Phase I/II, Multicenter, Open-Label, Dose-Escalation Study of Bendamustine in Combination with Lenalidomide and Dexamethasone (BRD) in Patients with Relapsed Multiple Myeloma: A Multiple Myeloma Research Consortium Study.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2965-2965
Author(s):  
Shaji K. Kumar ◽  
Amrita Krishnan ◽  
Vivek Roy ◽  
Todd M Zimmerman ◽  
Morie Abraham A Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Expert Testimony ◽  
Research Funding ◽  
Phase 1 ◽  
Response Rates ◽  
Hematological Toxicity ◽  
Phase 2 ◽  
Dose Reductions

Abstract Abstract 2965 Background: Alkylating agents have been the mainstay of multiple myeloma (MM) therapy for decades and despite introduction of several new therapies, it continues to play a significant role in its management as part of various drug combinations. While melphalan has been the most commonly used alkylator in MM, recent studies have suggested significant activity for bendamustine, a bifunctional alkylator. The combination of lenalidomide and melphalan has been associated with high response rates in relapse and newly diagnosed MM. Based on these promising results we designed a trial to evaluate the maximally tolerated dose of lenalidomide and bendamustine when used in combination as well as the efficacy of the combination in relapsed disease. Patients and Methods: Patients with relapsed MM and measurable disease were enrolled on this phase 1/2 trial provided they had not more than 4 prior lines of therapy for MM, had adequate performance status and organ and hematological function. Patients refractory to lenalidomide were allowed to enroll. The primary objectives were to (i) to determine the MTD of bendamustine and lenalidomide in combination with dexamethasone in subjects with relapsed MM (phase 1) and (ii) to evaluate the confirmed response rate of bendamustine in combination with lenalidomide and dexamethasone in patients with relapsed MM (phase 2). Bendamustine (B) was administered on days 1 and 2 of a 28-day cycle at doses of 50–100 mg/m2. Lenalidomide (R) was given days 1–21 at doses of 15–25 mg daily. Dexamethasone (D) was administered at 40 mg weekly. Dose escalation was done using a 3+3 design and MTD was defined as one dose level below that resulted in >=2 DLTS among 6 patients. The primary end point for this trial was the proportion of patients with confirmed hematologic response (sCR, CR, VGPR, or PR) over the first 6 cycles of treatment. Results: A total of 72 patients were accrued to this study from March 2010 to May 2012: 21 patients in phase 1 and 51 in phase 2. The 6 patients from the MTD dose level of phase 1 were also included in phase 2. The median age of all 72 patients was 62.1 (range, 40–86) and 57% were male. Majority (75%) of patients had previously been exposed to lenalidomide and 69% had prior exposure to bortezomib. Median # of prior therapies was 3 (range, 1–5) and 74% of patients had a prior autologous stem cell transplant. Patients have received a median of 4 cycles (range, 1–25), with 27 patients still continuing on active treatment. Disease progression led to study discontinuation in 22 (49%) and adverse events were the reason for discontinuation in 14 (31%). In phase I, two DLTs (Grade (Gr) 2 neuropathy and Gr 4 neutropenia) were seen at the highest dose level (100 mg/m2 B, 25 mg R), and the MTD was determined as 75 mg/m2 of B given days 1 and 2 and 25 mg of R days 1–21, along with D 40 mg weekly. Overall patients, 12/21 (57%) had a PR or better. In phase 2, 17 (40%) confirmed responses (>=PR) were seen among the 43 patients evaluable for response (received at least 6 cycles of treatment or have gone off study prior to 6 cycles); including 9 (21%) VGPR and 8 (19%) PR. An additional 5 patients had a minor response. Over all dose levels, a gr 3 or higher adverse event at least possibly attributed to the study was seen in 75% of patients. The most common toxicities were all hematological (thrombocytopenia and leukopenia), and most common non-hematological toxicity was infection. Prolonged time to recovery of blood counts was seen in a few patients, but majority of patients were able to tolerate the regimen with adequate dose reductions. Conclusion: The recommended dose of the combination for further studies is bendamustine at 75 mg/m2 days 1 and 2, lenalidomide 25 mg daily on days 1–21 and dexamethasone days 1, 8, 15, 22; with cycles repeated every 28 days. The regimen is well tolerated with hematological toxicity being the most common and manageable with dose reductions. The regimen is effective with high response rates and durable responses seen. Updated results with response rates and time to event analyses will be available for the entire cohort at the time of meeting. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Krishnan:celgene: Consultancy, Speakers Bureau. Zimmerman:Celgene: Honoraria; Millennium: Honoraria; Novartis: Expert Testimony, Expert Testimony Other. Vij:Teva: Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Millennium: Speakers Bureau; Onyx: Honoraria, Research Funding.

