Open-Label, Multicenter, Phase 1b Study of Daratumumab in Combination with Pomalidomide and Dexamethasone in Patients with at Least 2 Lines of Prior Therapy and Relapsed or Relapsed and Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 508-508 ◽  
Author(s):  
Ajai Chari ◽  
Sagar Lonial ◽  
Attaya Suvannasankha ◽  
Joseph W. Fay ◽  
Bertrand Arnulf ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Institutional Research ◽  
Advisory Committees ◽  
Multicenter Phase ◽  
Phase 1B ◽  
Grade 3

Abstract Introduction : Daratumumab (DARA) is a human anti-CD38 IgG1κ monoclonal antibody with remarkable safety and activity as monotherapy in heavily treated 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). DARA has demonstrated clinical activity in combination with lenalidomide (LEN) and dexamethasone (D) in relapsed or RR MM (Plesner T. Blood 2014;124(21):84). This ongoing 4-arm, multicenter, phase 1b study (NCT01998971) evaluated the safety and efficacy of DARA in combination with various backbone therapies and pomalidomide plus D (POM-D). Results in newly diagnosed patients treated with DARA and backbone therapies were previously reported (Mateos MV, et al. Haematologica 2015;100(s1):84). Methods : Patients in the DARA + POM-D arm had relapsed or RR MM with ≥2 prior lines of therapy including ≥2 consecutive cycles of LEN and bortezomib. During 28-day treatment cycles patients received DARA 16 mg/kg qw for 2 cycles, then q2w for 4 cycles, and q4w until disease progression (PD). Pomalidomide 4 mg was administered qd for 21 days with D 40 mg qw (20 mg for patients >75 years of age). The primary endpoint was safety and tolerability of DARA in combination with POM-D. Overall response rate (ORR) was a secondary endpoint. Disease responses were evaluated by an independent data safety monitoring board. Results: A total of 77 patients were enrolled into the DARA + POM-D arm. The median (range) age was 64 (35-86) years and the median number of prior therapies was 3.5 (2-10). Sixty-five percent of the patients were refractory to bortezomib, 30% to carfilzomib, 88% to lenalidomide, and 65% to both a PI and IMiD. With a median (range) duration of follow-up of 72 (1-423) days, 28 (36%) patients have discontinued treatment due to PD (15 [20%]), adverse events (AEs; 6 [8%]), death or physician's decision (3 [4%] each), and one (1%) patient withdrawal. The median (range) duration of treatment was 69 days (1-416), and the median (range) number of infusions was 7.5 (1-25). Forty-nine (64%) patients continue on study treatment and enrollment is ongoing. There was little additional toxicity when DARA was added to POM-D other than DARA-specific infusion related reactions (IRRs; 47/77 patients). Most occurred on Cycle 1 Day 1 (45/47 patients), and the most common (>10%) IRRs were chills (13%), cough (13%), and dyspnea (11%). The most common (>10%) and grade ≥3 adverse events (AEs) are presented in Table 1. Five patients died within 30 days of receiving study treatment due to AEs (4[5%]) or progressive disease (1 [1%]). In 53 patients with >1 post-baseline assessment, the ORR was 58.5%, with 3 stringent complete responses (sCR), 1 complete response (CR), 12 very good partial responses (VGPR), 15 partial responses (PR), 2 minimal responses, 18 stable disease, and 2 PD. Many responses deepened over time. Median (range) time to first response was 30 (28-92) days. After a median follow-up of 148 days, 4 out of 31 responders developed PD. Among the evaluable double refractory patients (n = 40), there was 1 sCR, 1 CR, 10 VGPRs, and 11 PRs with an ORR of 57.5%. Conclusions : The addition of DARA to POM-D was well tolerated and did not result in additional toxicities with the exception of DARA-related infusion reactions. Deep and durable responses were observed quickly, along with a high response rate. Study enrollment is ongoing and data will be updated at the meeting. Table 1. Most Common (>10%) Adverse Events (N = 77) Adverse Event, n (%) Any Grade Grade ≥3 Neutropenia 42 (54.5%) 39 (50.6%) Anemia 28 (36.4%) 16 (20.8%) Fatigue 28 (36.4%) 4 (5.2%) Cough 24 (31.2%) 0 Nausea 21 (27.3%) 0 Dyspnea 20 (26.0%) 5 (6.5%) Diarrhea 19 (24.7%) 1 (1.3%) Leukopenia 19 (24.7%) 12 (15.6%) Thrombocytopenia 17 (22.1%) 8 (10.4%) Pyrexia 16 (20.8%) 1 (1.3%) Dizziness 15 (19.5%) 0 Chills 14 (18.2%) 0 Nasal Congestion 14 (18.2%) 0 Upper Respiratory Tract Infection 14 (18.2%) 1 (1.3%) Back Pain 13 (16.9%) 2 (2.6%) Constipation 13 (16.9%) 0 Tremor 13 (16.9%) 2 (2.6%) Insomnia 12 (15.6%) 1 (1.3%) Lymphopenia 11 (14.3%) 7 (9.1%) Muscle Spasms 11 (14.3%) 0 Vomiting 11 (14.3%) 0 Arthralgia 9 (11.7%) 1 (1.3%) Pruritus 9 (11.7%) 0 Throat Irritation 9 (11.7%) 0 Anxiety 8 (10.4%) 0 Headache 8 (10.4%) 0 Hypertension 8 (10.4%) 4 (5.2%) Musculoskeletal Chest Pain 8 (10.4%) 2 (2.6%) Peripheral Edema 8 (10.4%) 1 (1.3%) Disclosures Chari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Novartis: Consultancy, Research Funding; Biotest: Other: Institutional Research Funding; Onyx: Consultancy, Research Funding. Lonial:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Suvannasankha:Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding. Arnulf:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Qin:Janssen: Employment. Masterson:Janssen: Employment. Nottage:Janssen: Employment. Schecter:Janssen: Employment. Ahmadi:Janssen: Employment. Weiss:Janssen and Millennium: Consultancy; Janssen and Onclave: Research Funding. Krishnan:Millenium: Speakers Bureau; BMS: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Onyx: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Lentzsch:Celgene: Consultancy; Janssen: Consultancy; Axiom: Honoraria; Novartis: Consultancy; BMS: Consultancy.

