The Effect of Bortezomib, Cyclophosphamide, and Filgrastim On Complete Remission Rates and CD34+ Stem Cell Collections in Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4349-4349
Author(s):  
Tomer Mark ◽  
Megan C. Manco ◽  
Maureen Lane ◽  
Maureen Ward ◽  
Donna Skerrett ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Partial Response ◽  
Phase I ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 4349 Background The combination of lenalidomide (Len, Revlimid®), bortezomib (Bz, Velcade®), and dexamethasone (dex; RVD) has shown excellent efficacy in relapsed/refractory multiple myeloma (MM) patients, with overall response rates (ORR) of 69%, including 26% complete/near complete responses (CR/nCR), and manageable toxicities (Anderson et al. ASCO 2009). The phase I portion of the study (Richardson et al. IMW 2009) found the maximum tolerated dose (MTD) of this combination in newly diagnosed MM patients to be Len 25 mg/day, Bz 1.3 mg/m2, and dex 20 mg. In all phase I patients, the ORR (PR or better) was 100%, including 31% CR, 9% nCR, and 75% ≥very good partial response (VGPR). Results reported here are for patients treated in the phase II portion of the study. Methods Patients were treated with Len 25 mg/day (days 1–14), Bz 1.3 mg/m2 (days 1, 4, 8, 11), and dex 20 mg (cycles 1–4) and 10 mg (cycles 5–8) on the day of and day after Bzfor up to eight 21-day cycles. Patients received prophylactic anticoagulants. Responses were assessed by modified EBMT and Uniform criteria to include nCR and VGPR. Patients with at least partial response (≥PR) could proceed to ASCT after ≥4 cycles; responding patients who did not go on to ASCT could continue therapy at their physician's discretion. Patients with ≥grade 2 peripheral neuropathy (PNY) by CTCAE v3 were excluded. Thirty five patients were enrolled in the phase II portion of this study and were evaluable for both efficacy and safety. Results Median age was 59 years (range 22-86), 54% were men, 34% / 54% / 11% were ISS Stage I / II / III, and 57% / 31% had IgG / IgA MM, respectively. Patients received a median of 8 cycles of Bz and dex and 11 cycles of Len; 11 (31%) patients remain on therapy. Among the 24 patients who have gone off therapy, 5 (21%) completed treatment per protocol, 8 (33%) proceeded to ASCT, 3 (13%) had progressive disease (all during cycle 14 or later), 1 (4%) withdrew due to toxicities, 1 (4%) received non-protocol therapy, and the remaining (n=6; 25%) withdrew consent or stopped treatment due to physician decision. All patients (100%) had a best confirmed pre-ASCT response of ≥PR, with 54% CR/nCR and 69% ≥VGPR (Table). Response rates in the 31 and 24 patients who completed 4 and 8 cycles, respectively, are shown in the Table. Among the 24 patients without CR at cycle 4, response improved between cycles 4 and 8 in 16 (67%) patients. Fifteen of the 35 (43%) patients were mobilized for ASCT, with a median stem cell yield of 4.4 × 106 (2.3–6.6 × 106) CD34+ cells/kg. After median follow-up of 19.3 months, median time to progression (TTP), progression-free survival (PFS), and overall survival (OS) have not been reached; the estimated 1-year TTP and PFS are 76% and the estimated OS is 100%. Treatment-emergent grade 3 and 4 adverse events that occurred in >1 patient included lymphopenia (n=7; 20%), hypokalemia (n=3; 9%), and fatigue and neutropenia (n=2; 6% each). Sensory PNY of any grade occurred in 27 (77%) patients, which was grade 1 (n=18; 67%) and grade 2 (n=8; 30%) in the majority of patients; only one patient had grade 3 sensory PNY. Neuropathic pain and motor PNY were reported in 10 (29%; all grade 1 and 2) and 6 (17%; 1 grade 3) patients, respectively, with no grade 3 PNY seen. Importantly, PNY was reversible with dose reduction, supportive care, and/or completion of therapy. Thrombosis/thromboembolism was reported in just 2 (6%) patients. No treatment-related mortality was seen. Conclusion These phase II results suggest that RVD is a highly effective combination, with a pre-ASCT ORR of 100% and high rates of CR/nCR, and encouraging time-to-event analyses to date. RVD was well tolerated, with limited rates of grade 3 PNY and DVT/PE despite prolonged use of Bz and Len. Data from patients treated at the MTD in phase I and the impact of adverse risk factors (including advanced stage and high-risk cytogenetics) on outcome, as well as following ASCT, will be reported at the meeting. Based upon these promising results, phase II/III studies of RVD and RVD-based combinations are either planned or ongoing. Disclosures: Mark: Celgene: Research Funding, Speakers Bureau. Skerrett:Angioblast Systems, Inc.: Consultancy, Equity Ownership; Mesoblast Ltd: Consultancy, Equity Ownership; Council of Human Blood and Transfusion Services for NYS DOH: Membership on an entity's Board of Directors or advisory committees. Schuster:Celgene: Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Speakers Bureau. Shore:Millennium: Membership on an entity's Board of Directors or advisory committees. Zafar:Celgene Corp: Speakers Bureau; Millenium: Speakers Bureau. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Proteolix: Consultancy, Research Funding.