Phase 1/2 Trial Of Lenalidomide In Combination With Cyclophosphamide and Prednisone (REP) In Patients With Lenalidomide-Refractory Multiple Myeloma (REPEAT-study)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 287-287 ◽  
Author(s):  
Inger S. Nijhof ◽  
Sonja Zweegman ◽  
Mark-David Levin ◽  
Harry R. Koene ◽  
Aart Beeker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Oral Cyclophosphamide ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Grade 3 ◽  
Dose Levels

Abstract Background The outcome of multiple myeloma (MM) patients who are no longer responding to thalidomide, lenalidomide (LEN) and bortezomib (BORT) is very poor, with a median event-free survival of 5 months and median overall survival (OS) of 9 months (Kumar SK et al, Leukemia 2012; 26;149-157). We have previously shown in a small retrospective study that the combination of continuous low dose oral cyclophosphamide (endoxan) and prednisone combined with lenalidomide (REP) had remarkable activity in heavily pretreated LEN-refractory multiple myeloma patients (median 6 lines of previous chemotherapy) (vd Donk et al; Br J Haematol 2010;148(2):335-7). To determine the optimal dose of lenalidomide with continuous cyclophosphamide and prednisone, we initiated a prospective study to evaluate the maximum tolerated dose (MTD) of the REP regimen and to assess its efficacy and safety in LEN-refractory MM patients. Here we report safety and efficacy data from the phase 1 dose-escalation part of the REPEAT-study (NCT01352338). Patients and Methods Patients aged ≥ 18 years with LEN-refractory MM, ECOG-performance status 0-3 and adequate kidney, liver and hematologic function were included. Five dose levels were evaluated using a standard 3+3 design, based on dose-limiting toxicities (DLTs) occurring in cycle 1. Patients received LEN in doses ranging from 10-25 mg/day on days 1-21 of 28-day cycle, while oral cyclophosphamide (50 or 100 mg) and prednisone (20 mg) were given continuously. Therapy was continued until progression. The MTD for the phase 2 part is defined as the highest dose level with 0 or 1 DLT's observed in 6 patients. Results Up till now, 35 patients were enrolled (22 in phase 1 and 13 in phase 2) from August 2011 to June 2013. The phase 2 part is still recruiting and data are not evaluable yet. One patient in phase 1 was excluded because of study violation and is not included in the analysis. The median age of the 21 evaluable patients in phase 1 was 69 years (range 41-73); 76% were male. The median duration of the disease from diagnosis was 41 months (range 18-96), median number of prior therapies was 3 (range 2-6), and 12 patients (57%) had previously received autologous SCT. All patients were LEN-refractory, 19 (90%) had prior BORT treatment, and 16 (76%) had BORT-refractory MM. Fifty-five % of the patients were considered high risk by FISH. At the time of analysis, 16 of 21 patients in phase 1 have discontinued treatment because of disease progression (13), alternative treatment (allo-SCT) (1), or adverse events (2). The MTD was defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously (dose level 4), based on three patients experiencing a DLT: two developed pneumonia (in dose levels 4 and 5; CTC grade 3), and one patient at dose level 5 experienced CTC grade 3 dyspnea. Neutropenia (18%) and thrombocytopenia (18%) were the most common grade 3 hematological adverse events (AEs), which were managed with growth factor support and/or dose modification. There were no grade 4 hematologic AEs. Grade 3 respiratory tract infections (29%) and grade 2 fatigue (19%) were the most common non-hematological AEs. Venous thromboembolism occurred in 1 patient. Figure 1 shows a waterfall plot of the responses of the patients that participated in the phase 1 part of the study. Overall response rate (≥ PR) was 67% with 6 out of 21 (29%) patients achieving at least VGPR. In addition 2 patients achieved MR (≥ MR: 76%). Median PFS and OS were 6.3 and 15.5 months respectively. Similar results were achieved in the subset of patients with LEN- and BORT-refractory disease. Interestingly, laboratory experiments with purified myeloma cells from these patients suggest synergism between LEN and cyclophosphamide. Conclusions The REP regimen induces high response rates and prolonged PFS and OS in LEN-refractory patients with acceptable toxicity. The MTD is defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously. Phase 2 is enrolling patients and evaluates efficacy and safety of the REP regimen at the MTD. REP should be considered a valuable salvage option for LEN-refractory MM patients. We will present an updated follow-up at ASH. Disclosures: Sonneveld: Onyx: Research Funding; Millenium: Research Funding; Janssen-Cilag: Research Funding; Onyx: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. van de Donk:Celgene: Research Funding.

A Phase I/II Trial of the Histone Deacetylase (HDAC) Inhibitor, Panobinostat, in Combination with Lenalidomide in Patients with Relapsed/Refractory Hodgkin’s Lymphoma (HL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3099-3099 ◽  
Author(s):  
Beth Christian ◽  
Lai Wei ◽  
Jennifer Sexton ◽  
Samantha M. Jaglowski ◽  
Steven M. Devine ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Erythema Nodosum ◽  
Altered Mental Status ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Dose Reductions