scholarly journals A Phase I/II Study of Lenalidomide Plus Obinutuzumab in Relapsed Indolent Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 348-348 ◽  
Author(s):  
Nathan H Fowler ◽  
Loretta J. Nastoupil ◽  
Collin Chin ◽  
Paolo Strati ◽  
Fredrick B. Hagemeister ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Marginal Zone ◽  
Advisory Board ◽  
Indolent Lymphoma ◽  
Advisory Committees ◽  
Grade 3

Background: Patients with advanced indolent non-Hodgkin lymphoma (iNHL) can develop chemoresistance and most relapse following standard therapy. Although multiple treatment options exist, most are associated with short remission or intolerable side effects. Lenalidomide activates NK cells ± T cells and leads to in vivo expansion of immune effector cells in NHL models. The combination of rituximab and lenalidomide (R2) in relapsed iNHL is highly active and was recently approved. Obinutuzumab is a glycosylated type II anti-CD20 molecule with enhanced affinity for the FcγRIIIa receptors leading to improved ADCC. The primary objective of this phase I/II study was to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide and obinutuzumab in relapsed indolent lymphoma. Methods: Patients with relapsed small lymphocytic lymphoma (SLL), marginal zone, and follicular lymphoma (gr 1-3a) were eligible. Patients enrolled in three predefined dose cohorts of lenalidomide (10mg,15mg, 20mg) given on days 2-22 of a 28 day cycle. Obinutuzumab was given at a fixed dose (1000mg) IV on days 1,8,15 and 22 of cycle 1 and day 1 of subsequent cycles for 6 cycles. The combination was given for up to 12 cycles in responding pts. Antihistamines were given in pts who developed rash. Prophylactic growth factor was not allowed. In the absence of progression or toxicity, single agent obinutuzumab was continued every 2 months for maximum of 30 months on study. Traditional 3+3 dose escalation was used with dose limiting toxicities (DLT) assessed during cycle 1. Once the MTD was established, 60 additional patients were enrolled in the phase II portion of the study. Adverse events were graded using CTCAE version 4.03. Results: 66 pts were enrolled between May 2014 until March 2019, and all are eligible for safety and response assessment. No DLTs were observed in dose escalation, and 60 pts were enrolled in the phase II portion of the study at 20mg of lenalidomide daily. Histologies included follicular lymphoma (FL) n=57, marginal zone n=4, SLL n=5. The median age was 64 (36-81), with 2 (1-5) median prior lines of treatment. For 53% of pts, the combination represented the third or greater line of treatment. The overall response (OR) rate for all pts was 98% with 72% attaining a complete response (CR). Eighteen pts (27%) had a partial response, and stable disease was noted in 1 (2%). At a median follow up of 17 months, 14 pts have progressed, with an estimated 24mo progression-free survival (PFS) of 73% (57-83% 95% CI). The estimated 24 mo PFS for ≥ third line pts was 63%. Twenty five pts (38%) remain on treatment and 95% remain alive at last follow up. The most common grade ≥ 3 non-hematologic toxicities included fatigue (5 pts), rash (4 pts), and cough (3 pts). Grade ≥3 neutropenia and thrombocytopenia occurred in 11 (17%) and 7 (11%) pts respectively. Two pts stopped treatment due to adverse events, including 1 transient bradycardia and 1 grade 3 fatigue. Conclusion: The combination of 20 mg of lenalidomide and 1000mg obinutuzumab is safe and effective in patients with relapsed indolent lymphoma. Adverse events appeared similar to our prior experience with lenalidomide and rituximab and were generally well tolerated. Overall response rates were high, with many pts achieving prolonged remission, including pts who had relapsed after 2 or more lines of prior therapy. Validation studies in the frontline and salvage setting are ongoing. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: 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, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; MorphoSys: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Neelapu:Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding; Cellectis: Research Funding; Novartis: Consultancy; BMS: Research Funding; Karus: Research Funding; Acerta: Research Funding; Poseida: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Celgene: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Allogene: Consultancy; Pfizer: Consultancy; Cell Medica: Consultancy.

scholarly journals Ixazomib-Lenalidomide-Dexamethasone (IRd) Consolidation Following Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma: A Large Multi-Center Phase II Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 123-123 ◽  
Author(s):  
Ravi Vij ◽  
Nitya Nathwani ◽  
Thomas G. Martin ◽  
Mark A. Fiala ◽  
Abhinav Deol ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Hematologic Toxicity ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Oral Regimen ◽  
Grade 3