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.

A Phase I Study of Vorinostat, Lenalidomide, and Dexamethasone In Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Excellent Tolerability and Promising Activity In a Heavily Pretreated Population

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1951-1951 ◽  
Author(s):  
Paul Richardson ◽  
Donna Weber ◽  
Constantine S. Mitsiades ◽  
Meletios A. Dimopoulos ◽  
Jean-Luc Harousseau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase I Study ◽  
Response Rate ◽  
Advisory Board ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1951 Background: Although novel treatment combinations for multiple myeloma (MM) have improved outcomes, the disease remains incurable and new drug combinations are urgently needed. Vorinostat is an oral histone deacetylase inhibitor approved in the United States for treatment of patients (pts) with advanced cutaneous T-cell lymphoma who failed prior therapies. Vorinostat alters gene expression and protein activity, promoting MM cell death through multiple pathways, and has been shown in preclinical studies to synergistically enhance the anti-MM activity of bortezomib and immunomodulatory drugs, including lenalidomide, with or without dexamethasone. Aims: The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) of vorinostat plus lenalidomide and dexamethasone in pts with relapsed or relapsed and refractory MM. Secondary objectives included overall safety, tolerability, response rate, duration of response, and time to progression (TTP). Methods: Pts in this Phase I multicenter open-label study were sequentially enrolled into 1 of 5 escalating doses of the combination regimen using a standard 3 + 3 design for ≤8 cycles. Pts who tolerated treatment and experienced clinical benefit were eligible for enrollment in an extension phase. Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria (version 3.0). Response was assessed using the modified European Group for Blood and Marrow Transplantation criteria and International Myeloma Working Group Uniform Criteria. Safety and efficacy data were analyzed using summary statistics, except for TTP, which was estimated by the Kaplan-Meier method. Results: As of July 15, 2010, 31 pts were treated and evaluable for toxicity; 4 pts remain on study. Most pts had received prior thalidomide (n=22; 71%), bortezomib (n=20; 65%), or lenalidomide (n=14; 45%), with a median of 4 prior therapies (range, 1–10). The patient population contained both high-risk and low-risk pts, based on cytogenetic and/or fluorescence in situ hybridization analyses. Most adverse events (AEs) were mild or moderate in severity. The most common grade ≥3 treatment-related AEs, experienced by 19 (61%) pts, were neutropenia (26%), thrombocytopenia (16%), diarrhea (13%), anemia (10%), and fatigue (10%); 8 pts discontinued due to toxicity. One dose-limiting toxicity (grade 3 diarrhea lasting >48 h) was observed at the maximum assessed dose (level 5), but MTD was not reached (Table) and there were no treatment-related deaths. Among 30 pts evaluable for response, the median TTP was 32 weeks (5 mo), and 4 pts remain on study as of the data cutoff date; 26 of 30 pts (87%) have achieved at least stable disease (SD). Best single responses included 2 complete responses, 3 very good partial responses (VGPR), 11 partial responses (PR), and 5 minimal responses (MR), with 5 pts achieving SD and 4 developing progressive disease, resulting in an overall response rate (ORR; PR or better) of 53%. Of 13 evaluable pts who had previously received lenalidomide, a best single response of SD or better was observed in 9 (69%; 2 VGPR, 3 PR, 1 MR, 3 SD), resulting in a 38% ORR. Notably, SD or better (2 PR, 1 MR, 3 SD) was observed in 60% of 10 evaluable pts who were relapsed, refractory, or intolerant to previous lenalidomide-containing regimens. Conclusions: Preliminary data from this Phase I study suggest that vorinostat plus lenalidomide and dexamethasone is a convenient and generally well-tolerated regimen with promising activity for relapsed or relapsed and refractory MM. The MTD for this combination was not reached. Importantly, responses were observed in pts who had received prior lenalidomide, bortezomib, and thalidomide. Further evaluation of this regimen is planned in future trials. Disclosures: Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Vorinostat, Lenalidomide, and Dexamethasone for treatment in Multiple Myeloma. Weber:Novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; Celgene- none for at least 2 years: Honoraria; Millenium-none for 2 years: Honoraria; Celgene, Millenium, Merck: Research Funding. Mitsiades:Millennium: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Merck & Co.: Consultancy, Honoraria; Kosan Pharmaceuticals: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Centrocor: Consultancy, Honoraria; PharmaMar: Patents & Royalties; OSI Pharmaceuticals: Research Funding; Amgen Pharmaceuticals: Research Funding; AVEO Pharma: Research Funding; EMD Serono: Research Funding; Sunesis: Research Funding; Gloucester Pharmaceuticals: Research Funding; Genzyme: Research Funding. Dimopoulos:MSD: 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. Harousseau:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Houp:Merck Research Laboratories: Employment. Graef:Merck Research Laboratories: Employment. Gause:Merck Research Laboratories: Employment. Byrne:Celgene Corporation: Employment, Equity Ownership. Anderson:Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; BMS: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board.