Abstract Introduction: Phase 2 single agent trials with lenalidomide and panobinostat in patients with relapsed or refractory HL have demonstrated overall response rates (ORR) of 19% (Fehniger et al., Blood 118:5119-5125, 2011) and 27% (Younes et al., JCO 30:2197-2203, 2012), respectively. We conducted a phase I/II trial to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and overall response rate (ORR) with combined lenalidomide and panobinostat in patients with relapsed HL. Methods: Patients with relapsed or refractory classical HL (cHL) or lymphocyte predominant HL (LP HL) after at least one prior therapy were eligible. Measurable disease > 1 cm, ejection fraction ≥ 45%, ECOG PS 0-2, QTc ≤ 450 msec, ANC ≥ 1200/mm3, platelets ≥ 100,000/mm3, AST/ALT ≤ 2.5 x the upper limit of normal (ULN), bilirubin ≤ 1.5 x ULN, and creatinine clearance 60 ≥ ml/min were also required. In the phase I trial, escalating doses of panobinostat (15 or 20 mg) days 1, 3, and 5 weekly were combined with lenalidomide 25 mg days 1-21 utilizing a 3+3 standard dose escalation design. DLT was defined during cycle 1 as grade 4 neutropenia or thrombocytopenia, grade 4 infection, grade 3 infection for > 7 days, treatment delays > 14 days, or other grade 3-4 non-hematologic toxicity. Twenty-eight days defined a cycle and patients could remain on therapy until disease progression. Response was assessed after cycles 2, 6, and every 4 cycles thereafter by International Harmonization Criteria (Cheson, JCO 25:579-586, 2007). Results: From Feb 2012 through June 2014, 22 patients (16 males) with cHL (n=21) and LP HL (n=1) and a median age of 45 (range 22-72) have been enrolled. Patients had received a median of 4 prior therapies (range 2-13), 9 patients were refractory to their most recent therapy, and 91% had stage III-IV disease at study entry. Ten patients had a prior autologous SCT, 1 patient had received prior allogeneic EBV-directed cytotoxic T-cells, 1 patient had a prior syngeneic transplant, and 1 patient had both prior autologous and allogeneic transplants. Eleven patients were enrolled in the phase 1 study at dose level (DL) 1 (25 mg lenalidomide + 15 mg panobinostat, n=6) and at DL 2 (25 mg lenalidomide + 20 mg panobinostat, n=5). Although there were no DLTs observed in cycle 1, 2 patients treated at DL 2 experienced grade 4 neutropenia and thrombocytopenia for > 14 days in cycle 2 and 3 of 5 patients were dose reduced to DL 1 in cycles 2 or 3. Therefore, DL 1 was expanded to 6 patients to ensure patient safety at this dose level and the phase 2 study was conducted at DL 1. Eleven patients have been treated in the phase 2 study. In all 22 patients, the median number of cycles completed on study was 4 (range 1-22). Grade 3-4 toxicities in all patients included neutropenia (59%), thrombocytopenia (41%), lymphopenia (27%), febrile neutropenia (27%), hypophosphatemia (9%), hypocalcemia (5%), QTc prolongation (5%), fatigue (5%), nausea/vomiting (5%), erythema nodosum (5%), transaminitis (5%), and unexplained altered mental status after administration of study medications (5%). Dose reductions were required in 10 patients (45%, 5 in the phase 2 study and 3 patients with multiple dose reductions) for febrile neutropenia, grade 3-4 neutropenia/thrombocytopenia, erythema nodosum, and transaminitis. Twenty-one patients have discontinued protocol therapy for PD (n=15), adverse events (n=5, including grade 4 neutropenia/thrombocytopenia or unexplained altered mental status after drug dosing), and to undergo elective CABG (n=1). ORR is 14% (2 CR and 1 PR) in 21 evaluable patients with complete responses in 1 patient with cHL and 1 patient with LP HL of 6 and 25 months duration, respectively. Conclusions: Combined panobinostat and lenalidomide appears to be well tolerated in patients with relapsed/refractory HL. Due to myelosuppression at higher doses, the recommended phase 2 dose of the combination is 25 mg lenalidomide days 1-21 with 15 mg panobinostat days 1, 3, and 5 weekly on a 28-day cycle. Accrual continues to the two-stage phase 2 trial, but based on preliminary data in the first 22 patients, the efficacy of combined lenalidomide and panobinostat appears similar to that previously reported with these drugs as single agents. Disclosures Christian: Celgene: Research Funding. Fehniger:Celgene: Research Funding. Wagner-Johnston:Celgene: Research Funding. Bartlett:Celgene: Research Funding; Novartis: Research Funding. Blum:Celgene: Research Funding; Novartis: Research Funding. Off Label Use: Panobinostat and lenalidomide are not approved for the treatment of Hodgkin's lymphoma.

scholarly journals Pomalidomide, Bortezomib and Dexamethasone (PVD) for Patients with Relapsed Lenalidomide Refractory Multiple Myeloma (MM)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 304-304 ◽  
Author(s):  
Martha Q. Lacy ◽  
Betsy R. LaPlant ◽  
Kristina M Laumann ◽  
Shaji Kumar ◽  
Morie A Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Cell Transplant ◽  
Refractory Multiple Myeloma