Abstract Background: Maintenance therapy post-autologous stem cell transplantation (ASCT) has shown to improve progression-free and overall survival in multiple myeloma (MM) and has largely become the standard of care. Consolidation therapy, a brief duration of more-intensive chemotherapy administered prior to maintenance, has been shown to further deepen responses and may improve long-term outcomes. Ixazomib, lenalidomide and dexamethasone (IRd) is an all oral regimen that has been shown to be active in newly diagnosed MM as well as relapsed disease. In this study, we are analyzing the safety and efficacy of IRd as consolidation therapy after ASCT (NCT02253316). Methods: Eligible patients, age 18-70 with newly diagnosed MM undergoing ASCT during first-line treatment, are being consented prior to ASCT. Approximately 4 months following ASCT, patients receive 4 cycles of consolidation therapy with IRd [ixazomib 4 mg on days 1, 8 and 15 of a 28-day cycle, lenalidomide 15 mg on days 1 through 21, and dexamethasone 40 mg on days 1, 8 and 15]. The primary end point is minimal residual disease (MRD) status. MRD is being assessed by ClonoSEQ where possible and by multi-color flow where not. Toxicity, IMWG response rate, PFS, and OS are secondary end points. One month after the last consolidation cycle, patients are randomized (1:1) to maintenance therapy with single-agent ixazomib (4 mg on days 1, 8 and 15) or lenalidomide (15 mg daily). In total, 240 patients will be enrolled on the trial. This presentation coincides with planned interim analysis 2 which included data from the consolidation phase only. Results: As of July 2018, 172 patients with NDMM have been enrolled from 10 centers within the US. The median age was 57 (range 28-70) and 67% were male. 76% were white, 10% African-American/Black, and 13% were another race. 39% were ISS Stage I, 30% were Stage II, and 20% were Stage III. All patients received proteasome inhibitors and/or IMIDs as front-line induction and melphalan as conditioning for ASCT. IRd consolidation started at a median of 110 days post-ASCT (range 80-138). IRd has been well tolerated. Only 4% (6/154) of patients have been unable to complete the 4 cycles of consolidation to date due to toxicity. Grade 3 hematologic toxicity has been uncommon; 4% neutropenia, 3% thrombocytopenia, and 2% anemia. There has been no grade 4 hematologic toxicity. Non-hematologic grade 3-4 toxicities have included: infection (8%), nausea/vomiting/diarrhea (3%), and transaminitis (1%). No grade 3-4 peripheral neuropathy has been reported. One case of grade 5 pneumonia was reported but was not considered related to study treatment. Following ASCT, the MRD-negative rate was 26% and this improved to 37% following consolidation. In the subset of patients with Clonoseq results available, the MRD negative rate improved from 19% to 27%. Clinical response rate improved similarly; prior to consolidation the VGPR or better rate was 76% including 39% CR/sCR. Following consolidation, the VGPR or better rate was 85% including 56% CR/sCR. 137 patients went on to receive maintenance with either ixazomib (n = 71) or lenalidomide (n = 66). At time of submission, the median follow-up from start of IRd is 14 months and 28 patients have relapsed/progressed and 6 have expired. An interim analysis is planned for 2019, representing the first comparison of ixazomib and lenalidomide maintenance. Conclusion: IRd consolidation following ASCT appears to be safe and effective. The all oral regimen is convenient for patients which greatly simplifies follow-up in the peri-transplant period. Study enrollment is scheduled to complete in Q1 of 2019. Disclosures Vij: Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees. Martin:Amgen: Research Funding; Sanofi: Research Funding; Roche: Consultancy. Deol:Kite Pharmaceuticals: Consultancy; Novartis: Consultancy. Kaufman:Janssen: Consultancy; Karyopharm: Other: data monitoring committee; BMS: Consultancy; Abbvie: Consultancy; Roche: Consultancy. Hofmeister:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: 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; Bristol-Myers Squibb: Research Funding. Gregory:Poseida Therapeutics, Inc.: Research Funding. Berdeja:Amgen: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Bluebird: Research Funding; Genentech: Research Funding; Glenmark: Research Funding; Novartis: Research Funding; Teva: Research Funding; Sanofi: Research Funding. Chari:Pharmacyclics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; The Binding Site: Consultancy.

Ricolinostat (ACY-1215), the First Selective HDAC6 Inhibitor, in Combination with Bortezomib and Dexamethasone in Patients with Relapsed or Relapsed-and-Refractory Multiple Myeloma: Phase 1b Results (ACY-100 Study)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1827-1827 ◽  
Author(s):  
Dan T. Vogl ◽  
Noopur S. Raje ◽  
Sundar Jagannath ◽  
Paul G. Richardson ◽  
Parameswaran Hari ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Clinical Benefit ◽  
Research Funding ◽  
Low Grade ◽  
Advisory Committees ◽  
Acetylated Tubulin ◽  
Clinical Benefit Rate ◽  
Phase 1B ◽  
Grade 3

Abstract Background: Ricolinostat, an oral selective HDAC6 inhibitor, is well tolerated as monotherapy (Raje Blood 2012;120:4061). HDAC6 inhibition impairs the aggresome/autophagy pathway, an alternate pathway to proteasome clearance of misfolded proteins (Santo Blood 2012;119:2578-89) providing the rationale for combining ricolinostat with bortezomib (Btz). Pan-HDAC inhibitors vorinostat and panobinostat are active in multiple myeloma (MM) in combo with Btz, but toxicities (thrombocytopenia, fatigue, and GI events) limit dosing exposure. This trial explores activity of ricolinostat in combo with Btz and dexamethasone (Dex) in patients with relapsed or relapsed-and-refractory MM. Methods: Phase 1b was a 3+3 design that explored ricolinostat combined with Btz (1.0-1.3 mg/m2 IV or SQ on days 1, 4, 8, 11) and Dex (20 mg PO on days 1, 2, 4, 5, 8, 9, 11, 12). Patients previously received at least 2 lines of therapy including a proteasome inhibitor and an immunomodulatory agent, had either progressed after or were ineligible for autologous stem cell transplant, and had adequate BM reserve, hepatic function and CrCl ≥30 mL/min. Patients with prior HDAC inhibitor therapy were excluded. Peripheral blood samples were obtained for PK/PD assessment of acetylated tubulin and histones. Results: 50 patients were enrolled to 8 combination dose cohorts to date. Median age was 65, median number of prior regimens was 5 (2-12) and 33 patients were refractory to Btz. The first combination cohort was expanded due to a DLT of asymptomatic increase in amylase. No other DLTs have been observed in the cohort escalations. Common toxicities were predominately low grade (grade 1/2) and included diarrhea (46%), anemia (38%), thrombocytopenia (22%), increased creatinine (18%), fatigue (16%), and nausea (16%). Important grade 3/4 related toxicity included thrombocytopenia (9 patients, 18%) and anemia (6 patients, 12%). Cohorts were expanded sequentially at two dose levels: 160 mg BID and 160 mg QD. Of the 22 patients receiving ricolinostat 160 mg BID common toxicities were diarrhea (68%, grade 1/2), thrombocytopenia (50%, grade 3/4), anemia (45%, grade 2/3), fatigue (36%, grade 1/2), and nausea (36%, grade 1/2). There was a marked increase in the incidence of SAEs related to diarrhea leading to dehydration and hospitalization (27%). Therefore a second cohort expansion at 160 mg QD was initiated. Of the 15 patients receiving ricolinostat at 160 or 240 mg QD common toxicities were diarrhea (33%, grade 1/2), thrombocytopenia (20%, grade 4), anemia (20%, grade 3), increased creatinine (20%, grade 3), hyponatremia (20%, grade 1), and increased ALT (20% grade 3), and peripheral neuropathy (20%, grade 1/2). PK for ricolinostat is similar to that observed in Phase 1a monotherapy, indicating that co-administration of Btz does not significantly impact ricolinostat exposure. Maximal blood levels of ricolinostat were ≥0.5 µM at ≥80 mg correlating with a >2x increase in the HDAC6 PD marker acetylated tubulin. 48 patients were evaluable for response with median follow-up of 3 (1-18) months; ORR (≥PR) was 39% and clinical benefit rate (≥MR) was 44% with 81% SD or better. Of the 22 patients receiving ricolinostat 160 mg BID with median follow-up of 3 (1-18) months, ORR (≥PR) was 32% and clinical benefit rate (≥MR) was 41% with 62% SD or better. Of the 12 patients receiving ricolinostat at 160 or 240 mg QD with median follow-up of 4 (1-8) months, ORR (≥PR) was 33% and clinical benefit rate (≥MR) was 33% with 67% SD or better. Of the 33 Btz refractory patients, 42% had SD or better, and 12% responded including 1 VGPR. Conclusion: Overall, ricolinostat in combination with Btz and Dex was well tolerated. Diarrhea and hematologic toxicity, mostly low grade, was less prevalent with QD than BID dosing and led to fewer hospitalizations and early treatment discontinuation. Response rates were similar between both QD and BID dosing. 160 mg QD is the recommended dose in combination with Btz and Dex. Disclosures Vogl: Constellation Pharmaceuticals: Research Funding; GSK: Research Funding; Millennium Pharmaceuticals: Research Funding; Calithera Biosciences: Research Funding; Celgene Corporation: Consultancy; Acetylon Pharmaceuticals, Inc.: Research Funding. Raje:Acetylon: Research Funding; Amgen: Consultancy; Eli Lilly: Research Funding; Onyx: Consultancy; Celgene Corporation: Consultancy; AstraZeneca: Research Funding; BMS: Consultancy; Takeda: Consultancy; Millenium: Consultancy; Novartis: Consultancy. Jagannath:Celgene: Honoraria; MERCK: Honoraria; Janssen: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria; BMS: Honoraria. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hari:Sanofi: Consultancy; Takeda: Consultancy; Spectrum: Consultancy; Novartis: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy. Orlowski:Millennium Pharmaceuticals: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Acetylon: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Spectrum Pharmaceuticals: Research Funding; Forma Therapeutics: Consultancy. Tamang:Acetylon Pharmaceuticals, Inc.: Employment. Jones:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Wheeler:Acetylon Pharmaceuticals, Inc: Employment. Markelewicz:Acetylon Pharmaceuticals, Inc: Employment. Lonial:Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

