Phase 1 Study of Tabalumab, a Human Anti-BAFF Antibody and Bortezomib in Patients with Previously-Treated Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 447-447 ◽  
Author(s):  
Noopur Raje ◽  
Edward Anthony Faber ◽  
Paul G. Richardson ◽  
Gary J. Schiller ◽  
Raymond J. Hohl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Median Number ◽  
Phase 1 Study ◽  
Advisory Committees ◽  
Baseline Serum ◽  
Lower Baseline ◽  
Previously Treated

Abstract Abstract 447 Background: Tabalumab, a human mAb that neutralizes membrane-bound and soluble B cell activating factor (BAFF), has demonstrated both anti-myeloma activity and osteoclastogenesis inhibition in xenograft models of multiple myeloma (MM). We initially conducted a Phase 1 study with the combination of tabalumab and bortezomib in previously-treated MM patients who were not refractory to bortezomib. The results from the dose escalation (Part A) have been previously reported, where a tabalumab dose of 100 mg was selected based on several factors, most notably the stabilization of the peak to trough concentration ratio. The cohort expansion (Part B) has since completed enrollment, and we now report the preliminary results for the entire study. Methods: The primary objective was to identify a safe and potentially efficacious dose of tabalumab to be combined with bortezomib. Bortezomib was given in a standard biweekly fashion, 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21 day cycle, and tabalumab at 1, 10, 30, 100, or 300 mg (Part A) or 100 mg (Part B) IV (30 min) on day 1 in Cycles 1 – 3, 5, and 7. The study was later amended to include dexamethasone to assess safety, and 12 patients received dexamethasone in combination with bortezomib and tabalumab. Response was assessed per IMWG criteria and adverse events per CTCAE v3.0. Pharmacokinetic (PK) and pharmacodynamic (PD) samples were obtained throughout the study, including BAFF, IL-1beta, IL-6, IL-10, VEGF, and TNF-alpha. Results: Forty-eight patients were enrolled to the study; 20 to dose escalation (Part A) and 28 to cohort expansion (Part B). The median age was 65.7 years and 56% were women. The median number of prior therapies was 3 (range 1–10). All patients received either bortezomib or an IMiD; 75% received prior bortezomib and 88% received prior IMiD therapy. The median number of cycles was 5.5 (range 1–28). Grade 3/4 toxicities occurring in two or more patients included peripheral sensory neuropathy, pneumonia, thrombocytopenia, neutropenia, diarrhea, musculoskeletal pain, renal failure acute, fatigue, anemia, neuralgia, and gastrointestinal hemorrhage. Most patients discontinued treatment due to progressive disease or adverse events (neuropathy, neuralgia, fatigue, and thrombocytopenia). Two patients died during study participation - one during treatment from acute respiratory distress syndrome and another during follow-up from multiple myeloma. Confirmed responses included 2 complete responses, 4 very good partial responses, and 16 partial responses. Response associated with lower baseline serum BAFF or IL-6 levels, independent of the tabalumab dose. Also, response in patients treated with tabalumab 100 mg appeared to associate with lower baseline serum levels of IL-10 and undetectable TNF-alpha. With 14 patients censored, the TTP was 4.9 months (95% CI: 4 – 8). With 6 patients censored, the median response duration was 7.3 months (95% CI: 3.5 – 13.9). Conclusions: A 100 mg dose of tabalumab in combination with bortezomib was well tolerated; 22 patients achieved a PR or better despite prior bortezomib and/or IMiD therapy. Response correlated with lower baseline serum BAFF levels, supporting the hypothesis that a higher dose of tabalumab should be evaluated. A three-arm study randomizing patients to the combination(s) of bortezomib, dexamethasone, and tabalumab 100 mg vs. tabalumab 300mg vs. placebo is currently enrolling. Disclosures: Raje: Onyx: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Schiller:Eli Lilly & Company: Research Funding. Cohen:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Carpenter:Eli Lilly & Company: Employment. Cronier:Eli Lilly and Company: Employment. Kaiser:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

Elotuzumab In Combination with Lenalidomide and Dexamethasone In Patients with Relapsed Multiple Myeloma: Interim Results of a Phase 2 Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 986-986 ◽  
Author(s):  
Paul G. Richardson ◽  
Philippe Moreau ◽  
Andrzej J Jakubowiak ◽  
Thierry Facon ◽  
Sundar Jagannath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Phase 1 ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Infusion Reactions

