Clapd (Clarithromycin, Pomalidomide, Dexamethasone) Therapy In Relapsed Or Refractory Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1955-1955 ◽  
Author(s):  
Tomer M Mark ◽  
Angelique Boyer ◽  
Adriana C Rossi ◽  
Dennis Kwon ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Response Analysis ◽  
Muscular Weakness ◽  
Advisory Committees ◽  
Disease Response ◽  
Grade 3

Abstract Background Pomalidomide is a distinct IMiD® immunomodulatory agent with activity in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide treatment. We have previously reported that the addition of clarithromycin enhances the anti-myeloma activity of pomalidomide+dexamethasone (Pom/Dex) in the treatment of RRMM (Mark et al, ASH 2012). We now report updated results with extended follow up from a phase 2 trial of large group of patients treated with ClaPd in RRMM. Methods One hundred nineteen patients with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPd. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included lenalidomide. ClaPd is clarithromycin 500mg twice daily; pomalidomide 4mg for days 1-21, and dexamethasone 40mg on days 1,8,15,22 of a 28-day cycle. All subjects had thromboprophylaxis with 81mg aspirin daily. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patient until disease progression. Results One hundred fourteen patients had completed at least 1 cycle of ClaPd and were eligible for disease response analysis at data cut-off. All patients were included in the safety analysis. Patients had undergone a median of 5 (range 3-15) prior lines of therapy. The proportion of patients who were refractory to lenalidomide, refractory to bortezomib, and double (lenalidomide+bortezomib) refractory were 85%, 79%, and 68% respectively. The median number of ClaPd cycles received was 7 (range 1-34). Overall response rate (ORR, ≥PR, entire cohort/double-refractory subgroup) was 61.4/56.4% [stringent complete remission (sCR): 4.4/4%, complete response (CR): 0.9/1.3%, very good partial response (VGPR): 14.9/11.5%, partial response (PR): 41.2/38.5%, minimal response (MR): 7/9%, stable disease (SD): 21.9/21.8%, progressive disease (PD): 9.6/12.8%, ³VGPR rate of 20.2/16.7%]. Clinical benefit (³ MR) was achieved in 68.4/65.4%. Median time to PR and maximum response was 1 (range 1-7) and 2 (range 1-18) cycles, respectively. After a mean follow up time of 11.9 months, 40 patients (34%) remain free from progression, with a median progression free survival of 8.1 months (95% CI: 5.1, 9.8). Median duration of response (DOR) was 9.3 months (95% CI: 7.2,16.1). Median overall survival (OS) has not been reached with 68 patients (57%) alive at last follow-up. Median PFS, DOR, OS were not significantly different in the double-refractory subgroup at 6.3 (CI 4.7, 8.7; p = 0.21), 8.6 (CI 6.5, 16.1; p = 0.87), and 16.8 months (CI 12.4, 28.7; p = 0.11) respectively. The most common (³% grade 3 and 4 toxicities were: neutropenia (49%), thrombocytopenia (39%), anemia (27%), pneumonia (10%), fatigue 8%, and muscular weakness 7%. Febrile neutropenia was uncommon at 2%. There were 6 cases of lower extremity venous thrombosis (5%, 1 grade 1, 4 grade 2, 1 grade 3) and no instances of pulmonary embolism. Mild peripheral neuropathy was present in 32% (19% grade 1, 13% grade 2), 0% grade 3 or 4). Grade 2 congestive heart failure, due to dexamethasone, emerged in 1 subject (0.8%). Four patients (3.3%) withdrew due to treatment related toxicity (1 with Grade 3 muscular weakness, 2 due to Grade 3 fatigue, 1 grade 4 neutropenic sepsis). There was no treatment related mortality. Conclusions ClaPd is a highly effective and tolerable regimen for heavily treated RRMM that has progressed after prior treatments. Response to ClaPd is rapid and sustained at > 8 months in the majority of subjects. The presence of double refractory disease did not significantly impact clinical outcomes. The ORR and PFS compare favorably and toxicity profile is similar to other published reports of Pom/Dex. Disclosures: Mark: Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Zafar:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx: Speakers Bureau. Pekle:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Niesvizky:Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Sequence Impact Of Pomalidomide and Carfilzomib On Treatment Response In Relapsed Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1954-1954 ◽  
Author(s):  
Tomer M Mark ◽  
John N. Allan ◽  
Angelique Boyer ◽  
Adriana C Rossi ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Salvage Chemotherapy ◽  
Advisory Committees ◽  
Effective Response ◽  
Disease Response ◽  
Prior Therapy

