Phase 1 Dose-Escalation Study of Multiple Dosing Schedules of the Investigational Drug MLN4924, a Nedd8-Activating Enzyme Inhibitor, In Patients with Relapsed and/or Refractory Multiple Myeloma or Lymphoma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2801-2801 ◽  
Author(s):  
Jatin J Shah ◽  
R. Donald Harvey ◽  
Owen A O'Connor ◽  
Andrzej J Jakubowiak ◽  
Mitchell R Smith ◽  
...  

Abstract Abstract 2801 Background: MLN4924 is an investigational inhibitor of Nedd8-activating enzyme (NAE), which plays an essential role in regulating the activity of the cullin-RING E3 ligases (CRLs). NAE controls the neddylation cascade that results in Nedd8 conjugation to the CRLs, which is required for ligase activity. NAE inhibition thus inhibits ubiquitination and proteasomal degradation of CRL substrates, which include proteins involved in cell-cycle regulation (p27), signal transduction (pIκBα), DNA replication (Cdt-1), stress response (Nrf-2), and other processes important to tumor cell growth and survival. In lymphoma cells, NAE inhibition with MLN4924 has been shown to result in apoptosis either through increased Cdt-1 levels, S-phase accumulation, and DNA re-replication, or via pIκBα stabilization and consequent NF-κB pathway inhibition. In vivo, MLN4924 treatment resulted in tumor growth inhibition and regressions in lymphoma xenograft models. This phase 1 dose-escalation study is the first investigation of MLN4924 in multiple myeloma (MM) and lymphoma patients. We have previously reported (Shah et al, ASH 2009) that the maximum tolerated dose (MTD) of MLN4924 on Schedule A of this study (days 1, 2, 8, and 9 of 21-day cycles) was 110 mg/m2, with dose-limiting toxicities (DLTs) including muscle cramps and febrile neutropenia. Analyses of peripheral blood mononuclear cells and skin biopsies indicated MLN4924 exerted the predicted pharmacodynamic (PD) effects in peripheral blood and skin, including inhibition of neddylated cullins and induction of pIκBα, Cdt-1, and Nrf-2. Two additional schedules of MLN4924 administration are now being investigated with the aim of increasing tolerability and the deliverable dose. Methods: Patients aged ≥18 years with ECOG performance status 0–2 and relapsed and/or refractory MM or lymphoma, including any B- or T-cell non-Hodgkin's lymphoma (NHL) and Hodgkin lymphoma (HL), following ≥2 prior lines of therapy were eligible. Primary objectives were to determine the MTD and safety profile of MLN4924 on the different dosing schedules, describe the pharmacokinetics (PK) and PD of MLN4924 in blood, and investigate PD effects in skin and tumor. Secondary objectives included evaluation of disease response. Patients received MLN4924 via a 60-minute intravenous infusion on either days 1, 4, 8, and 11 (Schedule B) or days 1 and 8 (Schedule C) of 21-day cycles for up to 12 months. Doses of 25–147 mg/m2 were investigated on Schedule A; for Schedules B and C, dose escalation started at the MTD of Schedule A, 110 mg/m2, and proceeded in 1.33-fold increments using a Bayesian continual reassessment method based on the occurrence of DLTs in cycle 1. The MTD was defined as the dose level closest to that predicted to result in a DLT rate of 25%. Adverse events (AEs) were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Results: To date, 7 patients (5 male, median age 60 years [range 48–68]) have been enrolled to Schedule B, 2 each at 110, 147, and 196, and 1 at 261 mg/m2; 2 have MM and 5 lymphoma (2 diffuse large B-cell lymphoma [DLBCL], 1 small lymphocytic lymphoma, 1 mantle cell lymphoma [MCL], 1 nodular sclerosis HL). Patients have received a median of 3 cycles (range 2–5) to date. A total of 7 patients (all male, median age 49 years [range 45–66]) have been enrolled to Schedule C, 2 each at 110 and 147, and 3 at 196 mg/m2; 4 have MM and 3 lymphoma (1 follicular lymphoma [FL], 1 MCL, 1 nodular sclerosis HL). Median number of cycles received is 4 (range 1–7). No DLTs and no grade ≥3 AEs have been reported on either schedule to date. On Schedule B, only grade 1 dyspnea and myalgia (both n=2) have been reported in >1 patient, with grade 1 diarrhea (n=3), constipation, fatigue, and nausea (each n=2) reported on Schedule C. PK data for the 110 mg/m2 cohorts of Schedules B and C are consistent with the lack of significant accumulation of MLN4924 in plasma shown on Schedule A. One patient with HL on Schedule A achieved a partial response; no responses have been reported to date on Schedules B and C though some heavily treated patients have demonstrated stable disease for 5 or more cycles (1 FL, 7 cycles; 1 DLBCL, 5 cycles; 1 MM, 5 cycles). Conclusion: Enrollment and dose escalation are proceeding on Schedules B and C (at doses above Schedule A MTD) to determine the MTD on each schedule; updated clinical data will be presented, together with data on the PK and PD of MLN4924, on these dosing schedules. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding. Off Label Use: Investigational agent in clinical development for the treatment of multiple myeloma and lymphoma. O'Connor:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Smith:Millennium Pharmaceuticals, Inc.: Honoraria, Research Funding, Speakers Bureau. Orlowski:Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Mulligan:Millennium Pharmaceuticals: Employment. Smith:Millennium Pharmaceuticals, Inc.: Employment. Pickard:Millennium Pharmaceuticals, Inc.: Employment. Dezube:Millennium Pharmaceuticals: Employment, Equity Ownership. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2831-2831 ◽  
Author(s):  
Swaminathan P. Iyer ◽  
Brad M. Haverkos ◽  
Jasmine Zain ◽  
Radhakrishnan Ramchandren ◽  
Mary Jo Lechowicz ◽  
...  