Abstract Abstract 986 Introduction: Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, an antigen highly and uniformly expressed on multiple myeloma (MM) cells but with restricted expression on normal cells. Elotuzumab exhibits significant antimyeloma activity in vitro and against MM xenografts, and its antitumor activity is enhanced independently by both lenalidomide and dexamethasone. In a dose-escalation phase 1 study that evaluated the combination of elotuzumab (5, 10, and 20 mg/kg), lenalidomide, and dexamethasone, the maximum tolerated dose was not reached, and the combination showed encouraging clinical activity (82% response rate) in patients with advanced MM. The most frequent infusion-related adverse events (AEs) were headache (21%), nausea (21%), and dizziness (11%), with 7% (2/28) of patients experiencing 3 serious infusion-related AEs during cycle 1 (1 with a grade 4 hypersensitivity reaction and 1 with 2 grade 3 stridor events). Key objectives of this dose randomized, open-label, multicenter, phase 2 study in patients with relapsed MM were to select the optimum dose of elotuzumab and to evaluate an enhanced premedication regimen to minimize the occurrence of infusion reactions. Methods: Patients with confirmed relapsed and/or refractory MM who had received 1–3 prior therapies were enrolled; prior lenalidomide therapy was excluded. Patients were randomized 1:1 to receive elotuzumab either 10 or 20 mg/kg (IV infusion on days 1, 8, 15, and 22 of a 28-day cycle in the first 2 cycles and then days 1 and 15 of subsequent cycles), along with lenalidomide 25 mg PO daily on days 1 to 21 and dexamethasone 40 mg PO weekly. Patients were treated until disease progression or unacceptable toxicity, if earlier. To control potential infusion reactions, patients received methylprednisolone (50 mg IV), diphenhydramine (25–50 mg PO or IV) or equivalent, ranitidine (50 mg IV) or equivalent, and acetaminophen (650–1000 mg PO) 30 to 60 minutes prior to each elotuzumab infusion. Objective responses (OR) were assessed according to the International Myeloma Working Group (IMWG) criteria. Results: As of July 8, 2010, a total of 59 patients were randomized (intent to treat population); 47 patients received at least 1 dose of study medication (safety population); and 26 patients completed or progressed prior to completing 2 cycles of treatment (efficacy population). Median age was 64 years; 36 (61%) had received ≥2 prior therapies; 28 (48%) and 31 (53%) had received bortezomib or thalidomide, respectively, and 40 (68%) had undergone transplantation. Among efficacy evaluable patients, 22/26 (85%) had a confirmed or an unconfirmed response (≥ PR) including 31% VGPR/CR. The remaining 4/26 (15%) had stable disease (Table). Treatment-emergent AEs were reported in 36/47 patients (77%); the most common events were fatigue (26%) and nausea (21%). Serious treatment-emergent AEs were reported in 22% of patients; 2 events, nausea and febrile neutropenia with thrombocytopenia, were considered to be related to elotuzumab and lenalidomide. The most common infusion-related AEs within 24 hours of elotuzumab infusion were dizziness (15%), nausea (15%), and headache (9%). These decreased in frequency after the first treatment cycle. There were no severe AEs associated with infusion reactions. Conclusion: The combination of elotuzumab, lenalidomide, and dexamethasone resulted in a high response rate in patients with advanced MM and was generally well tolerated. These results are consistent with the results previously reported from the phase 1 study. The revised premedication regimen appeared to be more effective in controlling infusion reactions, which were generally mild to moderate with no severe infusion reactions reported to date. Updated response and safety data on all patients by dose level will be presented at the meeting. Disclosures: Richardson: Millennium, Celgene, Johnson & Johnson, Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide. Moreau:Celgene, Facet, Bristol-Myers Squibb: Honoraria. Jakubowiak:Millennium, Celgene, Bristol-Myers Squibb, Johnson & Johnson Ortho-Centocor: Honoraria; Millennium, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium, Celgene, Centocor-Ortho Biotech: Speakers Bureau. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jagannath:Millennium, Takeda Pharm, Janssen: Honoraria. Vij:Bristol-Myers Squibb: Honoraria; Celgene: Research Funding; Celgene, Bristol-Myers Squibb: Speakers Bureau. Reece:Celgene: Honoraria, Research Funding. Rossi:Sanofi-Aventis, Celgene: Consultancy, Honoraria. Tsao:Facet Biotech: Employment. Fry:Facet Biotech: Employment. Berman:Bristol-Myers Squibb: Employment. Singhal:Facet Biotech: Employment. Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding.

A Phase 1 Study Of ARRY-520 With Bortezomib (BTZ) and Dexamethasone (dex) In Relapsed Or Refractory Multiple Myeloma (RRMM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1938-1938 ◽  
Author(s):  
Ajai Chari ◽  
Myo Htut ◽  
Jeffrey Zonder ◽  
Joseph W. Fay ◽  
Andrzej J Jakubowiak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Level ◽  
Dose Escalation ◽  
Initial Dose ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Advisory Committees ◽  
Ksp Inhibitor

Abstract Background ARRY-520 is a novel KSP inhibitor with encouraging activity in patients (pts) with RRMM. In preclinical models, the activity of ARRY-520 is synergistic with BTZ, providing a rationale to combine these drugs in the clinic. Methods ARRAY-520-111 is a Phase 1 study to identify the maximum tolerated dose of ARRY-520, BTZ and dex. Eligible pts have RRMM with ≥ 2 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent. ARRY-520 is administered intravenously (IV) on Days 1, 2, 15 and 16 (Schedule 1) or on Days 1 and 15 (Schedule 2); BTZ is administered IV or subcutaneously (SC) on Days 1, 8 and 15; and 40 mg oral dex, if applicable, is taken on Days 1, 8 and 15 in a 28-day cycle. Results A total of 41 pts have been treated to date at various dose levels of ARRY-520 and BTZ. Patients had a median of 5 prior regimens (range 2-10). All pts received a prior PI, 39 pts received prior BTZ, and 25 pts received at least 2 prior PI- including regimens (range 1-6). In Schedule 1, the initial dose level of ARRY-520 (1.0 mg/m2/day) with BTZ (1.3 mg/m2/day) and dex was not tolerated, with dose-limiting toxicities (DLT) in 2/3 pts (pneumonia and pseudomonal sepsis). After a protocol amendment, dose escalation resumed at reduced doses of ARRY-520 (0.5 mg/m2/day) and BTZ (1.0 mg/m2/day) without dex. The addition of prophylactic filgrastim (G-CSF) enabled escalation to full dose ARRY-520 and BTZ (1.5 and 1.3 mg/m2/day, respectively). Only 1 DLT of pneumonia was observed during the further dose escalation, at 1.0 mg/m2/day ARRY-520 and 1.0 mg/m2/day BTZ. Dex has been added to the combination at 1.25 mg/m2/day ARRY-520 and 1.3 mg/m2/day BTZ and this dose level has been well tolerated. Enrollment is ongoing in the final planned dose level. In Schedule 2, the initial dose level of ARRY-520 (2.25 mg/m2/day) with BTZ (1.3 mg/m2/day) and dex was well tolerated and enrollment is ongoing at 3.0 mg/m2/day ARRY-520 and 1.3 mg/m2/day BTZ + dex, the maximum planned dose of both drugs. The most commonly reported adverse events (AEs) (in ≥ 15% of pts) include anemia, diarrhea, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, neutropenia, constipation, headache, fatigue, hyperuricemia, nausea, vomiting, and dizziness. All Grade 3 – 4 non-hematologic AEs have an incidence of < 10%. Based on the laboratory data, Grade 4 neutropenia was observed in 15% of patients, Grade 4 thrombocytopenia was observed in 10%. Apart from the one pt described above with the DLT of pseudomonal sepsis, no other febrile neutropenic events were reported. Neuropathy (Grade 2) was observed in 1 pt. Monopolar spindles have been observed in a post-dose biopsy for a pt treated at 1.0 mg/m2/day ARRY-520 + 1.3 mg/m2/day BTZ, indicating that pharmacodynamic activity of ARRY-520 is maintained in the presence of full dose BTZ. Preliminary signs of efficacy have been observed in this ongoing dose-escalation study. To date, among the subset of 13 evaluable pts who received doses at ≥ 1.25 mg/m2/day ARRY-520 + 1.3 mg/m2/day BTZ, 4 (31%) partial responses (PR) and 1 minimal response (MR) have been observed. By contrast, in the 27 patients receiving lower doses of ARRY-520 and BTZ, only 1 MR has been reported. An additional 29 pts experienced stable disease (SD) on ARRY-520 + weekly BTZ without the use of steroids (dex), including 17 pts with disease refractory to BTZ. Conclusions ARRY-520 + BTZ with prophylactic G-CSF appears well tolerated with manageable non-hematologic AEs in this heavily pretreated pt population and has demonstrated preliminary evidence of activity, including PRs and SD in pts with disease refractory to BTZ. These data support further exploration of this novel KSP inhibitor in combination with BTZ in expansion cohorts. The authors would like to acknowledge the dedicated research staff and physicians at the participating centers of the Multiple Myeloma Research Consortium for their contribution to this study. Disclosures: Chari: Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Millenium Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: ARRY-520 is an investigational drug being combined with bortezomib in multiple myeloma. Zonder:Celgene Corporation: Consultancy; Onyx: Consultancy; Skyline Diagnostics: Consultancy. Jakubowiak:Millenuim: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Janssen Cilag: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Kaufman:Millenium: Consultancy; Merck: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy; Janssen: Consultancy.