Final Results of a Frontline Phase 1/2 Study of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone (CRd) in Multiple Myeloma (MM)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 631-631 ◽  
Author(s):  
Andrzej J Jakubowiak ◽  
Dominik Dytfeld ◽  
Sundar Jagannath ◽  
David H. Vesole ◽  
Tara B. Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Growth Factors ◽  
Partial Response ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Newly Diagnosed ◽  
Advisory Committees

Abstract Abstract 631 Introduction: In relapsed and/or refractory MM, the combination of carfilzomib (CFZ) with lenalidomide (Len), and low-dose dexamethasone (Dex) (CRd) has shown very promising efficacy (78% ≥partial response [PR], 40% ≥very good partial response [VGPR], and 24% CR/nCR) and good tolerability including a low rate of peripheral neuropathy (Wang et al, ASCO, 2011). In a Phase I/II study of newly diagnosed MM, the regimen was well tolerated in the Phase I portion of the study up to a maximum dose of CFZ 36 mg/m2, Len 25 mg, and Dex 40 mg, and very active with 96% ≥PR, 70% ≥VGPR, and 55% CR/nCR (Jakubowiak et al, ASH 2010). The lack of overlapping toxicities has allowed these agents to be used at full doses and for extended periods. Here we report the results for all patients (pts) enrolled in both phases of this first prospective trial of CFZ combination in new MM. Methods: In the initial eight 28-day cycles, pts were treated with CFZ at 20 mg/m2, 27 mg/m2 (Phase I), and 36 mg/m2 (Phase I and II), given IV on days 1, 2, 8, 9, 15 and 16, Len at 25 mg PO (days 1–21), and Dex at 40/20 mg PO weekly (cycles 1–4/5–8). Pts achieving ≥PR could proceed to stem cell collection (SCC) using growth factors alone (protocol recommendation) and autologous stem cell transplant (ASCT) after 4 cycles. Per protocol, ASCT candidates were offered the option to continue CRd treatment after SCC. After 8 cycles, pts received 28-day maintenance cycles of CFZ (days 1, 2, 15, 16), Len days 1–21, and Dex weekly at the doses tolerated at the end of 8 cycles. Responses were assessed by IMWG criteria with the addition of nCR. Results: Enrollment was completed (53 pts): 4 pts at CFZ 20 mg/m2, 13 at CFZ 27 mg/m2 and 36 at CFZ 36 mg/m2 (18 in Phase I and 18 in Phase II). Median age was 59 years (range 35–81; 23 pts ≥65), 60% had ISS stage II/III, and 33% (of 49 with available data) had unfavorable cytogenetics: del 13 or hypodiploidy by metaphase, or t(4;14), t (14;16), del 17p by FISH. As of June 30, 2011, toxicity data (cycles 1–8) were available for 51 pts. Hematologic toxicities were reversible and included Grade (G) 3/4: anemia (18%), neutropenia (12%), and thrombocytopenia (10%). The most common non-hematologic toxicities (all G) were hyperglycemia (76%), hypophosphatemia (61%), and infection (53%). G3/4 non-hematologic AEs included hyperglycemia (24%), DVT/PE while on ASA prophylaxis (10%), infection (6%), and mood alteration (2%). PN was limited to G1/2 sensory (24%). Forty-five pts continue treatment with 22 pts in the maintenance phase. Six pts discontinued treatment: 2 proceeded to ASCT, 1 due to toxicity, and 3 due to events unrelated to treatment or per pt wish. The majority of pts did not require dose modifications, either in the initial (31%) or in the maintenance (25%) phase. After a median of 8 cycles (range 1–20), the best responses per IMWG criteria for 49 response-evaluable pts (all pts who completed 1+ cycle) are shown in the Table. Responses were rapid with 46/49 pts achieving at least PR after 1 cycle, and improved with the duration of treatment reaching 100% ≥PR after 4 cycles and 100% ≥VGPR, 79% CR/nCR after 12 cycles. Responses were deep even at the 2 lower dose levels with the majority of pts at 36 mg/m2 still early in treatment. Responses in pts with unfavorable cytogenetics were similar to response rates in all remaining pts and included a 100% ≥PR in 6 pts with del 17p. Twenty-four pts proceeded to SCC after a median of 5 cycles of CRd (range 4–9); using growth factors only in 23 pts and cyclophosphamide and growth factors in 1 pt, with a median 6.55 × 106 CD34+ cells/kg collected (range 3.75–9.6); all resumed CRd treatment. After a median of 9.5 months of follow-up, only 1 pt has progressed, and all are alive Conclusions: CRd is highly active and well-tolerated allowing the use of full doses for an extended time in newly-diagnosed MM pts with limited need for dose modification. Responses are rapid and improve over time reaching 100% ≥VGPR and early time-to-event data are very encouraging. These results compare favorably to the best frontline regimens in MM. Disclosures: Jakubowiak: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria. Off Label Use: Use of the investigational agent carfilzomib, proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Honoraria; Merck: Honoraria; OrthoBiotec.Imedex: Membership on an entity's Board of Directors or advisory committees; Medicom World Wide: Membership on an entity's Board of Directors or advisory committees; Optum Health Education: Membership on an entity's Board of Directors or advisory committees; PER Group: Membership on an entity's Board of Directors or advisory committees. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Hussein:Celgene Corporation: Employment. Leveque:Onyx Pharmaceuticals: Employment. Vij:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: 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.