scholarly journals A Phase Ib/II Study of Ibrutinib in Combination with Obinutuzumab-Gazyva As First-Line Treatment for Patients with Chronic Lymphocytic Leukemia > 65 Years Old or with Coexisting Conditions

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1863-1863
Author(s):  
Juliana Velez Lujan ◽  
Michael Y. Choi ◽  
Chaja Jacobs ◽  
Colin McCarthy ◽  
Alaina Heinen ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Grade 3

Abstract Standard treatment for patients with chronic lymphocytic leukemia (CLL) is rapidly evolving and gradually has incorporated the combined use of monoclonal antibodies (mAbs) and targeted therapy with small molecules. Single agent Ibrutinib (Ibr), a first-in-class BTK inhibitor, is effective in previously untreated patients including those that are older than 65 or considered unfit to receive chemotherapy-based combinations. The complete response rate in patients receiving single agent Ibr is relatively low (overall response rate of 86% and complete response of 4% based on 2008 iwCLL criteria), though most patients have durable remissions. The combination of Ibr with mAbs like Obinutuzumab-Gazyva (G), a third-generation anti-CD20 mAb, can ameliorate the Ibr-induced lymphocytosis and increase the overall and complete response rates. Accordingly, we initiated an open-label phase Ib/II clinical study of Ibr in combination with G for first-line therapy of previous untreated pts with CLL. The study completed enrollment of 32 previously untreated patients with CLL. Patients received G administered based on FDA dosing recommendations for 6 cycles (28 days/cycle) and Ibr 420mg po (1-3 hours before starting G infusion), and daily for up to 3 years. All patients received prophylactic medications. Patients were assessed for response by 2008 iwCLL criteria two months after completion of G, as the primary efficacy endpoint. The median age of the patients was 65 (range: 46-78) years. 84% of the patients had a CIRS >6, 45% had a Rai stage III-IV and 19% had an ECOG performance ≤2. The median baseline absolute lymphocyte count (ALC) was 79x103/mm3(range: 1.4-412.4). Patients showed the following FISH/cytogenetic abnormalities: del(13q) in 55%, trisomy 12 in 23% and del(11q) in 19%. Only 2 (6%) of these patients showed del(17p). From the patients with IGVH mutational status available (n=17), 11 (65%) were unmutated (>98% homology). Most adverse events (AEs) were grade 1-2 (74%). Six patients (19%) had grade 1-2 G-infusion-related reaction (IRR) and only one patient (3%) showed grade 3 IRR (without the need for G discontinuation). We observed neutropenia (all grades: 52%, grade 3-4: 23%), thrombocytopenia (all grades: 71%, grade 3-4: 19%) and anemia (all grades: 26%). There were no cases of febrile neutropenia. Two patients (6%) had grade 1 bleeding (one patient with asymptomatic lower gastrointestinal bleeding and the second patient with epistaxis) that resolved spontaneously without requirement of blood transfusion or study treatment discontinuation. Two patients (6%) developed pneumonia, one was community-acquired pneumonia requiring inpatient treatment with IV antibiotics; the study treatment was held until resolution of symptoms and re-initiated at full dose. The most frequent non-hematological AEs were diarrhea, transaminitis, hyperbilirubinemia, hyperglycemia, and electrolyte alterations (grade 1-2). Three patients (9%) discontinued Ibr due to atrial fibrillation grade 1 (n=1), rash and headaches grade 2 (n=1), and persistent grade 4 thrombocytopenia (n=1). Twenty-three patients were evaluable for response assessment by 2008 iwCLL criteria (median follow-up of 11 months). 84% of the patients showed a rapid decrease in ALC from baseline during the first cycle of treatment and only four patients (13%) required more than 3 cycles of treatment to achieve an ALC response. The overall response rate was 100%. The majority of pts had a partial response and six of 23 evaluable patients (26%) achieved a complete remission with detectable Minimal Residual Disease in the bone marrow by multiparametric flow cytometry. In summary, Ibr-G combination has been generally well tolerated. AEs have been consistent with the known safety profiles of Ibr and G individually. The patients that discontinued Ibr remain in follow-up without disease progression. 100% of evaluable patients achieved response after 6 months of combination therapy, and 26% of patients met CR criteria. One important finding thus far has been a very low rate of IRR, (19% grade 1-2 and 3% grade 3-4), suggesting that Ibr can strongly mitigate the incidence and severity of G associated IRR. Disclosures Choi: AbbVie, Inc: Consultancy, Speakers Bureau; Rigel: Consultancy; Gilead: Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Speakers Bureau. Amaya-Chanaga:AbbVie: Equity Ownership, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.; Pharmacyclics, an AbbVie Company: Employment, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.. Kipps:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy; Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Genentech Inc: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Castro:F. Hoffmann-La Roche: Consultancy; Genentech, Inc: Consultancy; Pharmacyclics, LLC, an AbbVie Company:: Consultancy.

