ALBERT

Description: Background The investigational oral proteasome inhibitor ixazomib is under phase 3 clinical investigation in patients with multiple myeloma and amyloidosis. Metabolism is the major mechanism of ixazomib clearance; accordingly, hepatic impairment may increase ixazomib exposures. PK and safety data suggested no clinically relevant PK alterations in patients with mild hepatic impairment (Gupta et al BJCP 2015). This study (NCT01912222) was performed to characterize the PK of ixazomib in patients with moderate or severe hepatic impairment, as defined by the NCI Organ Dysfunction Working Group, to develop dosing recommendations for these specific patient populations. Methods Eligible adults had advanced malignancies for which no further effective therapy was available. Twelve PK-evaluable patients were planned to be enrolled to each of the normal (N), moderate (M) or severe (S) hepatic impairment groups. Patients received a single dose of ixazomib on day 1; those in the N, M, and S groups received ixazomib 4, 2.3, and 1.5 mg, respectively. Blood samples were collected at multiple time points for 15 days after dosing to characterize single dose PK (18 samples in total, 0.5-8 hr on day 1, days 2-8, days 11, 12, and 15). After completion of PK sampling, patients could continue on the study and receive ixazomib on days 1, 8, and 15 of 28-day cycles. Geometric mean ratios and 90% CIs of unbound dose-normalized (DN) PK parameters in the hepatic impairment vs normal groups were calculated using an ANOVA model. Treatment-emergent adverse events (TEAEs) were assessed using NCI CTCAE version 4.03. Results Forty-eight patients were enrolled (13, 15, and 20 patients to the N, M, and S groups, respectively); 32 were Caucasian, 10 African American, 2 Asian, and 4 other. Mean age was 56 years (range 24-83), mean weight 76 kg (range 43-127), and mean body surface area 1.9 m2 (range 1.4-2.5); 28 (58%) were male. The most common cancers were hepatocellular carcinoma (21%) and colorectal carcinoma, with or without liver metastases (10%). All patients in the S group had liver dysfunction due to primary or metastatic tumors. Forty-three patients had reportable PK parameters (Cmax or AUC) and were PK-evaluable (12 N, 13 M, 18 S). PK parameters are reported in the Table. Ixazomib was rapidly absorbed in all 3 hepatic function groups examined, with a median Tmaxof 0.95-1.5 hours. Ixazomib was highly bound to plasma proteins with a similar mean fraction bound (~99%) in all 3 groups. Only 1 (2%) patient continued on study for more than 3 cycles (endometrial carcinoma, 10 cycles). Discontinuations were due to progression (75% of discontinuations), TEAEs or death related to progression. The most common TEAEs were nausea (38%), fatigue (31%), peripheral edema (31%), vomiting (27%), dyspnea (23%), decreased appetite (21%), and hyperbilirubinemia (21%). Most patients (77%) had a grade ≥3 TEAE, including 15% with a grade ≥3 study drug-related TEAE (dehydration [6%], fatigue [4%], anemia [2%], and fall [2%]); no patient had a study drug-related grade 4 TEAE. There were 14 on-study deaths, all of which were considered related to disease progression. Conclusions Unbound systemic exposures of ixazomib were 27% higher in patients with moderate or severe hepatic impairment versus those in patients with normal hepatic function. A reduced starting ixazomib dose of 3 mg is recommended for patients with moderate or severe hepatic impairment. Table. Hepatic function group PK parameters Geometric mean (%CV) Hepatic impaired vs Normal Least-squares geometric mean ratio (90% CI) Unbound DN Cmax(ng/mL/mg) Unbound DN AUC (ng.hr/mL/mg) Unbound DN Cmax Unbound DN AUC Normal 0.127 (47) 2.41 (50) N/A N/A Moderate 0.162 (80) 3.19 (61) 1.27 (0.74-2.18) 1.32 (0.70-2.50) Severe 0.154 (84) 2.96 (63) 1.21 (0.74-2.01) 1.23 (0.66-2.29) Moderate/Severe (combined) 0.158 (81) 3.07 (61) 1.24 (0.79-1.95) 1.27 (0.75-2.16) Cmax, maximum plasma concentration; CV, coefficient of variation; AUC, area under the plasma concentration-time curve Disclosures Gupta: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Off Label Use: Investigational proteasome inhibitor ixazomib. Hanley:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Venkatakrishnan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Perez:Dompe: Research Funding; Eli Lilly: Research Funding; Incyte: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Immunogen: Research Funding; Bristol Meyers Squibb: Research Funding; Agensys: Research Funding; PRA: Consultancy; Tetralogics: Research Funding. Norris:Nektar Pharmaceuticals: Consultancy. Yang:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Falchook:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

Description: Introduction. AGS67E, a fully human IgG2 antibody conjugated to the anti-tubulin agent MMAE through a cleavable linker, targets CD37, a tetraspanin expressed by most B- and T- cell malignancies (Pereira et al, Mol Cancer Ther; 14(7) 2015). Among normal hematopoietic cells, CD37 is expressed mostly on B lymphocytes and to a lesser extent on T lymphocytes, neutrophils, monocytes and a subset of early myeloid precursors. Methods. A phase 1 dose-escalation multicenter study is ongoing to evaluate safety, PK and anticancer activity of AGS67E given as monotherapy once every 3 weeks in patients with relapsed / refractory non-Hodgkin lymphoma without or with growth factor (GF) prophylaxis. Therapy is continued until progression or unacceptable toxicity. Results. Overall 13 patients have been treated in 7 dose cohorts (0.05 to 1.2 mg/kg without GF and 1.2 mg/kg with GF). Diagnoses included: 10 B-cell lymphomas [5 diffuse large B cell lymphomas (DLBCL), 2 follicular lymphomas (FL), 1 mantle cell lymphoma, 1 Waldenström's macroglobulinemia, 1 small lymphocytic lymphoma and 3 T-cell lymphomas (2 mycosis fungoides, 1 peripheral T-cell lymphoma). Median age was 59 (47-85) years. Patients received a median number of 2 (1-10) prior therapies. MTD was exceeded at 1.2 mg/kg given without GF, with all 3 patients treated at this level developing grade 4 neutropenia 8 to 15 days after the first dose. No major non-hematological toxicities have been observed thus far. Table 1.Dose (mg/kg)nmedian n doses (Min-Max)neutropenia in cycle 1other ≥Gr 3 related toxicitiesgr 4gr 4 〉7 daysFever0.05111+----0.113---gr3 fall in cycle 30.312----0.613----1.235 (4-5+)311-0.9 enrolling3 (6)2 (1-2)21--1.2 with GF enrolling62 (2-3)----+ = indicates that subjects are continuing to receive treatment Objective responses were observed at the1.2 mg/kg dose level: one patient with DLBCL experienced a CR. The serum AGS67E concentrations indicated non-linear pharmacokinetics at and below 0.6 mg/kg dose levels. At 1.2 mg/kg, the half-life of AGS67E and free MMAE ranged from 1.44-3.08 days and 2.34-3.64 days, respectively. Conclusions: AGS67E administered every three weeks demonstrates a favorable extra-medullary safety profile and signs of anti-lymphoma activity. Expansion cohorts are planned at the Maximum Tolerated Dose both without growth factor and with growth factor. Disclosures Sawas: Seattle Genetics: Research Funding; Gilead Sciences: Honoraria. Savage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding. Perez:Incyte: Research Funding; Eli Lilly: Research Funding; Dompe: Research Funding; Bristol Meyers Squibb: Research Funding; Agensys: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Immunogen: Research Funding; Tetralogics: Research Funding; PRA: Consultancy. Butturini:Agensys: Employment. Lackey:Agensys, Inc.: Employment. Trave:Agensys: Employment. Anand:Agensys: Employment. Huang:Agensys: Employment. Reyno:Agensys: Employment.