Abstract Background Pomalidomide and Carfilzomib (Cfz) are two recently approved agents for the treatment of multiple myeloma (MM) that has relapsed after prior therapy including an IMiD and bortezomib. The sequencing of these agents to achieve maximum tumor reduction is thus far not known. We have previously reported response data from the combination clarithromycin, pomalidomide, dexamethasone (ClaPD) for relapsed or refractory MM. (Mark et al, ASH 2012). We examined the subset of these patients that had received a Cfz-based regimen prior to ClaPD as well as the subset of patients that received a Cfz-based regimen after ClaPD to determine whether the sequence of agents had any impact on response. Methods One hundred nineteen patients with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPD. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included lenalidomide. ClaPD is clarithromycin 500mg twice daily; pomalidomide 4mg for days 1-21, and dexamethasone 40mg on days 1,8,15,22 of a 28-day cycle. Two subsets of patients were compared: 1) Subjects that had received treatment with a Cfz-based prior to ClaPD (CP) and 2) Subjects that had received a Cfz-based therapy after progression on ClaPD (PC). Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Results Fourteen patients comprised CP and 20 in PC. Patients in the CP group were more heavily pre-treated with a median of 6 (range 3-15) lines of therapy, as compared to 5 lines (range 3-10) for PC. Responses are shown in Table 1. Median cycles of ClaPD and Cfz received in PC was 6.5 (range 2-16) and 5 (1-14), respectively. Median cycles of Cfz and ClaPD in the CP group was 8 (1-19) and 5 (1-23), respectively. CR complete response; VGPR: very good partial response; PR: partial response; SD: stable disease; PD: progressive disease; ORR: overall response rate Conclusions ClaPD and a Cfz-based regimen appear to have equally effective response regardless of sequence in salvage chemotherapy. Somewhat deeper responses are seen with ClaPD after Cfz as compared to Cfz after ClaPD, which is intriguing given that the CP group had more prior lines of treatment than PC. Longer follow-up to analyze duration of the response is needed prior to concluding which sequence (PC vs CP) is more effective. This data supports the use of pomalidomide after carfilzomib failure and vice-versa as potent salvage therapeutic options. Disclosures: Mark: Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Zafar:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx: Speakers Bureau. Pekle:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Niesvizky:Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Efficacy and Safety of Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 17p Deletion: Results from the Phase II RESONATE™-17 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 327-327 ◽  
Author(s):  
Susan O'Brien ◽  
Jeffrey A. Jones ◽  
Steven Coutre ◽  
Anthony R. Mato ◽  
Peter Hillmen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Previously Treated ◽  
Grade 3

Abstract Background: Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years in the relapsed/refractory (R/R) setting. Ibrutinib (ImbruvicaTM), a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for previously treated patients with CLL and for patients with del 17p CLL. We report results from the primary analysis of the Phase II RESONATETM-17 (PCYC-1117-CA) study, designed to evaluate the efficacy and safety of single-agent ibrutinib for treatment of patients with R/R del 17p CLL or small lymphocytic leukemia (SLL). Methods: Patients with del 17p CLL or SLL who failed at least one therapy were enrolled to receive 420 mg oral ibrutinib once daily until progression. All patients receiving at least one dose of ibrutinib were included in the analysis. The primary endpoint was overall response rate (ORR) per an independent review committee (IRC). Other endpoints included duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib. Results: Among 144 treated patients (137 with CLL, 7 with SLL), the median age was 64 (48% 65 years or older) and all had del 17p. Baseline characteristics included 63% of patients with Rai Stage III or IV disease, 49% with bulky lymphadenopathy of at least 5 cm, and 10% with lymphadenopathy of least 10 cm. The median baseline absolute lymphocyte count (ALC) was 32.9 x 109/L with 57% of patients with a baseline ALC at least 25.0 x 109/L. Baseline beta-2 microglobulin levels were at least 3.5 mg/L in 78% of patients (range 1.8-19.8 mg/L), and lactate dehydrogenase levels were at least 350 U/L in 24% of patients (range 127-1979 U/L). A median of 2 prior therapies (range 1-7) was reported. Investigator-assessed ORR was 82.6% including 17.4% partial response with lymphocytosis (PR-L). Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) were reported in 3 patients. IRC-assessed ORR is pending. At a median follow up of 13.0 months (range 0.5-16.7 months), the median PFS (Figure 1) and DOR by investigator determination had not been reached. At 12 months, 79.3% were alive and progression-free, and 88.3% of responders were progression-free. Progressive disease was reported in 20 patients (13.9%). Richter transformation was reported in 11 of these patients (7.6%), 7 of the cases occurring within the first 24 weeks of treatment. Prolymphocytic leukemia was reported in 1 patient. The most frequently reported adverse events (AE) of any grade were diarrhea (36%; 2% Grade 3-4), fatigue (30%; 1% Grade 3-4), cough (24%; 1% Grade 3-4), and arthralgia (22%; 1% Grade 3-4). Atrial fibrillation of any grade was reported in 11 patients (7.6%; 3.5% Grade 3-4). Seven patients reported basal or squamous cell skin cancer and 1 patient had plasma cell myeloma. Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients (4.9%, all Grade 2 or 3). Study treatment was discontinued in 16 patients (11.1%) due to AEs with 8 eventually having fatal events (pneumonia, sepsis, myocardial or renal infarction, health deterioration). At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib. Conclusions: In the largest prospective trial dedicated to the study of del 17p CLL/SLL, ibrutinib demonstrated marked efficacy in terms of ORR, DOR, and PFS, with a favorable risk-benefit profile. At a median follow up of 13 months, the median DOR had not yet been reached; 79.3% of patients remained progression-free at 12 months, consistent with efficacy observed in earlier studies (Byrd, NEJM 2013;369:32-42). The PFS in this previously treated population compares favorably to that of treatment-naïve del 17p CLL patients receiving fludarabine, cyclophosphamide, and rituximab (FCR) (Hallek, Lancet 2010;376:1164-74) or alemtuzumab (Hillmen, J Clin Oncol 2007;10:5616-23) with median PFS of 11 months. The AEs are consistent with those previously reported for ibrutinib (Byrd, NEJM 2014;371:213-23). These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL. Figure 1 Figure 1. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Jones:Pharmacyclics: Consultancy, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siddiqi:Janssen: Speakers Bureau. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Stevens-Brogan:Pharmacyclics: Employment. Li:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Clow:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Chu:Pharmacyclics: Employment, Equity Ownership. Hallek:Janssen, Pharmacyclics: Consultancy, Research Funding. Stilgenbauer:Pharmacyclics, Janssen Cilag: Consultancy, Honoraria, Research Funding.