scholarly journals Final Results of a Phase 1/2 Open-Label Study to Assess the Safety, Tolerability and Preliminary Efficacy of Evofosfamide, a Hypoxia-Activated Prodrug, and Dexamethasone with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2122-2122
Author(s):  
Jacob P. Laubach ◽  
Noopur Raje ◽  
Andrew J. Yee ◽  
Philippe Armand ◽  
Robert L. Schlossman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Stable Disease ◽  
Research Funding ◽  
Phase 1 ◽  
Median Number ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Purpose: This phase 1/2 study was conducted to determine the maximum tolerated dose (MTD), safety, tolerability, and clinical activity of the hypoxia-activated prodrug evofosfamide (TH-302) and dexamethasone with or without bortezomib in relapsed/refractory multiple myeloma. Patients & Methods: Patients were enrolled to stage A (evofosfamide + dexamethasone) followed by stage B (evofosfamide + bortezomib + dexamethasone). Stage A enrollment began in March 2012 and ended in May 2014. In total 34 patients were enrolled to stage A, with 31 patients being treated. Stage B enrollment began in June 2014 and ended in July 2015. In total 28 patients were enrolled and treated on stage B. Patients enrolled on study were diagnosed with relapsed/ refractory multiple myeloma (RRMM), had adequate hepatic, renal, and hematologic function, as well as an ECOG performance status of ≤2, and had all received at least 2 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. In stage B, patients previously receiving bortezomib must not have discontinued due to toxicity. Patients must have had measureable disease as determined by the International Working Group (IMWG) criteria. In stage A, evofosfamide was administered IV in conjunction with a fixed oral dose of 40 mg dexamethasone on Days 1, 4, 8 and 11 of a 21-day cycle. In stage B, evofosfamide was administered in conjunction with a fixed oral dose of 40 mg dexamethasone and a fixed IV or SC dose of 1.3 mg/m2 bortezomib. Stage A dose escalation began at a dose of 240 mg/m2 evofosfamide and increased stepwise in a 3+3 design until reaching the MTD of 480 mg/m2. The recommended phase 2 dose (RP2D) was set at 340 mg/m2 and a dose expansion cohort of 15 treated patients were treated at the RP2D. Stage B dose escalation began at a dose of 240 mg/m2 and concluded at the 340 mg/m2 RP2D of stage A. There were no DLTs observed in this cohort. A total of 24 patients were treated at the RP2D. Results: Of the 31 patients treated on stage A, the median age was 65, with a range of 53-86. The median number of prior treatments was 6 (range: 2-13). Of the 28 patients treated on stage B, the median age was 62, with a range of 45-83. The median number of prior treatments was 8 (range: 3 - 16). All patients had prior bortezomib exposure with a median number of bortezomib containing regimens in stage B of 3 (range: 1-6). The most common stage A grade 3/4 events were anemia (36%), neutropenia (32%), thrombocytopenia (39%), leukopenia (23%), cellulitis (10%) and pneumonia (10%). Four pts (13%) discontinued due to an adverse event. The most common Arm B grade 3/4 events were thrombocytopenia (61%), neutropenia (32%), anemia (25%), leukopenia (18%) and pneumonia (14%). Two patients (7%) discontinued due to an adverse event. Of the 31 patients evaluable for response in stage A, 4 Partial Responses and 2 Minimal Responses were reported for a clinical benefit rate of 19%. Twenty patients (65%) in stage A had stable Disease. Of the 28 patients evaluable for response in stage B, 1 Complete Response, 2 Partial Responses and 2 Minimal Responses were reported for a clinical benefit rate of 18%. Eighteen patients (64%) in stage B had Stable Disease. Conclusion: A 340 mg/m2 twice a week dose of the hypoxia- activated agent evofosfamide was established as the recommended Phase 2 dose when combined with dexamethasone with or without bortezomib. Clinical activity was noted along with a majority of patients having stable disease or better even in this heavily pre-treated refractory population of MM. The use of hypoxia-activated agents holds promise as a novel therapeutic target in MM. Disclosures Raje: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Eli Lilly: Research Funding. Armand:Pfizer: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Sequenta Inc: Research Funding; Merck: Consultancy, Research Funding. Rosenblatt:BMS: Research Funding; Astex: Research Funding; DCPrime: Research Funding. Shain:Amgen/Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Signal Genetics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Anderson:Oncopep: Other: Scientific Founder; Onyx: Membership on an entity's Board of Directors or advisory committees; Acetylon: Other: Scientific Founder; Sonofi Aventis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ghobrial:Amgen: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria; Noxxon: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding.