Description: Background: CXCR4 is a chemokine receptor overexpressed in more than 20 tumor types, including malignant plasma cells. The CXCR4/CXCL12 (SDF-1) axis has been known for many years as a critical regulator of tumor proliferation, cell, as well as migration into and out of the bone marrow. Ulocuplumab (BMS- 936564) is a first in class, fully human IgG4 monoclonal anti-CXCR4 antibody which inhibits the binding of CXCR4 to CXCL12. This study aimed to determine the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of Ulocuplumab alone and in combination with lenalidomide plus dexamethasone (Len-Dex), or in combination with bortezomib plus dexamethasone (Bor-Dex) in subjects with relapsed/refractory multiple myeloma. Patients / Methods: Patients were eligible for this trial if they were 18 years of age or older with relapsed or relapsed/refractory multiple myeloma after having received at least 2 prior lines of treatment. Patients in whom who both lenalidomide and bortezomib had failed were not excluded from re-treatment with the same regimen. Patients were enrolled at four cancer centers in the U.S. from October 2011 to March 2014. Ulocuplumab (1, 3 and 10 mg/kg) was dose escalated with a 3-plus-3 design with doses of Len-Dex or Bor-Dex to identify maximum tolerated dose (MTD). Ulocuplumab was given weekly in combination with either 25mg lenalidomide on days 1-21 and 40mg oral dexamethasone on days 1, 8, 15, and 22 of the 28-day cycles on Arm A or 1.3 mg/m2 bortezomib on days 1, 4, 8, and 11 and 20mg oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of the 21-day cycles on Arm B since cycle 2. The primary endpoints for this study were dose-limiting toxicities. Other key safety endpoints included incidence of adverse events (AE), AEs leading to discontinuation, SAEs, deaths, and laboratory abnormalities. The efficacy endpoints included overall responses, duration of response, and time to response. Responses were assessed using the IMWG criteria. Results: Forty-six patients were enrolled (median age, 60 years; range, 53-67). The median number of prior therapies was 3 (range, 1-11), with 70.0% of patients having received ≥ 3 lines of treatment. Ulocuplumab was escalated to a maximum of 10 mg/kg without reaching MTD. The most common treatment-related adverse events of any grade were neutropenia (13 patients, 43.3%), diarrhea (10 patients, 33.3%), thrombocytopenia (10 patients, 33.3%), and fatigue (7 patients, 23.3%) in Arm A; and thrombocytopenia (6 patients, 37.5%), fatigue (4 patients, 25.0%) and anemia (4 patients, 25.0%) in Arm B. The overall response rate (≥ partial response) for all subjects in escalation and expansion was 44.4% (20/45). The median time to response was 1.5 months (range 0.4-7.8 months) for Arm A and 1.0 month (range 0.5-3.7 months) for Arm B, respectively. Of note, the combination of Ulocuplumab with Len-Dex showed a high response rate of 55.2% and a clinical benefit rate ( ≥ minimal response) of 72.4%, including patients who have been previously treated with lenalidomide. Conclusion: This study shows that the blockade of the CXCR4-CXCL12 axis by Ulocuplumab is safe and has an encouraging response rate of over 50% in the Len-Dex arm of patients with relapsed/refractory myeloma. The distinct mechanisms of action of this antibody, as well as its non- cross resistance with currently approved approaches, make it a new class of anti-myeloma drug that warrants further exploration and evaluation in future clinical trials. Disclosures Ghobrial: Takeda: Consultancy; Celgene: Consultancy; BMS: Consultancy; Janssen: Consultancy. Richardson:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Anderson:Celgene: Consultancy; Takeda Millennium: Consultancy; Bristol Myers Squibb: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership; C4 Therapeutics: Equity Ownership. Becker:GlycoMimetics: Research Funding.