Car-Bird [Carfilzomib, Clarithromycin(Biaxin(R)), Lenalidomide/(Revlimid(R)), Dexamethasone) For Newly-Diagnosed Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3216-3216 ◽  
Author(s):  
Tomer M Mark ◽  
John N. Allan ◽  
Geoffrey Marano ◽  
Adriana C Rossi ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Disease Response ◽  
M Spike ◽  
Grade Iii

Abstract Background Carfilzomib (Cfz) synergizes with lenalidomide and dexamethasone (Len-dex) to provide impressive response rates as upfront treatment of multiple myeloma (MM) (Jakubowiak et al 2012). The addition of clarithromycin to Len-dex has shown superior time to progression compared to Len-dex alone (Gay et al 2010). We hypothesized that sequential treatment with Cfz-dex and BiRD would lead to enhanced efficacy, response duration, and tolerability. We thus tested a sequential approach of upfront carfilzomib / dexamethasone, consolidation with BiRd, and lenalidomide maintenance to evaluate overall response and safety as first line therapy for MM. Methods Twenty-four patients (pts) with symptomatic untreated MM were enrolled in a single institution study to evaluate the efficacy and tolerability of Car-BiRd. Car-BiRd therapy is: Cfz IV over 30 minutes on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle at a dose of 20mg/m2 on days 1, 2 of the 1st cycle only and 45mg/m2 for each successive dose thereafter and dex 40mg on D1, 8, 15, 22. Cfz-dex was continued until plateau in disease response defined as unchanged M-protein for 2 cycles. Elective autologous stem cell collection was then performed per physician and patient discretion and consolidation with BiRd initiated. Transplant ineligible pts proceeded directly to BiRd. BiRd is: Clarithromycin 500mg BID, lenalidomide 25mg daily on D1-21, and dex 40mg daily D1, 8, 15, 22 of 28-day cycle. Therapy was continued until a 2nd plateau in disease response after which lenalidomide maintenance at a dose of 10mg daily D1-21 of 28 day cycle was continued until disease progression or intolerability. Results 24 pts have currently been enrolled; 23 have completed at least 1 cycle of therapy and were evaluable for response. Sixteen pts (67%) harbored high-risk cytogenetics, as defined by the presence of one or more of the following on iFISH: del 17p, gain 1q, del 1p, t(4;14), t(14;16), or complex karyotypic abnormalities. Median study follow-up was 30.8 weeks (range 4.5-62.2). Response to the Car-BiRD regimen was: overall response rate (ORR) 87%, stringent complete response (sCR) 13%, very good partial response (VGPR) 48%, partial response (PR) 26%, stable disease (SD) 13%. Maximum response to the Cfz-dex induction was: ORR 87%, sCR 9%, VGPR 39%, PR 35%, SD 13%. Median time to PR and maximum response with Cfz-dex was 2 cycles (range 1-2) and 4 cycles (range 1-5) respectively. Median M-spike percentage decrease with Cfz-dex was 92% (range 13-100%). Twelve pts thereafter received BiRD consolidation with 5 pts (41%) further decreasing the M-spike by a median of 8% (range 1-45%). A median of 3 cycles (range 2-7) of BiRD was given until a 2nd response plateau was achieved. Seven pts subsequently received lenalidomide and all have maintained their response after a median of 5 cycles (range 1-8) of follow-up. Seven pts (30%) have come off study, 2 (8%) secondary to disease progression (1 during Car-Dex and 1 during BiRD) and 5 pts (22%) due to toxicity (2 pts due to Grade III renal failure, both attributable to Cfz, and 2 pts due to Grade III CHF during Cfz-Dex, 1 attributable to Cfz; 1 pt with Grade III Thromboembolic event during BiRD, attributable to Len-dex). Discussion This is the first prospective study evaluating the response to induction Cfz/Dex in treatment-naïve MM. Cfz/Dex therapy appears safe and effective in newly diagnosed myeloma patients. Responses deepen with subsequent IMiD(R)-based consolidation and maintenance. Toxicities due to each component of the regimen were manageable. The ORR of 87% and rate of VGPR or better of 61% in group with a high percentage of unfavorable cytogenetics compares favorably to similar studies using 1st generation proteasome inhibitor combinations, and may continue to improve with longer study follow-up. Disclosures: Mark: Onyx: Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Carfilzomib is not approved for front line use in myeloma. Rossi:Celgene: Speakers Bureau. Zafar:Onyx: Speakers Bureau; Millennium: Speakers Bureau; Celgene: Speakers Bureau. Pekle:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Phase I/II Trial Of Everolimus, Bortezomib and Rituximab In Relapsed Or Relapsed/Refractory Waldenstrom's Macroglobulinemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4402-4402 ◽  
Author(s):  
Irene M. Ghobrial ◽  
Erica N Boswell ◽  
Stacey Chuma ◽  
Ranjit Banwait ◽  
Courtney Hanlon ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Complete Response ◽  
Recommended Dose ◽  
Advisory Committees ◽  
Grade 3

