Phase 1 Dose-Escalation Study of MLN4924, a Novel NAE Inhibitor, in Patients with Multiple Myeloma and Non-Hodgkin Lymphoma.

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.

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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 ◽

10.1182/blood.v126.23.377.377 ◽

2015 ◽

Vol 126 (23) ◽

pp. 377-377 ◽

Cited By ~ 4

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.

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Bortezomib May Be Safely Combined with Y-90 Ibritumomab Tiuxetan In Patients with Relapsed/Refractory Follicular or Transformed Non-Hodgkin Lymphoma: A Phase I Trial of Combined Induction Therapy and Bortezomib Consolidation

Blood ◽

10.1182/blood.v116.21.1749.1749 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1749-1749

Author(s):

Rupali Roy ◽

Andrew M Evens ◽

David P. Patton ◽

Annette Larsen ◽

Alfred Rademaker ◽

...

Keyword(s):

Board Of Directors ◽

Hodgkin Lymphoma ◽

Induction Therapy ◽

Research Funding ◽

Phase I Trial ◽

Ibritumomab Tiuxetan ◽

Advisory Committees ◽

Non Hodgkin Lymphoma ◽

Previously Treated ◽

Grade 3

Abstract Abstract 1749 Background: Preclinical studies suggest that bortezomib, through inhibition of NF-kB activation, may act as a radiosensitizer and enhance the effects of radioimmunotherapy. Methods: This phase I trial was designed to determine the maximum tolerated dose (MTD) of weekly bortezomib induction combined with Y-90-ibritumomab tiuxetan in patients 18 years or older with relapsed/refractory follicular or transformed non-Hodgkin lymphoma. In addition, we assessed the tolerability of weekly bortezomib consolidation following induction therapy. Cohorts consisting of three patients each were treated with bortezomib induction at doses of 1.0, 1.3, or 1.6 mg/m2 on days 1, 8, 15, and 22, rituximab 250 mg/m2 on days 8 and 15, and Y-90 ibritumomab tiuxetan 0.4 mCi/kg on day 15. Consolidation, consisting of bortezomib 1.6 mg/m2 weekly on days 1, 8, and 15 of three 28 day cycles, was initiated on day 71 after recovery of the platelet count to 100,000/uL and ANC> 1,000/uL. At least three patients per cohort were followed for 7 weeks or had recovery of blood counts without dose-limiting toxicities (DLTs) before dose escalation was allowed. MTD was defined as the dose previous to that in which two patients had DLTs. To be evaluable, patients were required to have received at least two doses of bortezomib and the Y-90-ibritumomab tiuxetan therapeutic dose. Response was assessed by CT scanning following induction therapy and PET/CT and diagnostic CT scans after completion of consolidation. Results: Nine patients with a median age of 55 (range: 29–71) were treated with bortezomib combined with Y-90-ibritumomab tiuxetan. Eight patients had FL and one had evidence of a transformation to diffuse, large B-cell lymphoma. All had a performance status of 0 or 1, and all had been previously treated with rituximab either as a single agent or in combination with chemotherapy. All but one had received prior chemotherapy [R-CHOP (n=7), chlorambucil (n=1), or R-CVP (n=2)], and three had received radiotherapy. Only one had bone marrow involvement. The median number of prior therapies was one (range: 1–3). Grade 3 or 4 toxicities were observed in all but one of the patients and as expected, all but one of these toxicities were hematologic (leukopenia, lymphopenia, neutropenia, and/or thrombocytopenia). One patient had grade 3 cardiotoxicity characterized by palpitations and shortness of breath on day 15 of her first consolidation, with PVC's noted on subsequent EKG. Though uncommon, cardiotoxicity has been reported in association with bortezomib in the form of systolic heart failure, arrhythmias, and angina. It should be noted that this patient was previously treated with an anthracycline as have the majority of patients reported to have experienced cardiotoxicity in association with bortezomib. A DLT of grade 4 thrombocytopenia lasting more than ten days was observed in two of three patients treated with bortezomib at 1.6 mg/m2. One of these two patients was the only one to receive .3 mCi/kg rather than .4 mCi/kg of the radioisotope because of thrombocytopenia on the day of treatment. Thus, the MTD of bortezomib was 1.3 mg/m2. All patients are alive, and the median followup for those patients who have not progressed is 6.5 months (range: 3 – 15 mo.). All but one patient responded to therapy (4 CR/CRu, 4PR, 1 SD). The four complete responders remain in remission at 3.0, 5.0, 5.0 and 15.0 months. All of the partial responders have progressed (3.5, 3.5, 11.5, and 17.5 months), as has the patient with stable disease (5.0 months). Conclusions: The MTD for weekly bortezomib combined with Y-90 ibritumomab tiuxetan induction therapy is 1.3 mg/m2. Consolidation with bortezomib at 1.6 mg/m2 was well tolerated in this group of relapsed/refractory follicular and transformed non-Hodgkin lymphoma patients. Nearly all patients responded. A phase II trial at the MTD is underway to better define the toxicity and effectiveness of this regimen in patients with relapsed/refractory FL. Disclosures: Evens: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrm: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ziopharm: Membership on an entity's Board of Directors or advisory committees; Lilly: Research Funding; Ortho- Biotec: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Gordon:Cure Tech, Ltd: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, Inc: Research Funding; Genentech: Speakers Bureau; Millenium: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees. Winter:Millenium: Consultancy, Research Funding; Pfizer/Wyeth: Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Spectrum: Honoraria.