Phase 1/2 Study of Elotuzumab in Combination with Bortezomib in Patients with Multiple Myeloma with One to Three Prior Therapies: Interim Results.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3876-3876 ◽  
Author(s):  
Andrzej J Jakubowiak ◽  
William Bensinger ◽  
David Siegel ◽  
Todd M. Zimmerman ◽  
Jan M. Van Tornout ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clinical Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Surface Glycoprotein ◽  
Advisory Committees ◽  
Cell Surface Glycoprotein

Abstract Abstract 3876 Poster Board III-812 Background Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, a cell surface glycoprotein, which is highly and uniformly expressed in multiple myeloma (MM). In mouse xenograft models of MM, elotuzumab demonstrated significantly enhanced anti-tumor activity when combined with bortezomib compared to bortezomib alone (Van Rhee et al., Mol. Cancer Ther., in press, 2009). This phase 1/2 trial will determine the maximum tolerated dose (MTD), overall safety, pharmacokinetics (PK) and clinical response of elotuzumab in combination with bortezomib in patients with relapsed MM following 1-3 prior therapies. Methods The study consists of 4 escalating cohorts of elotuzumab (2.5 mg/kg to 20 mg/kg) administered on Days 1 and 11 and bortezomib (1.3 mg/m2) administered on Days 1, 4, 8 and 11 of a 21-day cycle. Patients with progressive disease at the end of Cycle 2 or 3 also receive oral dexamethasone (20 mg) on Days 1, 2, 4, 5, 8, 9, 11 and 12 of each subsequent cycle. Patients with stable disease or better at the end of 4 cycles will continue treatment for 6 or more cycles unless withdrawn earlier due to unexpected toxicity or disease progression. Key entry criteria: age ≥ 18 years; confirmed diagnosis of MM and documentation of 1 to 3 prior therapies; measurable disease M-protein component in serum and/or in urine; and no prior bortezomib treatment within 2 weeks of first dose. Results To date, a total of 16 MM patients with a median age of 64 years have been enrolled in the study. The median time from initial diagnosis of MM was 3.5 years and patients had received a median of 2 prior MM treatments. Patients have been treated in four cohorts; 3 each in 2.5, 5 and 10 mg/kg elotuzumab cohorts, and 7 in the 20 mg/kg elotuzumab cohort. No dose limiting toxicity (DLT) was observed during the first cycle of the study and the MTD was not established. Five SAEs have been reported in four patients in later treatment cycles; two events, chest pain and gastroenteritis, occurring in one patient, were considered elotuzumab-related. Other SAEs include grade 3 sepsis, vomiting, pneumonia and grade 2 dehydration. The most common AEs reported include Grade 1-3 diarrhea, constipation, nausea, fatigue, thrombocytopenia, neutropenia, anemia and peripheral neuropathy. The best clinical response (EBMT criteria) for the 16 patients who have received at least two cycles of treatment is shown in the table below. Preliminary PK analysis suggests a serum half-life of 10-11 days at higher doses (10 and 20 mg/kg). Preliminary analysis of peripheral blood mononuclear cells and bone marrow of patients on study indicates that objective responses in the study correlate well with complete saturation of CS1 sites by elotuzumab on bone marrow plasma and NK cells. Conclusions The combination of elotuzumab with bortezomib has a manageable adverse event profile and shows promising preliminary efficacy with ≥PR in 44% and ≥MR in 75% of all enrolled patients. Accrual is ongoing in the expanded 20 mg/kg cohort. Updated safety, efficacy, and PK data will be presented at the meeting. Disclosures: Jakubowiak: Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor Ortho Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bortezomib in combination with elotuzumab for the treatment of relapsed/refractory multiple myeloma. Bensinger:Millennium: Membership on an entity's Board of Directors or advisory committees. Siegel:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Zimmerman:Millennium: Speakers Bureau; Centecor: Speakers Bureau. Van Tornout:BMS: Employment. Zhao:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Anderson:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Identification of Alpha 1-Acid Glycoprotein (AAG) As a Potential Patient Selection Biomarker for Improved Clinical Activity of the Novel KSP Inhibitor ARRY-520 in Relapsed and Refractory Multiple Myeloma (MM)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1868-1868 ◽  
Author(s):  
Brian Tunquist ◽  
Karin Brown ◽  
Gary Hingorani ◽  
Sagar Lonial ◽  
Jonathan L. Kaufman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Blood Samples ◽  
Refractory Multiple Myeloma