Abstract Introduction The phase I aimed to determine the safety and maximum tolerated dose of the combination of everolimus and rituximab, or everolimus, bortezomib, and rituximab and the phase II study aimed to examine response and safety of the combination of all 3 agents in relapsed and/or relapsed/refractory Waldenstrom Macroglobulinemia. This trial was based on our preclinical studies that demonstrated synergistic activity of everolimus and bortezomib with rituximab in WM. Methods Eligibility criteria include: 1) patients with relapsed or relapsed/refractory WM with any number of prior lines of therapy, including everolimus and bortezomib 2) not completely refractory to rituximab 3) measurable disease by monoclonal IgM protein in the serum and lymphoplasmacytic cells in the bone marrow, 4) Not receiving chemotherapy > 3 weeks, or biological/novel therapy for WM > 2 weeks. A cycle is 28 days and a total of 6 cycles are given, followed by everolimus maintenance until Progression. The phase I trial included two stages with a total of four dose levels. In stage A, patients received everolimus at the recommended dose orally daily for 28 days and rituximab at the recommended dose IV on days 1, 8, 15, and 22 every 28 days at cycle 1 and 4 only. In stage B, patients received everolimus at the recommended dose orally daily for 28 days, bortezomib at the recommended dose IV on days 1, 8, 15 every 28 days, and rituximab at the recommended dose IV on days 1, 8, 15, and 22 every 28 days at cycle 1 and 4 only. For the phase II study, patients received everolimus 10 mg daily, bortezomib IV 1.6mg/m2 on days 1, 8, 15 every 28 days, and rituximab 375mg/m2 IV on days 1, 8, 15, and 22 every 28 days at cycle 1 and 4 only. Patients were assessed for response after every cycle. Subjects who had a response continued on therapy for a total of 6 cycles, and then continued on to maintenance therapy with everolimus alone until progression Results Forty-Six patients were enrolled in this phase I/II clinical trial from April 2009 to July 2013. The median age is 65 (range, 47–84) yrs and the median lines of prior therapy is 5 (range, 1–9) with 45 (98%) patients receiving prior rituximab and 23 (50%) receiving prior bortezomib. The median number of cycles on therapy was 19.5 (range, 0–39). Overall, this combination therapy is very well tolerated. Grade 4 toxicities included: neutropenia (4.3%), leukopenia (2.2%), thrombocytopenia (13%), lymphopenia (2.2%) and hypertriglyceridemia (2.2%). Grade 3 toxicities included: neutropenia (13%), leukopenia (13%), anemia (10.9%), lymphopenia (8.7%), pneumonitis (4.3%), SGPT (4.3%), neuropathy (4.3%), Herpes zoster reactivation (4.3%), (2.2%) bacterial endocarditis, (2.2%) congestive heart failure, (2.2%) hearing loss, hyperglycemia (4.3%) hypernatremia (4.3%) and 1(2.2%) subject had an incarcerated inguinal hernia with small bowel obstruction. Two patients discontinued therapy due to grade 3 anemia. For the phase II study, sixteen patients are currently evaluable for response, including 2 (13%) complete response (CR), 11 (68%) partial response and 1 (6%) minimal response (MR), for an overall response rate including MR of 14/16 (88%) in this relapsed/refractory population. Furthermore, overall response including MR in phase I was 1/23 (4%) complete response, 7/23 (30%) partial response and 10/23 (43%) minimal response. In phase II 1/23 (4%) complete response, 14/23 (61%) partial response and 2/23 (9%) minimal response. Additionally, 8 (17%) patients achieved stable disease. Conclusions The combination of everolimus, bortezomib, and rituximab is generally well tolerated, and importantly no grade 3/4 neuropathy was seen. The responses observed to date indicate that this combination is highly effective in this relapsed/refractory population. This study was supported from the FDA Office of Orphan Products Development and by Millennium/Takeda and Novartis Inc. Disclosures: Ghobrial: Onyx: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; BMS: Research Funding; Sanofi: Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees. Richardson:Millennium: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Treon:Millennium: Consultancy. Matous:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

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.