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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 ◽

10.1182/blood.v128.22.2122.2122 ◽

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.

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Phase 1/2 Study of Elotuzumab in Combination with Lenalidomide and Low Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma: Interim Results.

Blood ◽

10.1182/blood.v114.22.432.432 ◽

2009 ◽

Vol 114 (22) ◽

pp. 432-432 ◽

Cited By ~ 5

Author(s):

Sagar Lonial ◽

Ravi Vij ◽

Jean-Luc Harousseau ◽

Thierry Facon ◽

Jonathan Kaufman ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Low Dose ◽

Phase 1 ◽

Advisory Board ◽

Advisory Committees ◽

Expansion Phase ◽

Grade 3

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.

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Dynamo: A Phase 2 Study Demonstrating the Clinical Activity of Duvelisib in Patients with Relapsed Refractory Indolent Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood.v128.22.1218.1218 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1218-1218 ◽

Cited By ~ 16

Author(s):

Ian W. Flinn ◽

Carole B. Miller ◽

Kirit M Ardeshna ◽

Scott Tetreault ◽

Sarit E. Assouline ◽

...

Keyword(s):

Board Of Directors ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Clinical Activity ◽

Phase 2 ◽

Advisory Committees ◽

Non Hodgkin Lymphoma ◽

Phase 2 Study ◽

Previously Treated ◽

Grade 3

Abstract DYNAMO: A Phase 2 Study Demonstrating the Clinical Activity of Duvelisib in Patients with Relapsed Refractory Indolent Non-Hodgkin Lymphoma Introduction: Indolent non-Hodgkin lymphoma (iNHL) is characterized by a relapsing clinical course with shorter responses to therapy after each relapse. Duvelisib is an oral dual inhibitor of PI3K-d,γ in development for the treatment of hematologic malignancies, including previously-treated iNHL. Data from a Phase 1 study of duvelisib indicate the potential for duvelisib to be an effective treatment for previously-treated iNHL, with an acceptable safety profile. DYNAMO is a Phase 2 study designed to evaluate the safety and efficacy of duvelisib in a previously-treated, refractory iNHL population. Methods: DYNAMO is an ongoing, open-label, single-arm, safety and efficacy study that includes adult patients (pts) diagnosed with follicular lymphoma (FL), small lymphocytic lymphoma (SLL), or marginal zone lymphoma (MZL) whose disease is refractory to rituximab and to a chemotherapy regimen (containing an alkylator or purine analogue) or radioimmunotherapy. Pts received duvelisib 25 mg twice daily (BID) in 28-day treatment cycles until disease progression or unacceptable tolerability. The primary endpoint of the study is overall response rate (ORR) as assessed by an independent review committee, according to the revised IWG criteria. Secondary endpoints include duration of response (DoR), progression-free survival (PFS), overall survival (OS), time to response (TTR), adverse events (AEs), and changes in safety laboratory values. Pneumocystis jirovecii pneumonia (PJP) prophylaxis was mandated for all patients. Here we present the results from the final analysis, with a data cut-off of 07 April 2016. Results: 129 iNHL pts received at least 1 dose of duvelisib, including 83 pts with FL, 28 with SLL, and 18 with MZL. The median duration of exposure was 6 months (range 0.4 - 23.8). The median age was 65 years, and 68% were male. The median time from initial diagnosis to the first dose of duvelisib was 4.5 years, and from last anticancer therapy was 3.5 months. Pts had received a median of 3 prior regimens (range 1 - 18), with 40% having received ≥ 4 regimens. 