Abstract Abstract 1868 Background ARRY-520 is a kinesin spindle protein (KSP) inhibitor that has demonstrated clinical activity in patients with relapsed and refractory multiple myeloma (MM). Although ARRY-520 is administered IV, it displays variable pharmacokinetics (PK) among patients. The degree of binding of certain drugs to serum proteins can alter their free fraction (fu) and PK, with a possible impact on clinical activity. Alpha 1-acid glycoprotein (AAG) is an acute-phase reactant protein that is often elevated in the blood of patients with cancer, including multiple myeloma. We investigated the significance of the interaction of ARRY-520 with AAG, and other relevant blood proteins, using both in vitro models and clinical data. Methods Compound-protein binding was assessed using several in vitro assays. In addition, the effect of increasing concentrations of AAG on MM cell line viability was measured. Patient data were obtained from 3 clinical studies of ARRY-520: a Phase 1 solid tumor study, a Phase 1/2 AML study, and a Phase 1/2 study in MM. The MM Phase 2 portion consists of 2 separate, 2-stage cohorts. Cohort 1 evaluated ARRY-520 administered as a single agent, and cohort 2 investigated ARRY-520 in combination with low-dose dexamethasone (LoDex). The concentrations of multiple proteins, including AAG, and the degree of ARRY-520 total protein binding, were measured in pre- and post-dose blood samples for patients in the analysis. AAG levels in MM patients were further correlated with time-on-study and clinical response rate. Results ARRY-520 exhibits low micromolar affinity for AAG in in vitro assays, but not for other common serum proteins, such as albumin. To investigate whether AAG binding impacts biological activity, we found that increasing AAG concentrations within a clinically relevant range resulted in increasing IC50 values for ARRY-520 on MM cell line viability. Of other MM agents tested, none exhibited high affinity binding to AAG in vitro, and a range of AAG concentrations did not alter the cellular activity of these compounds. Pre-dose concentrations of AAG were measured using blood samples collected from patients on all 3 ARRY-520 studies (0.4 – 4.1 g/L AAG in solid tumor study; 0.5 – 2.4 g/L in AML study; 0.2 – 2.8 g/L in MM study). Post-dose blood samples from the MM study also indicated that AAG levels do not significantly change with time. The fu of ARRY-520 in blood was meaningfully reduced among patients with the highest AAG concentrations. Furthermore, AAG and fu were correlated with changes in clinical PK: CL and Vd decreased with increasing AAG, trends consistent with a lower fu. Among the MM patients, 72 patients were evaluable for AAG determination (27 from the dose-escalation portion, 27 from Cohort 1, and 18 from Stage 1 of Cohort 2). Across all of these cohorts, the group of patients with AAG above an empirically-determined cutoff of 1.1 g/L showed a decreased median time on study (1.5 months vs 4.7 months) and no clinical responses (0/19 vs 12/53) as compared to patients below this cutoff. For example, as reported separately, ARRY-520 in combination with LoDex showed a promising 22% overall response rate (≥PR) in the 1st-stage of Cohort 2. In this cohort, 6 patients were determined to have AAG concentrations above the empirical cutoff. None of these patients had clinical benefit. Excluding these 6 patients would significantly improve the overall response rate (≥PR) from 22% (4/18) to 33% (4/12). Summary AAG has been proposed as a prognostic marker for MM disease severitya. Our preliminary data suggest that AAG levels can affect the free fraction of ARRY-520 in blood over a clinically relevant range both preclinically and in clinical studies. In retrospective analysis, patients with higher AAG levels show a lower fu and therefore may not achieve sufficient exposure to gain therapeutic benefit from ARRY-520. In preclinical analyses, this effect is specific to ARRY-520, suggesting that AAG levels may be predictive for ARRY-520 activity relative to other MM drugs. We hypothesize that prospective screening for AAG may enable exclusion of patients who may not achieve therapeutic exposure to ARRY-520, increasing the overall activity of ARRY-520 and preventing exposure of non-responders to an ineffective therapeutic dose. Further, experiments are currently underway to investigate the relevance of other acute-phase proteins in blood. Disclosures: Tunquist: Array BioPharma: Employment. Off Label Use: ARRY-520 alone and with dexamethasone for the treatment of relapsed/refractory multiple myeloma. ARRY-520 is not currently approved for any indication. Brown:Array BioPharma: Employment. Hingorani:Array BioPharma: Employment. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kaufman:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy. Zonder:Celgene: Honoraria, Research Funding; Millenium: Honoraria, Research Funding. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Consultancy. Koch:Array BioPharma: Employment. Litwiler:Array BioPharma: Employment. Walker:Array BioPharma: Employment.

An Open-Label, Dose Escalation, Multi-Center Phase 1 Study of PRLX 93936, an Agent Synthetically Active Against the Activated Ras Pathway, in the Treatment of Relapsed or Relapsed and Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2140-2140 ◽  
Author(s):  
Peter M Voorhees ◽  
Robert L. Schlossman ◽  
Cristina J Gasparetto ◽  
Jesus G. Berdeja ◽  
John Morris ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Phase 1 ◽  
Single Agent ◽  
Open Label ◽  
Advisory Committees ◽  
Ras Pathway ◽  
Label Dose

Abstract Introduction: 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. Disclosures Voorhees: 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.

scholarly journals Trial in Progress: Phase I Dose-Escalation and Dose-Expansion Trial of a Novel Glutaminase Inhibitor (CB-839 HCl) in Combination with Carfilzomib and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3160-3160
Author(s):  
Wilson I Gonsalves ◽  
Srinivas Devarakonda ◽  
Rachid Baz ◽  
Natalia Neparidze ◽  
Alex A Adjei ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Mitochondrial Respiration ◽  
Research Funding ◽  
Phase 1 ◽  
Tca Cycle ◽  
Glutamine Metabolism ◽  
Cellular Respiration ◽  
Advisory Committees