Introduction: Tenalisib (RP6530) is a novel, highly specific, dual PI3K δ/γ inhibitor with nano-molar inhibitory potency at the enzyme and cellular level. PI3K plays a critical role in T-cell development and activation and several studies have validated the PI3K-AKT pathway as a potential therapeutic target in T cell lymphomas. Preliminary results of the ongoing Phase 1/1b T-cell lymphoma (TCL) study demonstrated an acceptable safety profile with encouraging clinical activity in relapsed/refractory TCL (Oki, ASCO 2018 and Iyer, ASH 2018). We now present the final results of the study (NCT02567656). Methods: This study comprised of four-dose escalation cohorts, followed by two dose expansion cohorts at MTD enrolling 20 patients each in PTCL and CTCL cohorts. Patients had histologically confirmed TCL, ECOG PS ≤2, and had received ≥1 prior therapy. Patients received Tenalisib [200 mg BID-800 mg BID (fasting), 800 mg (fed only)] orally until progression or unacceptable toxicity. The primary objectives were to determine the MTD and pharmacokinetic profile. The secondary objective was to evaluate overall response rate (ORR) and duration of response. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2007) and mSWAT respectively. Adverse events were graded according to CTCAE v4.03. Results: Fifty-eight patients were enrolled in study, 19 in dose escalation and 39 in dose expansion (28 PTCL and 30 CTCL). Median number of prior therapies was 4 (range, 1-15). Safety assessment of 58 patients receiving at least one dose of Tenalisib demonstrated an acceptable safety profile. Treatment related Grade≥3 AEs were elevated ALT/AST (21%), rash (5%), and hypophosphatemia (3%). These events were reversible and managed by withholding study drug. Additionally, in few patients (N=9), steroids were used to manage elevated ALT/AST. There were six treatment related serious adverse events, none of these led to fatal outcome. At end of the study, four (3 CTCL; 1 PTCL) patients who completed minimum 8 cycles of therapy were rolled over to a compassionate use study (NCT03711604) and were followed up. Efficacy assessments demonstrated an ORR of 46% (3 CR and 13 PR) and clinical benefit rate (CR+PR+SD) of 77%. Subset efficacy analysis showed an ORR in PTCL of 47% (3 CR; 4 PR) and in CTCL of 45% (9 PR). The median time to initial response was 1.8 months and was similar in both sub-types. The overall median DOR was 4.91 months (range 0.9-26.6); in PTCL patients the DOR was 6.53 months, (range: 0.97-21.0) and 3.8 months (range: 1.67-25.67) in CTCL patients. In 3 PTCL patients who achieved CR, the median DOR was 19.5 months (range 7.5-21). Conclusion: Tenalisib demonstrated promising clinical activity and an improved safety profile in patients with relapsed/ refractory TCL. Currently, a phase I/II combination study to further evaluate safety and efficacy with romidepsin is ongoing in this target population. Disclosures Iyer: Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Seattle Genetics, Inc.: Research Funding; Genentech/Roche: Research Funding; Incyte: Research Funding. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy. Korman:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa: Research Funding; Leo: Research Funding; Menlo: Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Research Funding; Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen: Research Funding; Sun: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntimmune: Research Funding; UCB: Research Funding; Valeant: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Dermira: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Routhu:Rhizen Pharmaceuticals S.A.: Employment. Barde:Rhizen Pharmaceuticals S.A.: Employment. Nair:Rhizen Pharmaceuticals S.A.: Employment. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3160-3160
Author(s):  
Wilson I Gonsalves ◽  
Srinivas Devarakonda ◽  
Rachid Baz ◽  
Natalia Neparidze ◽  
Alex A Adjei ◽  
...  