Phase I/II Clinical Trial of Temsirolimus and Lenalidomide in Patients with Relapsed and Refractory Lymphomas

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Ajay Major ◽  
Justin Kline ◽  
Theodore G. Karrison ◽  
Paul A S Fishkin ◽  
Amy S Kimball ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Phase I ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
The Other ◽  
Advisory Committees ◽  
Grade 3

Background Targeting the PI3K/Akt/mTOR axis in relapsed lymphomas is of interest based on constitutive activation in many lymphoma subtypes, and has had varying degrees of success. We previously showed that the first generation mTOR inhibitor, temsirolimus (TEM), has activity across histologies with an acceptable toxicity profile (Smith, et al., JCO 2010). Lenalidomide (LEN) is currently approved for use in indolent non-Hodgkin lymphomas, and has several potential synergistic and overlapping targets with PI3K/mTOR/Akt inhibition. We designed this phase I/II clinical trial to evaluate the efficacy and tolerability of the combination of TEM and LEN in relapsed/refractory lymphomas. Methods The phase I dose-finding study utilized a standard "3+3" design and was open to all patients with mature B-cell malignancies. TEM was 25 mg IV weekly for all dose levels. LEN was dosed orally on D1-D21 every 28 days at three dose levels: 15 mg, 20 mg, and 25 mg. The phase II study accrued patients in a two-stage "minimax" design with stratification into three histologically-defined cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and other lymphomas. Primary endpoints of the phase II study were rates of complete (CR) and overall response (ORR), and secondary endpoints were duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results In the phase I study, 18 patients were enrolled and available for toxicity assessment. Patients were treated to intolerance, progression, or discontinuation at physician discretion. Of these, 15 patients were evaluable for dose-limiting toxicity (DLT) assessment. At dose level 3, there were 2 DLTs: grade 3 diarrhea and grade 3 HSV mucositis. Dose level 2 was thus established as the recommended phase II dose: TEM 25 mg weekly and LEN 20 mg on D1-D21 every 28 days. Of the 18 patients, there were 5 partial responses, 4 stable disease, 3 progressive disease, 4 on active treatment, and 2 not adequately assessed. The phase II study enrolled an additional 93 patients (Table 1): 39 DLBCL, 15 FL, and 39 other lymphomas which included 20 relapsed/refractory Hodgkin lymphoma (HL) patients. The median number of prior treatments was 4 (range, 1-14), and 31 patients (33%) had relapsed following prior autologous stem cell transplantation (ASCT). The median number of cycles delivered was 4 (range, 1-21). The FL cohort closed prematurely due to slow accrual. The ORR were 25.6% (12.8% CR) and 64.1% (17.9% CR) for DLBCL and other lymphoma cohorts, respectively (Table 2). The ORR for HL patients in the other lymphoma cohort, the majority of whom had relapsed after brentuximab vedotin (BV) and autologous stem cell transplantation (ASCT), was 80% (35% CR). Eight HL patients (40%) proceeded to allogeneic transplantation after TEM and LEN therapy. The high response rate in the other lymphoma cohort was sufficient to reject the null hypothesis of a 30% response rate under the minimax design. Median PFS was 7.0 mo (90% CI 3.5-8.0) and 7.0 mo (90% CI 4.6-9.9) for DLBCL and other lymphoma cohorts, respectively (Table 2). Median OS was 9.1 mo (90% CI 6.0-16.0) and 25.5 mo (90% CI 10.8-60.6) for DLBCL and other lymphoma cohorts, respectively (Table 2). Median DOR was 13.8 mo (90% CI 4.1-19.0) and 5.5 mo (90% CI 2.6-23.7) for DLBCL and other lymphoma cohorts, respectively (Table 2). Median PFS, OS and DOR for HL patients in the other lymphoma cohort were 9.2 mo (90% CI 4.6-25.5), 39.6 mo (90% CI 17.4-NR), and 8.1 mo (90% CI 5.1-38.3), respectively. Kaplan-Meier curves are displayed in Figure 1. Grade ≥3 non-hematologic adverse events (AE) related to treatment were uncommon, with no cases of pneumonitis and one grade 3 thromboembolism. Grade ≥3 hematologic AEs were common and reversible. Three Grade 5 AEs occurred (colonic perforation, myocardial infarction and sepsis). Conclusions Combination therapy with TEM and LEN demonstrated encouraging activity in heavily-pretreated and relapsed/refractory lymphomas. Survival in the other lymphoma cohort was primarily driven by favorable activity in relapsed/refractory HL. TEM and LEN may be a suitable option for treatment of HL after BV and ASCT, including as a bridge to allogeneic stem cell transplantation. Further study of PI3K/Akt/mTOR inhibition in combination with lenalidomide is warranted, particularly in relapsed HL. Disclosures Kline: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Kite/Gilead: Speakers Bureau. Kimball:Amgen: Current Employment; Amgen: Current equity holder in publicly-traded company. Petrich:Daiichi-Sankyo: Current Employment; AbbVie: Current equity holder in publicly-traded company. Smith:Celgene: Consultancy, Research Funding; Janssen: Consultancy; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Karyopharm: Consultancy, Research Funding; BMS: Consultancy; Acerta: Research Funding. OffLabel Disclosure: Temsirolimus is FDA-approved for renal cell carcinoma.