Obinutuzumab (GA101) in Combination with Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP) or Bendamustine in Patients with Previously Untreated Follicular Lymphoma (FL): Results of the Phase Ib GAUDI Study (BO21000)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3686-3686 ◽  
Author(s):  
Martin JS Dyer ◽  
Andrew Grigg ◽  
Marcos González ◽  
Martin Dreyling ◽  
Simon A. Rule ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Assessment ◽  
Complete Response ◽  
Type Ii ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 3686 GA101 is a glycoengineered, humanized type II anti-CD20 monoclonal antibody (mAb) anticipated to have superior B-cell-depleting activity to rituximab in vivo on the basis of its enhanced FcR binding and because of the direct cell death induced by type II CD20 mAbs. GA101 has shown significant single-agent activity in Phase I and II studies in patients with FL, and activity in combination with CHOP and fludarabine plus cyclophosphamide in patients with resistant/refractory FL in the first part of this Phase I trial (Radford et al. ASH 2011; abstract 270). This report describes the safety, toxicity, and efficacy of remission induction of GA101 in combination with CHOP or bendamustine in 81 patients aged > 18 years with treatment-naïve CD20+ grade 1–3b FL with at least one measurable lesion (longest diameter > 1.5 cm by CT scan). All patients received a flat dose of GA101 (1,000 mg on Days 1 and 8 of Cycle 1 and Day 1 of subsequent cycles) combined with either 6–8 cycles of CHOP (every 3 weeks) or 4–6 cycles of bendamustine (90 mg/m2Days 1 and 2 every 4 weeks) on a per center choice basis. Patients achieving complete response (CR) or partial response (PR) were eligible to receive GA101 maintenance therapy (1,000 mg) every 3 months for 2 years or until progression. The primary objective was safety, and secondary objectives included overall response rate (ORR), CR rate, and pharmacokinetics. Response was assessed at the end of induction using International Working Group response criteria; unconfirmed CRs were classified as PRs. 40 patients received G-CHOP and 41 G-bendamustine. Baseline characteristics were similar for both groups: median age 53.5 and 57 years; bone marrow involvement 53% and 49%; bulky disease (≥ 7 cm) 45% and 41%; Median time from diagnosis was only 1.20 months for both groups, high-risk FLIPI status (3–5) 45% and 46%, and intermediate risk (FLIPI 2) 38% and 34%. 38 G-CHOP and 37 G-bendamustine patients completed all cycles of planned induction therapy. Three patients withdrew without any response assessment. In the G-CHOP arm, one withdrawal was due to a GA101-associated infusion-related reaction [IRR] after Cycle 1 and another patient was found to be ineligible and withdrawn after Cycle 1. In the G-bendamustine arm one patient withdrew consent after Cycle 2. Three other patients were withdrawn after interim response assessment, none for safety reasons (insufficient response in the G-bendamustine arm and administrative reasons for two in the G-CHOP arm). The most frequent adverse events were IRRs (all grades: 58% G-CHOP; 59% G-bendamustine; grade 3/4: 5% G-CHOP; 10% G-bendamustine). No Grade 3/4 IRRs occurred after cycle 3. Grade 3/4 neutropenia was reported in 43% of patients in the G-CHOP arm and 29% of patients in the G-bendamustine arm during induction, resulting in delayed delivery of 7.0% and 4.8% of chemotherapy cycles. All delays but one were no longer than 2 weeks. Grade 3/4 infections occurred in 23% of patients receiving G-CHOP and 10% of patients receiving G-bendamustine. Approximately half of these were neutropenic infections or sepsis and all resolved with appropriate management. ORR at the end of the induction period was 95% (38/40) in the G-CHOP arm (CR rate 35%) and 92.7% (38/41) in the G-bendamustine arm (CR rate 39%) (Table). Serum GA101 concentrations increased during the induction period and were similar for both regimens. Mean Cmax was 300–600 μg/mL and Cmin100–300 μg/mL. Following the final administration, a decline in GA101 serum concentration was seen that was similar for the two treatment combinations. In conclusion, efficacy and safety data for GA101 combined with CHOP and bendamustine are encouraging for first-line treatment of patients with FL. Based on these promising results GA101 is now being studied in combination with various chemotherapy regimens in a randomized Phase III study against the standard of care, rituximab-based immunochemotherapy. Patients, n (%) G-CHOP (n = 40) G-bendamustine (n = 41) Efficacy     Overall response 38 (95.0) 38 (92.7)     Complete response* 14 (35.0) 16 (39.0)     Partial response 24 (60.0) 22 (53.7)     Stable disease 0 1 (2.4)     Progressive disease 0 1 (2.4)     Not assessed 2 (5.0) 1 (2.4) Safety     Grade 3/4 IRRs 2 (5.0) 4 (9.8)     Grade 3/4 neutropenia 17 (43) 12 (29)     Grade 3/4 infections 9 (23) 4 (10) * CRu were classified as PR Disclosures: Dyer: Roche: Consultancy, Research Funding. Off Label Use: Obinutuzumab (GA101) in Combination with Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP) or Bendamustine in Patients with Previously Untreated Follicular Lymphoma (FL). Grigg:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Support of (other) clinical trials and Scientific Advisory Boards Other. Rule:Roche: Consultancy, Research Funding. Lei:Roche: Employment. Wassner-Fritsch:Roche: Employment. Wenger:Roche: Employment. Marlton:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Dasatinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) In the DASISION Trial: 18-Month Follow-up

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 206-206 ◽  
Author(s):  
Neil Shah ◽  
Hagop Kantarjian ◽  
Andreas Hochhaus ◽  
Jorge E. Cortes ◽  
M. Brigid Bradley-Garelik ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Initial Treatment ◽  
Research Funding ◽  
Response Analysis ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Once Daily ◽  
Grade 3