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.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3145-3145 ◽  
Author(s):  
Paul G. Richardson ◽  
Myo Htut ◽  
Cristina Gasparetto ◽  
Jeffrey A. Zonder ◽  
Thomas G. Martin ◽  
...  

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 .


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1938-1938 ◽  
Author(s):  
Ajai Chari ◽  
Myo Htut ◽  
Jeffrey Zonder ◽  
Joseph W. Fay ◽  
Andrzej J Jakubowiak ◽  
...  

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.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 84-84 ◽  
Author(s):  
Torben Plesner ◽  
Hendrik-Tobias Arkenau ◽  
Henk M. Lokhorst ◽  
Peter Gimsing ◽  
Jakub Krejcik ◽  
...  

Abstract Background: Daratumumab (DARA) (HuMax™-CD38), a human IgG1κ monoclonal antibody effectively mediates destruction of CD38-expressing malignant plasma cells. In the first-in-human dose-escalation study, 42% of heavily pretreated patients with relapsed, or relapsed, refractory (RR) multiple myeloma (MM) treated with DARA alone (≥4mg/kg) achieved partial response (PR) and 25% had minimal response (MR) (modified IMWG guidelines) (1). In preclinical studies, DARA + lenalidomide (LEN) enhanced killing of MM cells in vitro (2). We evaluated safety, pharmacokinetics (PK) and efficacy of DARA + LEN + low-dose dexamethasone (DEX) in patients with relapsed or RR MM. Methods: This ongoing phase I/II open-label multicenter study consisted of 2 parts: Part1 was dose-escalation study in which patients (≥ 18 years old) with life expectancy ≥3 months and ECOG status 0, 1 or 2 received DARA+LEN+DEX (DARA [2-16 mg/kg] per week [8 weeks], twice a month [16 weeks], then, once monthly until disease progression, unmanageable toxicity or 24 months in total; LEN [25 mg PO day 1 through 21 of 28-days cycles]; DEX [40 mg] once weekly). Part 2 was cohort expansion study which explored the testing of maximum tolerated DARA dose (MTD) (16 mg/kg) determined in part 1 along with LEN (25 mg mg PO day 1 through 21 of 28-days cycles) and DEX (40 mg) once weekly. Results: Data from 22 patients (13 patients [fully enrolled] from part 1 and 9 patients from part 2, [ongoing enrollment]) were presented at ASCO earlier this year (3). These results demonstrated that the most frequent (>30% patients) adverse events (AEs) were neutropenia and diarrhea; no dose limiting toxicities (DLTs) were reported. Infusion reactions (grade 1 and 2) were reported in 4 patients. 8 serious AEs were reported, all assessed as unrelated to DARA. MTD was not reached. DARA+LEN+DEX PK-profile was similar to DARA alone suggesting LEN and DEX do not affect the DARA PK-profile. Available preliminary efficacy data from 20 patients demonstrated marked decrease in M-protein in all patients; 15/20 patients achieved PR or better, 3/20 with CR, 6/20 with VGPR. Median time to response was 4.3 weeks (range: 2.1-11.3). Overall response rate (ORR) was 75% (15/20) combining all patients in part 1 and 2 and 92.3% (12/13) for part 1 patients, who had at least 2 months of follow-up or discontinued earlier. Conclusions: DARA+LEN+DEX has favorable safety profile with manageable toxicities in relapsed and RR MM. Encouraging early activity is seen with marked reduction in M-protein and majority of the patients (~75%) achieved PR or better. Results of approximately 30 patients from part 2 with at least 2 months of treatment exposure and 10 patients (out of 30 patients) with shortened duration of infusion will be presented. References Lokhorst et. al., EHA 2013 abstract #8512 van der Veer et. al., Haematologica 2011;96(2):284-90 Plesner et. al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8533). Disclosures Plesner: Genmab: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees. Lokhorst:Celgene: Research Funding; J&J: Research Funding; Genmab: Research Funding. Minnema:Janssen: Consultancy, Honoraria. Laubach:Onyx: Research Funding; Novartis: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Ahmadi:Janssen: Employment. Yeh:Janssen: Employment. Guckert:Janssen: Employment. Feng:Janssen: Employment. Brun:Genmab: Employment. Lisby:Genmab: Employment. Basse:Genmab: Employment. Palumbo:Bristol-Myers Squibb: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria. Richardson:Celgene: 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; Millennium: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3448-3448 ◽  
Author(s):  
Keren Osman ◽  
Ajai Chari ◽  
Samir Parekh ◽  
Christine Pun ◽  
Gillian Morgan ◽  
...  