Description: Background: CXCR4 is a chemokine receptor over-expressed on 〉 75% of cancers, including malignant plasma cells. Ulocuplumab (BMS- 936564) is a first in class, fully human IgG4 monoclonal anti-CXCR4 antibody which inhibits the binding of CXCR4 to CXCL12. Ulocuplumab induces apoptosis of CXCR4+ multiple myeloma cell lines and has single agent activity in vivo in MM tumor xenograft models. It is thus hypothesized that Ulocuplumab may improve the overall response rate to standard therapy in relapsed-refractory multiple myeloma (rel/ref MM) by distinct mechanisms of action, i.e., mobilization and apoptosis of malignant plasma cells and immune regulation. Objective:This study aimed to determine the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical activity of Ulocuplumab alone and in combination with lenalidomide plus low-dose dexamethasone (Len-Dex), or in combination with bortezomib plus dexamethasone (Bor-Dex) in subjects with rel/ref MM. Methods: Ulocuplumab (i.e., 1, 3 and 10 mg/kg) was dose escalated with a 3-plus-3 design with doses of Len-Dex orBor-Dex to identify MTD. For Cycle 1, Ulocuplumab was administered as monotherapy on Days 1 and 8. Starting on Day 15, Ulocuplumab was administered in combination with lenalidomide [25 mg/d/21 days of a 28 day cycle] plus low dose dexamethasone [40 mg/week] and monitored for incidence of DLT(s) within Cycle 1 (42 Days) of study treatment. For the Bor-Dex group, also starting on Day 15, Ulocuplumab was administered in combination with bortezomib (1.3 mg/m2Days 1, 4, 8, 11 of a 21 day cycle] plus dexamethasone [days 1,2,4,5,8,9,11,12] and monitored for incidence of DLT(s) within Cycle 1 (35 Days) of study treatment. For the expansion phase, subjects received 10mg/kg Ulocuplumab monotherapy on Days 1 and 8 followed by weekly doses in combination with Len-Dex (28-day cycles). Subjects were assessed at day 14 and after every cycle by IMWG criteria. Results: Forty four subjects were evaluated (median age, 59.5 yrs; range, 44-77). The median number of prior therapies was 4, (range, 1-9), with 76% of subjects having received ≥ 3. Subjects had received bortezomib in 93% of the cases, lenalidomide in 86% , thalidomide in 30%, carfilzomib in 20% and pomalidomide in 11%. Thirty subjects in escalation received Ulocuplumab alone and in combination with Len-Dex : One subject in the U-Bor-Dex group experienced a DLT in which there was delayed platelet recovery to ≤ Grade 1 or baseline which resulted in a delay of dosing of ≥ 21 days. Ulocuplumab was escalated to a maximum of 10 mg/kg without reaching MTD in monotherapy or in combination therapy. Twenty one subjects were treated in expansion phase. There were no grade 4 toxicities with Ulocuplumab monotherapy and Grade 3 toxicities with monotherapy included thrombocytopenia (6.5%), anemia (4.3%), respiratory infections (4.3%), femur fracture (4.3%), lymphopenia (2.2%), neutrophil count decreased (2.2%), platelet count decreased (2.2%) and cerebrovascular accident (2.2%). The safety profile of Ulocuplumab with Len-Dex or Bor-Dex was similar to either combination alone. Two subjects (4.5%) presented reversible G2 infusion reactions. The overall response rate (≥ PR) for all subjects in escalation and expansion was 50% (22/44), including 1 CR, 6 VGPR and 15 PR. The ORR by group was 55.1 % (16/29) and 40% (6/15) for U-Len-Dex and U-Bor-Dex, respectively. Furthermore, the ORR in expansion with 10 mg/kg U-Len-Dex was 57% (12/21) with 4 VGPRs and 8 PRs. Eight subjects in this expansion group had at least SD with a mean duration of 159 days (range, 46-437 days), resulting in 95% of subjects with clinical benefit. A median 2-fold mobilization of leukocytes into the peripheral circulation was reported after each infusion of Ulocuplumab at 3 and 10 mg/kg. Samples showed rapid mobilization of leukocytes at 2 hours post-Ulocuplumab with a partial decrease at 3-4 days post-administration without reaching baseline. Mobilization of plasma cells was also documented in some subjects. Conclusions: This study shows that the blockade of the CXCR4-CXCL12 axis by Ulocuplumab is safe and shows a high response rate of over 50% in the Len-dex arm of patients with relapsed/refractory myeloma who have been previously treated with lenalidomide and bortezomib. The distinct mechanisms of action of this antibody make it a new class of anti-myeloma drug that deserves further exploration in clinical trials. Disclosures Ghobrial: Onyx: Advisory board Other; BMS: Advisory board, Advisory board Other, Research Funding; Noxxon: Research Funding; Sanofi: Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Plerixafor is not FDA approved for relapsed myeloma. Anderson:Celgene: Consultancy; Sanofi-Aventis: Consultancy; Onyx: Consultancy; Acetylon: Scientific Founder, Scientific Founder Other; Oncoprep: Scientific Founder Other; Gilead Sciences: Consultancy. Sabbatini:Bristol-Myers Squibb: Employment. Dilea:Bristol-Myers Squibb: Employment. Cardarelli:BMS: Employment. Wade:Bristol-Myers Squibb: Employment. Xing:Bristol-Myers Squibb: Employment. Gutierrez:Bristol-Myers Squibb: Employment. Cohen:BMS: Employment.