treatment options for multiple myeloma (MM) patients (pts). Pomalidomide (POM) is a newer IMiD with high in vitro anti-MM potency that has shown promise as an effective treatment option for relapsed/refractory (R/R) MM pts. Recent data has shown POM to be effective in combination with dexamethasone (DEX), even for patients who are refractory to bortezomib and lenalidomide (Richardson et al, 2012). It has been demonstrated that the addition of pegylated liposomal doxorubicin (PLD) to lenalidomide and thalidomide is effective for both R/R and frontline MM pts (Offidani et al, 2006; 2007). Our recent trial evaluating lenalidomide in combination with dexamethasone, PLD, and bortezomib (DVD-R) showed that both efficacy and tolerability may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). These results imply that the combination of POM, DEX and PLD may be an effective regimen for treating R/R MM pts. We conducted a phase 1/2 trial investigating the safety and efficacy of POM in combination with IV DEX and PLD using our modified dose, schedule, and longer 28-day cycle for pts with R/R MM. Methods For enrollment into the phase 1 portion of the study, eligible pts had to show progressive MM at the time of enrollment. For participation in the phase 2 portion, pts had to be refractory to LEN (singe-agent or in combination) demonstrated by progressive disease while receiving this IMiD or relapsed within 8 weeks of their last dose. Pts who received previous POM treatment were ineligible. During the phase 1 part of the trial, POM was administered orally at 2, 3, or 4 mg daily in 3 successive cohorts of 3 pts each on days 1-21 of each 28-day cycle. DEX (40 mg intravenously over 30 min) and PLD (5 mg/m2infused over 30-90 min) both were given on days 1, 4, 8, and 11 of each cycle. POM doses were escalated per cohort until maximum tolerated dose (MTD) was reached. Phase 2 patients were all enrolled at what was established as the MTD. Results As of July 9, 2013, 33 pts were registered: 11 and 22 enrolled in the phase 1 and 2 portions, respectively. Fifteen patients have discontinued treatment thus far and 18 remain active. Pts had received a median of 5 prior treatments (range, 1-18) with a median of 1 prior PLD regimen (range, 0-2) and 1 prior IMiD regimen (range, 0-4). Pts have completed a median of 4 cycles (range: 0-8) with a median of 3.2 months of follow up (range: 0-9.7). During the phase 1 portion, no dose-limiting toxicities were identified, so the highest administered dose of 4 mg was initially established as the MTD. However, neutropenia ≥ G3 was observed in 10/17 phase 2 pts (58.8%) at this dose; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all phase 2 pts beyond the 29thpt (n = 4). Thirty-two pts have received study drug. Twenty-nine pts were evaluable for response at data cutoff as 3 were active but had not yet had any post-baseline disease assessments. Of the 29 considered evaluable, overall response rate and clinical benefit rates were 34.5% and 48.3%, respectively, Six pts (20.7%) showed stable disease while 8 (27.6%) pts exhibited progressive disease. There was ≥ grade 3 (G3) neutropenia in 12 (37.5%) pts. Two pts experienced this toxicity during the phase 1 portion (3 mg and 4 mg doses- 1 each) whereas the other 10 pts experienced this side effect at the 4 mg dose during phase 2 enrollment. Following the lowering of the MTD to 3 mg due to this issue, neutropenia (≥ G3) has not been observed to date. Other treatment-emergent AEs ≥ G3 occurring in more than 1 pt were leukopenia in 12 (37.5%), lymphopenia in 8 (25%), anemia in 3 (9.4%), hyponatremia in 3 (9.4%), thrombocytopenia in 2 (6.3%), and duodenal ulcers in 1 (3.4%) pts. One pt died during treatment due to sepsis. Conclusions Results from this phase 1/2 trial demonstrate that the combination of pomalidomide with dexamethasone and PLD using a 28-day cycle shows efficacy for MM pts with progressive disease who are refractory to lenalidomide. Notably, less neutropenia has been observed at the 3 mg dose of pomalidomide, with 4 mg POM dosing associated with a high incidence of ≥ G3 neutropenia when used in this three-drug combination. Disclosures: Berenson: Celgene: Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vescio:Celgene: Speakers Bureau.