Abstract Background: Pomalidomide is an immunomodulatory agent (IMiD®) that has been approved for treatment of relapsed and refractory multiple myeloma (MM). Combinations of IMiDs and proteasome inhibitors offer the potential for deeper and more durable responses due to enhanced efficacy. Preliminary results of a phase 1 study of twice weekly bortezomib with pomalidomide have been reported with promising results (Richardson, ASH 2012). This phase I/II trial was designed to evaluate the maximum tolerated doses (MTD) as well as safety and efficacy of the combination of pomalidomide, once weekly bortezomib and dexamethasone (PVD) in patients with relapsed, lenalidomide refractory, MM. Patients and methods: We included patients with relapsed MM who had 1-4 prior lines of therapy and were resistant or refractory to lenalidomide. In the phase I portion of the trial, dose level 1 consisted of pomalidomide 4 mg days 1-21 PO, bortezomib 1.0mg/m2 days 1,8,15, and 22 IV or SQ and dexamethasone 40 mg days 1,8,15, and 22 PO, given every 28 days. Bortezomib was increased to 1.3mg/m2 for dose level 2 and and was adopted for the phase 2 portion. The primary aim of the phase I cohort was to determine the MTD of the combination, and for the phase II cohort was to evaluate the confirmed response rate (PR, VGPR, or CR) in relapsed refractory MM. Response was assessed by the IMWG criteria and toxicity was graded using the CTCAE v4.0. Results: 50 patients were accrued between March 2012 and July 2014 (dose level (DL)1: 3, DL 2: 6, Phase II: 41). We describe results in 47 patients treated at MTD and phase II. Median age was 66, 51% were female and median time from diagnosis to study was 46 months (15-142). Twenty five percent had mSMART defined high-risk status. Median number of prior regimens was 3. All patients had prior lenalidomide, 68% had stem cell transplant, 17% received thalidomide, 56% had alkylators and 57% had bortezomib. With median follow up of 9 months, 72% remain progression free, 96% are alive and 66% remain on treatment. The most common AEs at least possibly attributable to the combination were anemia, fatigue, leukopenia and thrombocytopenia; however, the majority of these were grade 1-2. Grade ≥3 AEs (regardless of attribution) that occurred in at least 3 patients included neutropenia (29), leukopenia (15), lung infection (6), lymphopenia (8) dyspnea (3) and syncope (3). DVT/PE occurred in one patient. Among the 42 patients who were evaluable, confirmed responses (PR, VGPR, or CR) were seen in 34 (81%) including sCR (3), CR (5), VGPR (8), PR (18). Confirmed responses were seen in 9 of 11( 82%) high risk patients. Median progression free survival was 17.7 months (95%CI: 9.5-NA). Conclusions: PVD is a highly effective combination in patients refractory to lenalidomide with confirmed responses in over 80%. Weekly administration of bortezomib enhanced the tolerability and convenience of this regimen. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy or DVT. PVD is a highly attractive option in patients with relapsed and refractory MM. Disclosures Lacy: Celgene: Research Funding. Lust:Senesco: PI Other. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Stewart:Celgene: Consultancy; Novartis: Consultancy; Array BioPharma: Consultancy; BMS: Consultancy; Millenium: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding.

Phase I/II Trial of Weekly Escalated Dose Bortezomib Combined with Lenalidomide and Dexamethasone in Patients in First Relapse or Primary Refractory Disease after First Line Therapy for Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4735-4735
Author(s):  
Annemiek Broijl ◽  
Marie José Kersten ◽  
Wendim Ghidey Alemayehu ◽  
Mark-David Levin ◽  
Okke de Weerdt ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Median Number ◽  
Phase 2 ◽  
Advisory Committees ◽  
First Line Therapy ◽  
Grade 3