A Phase I/II Study of Pomalidomide-Cyclophosphamide-Prednisone (PCP) in Patients with Multiple Myeloma Relapsed/Refractory to Lenalidomide

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 632-632 ◽  
Author(s):  
Antonio Palumbo ◽  
Alessandra Larocca ◽  
Angelo Michele Carella ◽  
Davide Rossi ◽  
Vittorio Montefusco ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Treatment Options ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 632 Background: Patients with multiple myeloma (MM) relapsed/refractory after immunomodulatory drugs and bortezomib have limited treatment options. Recently, the combination pomalidomide-dexamethasone has led to at least partial response (PR) of 25–42% in relapsed/refractory MM and 32% in patients refractory to lenalidomide. Aims: In this study we evaluate the safety and efficacy of the combination pomalidomide-cyclophosphamide-prednisone (PCP) in patients with MM who received 1–3 lines of treatment and were relapsed/refractory to lenalidomide therapy. Methods: Between August 2010 and July 2011, 41 patients were enrolled; median age was 69 years (range 49–82); 23 patients relapsed after lenalidomide and 18 patients were refractory to lenalidomide. The first 24 patients entered the phase I of the study to define the maximum tolerated dose (MTD) of PCP: 4 dose levels of pomalidomide (1, 1.5, 2 and 2.5 mg/day, days 1–28) were tested in combination with cyclophosphamide (50 mg every other day, days 1–28) and prednisone (50 mg every other day, days 1–28) for six 28-day cycles. Thromboprophylaxis with aspirin (100 mg/day) was recommended, low-molecular weight heparin was given to high risk patients. Dose Limiting Toxicities (DLTs) were defined as: grade 4 neutropenia for more than 3 days, grade 4 thrombocytopenia, grade 3–4 neutropenic fever, any grade 3–4 non-hematologic toxicity. The MTD was achieved when 25% of patients experienced a DLT, using the Bayesian Continual Reassessment Method. In the phase II of the study, the Simon two-stage design was used and 17 additional patients were enrolled and received the MTD of pomalidomide. Results: DLTs occurred in 1/4 patient who received pomalidomide 1.5 mg (grade 4 thrombocytopenia) and in 3/12 patients who received pomalidomide 2.5 mg (grade 3 neuropathy, grade 3 hepatic toxicity and grade 4 thrombocytopenia). The MTD was defined at 2.5 mg/day, with an estimated DLT probability of 0.258 (95% credibility interval: 0.101–0.468). 32 patients received at least one cycle of therapy and could be evaluated for efficacy and safety. At least PR was reported in 19/32 (59%) patients, including 2 complete response (CR), 5 very good partial response (VGPR), 12 PR. In patients refractory to lenalidomide, at least PR was reported in 11/15 (73%) patients, including 1 CR, 2 VGPR, 8 PR. Grade 4 hematologic toxicities were neutropenia (9%) and thrombocytopenia (9%). Grade 3–4 non-hematologic toxicity included infection (9%), rash (9%), neurologic (6%) and hepatic (3%) toxicities. Thromboembolism occurred in 1 patient. Conclusions: At least PR was achieved in 73% of patients refractory to lenalidomide; grade 4 neutropenia and/or thrombocytopenia were less than 10%. The combination pomalidomide (2.5 mg/day), cyclophosphamide (50 mg every other day), prednisone (50 mg every other day) showed high response rates with limited toxicities in patients relapsed/refractory to lenalidomide. Updated data will be presented at the meeting. Disclosures: Palumbo: Amgen: Honoraria; Merck: Honoraria; 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. Larocca:Janssen-Cilag: Honoraria. Guglielmelli:Janssen-Cilag: Honoraria; Celgene: Honoraria. Giuliani:Celgene: Research Funding; Novartis: Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals A Phase 1b Study of Oprozomib with Dexamethasone or Pomalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 803-803 ◽  
Author(s):  
Parameswaran Hari ◽  
Mark A. Schroeder ◽  
James R Berenson ◽  
Andrzej Jakubowiak ◽  