Description: Introduction Ruxolitinib (RUX) is an FDA-approved oral, selective inhibitor of Janus kinase (JAK) 1/2 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea or intermediate or high-risk myelofibrosis (MF). Preclinical studies from our laboratory have demonstrated that RUX in combination with the immunomodulatory agent lenalidomide (LEN) and dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Furthermore, MUC1 (Mucin 1) is responsible for LEN resistance in MM cells, and RUX blocks its expression in multiple myeloma (MM) cells. Thus, RUX may restore sensitivity to LEN. RUX also downregulates PD-L1 and PD-L2 expression on MM cells and reduces tumor stimulatory M2 macrophage polarization in MM bone marrow. Therefore, a phase 1 trial was conducted to determine the safety and efficacy of RUX in combination with LEN and the steroid methylprednisolone (MP) for relapsed/refractory (RR) MM patients who had previously been treated with LEN/steroids and a proteasome inhibitor (PI) and showed progressive disease at study entry. Methods A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment to be 49 patients. Subjects received RUX twice daily continuously, LEN daily on d1-21 of a 28-d cycle and MP orally every other day. In DL0, patients received RUX 5 mg, LEN 5 mg, and MP 40 mg. In DL+1 and +2, both doses of LEN and MP remained unchanged and RUX was escalated to 10 and 15 mg, respectively. DL+3 escalated LEN to 10 mg with MP unchanged and RUX at 15 mg. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results As of March 1, 2019, 43 patients were enrolled, and 40 were evaluable for efficacy. The median age was 65 years (range, 46-81), and 25 (58%) were male. Patients received a median of 6 prior treatments including LEN and steroids to which they were all refractory. No DLTs occurred, and DL+3 was expanded. Among all 40 evaluable patients, the CBR and ORR were 47% and 37%, respectively (1 CR, 4 VGPR, 10 PR and 4 MR), and 16 and 5 patients showed SD and PD. Notably, all 19 patients achieving 〉 MR were refractory to LEN (i.e. progressed while on or within 8 weeks of last dosage). The median PFS for all evaluable patients was 4 months. G3/4 AEs included anemia (16%), sepsis (14%), lymphocytopenia (14%), pneumonia (12%), neutropenia (12%) and hypokalaemia (12%). Most common SAEs included sepsis (14%) and pneumonia (12%). Conclusions This phase 1 trial demonstrates for the first time that a JAK inhibitor, RUX, can overcome refractoriness to LEN and steroids for RRMM patients. This all oral regimen was well tolerated, and reversible Grade 3/4 cytopenias occurred in only a small minority of patients. These promising results are leading to expansion of the current clinical trial to 78 patients, and represent a potential novel therapeutic approach for treating MM. Disclosures Berenson: Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Sanofi: Consultancy; Amgen: Consultancy, Speakers Bureau; Sanofi: Consultancy; OncoTracker: Equity Ownership, Other: Officer; OncoTracker: Equity Ownership, Other: Officer; Takeda: Consultancy, Speakers Bureau; Incyte Corporation.: Consultancy, Research Funding; Incyte Corporation.: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Swift:Bristol Mayers Squib: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Jansen: Consultancy, Honoraria. Eades:Celgene: Other: Stock. Boccia:Genentech: Speakers Bureau; DSI: Speakers Bureau; AMAG: Consultancy; AstraZeneca: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau. OffLabel Disclosure: The goal of this clinical trial is to establish ruxolitinib in combination with lenalidomide and methylprednisolone as the therapy for relapse/refractory multiple myeloma patients.