77% of patients had disease refractory to ≥ 2 regimens and 96% were refractory to their most recent regimen. 64% of patients previously received bendamustine, 80% of whom were refractory. The ORR was 46% (all PRs, 95% CI 37 - 55), with a median DoR of 9.9 months (95% CI 4.5 - 10.3). The median TTR was 1.9 months (range 1.4 - 11.7). With a median follow-up of 11.5 months, the median PFS was 8.4 months (95% CI 5.8 - 11.3) with a 60% estimated probability of being alive and event-free at 6 months, and the median OS was 18.4 months (95% CI 15.7 - NE) with an estimated probability of survival of 74% at 12 months. 83% of pts experienced a reduction in tumor burden following treatment with duvelisib. The response rate across the disease subtypes was: 41% FL, 68% SLL, and 33% MZL (see Table). AEs were predominantly Grade 1-2. The most common ≥ Grade 3 AEs were transient cytopenias (neutropenia [28%], anemia [12%], and thrombocytopenia [13%]), and diarrhea (15%). 63% of pts had dose modifications (interruptions or reductions) due to AEs and 17% of pts discontinued due to an AE. AEs leading to duvelisib discontinuation in ≥ 2 pts included pneumonitis (n = 3), pneumonia (n = 2), and rash generalized (n = 2). Six pts had an AE with an outcome of death, four assessed as related to duvelisib (suspected viral infection, septic shock, and 2 severe cutaneous reactions [TEN and DRESS]). The incidence of ≥ Grade 3 infection was 20%. The incidence of pneumocystis was 0.8% (1 patient) and the incidence of CMV was 2.3% (3 subjects), none of which were fatal. Conclusions: In the Phase 2 DYNAMO study, duvelisib achieved meaningful clinical activity in a heavily pretreated and highly refractory iNHL population. The safety profile was acceptable, with the majority of AEs low grade (≤ Grade 2) and the majority of pts able to remain on duvelisib. These results suggest duvelisib has a favorable benefit-risk profile in this patient population and further development is ongoing. Table 1 Table 1. Disclosures Flinn: Janssen: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Miller:Infinity: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Ardeshna:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses, Research Funding. Assouline:BMS: Speakers Bureau; Pfizer: Speakers Bureau. Zinzani:Infinity: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: 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; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: 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; Millennium: Membership on an entity's Board of Directors or advisory committees. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding. Pettitt:Roche: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Infinity: Research Funding. Tournilhac:Roche: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Amgen: Research Funding; Celgene: Honoraria, Research Funding; GSK: Research Funding; Novartis: Research Funding; Mundipharma: Honoraria, Research Funding. Crump:Roche: Consultancy; Seattle Genetics: Consultancy; Janssen-Ortho: Consultancy; Celgene: Consultancy. Santabarbara:Infinity: Consultancy. Shi:Infinity: Employment. Steelman:Infinity: Employment. Wagner-Johnston:Pharmacyclics: Speakers Bureau.

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Novel Three– and Four–Drug Combinations of Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide, for Newly Diagnosed Multiple Myeloma: Encouraging Results From the Multi-Center, Randomized, Phase 2 EVOLUTION Study.