Abstract Background Both Bortezomib and Lenalidomide monotherapy, as well as in combination with dexamethasone and chemotherapy, have shown high overall response rates (ORR) in relapsed and refractory multiple myeloma (RRMM). Recently, the combination of Bortezomib (1.0 mg/m2), Lenalidomide (15 mg) and Dexamethasone was reported to show efficacy in RRMM. (Richardson, Blood 2014) Here, we report the long-time follow-up results of a multicenter, dose-escalating phase I-II trial, HOVON86, which evaluated the effect of weekly escalated dose Bortezomib combined with Lenalidomide and Dexamethasone as reinduction treatment followed by Lenalidomide monotherapy for maintenance treatment in patients with RRMM after first line therapy. (Trial EudraCTnr 2007-002533-37) Methods In the dose escalation part of the study, the maximum tolerated dose (MTD) and recommended dose level (RDL) of weekly Bortezomib and Lenalidomide with Dexamethasone were determined according to a ‘3 + 3' dose-escalation scheme. A maximum of 4 dose levels were planned. Bortezomib was administered once weekly by rapid intravenous administration on days 1, 8, and 15, at a starting dose of 1.3 mg/m2 and planned to be escalated to 1.6 mg/m2, Lenalidomide was administered days 1-21 followed by a one-week interval at a starting dose of 10 mg/day and planned to be increased to 15 mg at dose level 3 and 4. Low dose Dexamethasone was added at a fixed dose of 20 mg days 1,2,8,9,15, and 16. Cycles were repeated at 28 days for a maximum of 8 cycles. The MTD was defined as the level with 2 dose-limiting toxicities (DLT) minus 1 level. A phase II part of the study was performed at the MTD level. All patients received Lenalidomide maintenance at a dose of 10 mg/day, days 1-21 in 28 day cycles until relapse or progression. Patients received valaciclovir prophylaxis with Bortezomib and prophylactic salicylic acid throughout treatment. Results 81 patients with a first RRMM were enrolled, 4 patients were non-eligible based on not having measurable disease. The median age of all 77 evaluable patients at enrollment was 66 years (range, 46–84), 64% male, and 26%/5% of patients had ISS II/III disease. In the Phase 1 part, 15 patients received Bortezomib/Lenalidomide/Dexamethasone according to dose level 1: 1.3 mg/m2/10mg/20mg (n=3), dose level 2: 1.6 mg/m2/10mg/20mg (n=6) or dose level 3: 1.6 mg/m2/15mg/20mg (n=6). The DLT was reached at the 3rd dose level, due to two grade 3 non-hematological DLT's. There were no DLT's in dose level 1 or 2. Therefore, the RDL for the phase 2 part was established at Bortezomib 1.6 mg/m2, Lenalidomide 10 mg, Dexamethasone 20 mg. In the Phase 2 part of the study, the ORR after induction in 70 patients at the RDL of Phase I (n=6) and in Phase II (n=64), was 89%, with 64% CR +VGPR, table 1. The median number of cycles to achieve ≥PR was 1, while the median number of cycles to maximum response was 2. The median duration of response was 28 months. The median progression free survival (PFS) and overall survival (OS) were 19 and 42 months, respectively, Figure 1. The median time to progression was 27 months; the median time to next treatment was 19 months. Prognostic factors associated with PFS included complex karyotype, defined as showing 3 or more abnormalities; no prognostic factors were identified in association with OS. Hematologic toxicity NCI-CTC grade 1-4 occurred in 33/70 (47%) of patients, including 30% grade 3-4. Infectious complications concerned grade 2 in 29% and grade 3 in 16% of patients. Thrombo-embolic events (VTE) occurred in 2 patients (3%). 41/70 (59%) patients developed polyneuropathy (PN) grade ≥ 1; of these 41 patients, 18 patients experienced sensory PN, 2 patients had motor PN, and in 21 cases the type of PN was not further specified. 29 (41%) patients had grade 1-2, and the remaining 12 (17%) patients had grade 3-4 PN. 12/29 (41%) patients received a dose reduction upon development of PN grade 1-2, 11/12 (92%) patients upon development of grade 3-4 PN. 19/29 (66%) patients with grade 1-2 PN showed a complete recovery as compared to 6/12 (50%) patients with grade 3-4 PN. Conclusion Weekly Bortezomib 1.6 mg/m2 plus Lenalidomide 10 mg/day, combined with low-dose Dexamethason is a feasible, effective treatment for relapsed, refractory patients with manageable toxicity. Table 1 Phase 1: n(%) Phase 2: n(%) Total: n(%) Total 6 64 70 CR+VGPR No 3(50%) 2(34%) 25(36%) Yes 3(50%) 42(66%) 45(64%) ORR: ≥PR No 1(17%) 7(11%) 8(11%) Yes 5(83%) 57(89%) 62(89%) Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Kersten: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Vellenga:Janssen: Research Funding. Bos:celgene: Research Funding. Lokhorst:Genmab: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1874-1874 ◽  
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Peter Anglin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Oral Cyclophosphamide ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 1874 Poster Board I-899 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen in relapsed/refractory multiple myeloma (MM) patients (pts), with an overall response rate of 60.6% and median time to progression (TTP) of 13.4 months (Dimopoulos MA, et al, Leukemia 2009 Jul 23 [Epub ahead of print]). Oral cyclophosphamide and prednisone is an older regimen with excellent patient tolerance, and we sought to enhance the efficacy of lenalidomide by adding oral cyclophosphamide and prednisone in this phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15; lenalidomide on days 1–21; and prednisone 100 mg every other day in a 28 day cycle. ASA 81 mg/day was given to all pts as DVT prophylaxis. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2009, 31 pts with relapsed/refractory MM who had not previously received lenalidomide were entered onto study. Median age was 61 (40–78) years and 61% were male. Immunoglobulin subtype was IgG in 19 pts (61%), IgA in 8 pts (26%) and light chain only in 4 pts (13%). Median number of prior regimens was 2 (1–5) and 28 pts had undergone previous ASCT, including double transplants in 6 pts. Prior therapy included thalidomide in 9 (29%) and bortezomib in 15 (48%). FISH cytogenetics were available in 13 pts; one had 13q deletion but none had t(4;14) or p53 deletion. At the time of protocol entry, median β 2-microglobulin level was 246 (92–767) nm/L, albumin 39 (34–48) g/L, creatinine 83 (50–126) μmol/L, platelet count 230 (75–337) × 109/L and ANC 2.5 (1.1–6.1) x 109/L. Protocol treatment is summarized in Table 1. Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities included thrombocytopenia in 5 pts (16%) and neutropenia in 9 pts (29%). These were managed with dose reduction and/or growth factor support. Four episodes of febrile neutropenia occurred. Other grade 3–4 non-hematologic toxicities included abdominal pain/bacteremia in 1 pt in cohort 1; hypokalemia in 1 pt in cohort 2; and DVT in 2 pts, dizziness in 2 pts and fatigue in 1 pt in cohort 3. Using the International uniform response criteria (Durie BG, et al, Leukemia 2006; 20:1467–1473), the best response was documented at a median of 6 (1–5) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (5 CR, 9 VGPR, 9 PR, 1 MR and 1 stable disease). At a median follow-up (F/U) of 12 (8–21) months, 20 pts remain on study, 2 have withdrawn and 9 pts have progressed at a median of 9 (4–13) months; only 1 one has died (due to MM). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with minimal toxicity; 2) the overall response rate (CR + VGPR + PR) in 31 pts to date is 93%; 3) at a median F/U of 1 year, only 9 pts (29%) have progressed; 4) longer follow-up is required to assess the TTP and survival of the CPR regimen. Disclosures: Reece: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Lenalidomide in combination with drugs other than dexamethasone. Anglin:Celgene: Honoraria. Chen:Celgene: Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Mikhael:Celgene: Honoraria. Trudel:Celgene: Honoraria.