Description: Introduction: Carfilzomib is an irreversible second-generation proteasome inhibitor that is currently approved for the treatment of relapsed or refractory multiple myeloma (MM). The primary objective of the CHAMPION-2 study was to determine the maximum tolerated dose (MTD) of carfilzomib when used with cyclophosphamide and dexamethasone (KCyd) for newly diagnosed MM, and secondary objectives were to evaluate the overall response rate (ORR), time to response (TTR), and safety of KCyd. Methods: This was a multicenter, open-label, single-arm, phase 1b study that enrolled patients 18 years or older with newly diagnosed symptomatic MM. Patients deferring transplant and transplant-ineligible patients were allowed. Treatment was given in 28-day cycles and continued for 8 cycles, or until unacceptable toxicity, withdrawal of consent, or progressive disease. A traditional 3+3 dose escalation scheme was used to determine the MTD of carfilzomib, with the following dose levels evaluated: 36, 45, and 56 mg/m2. Carfilzomib (30-minute infusion) was administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle, beginning with 20 mg/m2 on days 1 and 2 of cycle 1, then stepping up to the assigned dose level. In each cycle, cyclophosphamide (oral, 300 mg/m2) was administered on days 1, 8, and 15, and dexamethasone (oral or intravenous, 40 mg) was administered on days 1, 8, 15, and 22. An expansion cohort was enrolled at the established MTD or the maximum planned dose (MPD). Results: There were no dose-limiting toxicities observed at any of the dose levels evaluated, and thus the MPD of 56 mg/m2 was brought forward into dose expansion. A combined total of 16 patients (dose escalation + dose expansion) received carfilzomib at 56 mg/m2. The median age of patients who received KCyd at 56 mg/m2 was 65 years (range, 49-81), 56.3% were male, and 93.8% had an ECOG performance status of 0 or 1. At 56 mg/m2,the ORR was 87.5% (95% CI, 61.7%-98.4%), and best overall responses were complete response (n = 1); very good partial response (n = 7); partial response (n = 6); and stable disease (n = 2). The median TTR for patients who received the 56 mg/m2 dose and achieved partial response or better was 1 month. At 56 mg/m2,the most common adverse events of any grade were nausea (68.8%), cough (62.5%), diarrhea (56.3%), anemia (50.0%), fatigue (50.0%), and headache (43.8%), and the most common grade ≥ 3 adverse events were anemia (25.0%), hypokalemia (18.8%), neutropenia (18.8%), acute kidney injury (12.5%), and decreased white blood cell count (12.5%). Any-grade peripheral neuropathy was reported for 1 patient treated with the 56 mg/m2 dose. The mean number of treatment cycles started among patients who received the 56 mg/m2 dose was 7 (range, 3-8). In total, 6 of the 16 patients who received carfilzomib at 56 mg/m2 did not complete the 8 cycles of study treatment: 1 patient discontinued due to progressive disease (which manifested during a break in treatment for renal insufficiency), 1 patient withdrew from the study, and 4 patients discontinued treatment because of adverse events. Adverse events that led to treatment discontinuation were acute renal failure (n = 1), creatinine increase and dehydration (n = 1), intermittent nausea (n = 1), and urinary tract infection (n = 1). One patient in the 45 mg/m2 cohort experienced death due to sudden cardiac arrest; no deaths in the 36 or 56 mg/m2 cohorts occurred during the study. Conclusions: Carfilzomib administered at 56 mg/m2 twice weekly in combination with cyclophosphamide and dexamethasone was effective and showed acceptable toxicity for treating patients with newly diagnosed MM. The CHAMPION-2 study suggests that KCyd may be considered for first-line treatment of MM, including for patients not eligible for transplant. Acknowledgments: This study was supported by Onyx Pharmaceuticals, Inc. an Amgen, Inc. subsidiary. The authors would like to thank Jesse Potash of Amgen, Inc. for medical writing assistance. Disclosures Boccia: Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Gilead: Speakers Bureau; Eisai: Consultancy, Honoraria, Speakers Bureau. Conkling:USOncology Research: Research Funding; Amgen Inc.: Research Funding. Harb:Amgen Inc.: Consultancy. Yang:Amgen Inc.: Employment, Equity Ownership. Pinchasik:Amgen Inc.: Employment, Equity Ownership. Kimball:Amgen Inc.: Employment, Equity Ownership. Berenson:OncoTracker: Employment, Equity Ownership.