Blood ◽

10.1182/blood.v114.22.127.127 ◽

2009 ◽

Vol 114 (22) ◽

pp. 127-127 ◽

Cited By ~ 9

Author(s):

Shaji Kumar ◽

Ian W. Flinn ◽

Parameswaran N. Hari ◽

Natalie Callander ◽

Stephen J. Noga ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Phase 2 ◽

Advisory Committees ◽

Highly Active ◽

Evolution Study ◽

Grade 3

Abstract Abstract 127 Two- and three-drug regimens incorporating bortezomib (Velcade®, Vc), lenalidomide (Revlimid®, Rev), dexamethasone (Dex), and cyclophosphamide (Cy) (Vc–Dex, Rev–Dex, Vc–Dex–Rev [VDR], and Vc–Dex–Cy [VDC]), have been shown to be effective and well tolerated in previously untreated multiple myeloma (MM). Combining Vc and Dex with Rev and Cy in a novel four-drug regimen (VDCR) may result in even greater activity with improved quality and duration of response. Results from the phase 1 dose-escalation portion of the multi-center EVOLUTION study showed that the VDCR regimen is a highly active and generally well-tolerated induction therapy in previously untreated MM patients (pts). Here we report the efficacy and safety of VDR, VDC, and VDCR from the non-comparative phase 2 portion of the study. Methods: Pts were randomized to receive up to eight 21-d cycles of VDR (Vc 1.3 mg/m2 d 1, 4, 8, 11; Dex 40 mg d 1, 8, 15; Rev 25 mg d 1–14) or VDC (VD as in VDR, plus Cy 500 mg/m2 d 1, 8) or VDCR (VDC plus Rev 15 mg d 1–14) as induction therapy, followed by Vc 1.3 mg/m2 (d 1, 8, 15, 22) for four 42-d maintenance cycles in all treatment arms. Pts received prophylactic antibiotics, acyclovir, transfusion support, and anticoagulants as required. Eligible pts wishing to undergo autologous stem cell transplant (ASCT) could undergo stem cell mobilization any time after cycle 2, and undergo ASCT any time after cycle 4. Response categories were based on the IMWG Criteria with the addition of near complete response (nCR). Adverse events (AEs) were graded using the CTCAE v3.0. Results: In the VDR, VDC, and VDCR arms 42, 32, and 43 pts (including 6 pts treated at the maximum planned dose of Cy (500 mg/m2) from phase 1) have been treated, and 42, 31, and 33 are evaluable for response, respectively, as of data cut-off (31 July 2009). Median ages in the VDR, VDC, and VDCR arms were 60, 62, and 62 years, respectively; 62%, 63%, and 66% had International Staging System stage lI/III disease, and 38%, 25%, and 33% had Karnofsky Performance Status ≤80%, respectively. The median number of VDR, VDC, and VDCR cycles received is 4.5, 6, and 4, respectively (range 1–12). Best unconfirmed response rates are shown in the Table; patients categorized as very good partial response (VGPR) include those who have no measurable M-protein but have not yet had bone marrow assessments to confirm CR/nCR status. The overall rates of treatment-emergent AEs were 95%, 97%, and 88% for the VDR, VDC, and VDCR arms, respectively, with ≥grade 3 reported in 67%, 59%, and 65%. Peripheral neuropathy (PN) was reported as grade 2/3 in 12%/12% in the VDR, 31%/3% in the VDC, and 12%/9% in the VDCR arms; there was no grade 4 PN reported. Grade 3/4 neutropenia was reported in 5%/5%, 28%/13%, and 23%/9% of pts in the VDR, VDC, and VDCR arms, and grade 3/4 thrombocytopenia in 5%/2%, 9%/0%, and 5%/0% of pts, respectively. One case of grade 3 deep-vein thrombosis was reported in the VDCR arm. Overall rates of serious AEs were 24%, 13%, and 37% in the VDR, VDC, and VDCR arms, respectively. Two pts have died in the VDCR arm, both due to renal failure, considered possibly treatment-related. To date, 6 pts have undergone ASCT in the VDR arm, 5 in the VDC arm, and 3 in the VDCR arm. Median CD34+ yield was 4.7, 6.3, and 6.8 × 106/kg in the VDR, VDC, and VDCR arms, respectively. Conclusions: VDR, VDC, and VDCR are highly active and generally well-tolerated regimens in previously untreated MM. Response rates in the VDCR arm appeared somewhat higher than in the VDR and VDC arms at this early time point, although there also appeared to be higher rates of serious AEs, including possible treatment-related mortality in the VDCR arm. Following an interim analysis, dosing in the VDC arm was modified to include Cy on day 15 to examine if this will improve CR rates. Ten pts have been enrolled to date. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari:Milennium Pharmaceuticals Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Callander:Millenium: Research Funding. Noga:Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Raje:Celgene: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding. Rifkin:Millennium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau. Shi:Millennium Pharmaceutical Inc.: Employment. Webb:Millennium: Employment, Equity Ownership. Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, 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; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Daratumumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Updated Results of a Phase 1/2 Study (GEN503)