Abstract Abstract 206 Background: Dasatinib is 325-fold more potent than imatinib in vitro against unmutated BCR-ABL, and is an established second-line treatment for patients (pts) with CML-CP who are resistant, intolerant or have a suboptimal response to imatinib. The Phase 3 DASISION study compares dasatinib with imatinib as initial treatment for pts with newly diagnosed CML-CP. After a minimum of 12 months (mos) of follow-up, dasatinib 100 mg once daily demonstrated significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared to imatinib 400 mg once daily (Kantarjian, H, et al. N Engl J Med 2010;362:2260). Eighteen-mo follow-up data are presented here. Methods: 519 pts with newly diagnosed CML-CP (median disease duration of 1 mo) stratified by Hasford risk were randomized to either dasatinib 100 mg once daily (n=259), or imatinib 400 mg once daily (n=260). The study design and endpoints have been described previously. All analyses were based on intention-to-treat pts. Results: Median treatment duration at the present analysis was 18 mos for each drug, with 81% of pts in the dasatinib arm and 80% in the imatinib arm still remaining on study drug. Median dose intensity was 99 mg/d for dasatinib and 400 mg/d for imatinib. Efficacy and safety results in the present analysis were consistent with those reported previously after 12 mos of follow-up. The rate of confirmed CCyR (cCCyR, CCyR on consecutive analyses at least 1 mo apart) by 18 mos continued to be higher for dasatinib than for imatinib (78% vs 70%); P=0.0366). Based on time-in-cCCyR (a measure of durability) analysis involving all randomized pts, dasatinib-treated pts were 28% less likely to experience a progression event (as defined by European LeukemiaNet 2006) after achieving a cCCyR or never achieving a cCCyR compared to those on imatinib. The MMR rate at any time was superior for dasatinib compared to imatinib (57% vs 41%, P=0.0002). Based on time-to-response analysis, pts on dasatinib were 1.84-fold more likely to achieve a MMR than those on imatinib (HR=1.84, P <0.0001). Rates of cCCyR in dasatinib-treated pts with low, intermediate and high risk were 92, 71 and 73%, respectively. The corresponding rates in the imatinib arm were 72, 71 and 64%. Rates of MMR in dasatinib-treated pts with low, intermediate and high risk were 63, 56 and 51%, respectively. The corresponding rates in the imatinib arm were 48, 40 and 30%. A BCR-ABL transcript level of ≤ 0.0032% was achieved in 13% dasatinib-treated and 7% imatinib-treated pts. Rates of progression-free survival at 18 mos were 94.9% for dasatinib and 93.7% for imatinib; the corresponding overall survival rates were 96.0% and 97.9%, respectively. Six pts (2.3%) in the dasatinib arm and 11 (4.3%) in the imatinib arm discontinued due to treatment failure as defined by 2006 European LeukemiaNet criteria. Six pts (2.3%) on dasatinib and 9 (3.5%) on imatinib had a transformation to accelerated or blast phase. Discontinuation of treatment due to drug-related adverse events (AEs) was infrequent for both dasatinib (6%) and imatinib (4%). Non-hematologic AEs (all grades) in ≥10% of pts (dasatinib vs imatinib) were fluid retention (23% vs 43%), diarrhea (18% vs 19%), nausea (9% vs 21%), vomiting (5% vs 10%), muscle inflammation (4% vs 19%), myalgia (6% vs 12%), musculoskeletal pain (12% vs 16%), fatigue (8% vs 11%) and rash (11% vs 17%). While superficial edema was less frequent with dasatinib than with imatinib (10% vs 36%), pleural effusion was seen only with dasatinib (12% vs 0%: grade 1, 2%; grade 2, 9%; grade 3, <1%), and did not impact the efficacy. Non-hematologic grade 3/4 AEs were infrequent in either arm (≤1%). Grade 3/4 cytopenias (dasatinib vs imatinib) were anemia (11% vs 7%), neutropenia (22% vs 20%) and thrombocytopenia (19% vs 10%). Two pts (0.8%) on dasatinib and 3 (1.2%) on imatinib had grade 3/4 bleeding. Cytopenia was the reason for discontinuation in 6 pts on the dasatinib arm (2.3%) and 3 on the imatinib arm (1.2%). Conclusions: After 18 mos of follow-up, dasatinib 100 mg once daily continues to demonstrate superior efficacy compared to imatinib. Dasatinib also continues to be generally well tolerated. These results support the potential use of dasatinib as initial treatment for pts with newly diagnosed CML-CP. Disclosures: Shah: Bristol-Myers Squibb, Novartis and Ariad: Membership on an entity's Board of Directors or advisory committees. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Hochhaus:Novartis, Bristol-Myers Squibb: Consultancy, Research Funding. Cortes:Brostol-Myers Squibb, Novartis and Wyeth: Honoraria. Bradley-Garelik:Bristol-Myers Squibb: Employment, Equity Ownership. Zhu:Bristol-Myers Squibb: Employment. Baccarani:Novartis, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Clinical Efficacy of Daratumumab Monotherapy in Patients with Heavily Pretreated Relapsed or Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 29-29 ◽  
Author(s):  
Saad Usmani ◽  
Brendan Weiss ◽  
Nizar J Bahlis ◽  
Andrew Belch ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Clinical Activity ◽  
Open Label ◽  
Advisory Committees ◽  
Combined Analysis ◽  
Overall Response