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy Induces High Response Rates in Agressive Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3443-3443 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
William Wierda ◽  
William Plunkett ◽  
Susan O'Brien ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rates ◽  
Off Label ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age > 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

scholarly journals A Multicenter, Open Label Phase I/II Study of Carfilzomib, Pomalidomide and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma (MM) Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1145-1145 ◽  
Author(s):  
Sara Bringhen ◽  
Valeria Magarotto ◽  
Anna Marina Liberati ◽  
Angelo Belotti ◽  
Alessandra Larocca ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Low Dose ◽  
Response Rate ◽  
Primary Objective ◽  
Advisory Board ◽  
Level 1

Abstract Background: Survival rates of multiple myeloma (MM) patients (pts) has improved over the past few years, but patients inevitably relapse and become more resistant to subsequent treatments. Carfilzomib and Pomalidomide were both approved for the treatment of relapsed/refractory MM (RRMM). Combinations including a proteasome inhibitor (PI) plus an immunomodulator (IMiD), such as Bortezomib-Lenalidomide-Dexamethasone (VRD) or Carfilzomib-Lenalidomide-Dexamethasone (CRD), showed a very high response rate with an acceptable toxicity. Moreover, in the CHAMPION1 study (Berenson et al Blood 2016), the weekly infusion of Carfilzomib showed to be as effective as the twice schedule. In this phase I/II study we assessed for the first time weekly Carfilzomib plus Pomalidomide and low dose Dexamethasone (wKPd) for the treatment of RRMM. Here we report preliminary results. Methods: the primary objective of the phase I part of the trial was to determine the maximum tolerated dose (MTD) of wKPd combination. The primary objective of the phase II was to determine the rate of partial response (PR). Patients with RRMM, who received 1-3 prior lines of treatments and were refractory to Lenalidomide were eligible. Treatment consisted of 28-day cycles of oral Pomalidomide at fixed dose of 4 mg on days 1-21 (1 week off), oral or intravenous (iv) Dexamethasone 40 mg on days 1,8,15,22 and iv Carfilzomib at escalating doses on days 1,8,15. Escalation started at the dose of 36 mg/m2 (0 level) and used a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Treatment was continued until relapse or intolerance. Results: A total of 57 patients were enrolled in 6 Italian centers. Fifty-two patients could be evaluated for this analysis (5 patients did not complete the first cycle yet). The median age was 62 years with a median time from diagnosis of 4 years. 17/39 (44%) of patients were considered high risk according to cytogenetic abnormalities [at least one among t (4;14) t (14;16) and deletion chromosome 17 (del17) detected by FISH]. In the phase I of the trial 15 patients were enrolled. The first 3 patients at the dose level 0 of Carfilzomib did not experience any DLT. In the next cohort with Carfilzomib 20/45 mg/m2 a G3 hypertension and a sudden death occurred. According to the protocol, 3 more patients were enrolled at dose level 0: 1 patient experienced G3 atrial fibrillation, 2 patients ≥ G3 hypertension. Considering the serious adverse events (SAEs) occurred, the trial was temporary stopped to evaluate the benefit of continuing the study. All the DLTs were cardiologic and occurred in patients with a prior history of cardiac disease. As per protocol, they were evaluated with ECG and echocardiogram before the enrolment and were considered eligible for the study. The safety committee established new procedures for the evaluation of cardiac function of potentially eligible patients, including 24 h continuing pressure monitoring before the enrolment and serial measurement of blood pressure during and after Carfilzomib infusions. Six more patients were enrolled at dose level -1 (Carfilzomib 20/27 mg/m2) and none experienced a DLT. The MTD was established at dose level -1 with Carfilzomib 20/27 mg/m2, Pomalidomide 4 mg and Dexamethasone 40 mg. In the phase II portion of the trial, 42 patients were enrolled. Considering both phase I and II portions of the study, the most frequent drug related, grade ≥ 3 AEs were hematologic (65% of neutropenia and 13% of thrombocytopenia) and cardiologic (17%, mainly hypertension). We recorded only 4% of infection and ≥ G3 peripheral neuropathy. The overall response rate (ORR) of phase I/II portions was 58% (30/52) including 25% (13/52) of ≥ very good partial remission (VGPR). The ORR of high risk patients was 44% (7/16) including 19% (3/16) of ≥ VGPR. With a median follow-up of 10 months, median progression free survival (PFS) was 9.5 months and the median overall survival was not reached. Conclusions: This is the first phase I/II trial that combined weekly Carfilzomib with Pomalidomide and Dexamethasone. This combination was highly effective in RRMM. After a median follow-up of 10 months, wKRd showed a double median PFS in comparison with Pomalidomide-low dose dexamethasone (Sanmiguel et al Lancet Oncology 2013): 9.5 vs 4 months respectively, confirming the efficacy of combining a PI with an IMiD. An updated analysis will be presented at the meeting. Disclosures Bringhen: BMS: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Other: ADVISORY BOARD; Mundipharma: Other: ADVISORY BOARD; Karyopharm: Other: ADVISORY BOARD. Larocca:Celgene: Honoraria; Janssen-Cilag: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Gaidano:Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Oliva:Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbivie: Honoraria; Mundipharma: Research Funding; SANOFI: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding.

scholarly journals Phase 1 Results of Anti-PD-Ligand 1 (Durvalumab) & Lenalidomide in Patients with Cutaneous T Cell Lymphoma and Correlation with Programmed Death Ligand 1 Expression and Gene Expression Profile