A Phase 1b, Dose-Finding Study Of Ruxolitinib Plus Panobinostat In Patients With Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (PPV-MF), Or Post–Essential Thrombocythemia MF (PET-MF): Identification Of The Recommended Phase 2 Dose

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4045-4045 ◽  
Author(s):  
Vincen t Ribrag ◽  
Claire N Harrison ◽  
Florian H Heidel ◽  
Jean-Jacques Kiladjian ◽  
Suddhasatta Acharyya ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 2 ◽  
Advisory Committees ◽  
Expansion Phase ◽  
Phase 1B ◽  
Grade 3

Abstract Background Myelofibrosis (MF) is a myeloproliferative neoplasm associated with progressive, debilitating symptoms that impact patient quality of life (QoL) and reduce survival. Ruxolitinib (RUX), a potent dual JAK1/JAK2 inhibitor, demonstrated superiority in spleen volume and symptom reduction, improved health-related QoL measures, and prolonged survival compared with traditional therapies or placebo in the phase 3 COMFORT studies. Panobinostat (PAN) is a potent oral pan-deacetylase inhibitor (DACi) that inhibits JAK pathway signaling through increased acetylation of the JAK2 protein chaperone HSP90. In phase 1/2 studies in MF, PAN has shown reduction in splenomegaly and JAK2 V617F allele burden, and improvement of marrow fibrosis. RUX and PAN demonstrated synergistic anti-MF activity in JAK2-mutation–driven MF murine models. Here, we present the results of a phase 1b study to determine the recommended phase 2 dose (RP2D) of the combination of RUX and PAN in MF patients. Methods Patients with intermediate-1, -2, or high-risk MF by International Prognostic Scoring System criteria and with palpable splenomegaly ≥ 5 cm below the costal margin were enrolled. Dose escalation was guided by a Bayesian logistic regression model with overdose control based on dose-limiting toxicities (DLTs) in the first cycle along with other safety findings. DLTs were defined as protocol-specified toxicities related to treatment but unrelated to disease progression, intercurrent illness, or concomitant medications, occurring up to and including cycle 1 day 28, that are considered severe enough to prevent continuation of treatment. Each dosing cohort consisted of ≥ 3 evaluable patients. Data for ≥ 9 patients were required to determine the preliminary RP2D and/or maximum tolerated dose (MTD). Following determination of the preliminary RP2D, additional patients were to be enrolled and treated at that dose in the safety-expansion phase. The range of dose levels tested for RUX was 5-15 mg twice daily (BID) and for PAN was 10-25 mg once daily, 3 times a week (TIW; days 2, 4, and 6), every other week (QOW) in a 28-day cycle. Serial blood samples collected following the first dose of RUX alone on day 1 and in combination with PAN on days 2 and 6 were evaluated for plasma concentrations of RUX (days 1, 2, and 6) and PAN (days 2 and 6) by LC-MS/MS. Pharmacokinetic parameters were derived using noncompartmental analysis. Spleen size was determined by palpation. Results A total of 38 patients have been enrolled across 6 cohorts in the dose-escalation phase. Preliminary data presented here are based on a cutoff date of March 7, 2013. Thirteen patients (34.2%) have discontinued study treatment. Reasons for discontinuation include disease progression (n = 4), adverse events (n = 7), withdrawal of consent (n = 1), and death due to pulmonary embolism (n = 1). The most common grade 3/4 adverse events were anemia (34.2%), thrombocytopenia (21.2%), abdominal pain (7.9%), and diarrhea (7.9%). QTc prolongation of > 500 ms was observed in 1 patient in cohort 4. DLTs are summarized in the Table. An approximate 50% increase in plasma exposure of both RUX and PAN on day 6 from respective baselines suggested drug-drug interaction (DDI) at 15 mg RUX and 25 mg PAN. The RP2D was defined at the cohort 6 dose and schedule. Evidence of preliminary activity was observed across all cohorts with 28 patients (73.7%) showing ≥ 50% decrease in palpable spleen length at some point during the study. Conclusions The combination of RUX and PAN has a tolerable safety profile, with few DLTs and acceptable rates of grade 3/4 anemia and thrombocytopenia. Also, encouraging splenomegaly reduction was seen in the dose-escalation phase. The MTD was not reached; however, due primarily to findings of anemia and potential DDI in dose cohort 6, preliminary RP2D was identified at RUX 15 mg BID/PAN 25 mg TIW/QOW and will be confirmed in the dose-expansion phase. Additional safety and efficacy data from patients in the expansion phase will be presented. Disclosures: Ribrag: Takeda: Membership on an entity’s Board of Directors or advisory committees; Bayer: Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Johnson & Johnson : Honoraria, Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Ruxolitinib is approved for MF but panobinostat is not approved anywhere globally at this time for any indication. Harrison:S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Shire: Speakers Bureau; Celgene: Honoraria; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Heidel:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kiladjian:AOP Orphan: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Acharyya:Novartis: Employment. Mu:Novartis: Employment. Liu:Novartis: Employment. Williams:Novartis: Employment. Giles:Novartis: Consultancy, Research Funding. Conneally:Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kindler:Novartis: Membership on an entity’s Board of Directors or advisory committees. Passamonti:sanofi-aventis: Honoraria; Incyte: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Vannucchi:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Phase 1b Study of PD-1 Blockade with Pembrolizumab in Patients with Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3986-3986 ◽  
Author(s):  
Pier Luigi Zinzani ◽  
Vincent Ribrag ◽  
Craig H. Moskowitz ◽  
Jean-Marie Michot ◽  
John Kuruvilla ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Employment Equity ◽  
Advisory Committees ◽  
Humanized Monoclonal Antibody ◽  
Heavily Pretreated ◽  
Phase 1B ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Like classical Hodgkin lymphoma (cHL), PMBCL frequently harbors genetic alterations of the 9p24.1 locus, leading to overexpression of the PD-1 ligands, PD-L1 and PD-L2. This provides a possible mechanism of immune evasion and suggests that PMBCL could have a genetically determined vulnerability to PD-1 blockade. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands. Pembrolizumab has already demonstrated robust antitumor activity in advanced solid tumors and in cHL. KEYNOTE-013 (NCT01953692) is a multicenter, multicohort phase 1b trial testing the safety and preliminary efficacy of pembrolizumab in patients with hematologic malignancies. Based on its genetics, PMBCL was included as an independent cohort in this trial. Here we report the preliminary results in this patient population. Methods: The PMBCL cohort of KEYNOTE-013 is enrolling patients with relapsed/refractory (R/R) disease who have relapsed after or are ineligible for autologous stem cell transplant (ASCT). Pembrolizumab is administered intravenously at a dose of 10 mg/kg every 2 weeks for up to 2 years or until confirmed disease progression or unacceptable toxicity. The primary end points are safety and antitumor activity. Response is being evaluated using computed tomography (CT) and positron emission tomography (PET) at week 12 and every 8 weeks thereafter, using IHP 2007 criteria. Other end points include complete remission (CR) rate, duration of response (DOR), and exploratory biomarker analyses. Results: As of July 23, 2015, 10 patients with R/R PMBCL with a median age of 28 (23-62) years have been enrolled in this cohort. Patients were heavily pretreated: 40% had ≥4 prior lines of therapy, and 60% had prior radiation. Six patients (60%) experienced at least 1 adverse event (AE) of any grade related to study treatment. These treatment-related AEs, all grade 1/2, were: hypothyroidism and decreased appetite (2 patients each), and diarrhea, nausea, vomiting, fatigue, edema, weight loss, and arthralgia (1 patient each). There were no grade 3-5 treatment-related AEs. Two patients experienced a serious AE (grade 3 infectious pneumonia) unrelated to study drug. No patient discontinued for toxicity. Nine patients were evaluable for response (1 discontinued treatment based on clinical progression before week 12). The objective response rate (ORR) was 44% (4/9), with 1 patient achieving a CR and 3 patients achieving a partial response. The intent-to-treat ORR was 40%. With a median follow-up of 144 days, the median DOR has not been reached (1+ to 291+) days, with all 4 responses ongoing at the time of data cutoff. Six of 10 patients have discontinued study treatment because of disease progression, and 4 patients remain on study. Conclusion: The preliminary results of KEYNOTE-013 indicate that PD-1 blockade with pembrolizumab is associated with a tolerable safety profile and a promising response rate in heavily pretreated patients with R/R PMBCL. Those patients often have a very poor outcome with conventional therapy, justifying further studies of pembrolizumab in this population. Disclosures Zinzani: Gilead: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Off Label Use: The PD-1 pathway is an important mechanism of immune evasion for many tumors. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction of PD-1 with its ligands PD-L1 and PD-L2 on the tumor cell surface and, based upon pembrolizumab's antitumor immune activity in several solid tumors, it may be an effective option for treating hematological malignancies.. Ribrag:Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Moskowitz:Genentech: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Hoffmann LaRoche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy; Karyopharm: Honoraria. Balakumaran:Merck: Employment, Equity Ownership; Amgen: Equity Ownership. Snyder:Merck: Employment, Equity Ownership. Marinello:Merck: Employment, Equity Ownership. Shipp:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Armand:Infinity: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Sequenta, Inc.: Research Funding; BMS: Research Funding.