Background: c-MYC activation is an early event of myeloma pathogenesis. It upregulates the expression of the glutaminase 1 (GLS1) enzyme which converts glutamine to glutamate in the mitochondria. Glutamate is required for the biosynthesis of various molecules in the tricarboxylic acid (TCA) cycle (i.e., glutamine anaplerosis). CB-839 HCl is a first-in-class, orally available, selective, noncompetitive inhibitor of GLS1. This inactivation of GLS1 results in an increase of glutamine and a decrease of glutamate and several TCA cycle intermediates within cancer cells, leading to a decrease in their proliferation and/or an increase in cell death. In the phase 1 study, CX-839-002, the safety and tolerability of CB-839 HCl was evaluated in patients with hematological tumors (multiple myeloma (MM) and non-Hodgkin's lymphoma), either as monotherapy or in combination with pomalidomide and dexamethasone or with dexamethasone alone. It was determined to be well tolerated and the maximal tolerated dose (MTD) was not reached. Proteasome inhibitors (PI) are the cornerstone agents in the treatment of myeloma. They disrupt normal protein homeostasis causing an induction of cellular proteotoxic stress, thus, making it an effective strategy against myeloma plasma cells, which naturally mass-produce large quantities of immunoglobulin proteins. PI-resistant MM cells are associated with changes in cellular bioenergetics that favor the increased use of mitochondrial respiration for energy production. Given the increased reliance of PI-resistant MM cells on mitochondrial respiration, and the critical role of glutamine for cellular respiration, inhibition of glutamine metabolism is a rational molecular strategy for the treatment of PI-resistant MM. Furthermore, pre-clinical studies demonstrate the in vitro and ex vivo synergism of CB-839 HCl with carfilzomib (CFZ) in terms of its cytotoxicity and anti-proliferation capacity in various primary human myeloma cell lines and primary patient myeloma cells respectively. As a result, this novel combination of glutaminase inhibition with proteasome inhibition appears promising as a therapeutic combination in MM and warrants further clinical investigation. Methods: This study is a phase 1, multicenter clinical trial of CB-839 HCl in combination with carfilzomib and dexamethasone for patients with relapsed and/or refractory myeloma. Part A of this trial is a 3+3 dose escalation design and Part B is a dose expansion cohort at the RP2D determined in Part A. Up to a maximum of 42 patients will be enrolled at participating ETCTN sites. CFZ will be administered in its usual weekly dosing schedule of days 1, 8 and 15 of a 28 day schedule along with dexamethasone on days 1, 8, 15 and 22. CB-839 will be started at a dose level of 400 mg twice daily and will be investigated to a maximum dose of 800 mg twice daily. Prior to day 1 of Cycle 1, we will administer a 7 day lead in of CB-839 monotherapy before combining it with CFZ. Key inclusion criteria are having relapsed/refractory myeloma with at least 2 prior lines of therapy and prior exposure to PIs, immunomodulators and Anti-CD38 monoclonal antibodies, having measurable disease, adequate hematologic reserve, kidney function and liver function. Key exclusion criteria are being refractory or intolerant to CFZ, adverse cardiac history, central nervous system disease and AL amyloidosis. The primary objective of this trial is to determine the MTD or recommended phase II dosing (RP2D) of CB-839 HCl in combination with carfilzomib and dexamethasone. The secondary objective is to evaluate the safety and tolerability as well as the overall response rate (ORR) associated of CB-839 HCl in combination with carfilzomib and dexamethasone. Correlative objectives will evaluate plasma pharmacokinetic profiles of CB-839 HCl and carfilzomib when used in combination. They will also evaluate potential predictive and prognostic biomarkers as well as resistance mechanisms using genomic DNA, RNA, flow cytometry, immunohistochemistry and metabolomics-based assessment platforms. Recruitment is ongoing and this trial is registered on clinicaltrials.gov: NCT03798678. Disclosures Baz: Bristol-Myers Squibb: Research Funding; Sanofi: Research Funding; Karyopharm: 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, Research Funding; AbbVie: Research Funding; Merck: Research Funding. Neparidze:Janssen Scientific Affairs, LLC: Research Funding; Eidos Therapeutics: Other: Member of Independent Diagnostic Committee; MMRF/Synteract: Membership on an entity's Board of Directors or advisory committees. Kumar:Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Research Funding.

scholarly journals Combination Treatment of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib and Carfilzomib in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Initial Results from a Multicenter Phase 1/2b Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 377-377 ◽  
Author(s):  
Ajai Chari ◽  
Saurabh Chhabra ◽  
Saad Usmani ◽  
Sarah Larson ◽  
Ruben Niesvizky ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Tyrosine Kinase ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 2 ◽  
Advisory Committees ◽  
Bruton's Tyrosine Kinase ◽  
Grade 3