Abstract Introduction: Elotuzumab is a humanized monoclonal antibody directed against SLAMF7 that is approved for use in relapsed multiple myeloma patients in combination with lenalidomide and dexamethasone. This agent appears to have several modes of action, including facilitation of antibody-dependent, cell-mediated cytotoxicity (ADCC) through binding to SLAMF7 on myeloma cells and activation of natural killer (NK) cells to kill tumor cells through ligation of the target. We initiated a single-center, open label, phase 1 trial based on the hypothesis that the addition of elotuzumab and autologous peripheral blood mononuclear cell (PBMC) reconstitution to standard-of-care autologous hematopoietic stem cell transplantation (auto-SCT) and lenalidomide maintenance for consolidation therapy in myeloma patients after induction therapy will be safe and feasible. We hypothesize that early PBMC reconstitution post-auto-SCT will restore a viable NK cell population for activation by elotuzumab, which may target residual myeloma cells and promote tumor-specific humoral and cellular immune responses against myeloma cells. Subsequent maintenance therapy with elotuzumab and lenalidomide may amplify this response, resulting in long-term maintenance of the minimal residual disease state. Methods. This is a Phase 1b, open-label, trial investigating elotuzumab and autologous PBMC reconstitution with auto-SCT consolidation therapy and lenalidomide maintenance. The primary objective of this study is to assess the safety and tolerability of elotuzumab and autologous PBMC reconstitution in the setting of auto-SCT and lenalidomide maintenance in multiple myeloma patients. The secondary objectives are to assess myeloma disease status and progression-free survival (PFS) after one year of treatment. Subjects must achieve partial response or better by IMWG criteria with induction chemotherapy, be eligible for auto-SCT by institutional standards, and meet inclusion/exclusion criteria. Fifteen subjects are planned in this pilot study. The treatment plan is as follows: In addition to standard peripheral blood stem cell mobilization and harvest, subjects undergo steady-state leukopheresis for PBMC collection. Subjects receive standard melphalan conditioning (day -1) and autologous stem cell rescue (day 0). Autologous PBMC are reinfused on day +3 post-stem cell infusion and cycle 1 of elotuzumab 20 mg/kg IV is given on day +4. Subjects receive subsequent cycles of elotuzumab every 28 days up to cycle 12. Lenalidomide maintenance at 10 mg orally daily days 1-21 of every 28-day cycle begins with cycle 4 of elotuzumab, and may continue off study beyond cycle 12 at the investigator's discretion. Bone marrow aspirates and peripheral blood are collected for correlative studies at screening, cycle 2, cycle 4, and at the end of study after cycle 12. For the primary endpoint analysis, the safety population includes all subjects who received at least one dose of study treatment. The evaluable population constitutes all subjects who received at least four of the first five planned doses of elotuzumab. Results: Fourteen of the planned 15 subjects have been enrolled in the study. Demographic and staging data reflect the general transplant-eligible myeloma patient population at our institution. All 14 of these subjects are included in the safety population, having received at least 1 dose of elotuzumab. Nine of 14 subjects have completed at least 4 of the first 5 planned elotuzumab infusions and are evaluable. The majority of adverse events, including infusion reactions attributable to elotuzumab, have been grade 2 or lower. Grade 3 or higher hematologic AEs, including anemia, neutropenia, lymphopenia, thrombocytopenia, and non-hematologic AEs including nausea, vomiting, and dehydration, were attributable to the auto-SCT procedure. There were no delays in hematopoietic reconstitution observed. One episode of grade 3 hypertension was attributed to elotuzumab infusion and resolved with supportive care. No AEs were attributed to PBMC reconstitution. Conclusions: The combination of elotuzumab and PBMC reconstitution with standard auto-SCT and lenalidomide maintenance for consolidation therapy of multiple myeloma appears to be safe and feasible. One subject withdrew for personal reasons. The trial is ongoing and is expected to complete accrual and the clinical results will be updated for presentation. Disclosures Chari: Celgene: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Takeda: Consultancy, Research Funding. Geerlof:Bristol-Myers Squibb: Employment. Jagannath:Novartis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Merck: Consultancy. Cho:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agenus, Inc.: Research Funding; Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Research Funding; Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1854-1854 ◽  
Author(s):  
Jatin J Shah ◽  
Andrzej J Jakubowiak ◽  
Owen A O’Connor ◽  
Robert Z Orlowski ◽  
Molly Patterson ◽  
...  