scholarly journals Natural History of Non-Infectious, Ibrutinib-Attributable Adverse Events Leading to Alternative BTK Inhibitor Use in CLL

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4385-4385 ◽  
Author(s):  
Polina Shindiapina ◽  
Soun Khountham ◽  
Kerry A. Rogers ◽  
Jeffrey Jones ◽  
Leslie Andritsos ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Subsequent Treatment ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Btk Inhibitor ◽  
Grade 3 ◽  
Target Effect

Abstract Introduction: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (IB) is currently approved for the treatment of patients with chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL), including patients with del17p disease. Treatment with IB is effective and generally well-tolerated. However, a proportion of patients experience intolerable adverse events (AEs) requiring IB discontinuation. Non-infectious toxicities are generally considered to be due to kinase inhibition and it is uncertain if the AE is directly attributable to inhibition of BTK (on-target effect) or to inhibition of an alternative target of ibrutinib (off-target effect). To indirectly examine this, we reviewed toxicity and tolerability data for patients who discontinued IB due to significant AEs and subsequently received an alternative BTK inhibitor. Methods: Patients with previously treated CLL/SLL who were intolerant to IB due to non-infectious IB-attributable AEs and subsequently received a different BTK inhibitor were included in this analysis. Patients with infectious AEs were excluded. AEs arising during IB therapy that were attributable to IB and resulted in discontinuation based on both patient and investigator preference were detailed and graded according to CTCAE v.4.03. These AEs were assessed for resolution or increasing severity after discontinuing IB both before and during subsequent BTK inhibitor treatment. Results: Twenty-one patients were included in the analysis and the median age was 61-years (range 50-76). Patients had received a median of 4 prior therapies (range 2-11). Fifty-eight percent of the patients had Rai stage 3-4 disease, 76% were IGHV un-mutated, and 57% had del17p. Prevalent co-morbidities by organ system prior to start of acalabrutinib included blood and lymphatic system disorders (48%), infectious issues (52%), cardiac disorders (38%), gastrointestinal disorders (43%) and musculoskeletal disorders (33%). Median time on IB was 13 months (range 1.6-62). Reasons for IB discontinuation are detailed in Table 1. With regards to more severe (grade 3 or 4) IB-attributable AEs, 2 patients experienced grade 4 AEs resulting in discontinuation of IB including neutropenia and subdural hematoma. Both these patients had resolution of their AEs prior to starting subsequent treatment. Among the 14 patients discontinuing IB for grade 3 AEs, 1 had ongoing grade 3 diarrhea, 1 had grade 3 arthralgia, and 2 had grade 2 AEs of diarrhea and fatigue at the time of starting subsequent treatment. Of the 21 included patients, 10 had ongoing IB-attributable grade 1-3 AEs at the time of starting a different BTK inhibitor. Three of these patients experienced resolution of one or more IB-attributable AEs (grade 3 diarrhea, and grade 2 AEs including panniculitis, arthralgia and diarrhea) within 28 days of starting therapy, 6 patients had stable grade 1-2 AEs (grade 1 rash in 2 patients, grade 2 diarrhea, grade 1 arthralgia, grade 1 abdominal pain, grade 2 fatigue) at last follow up while taking alternate BTK inhibitor, and 1 patient with an ongoing grade 2 AE at time of treatment initiation developed CNS involvement with their malignancy and was taken off therapy prior to assessment for resolution of the AE. The remaining 11 patients had either complete resolution or improvement of the AE to grade 1 prior to starting the treatment. No recurrence or worsening of IB-attributable AEs were observed during a median follow-up of 13-months on alternative treatment except for 1 patient with hemophilia A, who developed grade 3 hematoma while on IB therapy and experienced recurrent hematoma after 5 days of treatment with a different BTK inhibitor, at which time the drug was discontinued. Conclusions: For patients who discontinued IB due to non-infectious IB-attributable AEs, subsequent treatment with an alternative BTK inhibitor does not appear to aggravate or precipitate IB-attributable AEs that had previously resulted in discontinuation. This supports attribution of these AEs to off-target effects of ibrutinib and not inhibition of BTK. The use of an alternate BTK inhibitor may be a viable therapeutic strategy for patients who discontinued IB due to intolerable AEs without experiencing clinical progression. Disclosures Jones: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Woyach:Karyopharm: Research Funding; Morphosys: Research Funding; Acerta: Research Funding. Awan:Innate Pharma: Research Funding; Novartis Oncology: Consultancy; Pharmacyclics: Consultancy.