Description: Introduction: Agrylin® (United States) and Xagrid® (European Union) are immediate release (IR) preparations of anagrelide hydrochloride that block megakaryocyte differentiation and proliferation and inhibit the action of cyclic AMP phosphodiesterase. Anagrelide was developed as an inhibitor of platelet aggregation but was found to reduce platelet count at lower doses than the amount needed for platelet aggregation. This led to the development of a controlled release formulation of anagrelide (GALE-401). Early healthy volunteer results demonstrated platelet lowering activity and a pharmacokinetic profile with lower Cmax compared to anagrelide IR. The current study, GALE-401-201, was undertaken in subjects with MPN-related thrombocytosis and the final safety, efficacy, and pharmacokinetics are reported here. Methods: GALE-401-201 is a phase 2 open-label, single arm, clinical proof-of-concept study in chronic myelogenous leukemia (CML), polycythemia vera (PV), primary myelofibrosis (PMF) or essential thrombocythemia (ET). Eligible subjects must not be refractory to anagrelide IR and must have a platelet count ≥ 600 K/μL. GALE-401 was administered orally at a starting dose of 0.5 mg twice daily and titrated to a dose that maintained a platelet count of 150-400 K/μL. Platelet response was defined by World Health Organization 2008 (complete response, ≤ 400 K/μL or partial response ≤ 600 k/μL or ≥ 50% reduction from baseline), safety assessments were graded by CTCAE version 4.03, and the pharmacokinetic profile was assessed at the starting dose, weekly sampling during dose titration, and at the final titrated dose using a non-linear mixed effect modeling. Results: Eighteen subjects were enrolled, median age 64 years (range, 40-79), 10 females/8 males, 14 ET, 3 PV, and 1 PV/ET. Three groups of anagrelide subjects were enrolled: naïve, intolerant and tolerant subjects with 10, 5, and 3 subjects, respectively. Baseline mutation of JAK2 V617F was present in 12 (66.7%) subjects, CALR in 3 (16.7%) subjects, and thrombopoietin receptor gene (MPL) in 1 (5.6%) subject. After a median duration of 7 months on GALE-401, an overall response rate of 14 of 18 subjects (77.8%; 7 CRs and 7 PRs) was observed across the anagrelide subject groups with median GALE-401 dose of 2 mg daily (range, 0-5 mg). The median duration of response (CR or PR) is 6.3 months (ongoing) with a median time to first objective response of 3.1 weeks (range, 1.1-5.0 weeks). JAK2 V617F was present at baseline in 7 (38.9%) and CALR mutation 1 (5.6%) of ET subjects who demonstrated a clinical response. Majority of the AEs, regardless of relationship were of Grade 1/2 in severity. Treatment related Grade 3/4 adverse events occurred in 2 subjects; Grade 3 (anemia, pancreatitis, increased creatinine, headache); Grade 4 (cholestatic jaundice). Grade 3/4 events were not correlated with higher anagrelide doses. A logistical regression evaluating the relationship between adverse events severity versus dose, anagrelide maximum plasma concentration (Cmax occurring between the time of the adverse event occurrence and up to 7 days prior) versus adverse events, did not reveal a clear positive correlation. Further exposure-adverse events analyses in addition to pharmacokinetic parameters will be presented. Conclusions: In this pilot clinical proof-of-concept study, GALE-401 produces an overall response rate at a dose comparable to anagrelide IR in a diverse group of subjects both treated and untreated with anagrelide IR. The majority of adverse events were mild to moderate in nature, and the adverse events severity was not correlated with dose or plasma concentration. A comparative controlled study evaluating GALE-401 with anagrelide IR in a well-defined MPN population, such as anagrelide treatment naïve ET, will be further needed to fully elucidate the safety and efficacy profile of GALE-401. Disclosures Troung: Galena Biopharma, Inc.: Research Funding. Saltzman:Galena Biopharma, Inc.: Research Funding. Jawien:Galena Biopharma, Inc.: Research Funding. Lyons:Galena Biopharma, Inc.: Research Funding; Amgen: Consultancy. Berenzon:Galena Biopharma, Inc.: Research Funding. Mena:Galena Biopharma, Inc.: Research Funding. Wingate-Pearse:Galena Biopharma, Inc.: Employment. Barriere:Galena Biopharma, Inc.: Other: Contract Research Organization. Beeson:Galena Biopharma, Inc.: Other: Contract Research Organization. Glidden:Galena Biopharma, Inc.: Consultancy, Equity Ownership, Patents & Royalties: N/A. Choy:Galena Biopharma, Inc.: Employment.