Abstract Introduction : Daratumumab (DARA) is a novel human CD-38-targeting monoclonal antibody in clinical development for multiple myeloma (MM). In two clinical studies (NCT00574288 [GEN501] and NCT01985126 [Sirius]), DARA monotherapy showed remarkable clinical activity and was well tolerated in heavily treated patients (pts) with relapsed and refractory (RR) MM (Lokhorst HM. J Clin Oncol 2014;32 Suppl:abstr 8513. Lonial S. J Clin Oncol 2015;33 Suppl: abstr LBA8512). A combined analysis of efficacy of 16 mg/kg DARA in these two studies is presented. Methods : GEN501, a first-in-human open-label, two-part (Part 1 dose escalation; Part 2 dose expansion) study, enrolled pts with MM that had relapsed after or were refractory to ≥2 prior therapies. Sirius, an open-label, two-part study, enrolled pts with MM with ≥3 prior therapies, including a PI or IMiD, or were refractory to both a PI and an IMiD. Eligibility criteria included pts with absolute neutrophil count ≥1000/mm3, hemoglobin ≥7.5 g/dL, platelet count ≥75×109/L (GEN501) or ≥50×109/L (Sirius), and alanine aminotransferase ≤3.5 (GEN501) or ≤2.5 (Sirius) times the upper limit of normal. In GEN501 Part 2, the first 16 mg/kg DARA infusion was followed by a 3 week rest period, and then qw for 7 weeks, q2w for 14 weeks, and q4w thereafter. In Sirius, 16 mg/kg DARA was infused qw for 8 weeks, q2w for 16 weeks, and q4w thereafter. The combined analysis comprised pts treated with 16 mg/kg DARA in Sirius and Part 2 of GEN501. In both studies overall response rates (ORR) were assessed according to IMWG response criteria. Results: The combined analysis included 148 pts (42 and 106 pts from GEN501 and Sirius, respectively). The median (range) age was 64 (31-84) years. Median time since initial diagnosis was 5.8 and 4.8 years in GEN501 and Sirius, respectively, and 62% and 82% of pts had received >3 prior therapies, respectively. In GEN501, 76% of pts were refractory to their last therapy and 64% were refractory to both a PI and IMiD; a greater proportion of pts in Sirius were refractory to their last therapy (97%) and double refractory to a PI and IMiD (95%). The ORR was 36% in GEN501 and 29% in Sirius; the ORR for the combined analysis was 31%. Best overall response is shown in Table. Responses deepened over time and the combined rate of very good partial response (VGPR) or better was 11% with 2 pts with complete responses (CR) and 3 with stringent CRs (sCR) across the two studies. In the combined analysis, median duration of response was 7.6 months and 46% of responders remained progression free at 1-year after a median follow-up of 9.3 months. Median overall survival (OS) had not been reached at median follow-up times of 10.2 months (GEN501) and 9.3 months (Sirius). The estimated 1-year OS rate (95% CI) was 77% (58-88), 65% (51-76), and 69% (58-77) for GEN501, Sirius, and the combined analysis, respectively. Forty-four of 46 responders were still alive at the time of the primary analysis. At a subsequent data cutoff for the combined analysis, after a median follow-up of 14.8 months, the estimated median OS was 19.9 months (95% CI, 15.1 - not estimable). ORR was similar across prespecified subgroups which included age, ISS stage, number of prior therapies, and refractory status. Conclusions : Single-agent DARA (16 mg/kg) demonstrated remarkable clinical activity (31% ORR) in a combined analysis of two studies in heavily pretreated MM pts. The quality of the observed responses (11% VGPR or better, 2 CRs, and 3 sCRs) was noteworthy in this highly refractory population. DARA shows promising activity in pts who have exhausted other approved myeloma treatment options. Table. Best Overall Response. 16 mg/kg MMY2002 n (%) GEN501 Part 2 n (%) Total n (%) Combined analysis set 106 42 148 Best response Stringent Complete Response (sCR) 3 (2.8) 0 3 (2.0) Complete response (CR) 0 2 (4.8) 2 (1.4) Very good partial response (VGPR) 10 (9.4) 2 (4.8) 12 (8.1) Partial response (PR) 18 (17.0) 11 (26.2) 29 (19.6) Minimal response (MR) 5 (4.7) 4 (9.5) 9 (6.1) Stable disease (SD) 46 (43.3) 22 (52.4) 68 (45.9) Progressive disease (PD) 18 (17.0) 0 18 (12.2) Not evaluable (NE) 6 (5.7) 1 (2.4) 7 (4.7) Overall response (sCR+CR+VGPR+PR) 31 (29.2) 15 (35.7) 46 (31.1) Disclosures Usmani: Celgene Corporation: Consultancy, Honoraria; Janssen: Research Funding; Onyx: Consultancy, Honoraria, Research Funding. Weiss:Janssen and Millennium: Consultancy; Janssen and Onclave: Research Funding. Bahlis:Johnson & Johnson: Research Funding; Amgen: Consultancy; Johnson & Johnson: Consultancy; Johnson & Johnson: Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Lonial:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Lokhorst:Genmab: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Voorhees:Janssen, Celgene, GlaxoSmithKline,Onyx Pharmaceuticals and Oncopeptides: Consultancy, Research Funding; Array BioPharma, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Millennium/Takeda and Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. 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. Axel:Janssen: Employment. Feng:Janssen: Employment. Uhlar:Janssen: Employment. Wang:Janssen: Employment. Khan:Janssen: Employment. Ahmadi:Janssen: Employment. Nahi:Janssen: 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.

A Pilot Study of Acalabrutinib with Bendamustine/Rituximab Followed By Cytarabine/Rituximab (R-ABC) for Untreated Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Daniel Guy ◽  
Marcus Watkins ◽  
Fei Wan ◽  
Nancy L. Bartlett ◽  
Amanda F Cashen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Complete Response ◽  
High Dose ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Grade 3 ◽  
Stem Cell Collection