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4024-4024
Author(s):  
Christiane Querfeld ◽  
Xiwei Wu ◽  
Tracy Stiller ◽  
Joycelynne Palmer ◽  
James F Sanchez ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Board Of Directors ◽  
Gene Expression Profile ◽  
Dose Level ◽  
Expression Profile ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 2 ◽  
Advisory Committees

Background: T cells in CTCL are functionally exhausted and are characterized by the expression of immune inhibitory molecules such as PD1 and PD-L1 (Cancer Immunol Res 6; 2018). These findings justify the evaluation of immune checkpoint inhibition to reverse T cell exhaustion in CTCL. We initiated a phase 1/2 clinical trial of lenalidomide and durvalumab to determine the safety and efficacy of this regimen. Durvalumab is a human monoclonal antibody with high affinity and selectivity for PD-L1, targeting exhausted T cells and distinct cells within their environment. Lenalidomide, an oral immunomodulatory drug (IMiD) and analog of thalidomide, has previously shown activity in CTCL (Blood 123; 2014). Durvalumab may restore an anti-tumor immune response, and the combination of durvalumab and lenalidomide may enhance immune checkpoint blockade-induced immune responses. Associations between immune checkpoints, gene expression profile and the clinical efficacy of durvalumab/lenalidomide combination were evaluated. The primary objectives were to determine the recommended phase 2 dose of lenalidomide in combination with durvalumab and safety with primary endpoint of toxicity (using CTCAE 4.03). Secondary end points included objective response rate (ORR) and median duration. Relationships between gene expression profile (GEP), PD-L1 expression, and antitumor activity were exploratory end points. Methods: A Phase 1 portion (NCT03011814) is ongoing to evaluate the safety and tolerability of the durvalumab and lenalidomide combination. Pts are enrolled in sequential cohorts to receive durvalumab (fixed dose at 1500 mg) and dose escalation of lenalidomide (dose level 1 = 10 mg for all cycles; dose level 2 = 10 mg for cycle 1, 15 mg for all subsequent cycles; dose level 3 =10 mg for cycle 1, 15 mg for cycle 2, and 20 mg for all subsequent cycles) to characterize safety, efficacy and antitumor activity. Serial skin samples were collected to assess the impact on the tumor microenvironment and anti-tumor activity. Results: Ten pts. were evaluable for toxicities. Nine patients were evaluable for response with three patients at each dose level. 8 males/2 females, age 29-59 y, with refractory/advanced CTCL, clinical stages IB (1), IIA (3), IIB (4), IIIA (1), and aggressive epidermotropic CD8+ CTCL (1) and a median of prior systemic treatments of 3 (range, 2-4) have been enrolled. Median follow up time was 12 (range, 3-24+) months. No serious AEs or DLTs were observed during the DLT evaluation period (cycles 1-3). The most frequently reported AEs were fatigue (n=7), skin pain (n=4), chills (n=3), anemia (n=3), and leukopenia (4). One grade 3 maculopapular rash (possibly due to lenalidomide) was observed, all other treatment-related AEs were grade 1/2 in severity. Median cycles of treatment were 7 (range, 3-20+) months. Median duration of response was 4 (range, 1- 21+) months. Six pts achieved PR, while 3 pts maintained stable disease. Three pts remain on treatment. Expression panels of several checkpoints (PD1, PD-L1 & ICOS) (Cycle1 Day1 vs Cycle 2 Day15) were analyzed. Detectable levels of PD-L1 but low levels of ICOS are observed in responding pts vs. high PD-L1 and ICOS levels in non-responders. GEP highlights downregulation of TNF-alpha signaling via NFkB, IFN-gamma, and PI3-AKT-mTOR signaling pathways among other pathways. Conclusions: Durvalumab/lenalidomide has significant clinical activity in refractory/advanced CTCL, which will be formally evaluated in the Phase 2 portion. Responses were durable and ongoing, and treatment was well tolerated. Dose escalation is up to lenalidomide 20 mg daily. Our preliminary results from pts on trial demonstrated that immune signatures on skin biopsies at baseline may be predictive of response to checkpoint blockade and yield insights into mechanisms of therapeutic resistance. Disclosures Querfeld: Bioniz: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Soligenix: Other: Investigator; Celgene: Other: Investigator, Research Funding; City of Hope Cancer Center and Beckman Research Institute: Employment; Medivir: Consultancy; Trillium: Consultancy, Other: Investigator, Research Funding; miRagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Kyowa: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Eisai: Other: Investigator; Elorac: Other: Investigator, Research Funding; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator. Palmer:Gilead Sciences: Consultancy. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy.

scholarly journals Combination Treatment of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib and Carfilzomib in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Initial Results from a Multicenter Phase 1/2b Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 377-377 ◽  
Author(s):  
Ajai Chari ◽  
Saurabh Chhabra ◽  
Saad Usmani ◽  
Sarah Larson ◽  
Ruben Niesvizky ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Tyrosine Kinase ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 2 ◽  
Advisory Committees ◽  
Bruton's Tyrosine Kinase ◽  
Grade 3