Bortezomib, Lenalidomide, and Dexamethasone (VRD) Consolidation and Lenalidomide Maintenance in Frontline Multiple Myeloma Patients: Updated Results of the IFM 2008 Phase II VRD Intensive Program

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1872-1872 ◽  
Author(s):  
Murielle Roussel ◽  
Nelly Robillard ◽  
Philippe Moreau ◽  
Lotfi Benboubker ◽  
Cyrille Hulin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Safety Profile ◽  
Research Funding ◽  
Response Rate ◽  
Advisory Board ◽  
Consolidation Therapy ◽  
Advisory Committees ◽  
Duration Of Response ◽  
Grade 3

Abstract Abstract 1872 Background: Introduction of new drugs in the intensive pathway have markedly increased survival rates for MM patients within the last 10 years. Efforts to further improve response and survival are still needed, mainly by increasing the depth of tumor reduction and the duration of response. Bortezomib (Bor), Lenalidomide (Len) and Dexamethasone (Dex) combination demonstrated substantial activity in frontline MM (Richardson P et al., Blood 2010); the IFM reported primary results of the VRD regimen as induction and consolidation therapy in the transplant setting (Roussel M et al. ASH 2010). We currently present updated data of the IFM 2008 trial. Methods: This phase II study was conducted at 10 transplant centers in France, with enrollment between Sept. 7 and Dec. 15, 2009. Pts with symptomatic upfront MM were enrolled to receive three 21-day induction cycles of VRD= Bor 1.3 mg/m2 (D1, 4, 8, 11), Len 25 mg/day (D1–14), and Dex 40 mg/day once a week (D1, 8 and 15). Stem cell collection (STC) was planned after high dose cyclophosphamide (3g/m2). All pts then proceeded to melphalan 200 mg/m2 followed by ASCT. Two months after hematological recovery, pts received two 21-day consolidation cycles of VRD (same schedule) followed by 1 year of maintenance with Len at 15 mg/day. All pts received, unless contraindicated, anticoagulation for prevention of deep-vein thrombosis (DVT), and anti-viral therapy. Pts with grade ≥2 peripheral neuropathy (PNY) were excluded. The primary endpoint was the best response achieved after consolidation. The secondary endpoints were: response rate after 3 cycles of VRD as induction, after ASCT and after maintenance; safety profile of the program; feasibility and quality of STC; duration of response, PFS, and OS. Response was assessed according to International Uniform Response Criteria including stringent Complete Response (sCR). Flow cytometric analysis of bone marrow plasma cells for minimal residual disease (MRD) was performed before and after ASCT, after consolidation and after maintenance. Adverse events (AEs) were graded using the CTC for Adverse Events (AE) v4. Patients: Thirty-one pts were enrolled. Baseline characteristics were: median age= 58 (range 33–65); women= 55%; 55%/32%/13% had IgG/IgA/light chain MM; ISS= 1 in 52%, 2 in 32% and 3 in 16% of pts; chromosome 17p del in 18% and t(4;14) translocation in 11% among 27 assessable pts. Results: All pts but 7 remain on study program at data cut-off (01/08/11). One pt discontinued treatment due to mobilization failure, 5 pts stopped maintenance because of serious AE (1 extensive DVT unless efficient anticoagulation) or AEs ( 3 grade 3/4 neutropenia and/or thrombocytopenia, 1 grade 3 hypothyroidism) and 1 pt went off study because of progressive disease. Currently, Len maintenance is on going for 6 pts and 4 pts just completed their last cycle. Therefore, 30 pts are evaluable for response after consolidation, and 20 after maintenance. All results are summarized in table 1. In ITT analysis, the overall response rate (ORR) after consolidation is 94%, including 36% VGPR, 48% RC or better (9% CR, 39% sCR). Consolidation therapy with 2 VRD cycles upgraded response in 26% of pts but only 1 pt achieved MRD negative (among 24 assessed). At time of reporting, Len maintenance did not improve response rate but 1 pt get MRD negative. One pt progressed during maintenance phase and 2 pts turned into MRD positive again without evidence of relapse. Considering the safety profile, 18 serious AEs were reported. There was no treatment-related mortality. The most common toxicities during consolidation therapy were: emergent PNY (23%), including 10% grade 1 and 13% grade 2; grade 3/4 neutropenia (17%), and thrombocytopenia (10%). The most common toxicities during Len maintenance were: grade 3/4 neutropenia (43%), and thrombocytopenia (10%); fatigue (13%); erythrodermia (10%); zona (10%). One extensive DVT and one pulmonary embolism were reported. There was no evidence of secondary malignancy. Conclusions: VRD consolidation plus Len maintenance after VRD induction and HDT produce high quality responses with 38% of sCR and is well tolerated in de novo MM pts. Updated efficacy and safety data will be presented at the meeting. Disclosures: Roussel: Janssen: Honoraria; Celgène: Honoraria. Off Label Use: bortezomib, lenalidomide and dexamethasone as induction and consolidation therapy lenalidomide maintenance. Moreau:Millennium Pharmaceuticals, Inc.: Advisory board, Honoraria; Janssen: Advisory board, Honoraria. Hulin:Celgene: Honoraria; Amgen: Honoraria; Janssen-Cilag: Honoraria. Leleu:celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Facon:celgene: 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. Avet-Loiseau:Janssen: 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. Attal:Janssen: 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.