Jonathan L Kaufman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Objective Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Phase 1B ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Oprozomib is a selective oral tripeptide epoxyketone inhibitor of the chymotrypsin-like subunit of the constitutive proteasome and immunoproteasome. This phase 1b study evaluated the safety and tolerability of two new formulations of oprozomib in combination with dexamethasone (Odex) or pomalidomide and dexamethasone (OPomD) in patients with relapsed or refractory multiple myeloma (RRMM). Methods: Adult patients with RRMM who had received at least 2 prior lines of therapy and whose prior treatment included both lenalidomide and a proteasome inhibitor were eligible for inclusion. Patients received either immediate-release (IR) or extended-release gastroretentive (GR) oprozomib, orally, in combination with dexamethasone (20 mg) alone or pomalidomide (4 mg) and dexamethasone (20 mg) in 4-week cycles. Oprozomib was given according to a 2/7 schedule on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 4-week cycle. In part 1 of the study, patients received Odex with either IR oprozomib at 150 mg/day or GR oprozomib at 150 mg/day. In part 2 of the study, patients received OPomD at increasing dose levels. Dosing for the IR formulation began at 150 mg/day and could be increased to 300 mg/day in increments of 25 mg as needed; at least one cohort could be enrolled at each dose level of oprozomib. Dosing for the GR formulation was determined based on the efficacy and safety data observed in the initial IR dose escalation and was at least one dose level lower than the highest dose tested of the IR formulation. The primary objectives of the study were to identify the maximum tolerated dose (MTD) and to evaluate the safety and tolerability of the OPomD formulations. Results: Overall, 34 patients were assessed at the time of this analysis. Baseline patient demographics and disease characteristics are shown in Table 1. Fourteen patients (41%) received prior carfilzomib, and 10 of these were carfilzomib-refractory; 27 patients (79%) received prior bortezomib and 14 were bortezomib-refractory. Patients were enrolled into 6 cohorts and received either IR 150 mg/day (n=5) or GR 150 mg/day (n=8) Odex, or IR 150 mg/day (n=4), IR 200 mg/day (n=8), IR 225 mg/day (n=5), or GR 150 mg/day (n=4) OPomD. Median (interquartile range) number of cycles of oprozomib received for each cohort was 2.0 (1.0-11.0), 3.5 (1.5-4.0), 6.5 (2.5-9.5), 4.5 (3.0-5.5), 1.0 (1.0-1.0), and 2.0 (1.5-2.0), respectively. Three patients experienced dose-limiting toxicities (IR 150 mg/day OPomD, increased lipase; IR 200 mg/day OPomD, acute kidney injury; GR 150 mg/day OPomD, febrile neutropenia). At the time of this analysis the MTD was not yet reached for either the IR or GR formulation. Most patients (97%) experienced ≥1 treatment-emergent adverse event (AE) and 23 (68%) experienced ≥1 treatment-emergent grade ≥3 AE. AEs that occurred in ≥50% of patients in any cohort are listed in Table 2; the most common overall were nausea (62% any grade; 3% grade ≥3), diarrhea (50% any grade; 6% grade ≥3), and vomiting (47% any grade; 6% grade ≥3). Four patients (12%) experienced treatment-emergent AEs leading to discontinuation of study drug; no fatal AEs occurred. Seven patients who received OPomD had an objective response at the time of this analysis (IR 150 mg/day, n=1 [33%], median duration of response [DOR]=169 days; IR 200 mg/day, n=6 [67%], median DOR=86.5 days; DOR assessments ongoing). Of the seven patients with an objective response, six had a partial response (IR 150 mg/day and IR 200 mg/day) and one had a very good partial response (IR 200 mg/day). Progression-free survival data were not yet mature. In total, 16 of 34 patients continue to receive oprozomib therapy. The results reported are based on preliminary data available at the time of analysis. The study is ongoing and updated results will be provided at the meeting. Conclusion: Results from this study showed that treatment with OPomD had manageable toxicity in patients with RRMM. The most common AEs observed were gastrointestinal disorders, and most of these were grade 1-2 with no gastrointestinal bleeding reported. Furthermore, OPomD therapy showed promising efficacy, with an objective response rate of 67% for patients in the IR 200-mg/day cohort. Disclosures Hari: Sanofi: Honoraria, Research Funding; Janssen: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen Inc.: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Research Funding. Schroeder:Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Berenson:Amgen Inc.: Consultancy, Honoraria, Research Funding. Jakubowiak:Takeda: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kaufman:BMS: Consultancy; Roche: Consultancy; Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy. Voorhees:Amgen Inc.: Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TeneoBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; Novartis: Consultancy, Other: served on an IRC. Fujii:Amgen Inc.: Employment, Equity Ownership. Yang:Amgen Inc.: Employment, Equity Ownership. Galimi:Amgen Inc.: Employment, Equity Ownership.