Blood ◽

10.1182/blood.v126.23.507.507 ◽

2015 ◽

Vol 126 (23) ◽

pp. 507-507 ◽

Cited By ~ 24

Author(s):

Torben Plesner ◽

Hendrik-Tobias Arkenau ◽

Peter Gimsing ◽

Jakub Krejcik ◽

Charlotte Lemech ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Laryngeal Edema ◽

Advisory Committees ◽

Safety And Efficacy ◽

Duration Of Response ◽

Grade 3 ◽

Expansion Cohort

Abstract Introduction : Daratumumab (DARA) is a human anti-CD38 IgG1κ monoclonal antibody that showed synergistic anti-tumor activity in combination with lenalidomide (LEN) in in vitro preclinical studies (van der Veer M. Haematologica 2011;96(2):284-90). DARA has shown favorable safety and robust efficacy as a single agent in patients with relapsed and refractory (RR) multiple myeloma (MM) (Lokhorst HM. J Clin Oncol 2014;32 Suppl:abstr 8513. Lonial S. J Clin Oncol 2015;33 Suppl:abstr LBA8512) and in combination with LEN/Dexamethasone (DEX) in patients with relapsed or RR MM (Plesner T. Blood 2014;124(21):84). This study assessed the updated safety and efficacy of DARA in combination with LEN/DEX following more than 12 months of exposure in patients with relapsed or RR MM. Methods : The study design of this ongoing, open-label phase 1/2 study of DARA in combination with LEN/DEX has been presented previously (Plesner T. Blood 2014;124(21):84). Briefly, the study comprised a 3 + 3 design dose escalation study (DARA 2-16 mg/kg + LEN/DEX; Part 1) and a cohort expansion study using the recommended phase 2 dose (DARA 16 mg/kg + LEN/DEX; Part 2). In Part 2, patients refractory to LEN were excluded and patients with ≥1 prior line of therapy were included. In Part 2, DARA 16 mg/kg was administered weekly during the first two 28-day cycles, every other week during Cycles 3 through 6, and monthly in Cycle 7 and beyond until disease progression or unacceptable toxicity. LEN 25 mg was administered orally on Days 1 through 21 of each cycle, and DEX 40 mg was given weekly. The primary objective was safety. Efficacy was evaluated per the International Myeloma Working Group criteria. The last patient was enrolled in August 2014. Results: Updated safety and efficacy results (data cut January 9, 2015) of DARA 16 mg/kg plus LEN/DEX in the expansion cohort (n = 32) are presented. The median (range) number of prior lines of therapy was 2 (1-3) and the median (range) duration of follow up was 7.8 (3.0-10.4) months. Eleven (34%) patients received prior LEN treatment. Six (19%) patients discontinued treatment due to either disease progression (n = 3), treatment-emergent adverse events (TEAE; 1 patient with gastric adenocarcinoma and 1 patient with laryngeal edema that was a grade 3 infusion-related reaction [IRR]), or physician decision (n = 1). The most common (>25%) TEAEs included neutropenia (81%), muscle spasms (44%), cough (38%), diarrhea (34%), fatigue and hypertension (28% each). Only 1 (3%) patient experienced febrile neutropenia (grade 1). Neutropenia was the most frequently (>25%) reported grade 3 or 4 TEAE (75%). Eighteen (56%) patients had IRRs and these were generally mild to moderate and occurred mostly during the first cycle. IRRs included cough (25%), allergic rhinitis, nausea, and vomiting (9% each), as well as dyspnea, nasal congestion, and hypertension (6% each). Two (6%) patients had grade 3 IRRs (laryngeal edema and hypertension). All patients with IRRs recovered and continued to receive treatment, with the exception of the patient with grade 3 laryngeal edema, who recovered but was discontinued from treatment per protocol. The overall response rate (Rajkumar SV. Blood. 2011;117:4691-5) was 88%, with 11 (34%) partial responses and 17 (53%) ≥very good partial responses (VGPRs) that included 7 (22%) stringent complete responses, 1 (3%) complete response, and 9 (28%) VGPRs. The median time to first and best response was 1 (95% confidence interval [CI], 0.9-1.9) month and 4.5 (95% CI, 1.9-5.6) months, respectively. The median duration of response was not reached, as 26 (93%) of 28 responders had not progressed or relapsed at the time of this analysis and remained on treatment at data cutoff. Importantly, responses deepened over time in 17 (61%) of 28 responders. The 12-month duration of response will be updated at the time of ASH. Conclusions : In the expansion cohort, the combination of DARA and LEN/DEX continues to be associated with a remarkably favorable benefit/risk profile for treatment of relapsed or RR MM. Deep and durable responses were maintained throughout the study. Additional updates on the safety and efficacy results of the expansion cohort with over 12 months of exposure will be presented at the time of the meeting. Disclosures Plesner: Roche and Novartis: Research Funding; Janssen and Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees. Gimsing:Amgen: Honoraria. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria. Lisby:Genmab: Employment. Basse:Genmab A/S: Employment. Wang:Janssen: Employment. Sasser:Janssen Pharmaceuticals: Employment. Guckert:Janssen: Employment. Yeh:Janssen: Employment. Ahmadi:Janssen: Employment. Lokhorst:Genmab: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Richardson:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