scholarly journals Minimal Residual Disease Eradication with Venetoclax in Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-14
Author(s):  
Alexander Coltoff ◽  
Joseph G. Jurcic ◽  
Peter Campbell ◽  
Daniel J. Lee ◽  
Mark L Heaney ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Median Overall Survival ◽  
Residual Disease ◽  
Institutional Research ◽  
Negative Group ◽  
Advisory Committees ◽  
Research Grants

Introduction The combination of the BCL-2 inhibitor venetoclax with an HMA (HMA/Ven) has improved outcomes in previously untreated patients with AML not eligible for intensive induction therapy. In a phase Ib study, 67% of patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) with a median overall survival (OS) of 17.5 months (DiNardo CD et al. Blood 2019; 133(1):7-17). HMA/Ven has also demonstrated efficacy in a heavily pretreated population with relapsed or refractory (R/R) AML, the majority of whom had prior HMA exposure (DiNardo CD et al. Am J Hematol 2018; 93(3):401-7). Measurable residual disease (MRD) is recognized as an independent prognostic indicator important for risk stratification and treatment planning (Schuurhuis GJ et al. Blood 2018; 131(12):1275-91). To date, however, there have been few reports on the effect of HMA/Ven on MRD. Methods This is a retrospective case series of patients with AML at a single-center tertiary-care institution. Patients ≥ 18 years of age who were treated with HMA/Ven between January 2017 and June 2020, either in the upfront or salvage setting, for AML were included. Outcomes included CR/CRi rate, MRD response, relapse free survival (RFS), and OS. MRD was assessed via multicolor flow cytometry with a sensitivity of 10-3 (0.1%). Results Nineteen patients were identified, 12 (63%) of whom were female. The median age at the time of HMA/Ven initiation was 71 years (range, 21 - 87 years). Ten (53%) patients had de novo AML and 9 had secondary or therapy-related AML. By 2017 ELN criteria, 3 (16%) patients had favorable-risk, 9 (47%) had intermediate-risk, and 7 (37%) had adverse-risk AML. Nine (47%) patients had R/R AML; 5 received HMA/Ven as first salvage therapy, and 4 as 2nd or greater salvage. Three (16%) patients had prior HMA exposure. No patient had prior venetoclax exposure. Median follow-up was 9.1 months (range, 1-21.1 months). Ten (53%) patients received azacitidine and 9 (47%) were given decitabine. Venetoclax doses ranged from 50 to 400 mg daily, depending on participation in a clinical trial and concomitant medications. Eight patients achieved a CR and 7 patients achieved a CRi for a combined CR/CRi rate of 79%. The CR/CRi rate was 90% (9/10) in the upfront setting, and 66% (6/9) in the salvage setting. The median time and number of cycles to best clinical response was 2.3 months (range, 0.9-3.9 months) and 2 (range, 1-3 cycles), respectively. Eleven (73%) of the 15 responders achieved MRD clearance after a median of 2 cycles (range, 1-3 cycles) (Table 1). Two of 4 (50%) MRD-positive patients relapsed, while 4 (36%) of 11 MRD-negative patients relapsed (Figure 1). Relapse occurred at a median of 2.0 months (range, 1.3-2.7 months) in the MRD positive group and 11.0 months (range, 2.8-14 months) in the MRD negative group. One patient died of infectious complications while MRD negative. Three patients, all of whom were treated for R/R disease, proceeded to an allogeneic stem cell transplant (HSCT). Two were MRD negative at the time of HSCT and all remained in remission. At the time of data cutoff, 7 (64%) of 11 MRD-negative patients were alive, and all 4 MRD-positive patients were alive. Causes of death in the MRD-negative group included disease relapse (3 patients) and infection (1 patient). Median overall survival in the entire cohort (range, 32 days-NR) was not reached. Conclusions HMA/Ven was highly effective as both upfront and salvage therapy. Surprisingly, the salvage CR/CRi rate in this series was 66%, allowing half of the responders to proceed to HSCT. The majority (73%) of responders achieved MRD negativity. While MRD status influenced RFS, 36% of MRD-negative patients relapsed. Additionally, the same percentage of MRD-negative patients died during follow-up, versus none of the patients with MRD-positivity. This indicates the need for more sensitive methods to assess MRD and for novel therapeutic strategies to eliminate MRD, thereby improving long-term outcomes. Larger prospective studies are needed to define the role of MRD assessment with venetoclax-containing regimens. Disclosures Jurcic: AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Syros Pharmaceuticals:Research Funding;PTC Therapeutics:Research Funding;Arog Pharmaceuticals:Research Funding;Kura Oncology:Research Funding;Forma Therapeutics:Research Funding;Astellas:Research Funding;Genentech:Research Funding;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS:Consultancy, Research Funding.Campbell:AstraZeneca:Consultancy.Lee:Genentech:Research Funding;Sumitomo Dainippon Pharma Oncology, Inc.:Research Funding;AbbVie:Research Funding;Novartis:Research Funding;Bayer:Research Funding;Celgene:Consultancy;Forty Seven:Research Funding.Heaney:Blueprint Medicines Corporation:Research Funding;BMS:Research Funding;CTI Biopharma:Consultancy, Research Funding;Deciphera:Research Funding;Incyte:Research Funding;Novartis:Consultancy, Research Funding;Sierra Oncology:Research Funding;AbbVie:Consultancy;Partner Therapeutics:Consultancy.Lamanna:Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Octapharma:Research Funding;Juno:Other: Institutional research grants, Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astra Zeneca:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Pharmacyclics:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Bei-Gene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Abbvie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Oncternal, Verastem, TG Therapeutics:Other: Institutional research grants, Research Funding;MingSight:Other: Institutional research grants, Research Funding;Loxo:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Columbia University Medical Center:Current Employment.

scholarly journals 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 ◽  
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.

Sign in / Sign up

Export Citation Format

Share Document