Phase I/IIa Study of the Human Anti-CD38 Antibody MOR202 (MOR03087) in Relapsed or Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3035-3035 ◽  
Author(s):  
Marc S Raab ◽  
Manik Chatterjee ◽  
Hartmut Goldschmidt ◽  
Hermine Agis ◽  
Igor W Blau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Dependent Cell ◽  
Grade 3 ◽  
Dose Levels ◽  
Support Research

Abstract Background: CD38 is a type II transmembrane glycoprotein that is expressed at high levels on multiple myeloma cells. MOR202 is a HuCAL-derived, human, IgG1 anti-CD38 monoclonal antibody showing effective antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and high activity in preclinical models of multiple myeloma. Patients and Methods: Here we reportinterimsafety and preliminary efficacy data from this ongoing, multicenter, MOR202 dose-escalation, phase I/IIa study in patients with relapsed or refractory disease who had failed ≥2 prior therapies for multiple myeloma, including an immunomodulatory drug and a proteasome inhibitor. The objectives are to evaluate the safety, maximum tolerated dose (MTD)/recommended dose and preliminary efficacy of MOR202 when administered as monotherapy or in combination with dexamethasone (DEX); pomalidomide (POM) + DEX; and lenalidomide (LEN) + DEX. Patients received MOR202 as a 2-hour intravenous infusion every 2 weeks (q2w; dose levels 0.01-16 mg/kg), 4 mg/kg weekly (q1w) and 4, 8 and 16 mg/kg q1w + DEX. The combination cohorts receiving MOR202 8 mg/kg with LEN + DEX and POM + DEX have been opened, and the 16 mg/kg q1w with LEN + DEX or POM + DEX, as well as confirmation cohorts, are planned. Results: As of 26 June 2015, 44 patients have been treated; 31 and 13 patients in the q2w and q1w dose levels, respectively. Median age was 69 years (range 44-80); median number of prior therapy lines was 4 (2-11). The MTD has not been reached. The most common treatment-emergent adverse events (TEAEs) at any grade were anemia (15 patients, 34%), fatigue (14 patients, 32%), infusion-related reactions (IRRs) and leukopenia (13 patients, 30% each), lymphopenia and nausea (11 patients, 25% each). Grade ≥3 TEAEs were reported for 28 patients (64%); the most common included lymphopenia (8 patients, 18%), leukopenia (5 patients, 11%) and hypertension (4 patients, 9%). IRRs arose mainly during the first infusion; all were grade 1-2 except for one patient (grade 3); no IRRs occurred in patients receiving MOR202 in combination with DEX. Infections were commonly reported (26 patients, 59%) but in the majority of the cases were not considered to be treatment-related. There have been no treatment-related deaths. Pharmacokinetic (PK) data demonstrated a significant target-mediated drug disposition effect for most patients treated q2w. By contrast, patients treated q1w (4 or 8 mg/kg) showed constant or slightly accumulating MOR202 trough levels, suggesting the potential for full target occupancy at 16 mg/kg. Long-lasting tumor control has already been observed in early monotherapy cohorts, including one partial response and one very good partial response in the weekly cohorts; efficacy analyses are ongoing. First data from the dose escalation of the weekly cohorts with DEX and the combination cohorts with LEN + DEX and POM + DEX will be presented. Conclusions: At doses up to 16 mg/kg,MOR202 was safe and well tolerated. Encouraging preliminary activity of MOR202 was observed, especially with the weekly regimen. PK data show the potential for full target occupancy in patients receiving MOR202 16 mg/kg q1w. This dosing schedule of MOR202 is currently being tested in combination with DEX, LEN + DEX, and POM + DEX. Disclosures Raab: MorphoSys: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; BMS: Consultancy. Goldschmidt:Chugai: Honoraria, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Einsele:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Ferstl:Bristol-Myers Squibb: Other: Advisory board; Novartis: Other: Case report presentation. Weisel:Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Support; Novartis: Other: Travel Support; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support; Onyx: Consultancy, Honoraria; Noxxon: Consultancy. Klöpfer:MorphoSys: Employment. Weinelt:MorphoSys: Employment. Härtle:MorphoSys: 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.