Abstract Abstract 1854 Poster Board I-880 Background: MLN4924 is a first-in-class small molecule inhibitor of NEDD8-activating enzyme (NAE), an essential component of the NEDD8 conjugation pathway in the ubiquitin-proteasome system. Inhibition of NAE with MLN4924 prevents conjugation of NEDD8 to the Cullin Ring Ligases (CRLs). This subsequently prevents ubiquitination and proteasomal degradation of CRL substrates, which include proteins involved in cell cycle regulation (p27), signal transduction (pIκBá), DNA replication (Cdt-1), stress response (Nrf-2), and other processes important to tumor cell growth and survival. MLN4924 has demonstrated potent antitumor activity in vitro against multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) cell lines as well as in mouse xenograft models of NHL. This phase 1 dose-escalation study is the first investigation of MLN4924 in MM or NHL patients (pts). The primary objectives were to determine the maximum tolerated dose (MTD) and safety profile of MLN4924, describe the pharmacokinetics (PK) and pharmacodynamics (PD) in blood (inhibition of NEDD8-Cullin levels in peripheral blood mononuclear cells [PBMCs]; Nrf-2 target gene transcription in whole blood), and investigate PD effects in skin (Cdt-1, Nrf-2 accumulation). Methods: Pts aged ≥18 yrs with relapsed and/or refractory MM or NHL after ≥2 prior lines of therapy were eligible. Pts received escalating doses of MLN4924 by IV infusion on days 1, 2, 8, and 9 of 21-day cycles; once the MTD for this schedule was reached, MTDs for other schedules will be investigated. MTD determination was based on an adaptive approach using a Bayesian continual reassessment method, with the MTD defined as the dose level closest to that predicted to result in a dose-limiting toxicity (DLT) rate of 25%. DLT was defined as: grade 4 neutropenia or thrombocytopenia for >7 days; grade 3 neutropenia with fever/infection or thrombocytopenia with bleeding; grade ≥3 non-hematologic toxicity except arthralgia/myalgia, brief fatigue, or fever without neutropenia; and grade ≥2 MLN4924-related toxicities requiring dose reduction/discontinuation. For PD analysis, PBMCs and whole blood were isolated at screening, baseline, and following MLN4924 administration; skin biopsies for Cdt-1 and Nrf-2 assays were performed at baseline and after the second dose. Results: Among 22 pts enrolled to date, median age was 65 years, 13 were male, 14 had MM, and 8 had NHL (4 FL, 1 MCL, 1 DLBCL, 1 B-cell CLL/SLL, 1 transformed CLL). All MM pts had received prior autologous SCT, and 13, 9, and 9 had prior bortezomib, lenalidomide, and thalidomide, respectively. Seven NHL pts had received prior autologous SCT, 1 had a prior allogeneic SCT, and 8 had prior rituximab. Pts received MLN4924 at 6 dose levels: 25 (n=3), 50 (n=2), 65 (n=3), 83 (n=2), 110 (n=9), and 147 mg/m2 (n=3). Of the 15 (68% of the 22 enrolled) pts who received all 4 scheduled doses or had a DLT in cycle 1 (DLT-evaluable pts), 4 experienced a DLT: 1 grade 4 febrile neutropenia at 65 mg/m2; 1 grade 3 liver function tests at 110 mg/m2, and 1 grade 4 muscle cramps and 1 grade 2 myalgia that was considered dose limiting at 147 mg/m2. Thus, the MTD for this schedule was determined to be 110 mg/m2. The most common adverse events (AEs, NCI CTCAE v3.0) included fatigue, nausea, myalgia, and elevated liver enzymes. With the exception of the grade 4 neutropenia seen at 65 mg/m2, myelosuppression was limited. No infusion-related reactions were noted. Elevated CRP levels appeared transient in most cases. There have been no treatment-related deaths; 1 MM pt died due to progressive disease. MLN4924 displayed a multiexponential PK profile with a half life of 4–9 hours, relatively low PK variability, and approximately dose-proportional increases in total plasma exposure over the 25–147 mg/m2 dose range. NEDD8-Cullin levels in PBMCs were inhibited and Nrf-2 target gene transcripts in whole blood were higher vs baseline after MLN4924 administration, indicative of NAE inhibition. Cdt-1 and Nrf-2 levels in skin increased above baseline following the second dose of MLN4924, indicative of NAE inhibition in peripheral tissue. The 110 mg/m2 dose level is being expanded to more fully characterize safety, PK, and PD in MM and NHL. Subsequent pts will be enrolled to receive MLN4924 on 2 other schedules. Conclusions: This early analysis provides evidence of PD inhibition of NAE activity by MLN4924 in blood and skin, and supports continued investigation of MLN4924. Disclosures: Shah: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Elan: Consultancy; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: MLN4924 is not approved for the treatment of multiple myeloma or non-Hodgkin lymphoma.. Jakubowiak:Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Berger:Millennium Pharmaceuticals, Inc.: Employment. Mulligan:Millennium Pharmaceuticals, Inc.: Employment. Petruzzelli:Pfizer: Equity Ownership; Millennium Pharmaceuticals, Inc.: Employment; Amgen: Equity Ownership. Pickard:Millennium Pharmaceuticals, Inc.: Employment. Smith:Millennium Pharmaceuticals, Inc.: Employment. Venkatakrishnan:Millennium Pharmaceuticals, Inc.: Employment. Lonial:Novartis: Consultancy; Gloucester: Research Funding; BMS: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene: Consultancy.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 432-432 ◽  
Author(s):  
Sagar Lonial ◽  
Ravi Vij ◽  
Jean-Luc Harousseau ◽  
Thierry Facon ◽  
Jonathan Kaufman ◽  
...  