Abstract Background: Recent advances have improved outcomes for patients (pts) with multiple myeloma (MM); however, novel agents targeting different pathways are still needed. Ibrutinib (ibr) is a first-in-class, once-daily, oral, covalent inhibitor of Bruton's tyrosine kinase (BTK), an enzyme overexpressed in malignant plasma cells, whose expression may positively regulate the myeloma stem cell-like population (Yang 2015). Clinical activity was observed at the 840-mg dose of ibr in heavily pretreated pts with relapsed or relapsed/refractory MM (RRMM), when combined with weekly dexamethasone (dex) (Vij 2014). Furthermore, BTK-mediated upregulation of NF-κB p65 contributes to proteasome inhibitor (PI) resistance in MM cell lines; thus, BTK inhibition with ibr may help overcome PI resistance (Murray 2015). In vitro, ibr has demonstrated synergy with PIs in MM (Rushworth 2013) and mantle cell lymphoma cells (Ou 2013). PCYC-1119 (NCT01962792) is an ongoing phase 1/2b study of ibr + carfilzomib (CFZ) ± dex in RRMM. Methods: Eligible pts received ≥2 prior therapies, including bortezomib (BTZ) and an immunomodulatory agent (IMiD) and had either no response or documented disease progression following the most recent treatment. Dose escalation followed a 3+3 design, followed by expansion of 2 cohorts (Table). Phase 1 primary objectives were maximum tolerated dose/recommended phase 2 dose (RP2D) determination and safety. Results: As of July 8, 2015, 40 pts were enrolled and received ibr combined with CFZ ± dex across multiple dose levels during the phase 1 portion. No dose-limiting toxicities (DLTs) were observed, and cohorts 2b and 3b were chosen for expansion to further evaluate safety and efficacy. Pts had a median age of 63 y (range, 44-83) and a median time from diagnosis of 4.3 y (range, 0.5-25.3). Cytogenetic assessment by FISH identified that 20% and 8% of pts had t4;14 and del17p, respectively. Overall, pts received a median of 3 prior lines of therapy (range, 2-11), including 10% prior CFZ, 25% pomalidomide, 25% thalidomide, 73% autologous stem cell transplant, and 100% BTZ and lenalidomide. Moreover, 88% of pts were refractory to their last therapy, with 73% refractory to BTZ, 73% refractory to lenalidomide, and 58% refractory both to IMiD and PI. No relevant differences were observed across cohorts. Thirty-six pts were evaluable for efficacy. With early follow-up, the initial objective response rate (ORR) was 58% and the clinical benefit rate (CBR) was 67%. In cohort 3b, the ORR and CBR were 65% and 77%, respectively, including 3 very good partial responses (VGPRs) and 1 stringent complete response (sCR). No clinically meaningful tolerability differences were seen between cohorts, and no new safety findings were observed. Across all cohorts, the most common all-grade nonhematologic adverse events (AEs) were diarrhea (43%), cough (35%), constipation and fatigue (30% each), and nausea (28%). Grade ≥3 hematologic AEs included thrombocytopenia (15%), anemia (13%), and neutropenia (5%). Grade ≥3 nonhematologic AEs occurring in ≥10% of pts were pneumonia and hypertension (15% each), diarrhea (13%), and fatigue (10%). Eleven pts reported treatment related SAEs. No clinically relevant differences in AEs were observed across cohorts. Ten pts discontinued study treatment due to progressive disease; an additional 6 pts discontinued due to an AE, and 6 pts discontinued due to investigator or pt decision. Duration of treatment ranged from 0.3 to 13.6 months, and 17 pts remain on treatment. Updated data will be presented. Conclusions: The initial phase 1 data indicated promising clinical potential for ibr + CFZ + dex, as it is well tolerated with no DLTs, no new toxicities, and no increase in the severity of known toxicities for the individual agents. The preliminary ORR of 58%, with 1 sCR and 3 VGPRs in cohort 3b, is encouraging in this mostly refractory patient population, especially with the high number refractory to BTZ. Cohort 3b was established as the RP2D and will be further evaluated in the phase 2 portion of the study. Table. Dosing Cohorts Cohort ibr* mg/qd CFZ† mg/m2 dex‡ mg 1(n=3) 560 20/27 - 2a(n=5) 560 20/36 - 2b(n=14) 560 20/36 20 3b(n=18) 840 20/36 20 *Starts on Day (D) 8 of Cycle (C) 1; continuous thereafter. †D1-2, 8-9, 15-16 through C12; thereafter D1-2, 15-16. ‡D1-2, 8-9, 15-16, 22-23; 10 mg for pts age ≥75 y; 4 mg prior to CFZ during C1 only (cohorts 1 and 2a) with re-initiation as needed. Disclosures Chari: Novartis: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding. Off Label Use: ibrutinib in relapsed or relapsed/refractory MM. Usmani:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Novartis: Speakers Bureau. Larson:BMS: Consultancy. Niesvizky:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Honoraria, Research Funding, Speakers Bureau. Matous:Celgene: Consultancy, Speakers Bureau; Millenium: Speakers Bureau; Onyx: Speakers Bureau. Gasparetto:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Holkova:Seattle Genetics, Inc.: Research Funding. Lunning:TG Therapeutics: Consultancy; Gilead: Consultancy; Spectrum: Consultancy; Genentech: Consultancy; Celgene: Consultancy; BMS: Consultancy; Juno: Consultancy; Onyx: Consultancy. Valent:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Anderson:Celgene: Speakers Bureau; Onyx: Speakers Bureau; Takeda: Speakers Bureau. Kwei:Pharmacyclics LLC, an AbbVie Company: Employment. Chang:Pharmacyclics LLC, an AbbVie Company: Employment. Graef:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Bilotti:Pharmacyclics LLC, an AbbVie Company: Employment. McDonagh:Pharmacyclics LLC, an AbbVie Company: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Karyopharm: Research Funding.

Results from Phase 1/2 Trial of Tagraxofusp in Combination with Pomalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3145-3145 ◽  
Author(s):  
Paul G. Richardson ◽  
Myo Htut ◽  
Cristina Gasparetto ◽  
Jeffrey A. Zonder ◽  
Thomas G. Martin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Advisory Board ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Background: The bone marrow microenvironment of many multiple myeloma (MM) patients contains high levels of CD123-expressing plasmacytoid dendritic cells (pDCs). These pDCs have been shown to augment MM growth and contribute to drug resistance (Chauhan, et al., Cancer Cell, 2009). Tagraxofusp, a novel CD123 targeted therapy, has demonstrated high levels of anti-tumor activity in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive CD123+ malignancy of pDC origin. Tagraxofusp demonstrated potent in vitro and in vivo activity against MM cell lines and primary tumor samples via both a direct anti-MM effect and indirect pDC-targeting effect (Ray, et al., Leukemia, 2017), as well as demonstrating synergy in these systems when used in combination with traditional MM therapies including pomalidomide (POM). As such, targeting pDCs with tagraxofusp may offer a novel therapeutic approach in MM. Methods: This multicenter, single arm Phase 1/2 trial enrolled patients with relapsed or refractory (r/r) MM and tested two different doses of tagraxofusp (7 or 9 mcg/kg). Patients received tagraxofusp as a daily IV infusion for days 1-5 of a 28-day cycle as a single agent for the initial run-in cycle (cycle 0) and in combination with standard doses/administration of POM and dexamethasone (DEX) in cycles 1 and beyond. Objectives included evaluation of safety and tolerability, identification of the maximum tolerated or tested dose, and efficacy. Results: 9 patients with r/r MM received tagraxofusp (7 mcg/kg, n=7; 9 mcg/kg, n=2). 5 males, median age 65 years (range: 57-70), median 3 prior therapies (range 2-6). Median follow-up was 12 months (range: 7 - 19). The most common treatment-emergent AEs (TEAEs) were hypoalbuminemia 67% (6/9); chills, fatigue, insomnia, nausea and pyrexia each 56% (5/9); and dizziness, headache, hypophosphatemia, and thrombocytopenia each 44% (4/9). The most common grade 3 and 4 TEAEs were thrombocytopenia 44% (4/9) and neutropenia 33% (3/9). No grade 5 events reported. 5 patients treated with tagraxofusp and POM+DEX had a partial response (PR) after tumor evaluation. These patients demonstrated a rapid decrease in a set of myeloma-related laboratory values from pre-tagraxofusp treatment levels after the first combination cycle of tagraxofusp and POM+DEX. Additionally, these 5 patients demonstrated >50% decreases in peripheral blood pDC levels after both tagraxofusp monotherapy and combination therapy. Conclusions: Tagraxofusp was well-tolerated, with a predictable and manageable safety profile, when dosed in combination with POM+DEX in patients with r/r MM. Evidence of pDC suppression in peripheral blood and BM was observed in this patient population. 5 patients that received tagraxofusp and POM+DEX combination had PRs and decreases in pDC levels while on treatment with tagraxofusp. Given CD123 expression on pDCs in the tumor microenvironment and the potential synergy of tagraxofusp with certain MM agents including POM, tagraxofusp may offer a novel mechanism of action in MM. NCT02661022. Disclosures Richardson: Oncopeptides: 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; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Zonder:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Chen:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Rupprecht:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Chauhan:C4 Therapeutics.: Equity Ownership; Stemline Therapeutics: Consultancy. Anderson:Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board; OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder .

Phase II Study of Daratumumab in Combination with Azacitidine and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients Previously Treated with Daratumumab: Darazadex

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Swetha Kambhampati ◽  
Sandy W. Wong ◽  
Thomas Martin ◽  
Jeffrey L. Wolf ◽  
Priya Choudhry ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma ◽  
Duration Of Response ◽  
Previously Treated ◽  
Dose Modifications

Background: Daratumumab, a human anti-CD38 monoclonal antibody, is approved in many countries for use as monotherapy in relapsed/refractory multiple myeloma (RRMM), and in combination with standard-of-care regimens in RRMM. The phase 2 DARAZADEX study will evaluate the efficacy and safety of daratumumab plus azacitidine and dexamethasone in RRMM patients previously treated with daratumumab. Pre-clinical data from our laboratory has demonstrated that azacitidine induces a 1.2 - 2.4 increase in CD38 median fluorescent intensity (MFI) in a dose-dependent manner across four different MM cell lines. (Figure 1A) Using an immortalized transgenic natural killer (NK) cell line to mediate lysis, we observed a significant increase in antibody-dependent cell-mediated cytotoxicity (ADCC) in the azacitidine-treated MM cells as opposed to control. Importantly, this increase in ADCC correlated with CD38 MFI upregulation. (Figure 1B). Based on this data we hypothesize that azacitidine, by upregulating the expression of CD38, can potentially increase the ADCC and efficacy of daratumumab on multiple myeloma cells and help reverse daratumumab resistance. Methods: In this single-arm, 2-stage, phase II study, approximately 23 RRMM patients in the United States will be treated with combination of daratumumab, azacitidine, and dexamethasone. Eligible patients must have progressed on ≥2 lines of prior therapy, including an immunomodulatory drug (IMiD) and proteasome inhibitor, and have previously been treated with daratumumab with most recent daratumumab treatment being at least 6 months prior to enrollment to allow for CD38 normalization. Patients who were previously primary refractory to daratumumab will be excluded from the study. Patients will receive azacitidine at the standard 75 mg/m2 dose 5 days consecutively every 4 weeks starting day -7 to day -3 of Cycle 1 and then Day 22-26 of Cycle 1-3, and subsequently Day 1-5 of Cycle 5 and thereafter until disease progression or intolerance, with dose modifications for toxicities. Daratumumab will be administered intravenously at the standard dose of 16 mg/kg, with first dose administered on day 1. Daratumumab will be dosed in standard fashion: weekly for 8 doses (induction phase), every two weeks for 8 doses (consolidation phase), and then every 4 weeks thereafter (maintenance phase). Daratumumab will be switched to the subcutaneous formulation at a later timepoint. There will be no dose modifications for daratumumab. Dexamethasone at a dose of 40 mg PO (or IV if PO is not available) will be given weekly for Cycle 1 and 2, after which the pre-infusion medication dose can be reduced to 20 mg and non-pre-infusion dose can be reduced or stopped based on investigator's discretion. Bone marrow biopsies will be done within 14 days prior to Cycle 1 day -7 (first azacitidine dose) and on Cycle 1 day 1 prior to first daratumumab infusion (or after completion of first 5 days of azacitidine and prior to first daratumumab infusion), for correlative studies. (Figure 1C) Simon's minimax two-stage design will be used with a safety lead-in cohort of 6 patients. In the first stage, a total of 13 patients will be enrolled (including the safety cohort), and if there is ≥2 responses in 13 patients the study will enroll an additional 10 patients; if there is ≤ 1 responses in 13 patients the study will be stopped. Primary objective is to evaluate the efficacy, as determined by the overall response rate (ORR) of this combination. Secondary objectives include duration of response per international myeloma working group (IMWG) criteria, safety and toxicity, and the 1-year OS and PFS of this combination. An additional secondary objective is to evaluate the changes in CD38 expression on plasma cells induced by azacitidine in patients with RRMM and identify any correlation of this change with depth and duration of response. The exploratory objective will be to evaluate the tumor microenvironment changes induced by azacitidine via mass cytometry (CyTOF). NCT04407442. Figure 1 Disclosures Wong: Bristol Myers Squibb: Research Funding; GSK: Research Funding; Janssen: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Roche: Research Funding; Fortis: Research Funding. Martin:Janssen: Research Funding; GSK: Consultancy; Seattle Genetics: Research Funding; Sanofi: Research Funding; AMGEN: Research Funding. Wolf:Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. OffLabel Disclosure: Azactidine is being used off-label in multiple myeloma

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