Indatuximab Ravtansine (BT062) in Combination with Low-Dose Dexamethasone and Lenalidomide or Pomalidomide: Clinical Activity in Patients with Relapsed / Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4486-4486 ◽  
Author(s):  
Kevin R. Kelly ◽  
David S. Siegel ◽  
Asher A. Chanan-Khan ◽  
George Somlo ◽  
Leonard T. Heffner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Clinical Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Prior Exposure ◽  
Tolerability Profile ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background: BT062 (Biotest AG, Dreieich, Germany) is an antibody-drug conjugate (ADC) comprising a CD138-binding chimerized antibody and the cytotoxic maytansinoid, DM4. It is designed to target and kill CD138-positive cancer cells. CD138 (Syndecan-1) is highly expressed on a number of solid tumors and hematological malignancies and is one of the most reliable markers for multiple myeloma (MM) cells. BT062 was previously evaluated as a monotherapy in patients with heavily pretreated relapsed/refractory MM and found to have an acceptable tolerability profile with preliminary evidence of activity (Heffner et al, Blood. 2012; 120: Abstract 4042). Phase I/IIa testing was initiated with BT062 in combination with lenalidomide (Len) and low-dose dexamethasone (dex). The combination was well tolerated at BT062 doses up to 100 mg/m², defined to be the recommended Phase 2 dose (RPTD), and induced meaningful responses, including in patients previously treated with both Len and bortezomib (Bort) (Kelly et al, Blood. 2014; 124: Abstract 4736). Based on these promising results, further investigation of BT062 in combination with pomalidomide (Pom) and dex was initiated in patients with prior Len and Bort exposure, a patient population known to have a poor outcome. Objectives: To evaluate the safety and activity of BT062 (on days 1, 8, and 15 in a 4-week cycle) used in combination with dex (20-40 mg on days 1, 8, 15, and 22) and Len (25 mg, daily on days 1-21) or Pom (4 mg, daily on days 1-21) in patients with relapsed/refractory MM. Methods: This is a prospective, open label, multicenter Phase I/IIa study. The RPTD of BT062 in combination with Len/dex was defined to be 100 mg/m², and 38 patients were treated with BT062/Len/dex at the BT062 RPTD. An additional 17 patients were treated with BT062/Pom/dex at the BT062 RPTD. Patients aged ≥18 years with relapsed/refractory MM were eligible to participate. Prior treatment with Len, Pom, and/or dexamethasone (any dose) was allowed. To qualify for treatment with BT062/Len/dex at the BT062 RPTD, patients must have received at least one but no more than six prior therapies.To qualify for treatment with BT062/Pom/dex, patients must have received at least two prior therapies, including both Len and Bort, and progressed on or within 60 days of completion of their last therapy, with no limit on number of prior therapies. Patients with clinical response (or no evidence of disease progression) without unacceptable toxicities were eligible to receive additional treatment cycles. Toxicities were assessed by CTCAE v4. Clinical response was assessed by the investigator according to International Myeloma Working Group criteria. Results: Sixty-four patients have received BT062 in combination with dex and Len or Pom in this ongoing study. The combinations have been generally well tolerated, with approximately 90% of adverse events (AEs) reported CTC grade 1 or 2. The most common AEs reported are diarrhea, fatigue, and nausea. Forty-seven patients have received BT062 with Len/Dex (3 at 80 mg/m², 38 at 100 mg/m², 6 at 120 mg/m²), with 8 patients still on treatment. Among these 47 patients, median progression-free survival (PFS) was 16.4 months. Forty-three patients completed at least two treatment cycles and were evaluable for response. Of these patients 33 achieved a partial response (PR) or better, with an overall response rate (ORR) of 77% and a median duration of response (DOR) of 21.0 months. Thirteen of the evaluable BT062/Len/dex-treated patients had prior exposure to both Len and Bort and progressed on or within 60 days of their last therapy. ORR was 54% among these patients, including 1 complete response (CR), 4 very good partial responses (VGPR) and 2 PRs. Seventeen patients were treated with BT062/Pom/dex, all had prior exposure to both Len and Bort and progressed on or within 60 days of their last therapy. ORR was 79%, with 4 VGPR and 7 PR among the 14 patients evaluable for efficacy. Median PFS has not been reached after 7.5 months median follow up, with 7 patients still on treatment. Updated safety and activity data will be presented. Conclusion: BT062 has been found to be well tolerated when used in combination with Len/dex or Pom/dex, with encouraging activity even in patients with Len- and Bort-pretreated disease progressing on or within 60 days of completion of their last therapy. Disclosures Kelly: Novartis: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Siegel:Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Merck: Honoraria. Somlo:Millennium: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Heffner:Millennium: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Madan:Onyx: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Lonial:Celgene: Consultancy; Celgene: Consultancy; BMS: Consultancy; Onyx: Consultancy; Millenium: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Janssen: Consultancy; Merck: Consultancy; BMS: Consultancy. Barmaki-Rad:Biotest AG: Employment. Rühle:Biotest AG: Employment. Herrmann:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Haeder:Biotest AG: Employment. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Acetylon: Equity Ownership; Acetylon: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Millennuim: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; C4 Therapeutics: Equity Ownership; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

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