Abstract Abstract 432 Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, a cell surface glycoprotein, which is highly and uniformly expressed in multiple myeloma (MM). Elotuzumab induces significant antibody-dependant cytotoxicity (ADCC) against primary myeloma cells in the presence of either autologous or allogeneic peripheral lymphocytes (PBMC), which is significantly enhanced when PBMC effector cells were pretreated with lenalidomide (Tai et al., Blood 112:1329, 2008). The primary objective of the phase 1 portion of the study is to evaluate the maximum tolerated dose (MTD) of elotuzumab in combination with lenalidomide and low dose dexamethasone in patients with relapsed MM. The study is also evaluating safety, pharmacokinetics (PK) and clinical response. Lenalidomide (25 mg PO) is given on Days 1-21 of a 28-day cycle. Elotuzumab in three escalating dose cohorts (5, 10 and 20 mg/kg) is administered by IV infusion on Days 1, 8, 15 and 22 of the 28-day cycle in the first two cycles and then on Days 1 and 15 of each subsequent cycle. Dexamethasone is given weekly at 40 mg PO. Initially, patients received 6 cycles of treatment unless withdrawn earlier due to disease progression or unacceptable. toxicity. The protocol was amended to allow for patients in the 10 and 20 mg/kg cohorts to receive treatment for up to 12 months following enrollment of the last patient. Key entry criteria: age ≥ 18 years; MM with at least one relapse; measurable disease M-protein component in serum and/or in urine; and prior lenalidomide treatment, if any, more than 6 weeks of first dose. To date, 24 patients with a median age of 60 years have been enrolled in the study and 23 patients have received study drug. The median time from initial diagnosis of MM was 5 years and patients had received a median of 3 prior MM treatments. Patients had been previously treated with thalidomide (58%), bortezomib (67%) or lenalidomide (21%) and 42% were refractory to their most recent MM therapy. Patients have been treated in the 3 cohorts; 3 patients each in the first two cohorts (5 and 10 mg/kg elotuzumab) and 17 patients (7 in dose-escalation phase and 10 in the expansion phase) in the third cohort (20 mg/kg). No dose limiting toxicities were identified during the dose-escalation phase of the study and no MTD was established. One patient discontinued in the first cycle due to grade 4 allergic reaction resulting from elotuzumab infusion in the expansion phase of the study. Additional SAEs (1 of each) included grade 2 atrial fibrillation (related to lenalidomide/dexamethasone) and unrelated grade 4 ruptured diverticulum, grade 3 neutropenic fever and grade 3 diarrhea.. Other common grade 3 or 4 AEs included neutropenia (25%) and thrombocytopenia (25%), which were managed by dose withholding or dose reduction of lenalidomide. Approximately 25% of patients experienced grade 1 or 2 chills and/or pyrexia associated with elotuzumab infusion. The best clinical response (IMWG criteria) in the 13 patients who have received at least two cycles of treatment is shown in the table below. Preliminary PK analysis of elotuzumab suggests a serum half-life of 10-11 days at 10 and 20 mg/kg. Elotuzumab at all three doses resulted in near complete saturation of CS1 sites on plasma cells and NK cells in bone marrow and NK cells in the peripheral compartment. In conclusion, the combination of elotuzumab with lenalidomide and low-dose dexamethasone has a manageable adverse event profile and compared to historical data for lenalidomide and high-dose dexamethasone, the preliminary efficacy data (≥ PR of 92%) are very encouraging. Additional safety, efficacy and PK/PD data will be presented at the meeting. Disclosures: Lonial: Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Off Label Use: Lenalidomide/dexamethasone in combination with elotuzumab in patients with relapsed/refractory multiple myeloma. Vij:Celgene: Research Funding, Speakers Bureau. Harousseau:Celgene France: Advisory Board; Janssen Cilag France: Advisory Board; Celgene: Honoraria; Janssen Cilag: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kaufman:Celgene: Consultancy, Research Funding; Millennium: Consultancy; Genzyme: Consultancy; Merck: Research Funding. Mazumder:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Leleu:Celgene: Research Funding, Speakers Bureau. Fry:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Jagannath:Millennium: Advisory Board; Merck: Advisory Board.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 376-376 ◽  
Author(s):  
Jatin J. Shah ◽  
Lei Feng ◽  
Sheeba K. Thomas ◽  
Donna Weber ◽  
Michael Wang ◽  
...  