Introduction The management of younger fit patients with mantle cell lymphoma (MCL) varies widely with no consensus on an optimal induction therapy. To date, the treatments with the longest progression-free survival incorporate a chemotherapy backbone that includes high dose cytarabine, followed by consolidation with an autologous stem-cell transplantation (ASCT) (Hermine et al. Lancet 2016, Eskelund et al. Br J Haematol 2016). Recent data showed that a regimen of bendamustine/rituximab followed by cytarabine/rituximab achieved high complete response rates with high minimal residual disease (MRD) negativity (Merryman RW et al. Blood Adv 2020). We hypothesized that adding the Bruton tyrosine kinase inhibitor acalabrutinib to the same chemotherapeutic backbone would be safe and increase complete response rates as well as minimal residual disease (MRD) negativity pre-transplant, and potentially improve clinical outcomes. Methods We conducted a single arm, single institution pilot study registered at clinicaltrials.gov (NCT03623373). Patients with untreated MCL, who were between ages 18-70 and were candidates for ASCT, were eligible. Patients received six 28-day cycles of treatment. Cycles 1-3 consisted of bendamustine 90 mg/m2 on days 1 and 2, rituximab 375 mg/m2 on day 1 and acalabrutinib 100mg BID on days 1 through 28. Cycles 4-6 consisted of rituximab 375 mg/m2 on day 1, cytarabine 2 g/m2 (1.5 g/m2 if age&gt;60) q12 hours on days 1 and 2, and acalabrutinib 100mg BID on days 1 through 7 and 22 through 28. Restaging PET/CT and response assessment based on the Lugano classification were obtained following cycles 3 and 6. After cycle 6 patients underwent leukapheresis and stem-cell collection as preparation for ASCT. Blood for MRD status was collected after cycles 2, 4 and 6 and will be evaluated using the ClonoSeq assay (Adaptive Biotechnologies). The primary objective was to determine the stem cell mobilization success rate. Secondary objectives included safety and tolerability, overall response rate (ORR), pre-transplant complete response rate (CR), and the MRD negativity rate during and after completion of therapy. Results The trial enrolled 14 patients from December 2018 to February 2020. One patient withdrew consent prior to start of treatment and another was found to have an undiagnosed adenocarcinoma shortly after starting MCL treatment. Both are excluded from the analysis. The median age was 57 years (range 52-66). 11 patients were males (92%), all patients had an ECOG performance status of 0-1. 11 patients (92%) presented with stage IV disease. The mean MCL International Prognostic Index (MIPI) score was 6.3 (25% high-risk, 42% intermediate-risk and 33% low-risk). Of the 12 patients who began treatment, 9 completed all 6 cycles. Three patients did not complete therapy due to: insurance issues (n = 1), and thrombocytopenia (n = 2) following cycle 5 and 4. The side effect profile showed expected hematologic toxicities with grade 3-4 cytopenias in all patients, mostly during cytarabine cycles. In total, 100% of patients developed grade 3-4 thrombocytopenia and 83% of patients developed grade 3-4 neutropenia. Three episodes of febrile neutropenia were observed. One patient had a grade 3 transaminase increase, and one patient had grade 3 diarrhea. No bleeding events or treatment related deaths occurred. The remainder of the side effects were low grade and the treatment was generally well tolerated. Of the 12 evaluable patients, 10 responded (ORR 83%) with 9 achieving CR (75%). One patient achieved PR prior to being removed from the study due to thrombocytopenia and then achieved CR off study. Two patients experienced PD during induction. With a median follow up of 9 months, no responding patients have relapsed. The median CD34+ stem cell collection was 3.84x106 cells/kg (range 2.77 - 5.9). MRD results will be presented at the meeting. Conclusions This is the first study attempting to combine BTK inhibition with a high dose cytarabine containing regimen. The addition of acalabrutinib to a regimen of bendamustine/rituximab followed by cytarabine/rituximab appears to be safe. The R-ABC combination will be further tested in the recently activated intergroup trial EA4181. Disclosures Bartlett: Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding; ADC Therapeutics: Consultancy. Fehniger:ImmunityBio: Research Funding; HCW Biologics: Research Funding; Kiadis: Consultancy; Nkarta: Consultancy; Indapta: Consultancy; Wugen: Consultancy; Orca Biosystems: Consultancy; Compass Therapeutics: Research Funding. Ghobadi:Amgen: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; EUSA: Consultancy; WuGen: Consultancy. Mehta-Shah:Bristol Myers-Squibb: Research Funding; C4 Therapeutics: Consultancy; Celgene: Research Funding; Genetech/Roche: Research Funding; Innate Pharmaceuticals: Research Funding; Kyowa Hakko Kirin: Consultancy; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Corvus: Research Funding. Kahl:Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy.

A Phase I Study of Bendamustine Combined with Lenalidomide and Dexamethasone in Patients with Refractory or Relapsed Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1856-1856 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Amy O’Sullivan ◽  
Silvana Lalo ◽  
Carrie Kruppa ◽  
Diane Gardner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Advisory Board ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1856 Poster Board I-882 Background: Lenalidomide is an analog of thalidomide that has shown significant clinical activity in patients with relapsed or refractory multiple myeloma (MM), both as a single agent and in combination with dexamethasone. Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. Bendamustine combined with lenalidomide may be an effective treatment option for MM patients, particularly those with preexisting or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: Patients aged ≥18 years with confirmed, measurable stage 2 or 3 MM that was refractory to or progressed after 1 or more prior therapies, including lenalidomide, received bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau of best response, as determined by the IBMTR/ABMTR, was reached. Study drug doses were escalated through 4 levels (Table), with 3–6 patients enrolled at each level depending on the rate of dose-limiting toxicity (DLT). After determining the MTD, up to an additional 12 patients will be enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival. Results: To date, 11 patients have been enrolled, with a median age of 63 years (range, 38–75 years). The MTD of bendamustine and lenalidomide has not been identified at this point; currently, patients are enrolling on dose level 3 with 100 mg/m2 bendamustine and 10 mg lenalidomide. Thus far, DLT included 1 grade 4 neutropenia at dose level 2. Nine of 11 patients are currently eligible for response assessment. A partial response was observed in 67% of patients, including 1 very good partial response and 5 partial responses (PR). Two patients experienced stable disease and 1 exhibited progressive disease. Grade 3/4 adverse events included grade 3 neutropenia, thrombocytopenia, anemia, hyperglycemia, and prolonged QTC, and 1 grade 4 neutropenia. Conclusions: Bendamustine, lenalidomide, and dexamethasone form a well-tolerated and highly active regimen even in heavily pretreated MM patients, with a PR rate of 67%. Additional updates on response and MTD will be available at the time of presentation. Disclosures: Lentzsch: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bendamustine is not FDA approved for the treatment of multiple myeloma in the USA. Burt:Millennium: Honoraria; Celgene: Honoraria. Mapara:Resolvyx: Consultancy, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees; Gentium: Equity Ownership; Celgene: Spouse is consultant , has received research funding, and participates on advisory board; Cephalon: Spouse has received funding for clinical trial and participates on advisory board. Redner:Biogen: Equity Ownership; Wyeth: Equity Ownership; Glaxo-Smith-Kline: Equity Ownership; Pfizer: Equity Ownership; Genzyme: Membership on an entity's Board of Directors or advisory committees. Roodman:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Acceleron: Consultancy. Zonder:Amgen: Consultancy; Pfizer: Consultancy; Cephalon: Consultancy; Millennium: Consultancy, Speaking (CME only); no promotional talks.

Sign in / Sign up

Export Citation Format

Share Document