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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 ◽

10.1182/blood.v116.21.2801.2801 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2801-2801 ◽

Cited By ~ 1

Author(s):

Jatin J Shah ◽

R. Donald Harvey ◽

Owen A O'Connor ◽

Andrzej J Jakubowiak ◽

Mitchell R Smith ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Dose Escalation ◽

Peripheral Blood ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Advisory Committees ◽

Dose Escalation Study

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.

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Molecular Profiling of Aggressive Non-Hodgkin Lymphoma - Results from a Phase 1/2 Preben Study

Blood ◽

10.1182/blood-2019-129113 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5314-5314

Author(s):

Suvi-Katri Leivonen ◽

Judit Jørgensen ◽

Thomas Stauffer Larsen ◽

Annika Pasanen ◽

Marja-Liisa Karjalainen-Lindsberg ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

Board Of Directors ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Advisory Committees ◽

Non Hodgkin Lymphoma ◽

Gene Expression Analyses

Background: Aggressive non-Hodgkin lymphoma (NHL) relapsing after standard first line chemotherapy represents an unmet clinical need. Currently, a phase 1/2 study with the combination of pixantrone, etoposide, bendamustine, and in CD20 positive tumors, rituximab, in patients with relapsed aggressive NHL of B- or T- cell phenotype (the PREBEN study) is ongoing. Here our aim was to molecularly characterize samples from the PREBEN trial and find clinical correlates for predicting treatment response. Methods: The profiling cohort consisted of 21 patients with pre-treatment RNA samples and clinical data. Nanostring PanCancer Pathways and PanCancer Immune profiling panels (altogether 1348 genes) were utilized for the gene expression analyses. The findings from gene expression analyses were correlated with clinical parameters. Results: Fourteen patients had diffuse large B-cell lymphoma (DLBCL), whereas seven had peripheral T-cell lymphoma (PTCL). In general, the expression of DNA replication genes distinguished DLBCL from PTCL. Additionally, gene expression analyses identified genes having differential expression based on the response to the treatment. Supervised hierarchical clustering of the ten most differentially expressed genes could separate the responding (n=4) and non-responding (n=10) DLBCL patients into two distinct subgroups (Fig. 1A). Similarly, the responding (n=3) and non-responding (n=4) PTCL patients could be separated into distinct subgroups by supervised clustering with the ten most differentially expressed genes (Fig. 1B). Conclusion: Molecular profiles of aggressive NHL are heterogeneous and may be utilized for predicting the treatment response. More detailed molecular analyses are currently ongoing. Disclosures Jørgensen: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. d'Amore:Servier: Research Funding. Leppa:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Research Funding; Bayer: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: combination of bendamustine and pixantrone for relapsed NHL

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Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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