Abstract Background: Filanesib (ARRY-520), a kinesin spindle protein (KSP) inhibitor, has demonstrated promising clinical activity, both as a single agent and combined with dexamethasone in patients (pts) with bortezomib/carfilzomib/lenalidomide and pomalidomide-refractory MM. Carfilzomib (car), an irreversible proteasome inhibitor (PI), also has demonstrated single agent activity in RRMM at 27 mg/m2 as well as at 56 mg/m2 in combination with dexamethasone. Part A of the phase 1 trial previously presented demonstrated Car 20/27mg/m2 can be safely combined with filanesib 1.5 mg/m2. We subsequently enrolled and now present additional pts in Part A dose expansion with a cohort of Car naïve and Car refractory pts; we also continued in Part B of the trial with subsequent dose escalation of Car to 56 mg/m2. Methods: The primary objective was to determine the MTD and the safety/tolerability of Car and filanesib in RRMM. Secondary objectives were to determine efficacy as measured by the overall response rate (ORR), time to progression, progression free survival and time to next therapy. Pts had to be ineligible for autologous stem cell transplant (ASCT), have disease refractory/intolerant to bortezomib and have had prior lenalidomide exposure. Filanesib was administered intravenously (iv) on days 1, 2, 15 and 16; car was administered intravenously on days 1, 2, 8, 9, 15 and 16 of a 28 day cycle. All pts received growth factor support in cycle 1. Dose-escalation used a standard 3+3 schema with dose-limiting toxicities (DLTs) assessed during cycle 1. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria. Results: 51 pts were enrolled in the study (20 patients in Part A dose escalation; 15 carfilzomib-naïve pts in Part A dose expansion; 7 carfilzomib-refractory pts in Part A dose expansion; 9 pts in Part B dose escalation). The median age was 63 (range 41-84); 18 females; 32 males. Of the 15 car-naïve pts dosed in the Part A dose expansion: 1 patient was non-compliant/lost to followup after 2 cycles and inevaluable for response. The ORR (≥ PR) was 36% (5/14; 4 pts with PR and 1 with VGPR). With the addition of 19/20 carfilzomib naïve patients from the Part A dose escalation phase, a total of 33 evaluable pts were dosed who were Car-naïve; 27/33 pts were lenalidomide refractory/intolerant and all pts were bortezomib refractory/intolerant. The ORR (≥PR) was 42% (14/33) and clinical benefit rate (≥MR) was 52% (17/33). 8 pts remain on therapy. In the dose expansion with 7 patients with car refractory disease in Part A, the best response observed was SD in 2 pts dosed for 5 and 6 cycles. In Part B, car was escalated in 3 cohorts to 36 mg/m2, 45 mg/m2 and 56 mg/m2; the filanesib dose remained at 1.5 mg/m2. 9 pts were dosed in the dose escalation. 7/9 pt were lenalidomide refractory; 9/9 pts were refractory to bortezomib; 8/9 pts were refractory to lower doses of carfilzomib. No DLTs were observed in 3 pts dosed in each of the 3 cohorts. The final planned cohort with car 56 mg/m2 and filanesib at 1.5 mg/m2 is ongoing with additional 3 pts, for a total of 6 patients, to confirm the recommended phase 2 dose. Hematologic adverse events included: Grade 3/4 (G3/4) anemia in 14/51 pts; G3/4 thrombocytopenia in 20/51 pts; and G3/4 neutropenia in 21/51 pts. G3/4 non hematologic adverse events were limited and included 1 pt respectively with elevated alanine aminotransferase, aspartate aminotransferase, bacteremia, diarrhea, dizziness, febrile neutropenia, fluid overload, fever, mucositis, peripheral neuropathy, sepsis; 2 pt with dyspnea, sinusitis; 3 pt with elevated creatinine, myalgia and elevated serum lipase; 5 pts with fatigue ; 8 pts with lung infection. Treatment emergent SAEs among all 51 pts included 11 pts with lung infection; 4 pts with renal dysfunction (G2, G3, G3, and G5 each); 3 pts with febrile neutropenia G3 (n=2) and G5 FN (n=1); 2 pts with heart failure; and 1 patient each with G3 bacteremia, G2 lethargy, G2 sinusitis, G3 diarrhea. Conclusions: Full dose filanesib, 1.5 mg/m2,can be safely combined with Carfilzomib 27 mg/m2, in a steroid sparing regimen, with an ORR of 42% and CBR of 52% in bortezomib-refractory patients. The preliminary data from ongoing part B dose escalation supports full dose filanesib can also be combined with carfilzomib 56 mg/m2 and is well tolerated with limited hematologic and the final data set to be presented at ASH. Disclosures Shah: Array: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Thomas:Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Wang:Pharmacyclics, Janssen, Celgene, Oncopep, Kite, Juno: Research Funding; Janssen: Honoraria. Orlowski:Array BioPharma: Consultancy, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Forma Therapeutics: Consultancy; Acetylon: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Research Funding; BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 973-973 ◽  
Author(s):  
Andrzej Jakubowiak ◽  
Jagoda Jasielec ◽  
Cara A. Rosenbaum ◽  
Craig E. Cole ◽  
Ajai Chari ◽  
...  

Abstract Background There are an increasing number of multiple myeloma (MM) patients (pts) refractory to currently available drugs, including the proteasome inhibitors bortezomib and carfilzomib (CFZ), necessitating development of novel therapeutics. Pre-clinical evaluation of selinexor (SEL), an orally available Selective Inhibitor of Nuclear Export (SINE) compound, demonstrated synergistic myeloma cell death with CFZ and mechanistic rationale for overcoming resistance to CFZ (Rosebeck et al., 2016), providing support for this phase 1 trial. Aims The primary objectives were to assess the maximum tolerated dose (MTD) of a SEL, CFZ and dexamethasone (DEX) combination and to obtain preliminary efficacy data for this novel regimen in RRMM pts. Methods Pts with RRMM who progressed after at least two prior treatment regimens of myeloma therapy were eligible for enrollment. Dose escalation followed the 3+3 design with pts receiving 30 mg/m2 - 40 mg/m2 SEL PO on days (D) 1, 3, 8, 10, 15, 17; 20 mg/m2 - 56 mg/m2 CFZ IV on D 1, 2, 8, 9, 15, 16, and DEX PO (20mg cycles 1-4/ 10mg cycles 5+) in 28-day cycles (C) in up to 5 dose levels. An expansion cohort has enrolled additional pts to a total of 12 CFZ-refractory pts treated at the recommended Phase 2 dose (RP2D). Dose Limiting Toxicities (DLTs) were evaluated through C2D1. Responses were assessed by IMWG criteria plus near complete response (nCR). Results As of July 1st, 2016, the study has completed dose escalation and enrolled a total of 18 pts; 5 at dose level 1 (30 mg/m2 SEL, 20/27 mg/m2 CFZ, 20/10 mg DEX), 3 at dose level 2a (30 mg/m2 SEL, 20/36 mg/m2 CFZ, 20/10 mg DEX), and a total of 10 (7 in dose escalation, 3 in cohort expansion) at dose level 2b (60mg flat dose SEL, 20/27 mg/m2 CFZ and 20/10 DEX). Pts age ranged between 55 to 74 years with a median of 63.5 years; and had a median of 4 prior treatment regimens (range 2-10). Sixteen pts were evaluable for response, all refractory to their last line of therapy. All 16 response evaluable pts were refractory to CFZ, of which 11 were refractory to CFZ combinations as their last line of therapy, including 8 to a KPd combination of CFZ, pomalidomide, and DEX. Fifteen pts were evaluable for DLT and 3 of 18 pts required replacement for DLT evaluation (1 had DEX reduced not due to DLT; 2 did not receive all scheduled C1 doses). In the dose escalation phase, there was one DLT of cardiac amyloidosis (CA) in a pt with history of prior congestive heart failure and CA at baseline. While the maximum tolerated dose (MTD) has not been reached, the RP2D was identified at dose level 2b based on tolerability. Grade 3/4 adverse events (AEs) included: thrombocytopenia (67%), neutropenia (33%), anemia (17%), fatigue (17%), and infections (11%). The most common all grade AEs included: gastrointestinal disorders (78%), thrombocytopenia (73%), fatigue (72%), anemia (47%), dyspnea (33%), and elevated liver and pancreatic enzymes (28%). There were 2 (11%) serious AEs, 1 upper respiratory infection and 1 lower gastrointestinal bleeding. All adverse events were manageable with concomitant medications. Response rates for all evaluable pts were 75% ≥MR (12 of 16), 63% ≥PR, and 25% ≥VGPR. Response rates in CFZ-refractory pts at last line of treatment were 73%, 64%, and 18% respectively. Responses occurred rapidly; after C1 with 75% ≥MR. As of the data cutoff date, 15 pts progressed (between 1 and 14 months on study) and 3 pts remained on treatment (1 - 4 months). Conclusions The combination of SEL, CFZ, and DEX demonstrates encouraging activity and safety in heavily pretreated, mostly CFZ-refractory myeloma. In addition, with 64% PR or better for pts progressing on CFZ, these results provide early clinical evidence that selinexor has the ability to overcome CFZ resistance, warranting further investigation of this regimen in RRMM. Disclosures Jakubowiak: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: 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; Amgen Inc.: 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. Rosenbaum:Celgene: Speakers Bureau. Chari:Novartis: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Zonder:Pharmacyclics: Other: DSMC membership; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Prothena: Consultancy, Honoraria.


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