Abstract Background: Recent advances have improved outcomes for patients (pts) with multiple myeloma (MM); however, novel agents targeting different pathways are still needed. Ibrutinib (ibr) is a first-in-class, once-daily, oral, covalent inhibitor of Bruton's tyrosine kinase (BTK), an enzyme overexpressed in malignant plasma cells, whose expression may positively regulate the myeloma stem cell-like population (Yang 2015). Clinical activity was observed at the 840-mg dose of ibr in heavily pretreated pts with relapsed or relapsed/refractory MM (RRMM), when combined with weekly dexamethasone (dex) (Vij 2014). Furthermore, BTK-mediated upregulation of NF-κB p65 contributes to proteasome inhibitor (PI) resistance in MM cell lines; thus, BTK inhibition with ibr may help overcome PI resistance (Murray 2015). In vitro, ibr has demonstrated synergy with PIs in MM (Rushworth 2013) and mantle cell lymphoma cells (Ou 2013). PCYC-1119 (NCT01962792) is an ongoing phase 1/2b study of ibr + carfilzomib (CFZ) ± dex in RRMM. Methods: Eligible pts received ≥2 prior therapies, including bortezomib (BTZ) and an immunomodulatory agent (IMiD) and had either no response or documented disease progression following the most recent treatment. Dose escalation followed a 3+3 design, followed by expansion of 2 cohorts (Table). Phase 1 primary objectives were maximum tolerated dose/recommended phase 2 dose (RP2D) determination and safety. Results: As of July 8, 2015, 40 pts were enrolled and received ibr combined with CFZ ± dex across multiple dose levels during the phase 1 portion. No dose-limiting toxicities (DLTs) were observed, and cohorts 2b and 3b were chosen for expansion to further evaluate safety and efficacy. Pts had a median age of 63 y (range, 44-83) and a median time from diagnosis of 4.3 y (range, 0.5-25.3). Cytogenetic assessment by FISH identified that 20% and 8% of pts had t4;14 and del17p, respectively. Overall, pts received a median of 3 prior lines of therapy (range, 2-11), including 10% prior CFZ, 25% pomalidomide, 25% thalidomide, 73% autologous stem cell transplant, and 100% BTZ and lenalidomide. Moreover, 88% of pts were refractory to their last therapy, with 73% refractory to BTZ, 73% refractory to lenalidomide, and 58% refractory both to IMiD and PI. No relevant differences were observed across cohorts. Thirty-six pts were evaluable for efficacy. With early follow-up, the initial objective response rate (ORR) was 58% and the clinical benefit rate (CBR) was 67%. In cohort 3b, the ORR and CBR were 65% and 77%, respectively, including 3 very good partial responses (VGPRs) and 1 stringent complete response (sCR). No clinically meaningful tolerability differences were seen between cohorts, and no new safety findings were observed. Across all cohorts, the most common all-grade nonhematologic adverse events (AEs) were diarrhea (43%), cough (35%), constipation and fatigue (30% each), and nausea (28%). Grade ≥3 hematologic AEs included thrombocytopenia (15%), anemia (13%), and neutropenia (5%). Grade ≥3 nonhematologic AEs occurring in ≥10% of pts were pneumonia and hypertension (15% each), diarrhea (13%), and fatigue (10%). Eleven pts reported treatment related SAEs. No clinically relevant differences in AEs were observed across cohorts. Ten pts discontinued study treatment due to progressive disease; an additional 6 pts discontinued due to an AE, and 6 pts discontinued due to investigator or pt decision. Duration of treatment ranged from 0.3 to 13.6 months, and 17 pts remain on treatment. Updated data will be presented. Conclusions: The initial phase 1 data indicated promising clinical potential for ibr + CFZ + dex, as it is well tolerated with no DLTs, no new toxicities, and no increase in the severity of known toxicities for the individual agents. The preliminary ORR of 58%, with 1 sCR and 3 VGPRs in cohort 3b, is encouraging in this mostly refractory patient population, especially with the high number refractory to BTZ. Cohort 3b was established as the RP2D and will be further evaluated in the phase 2 portion of the study. Table. Dosing Cohorts Cohort ibr* mg/qd CFZ† mg/m2 dex‡ mg 1(n=3) 560 20/27 - 2a(n=5) 560 20/36 - 2b(n=14) 560 20/36 20 3b(n=18) 840 20/36 20 *Starts on Day (D) 8 of Cycle (C) 1; continuous thereafter. †D1-2, 8-9, 15-16 through C12; thereafter D1-2, 15-16. ‡D1-2, 8-9, 15-16, 22-23; 10 mg for pts age ≥75 y; 4 mg prior to CFZ during C1 only (cohorts 1 and 2a) with re-initiation as needed. Disclosures Chari: Novartis: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding. Off Label Use: ibrutinib in relapsed or relapsed/refractory MM. Usmani:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Novartis: Speakers Bureau. Larson:BMS: Consultancy. Niesvizky:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Honoraria, Research Funding, Speakers Bureau. Matous:Celgene: Consultancy, Speakers Bureau; Millenium: Speakers Bureau; Onyx: Speakers Bureau. Gasparetto:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Holkova:Seattle Genetics, Inc.: Research Funding. Lunning:TG Therapeutics: Consultancy; Gilead: Consultancy; Spectrum: Consultancy; Genentech: Consultancy; Celgene: Consultancy; BMS: Consultancy; Juno: Consultancy; Onyx: Consultancy. Valent:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Anderson:Celgene: Speakers Bureau; Onyx: Speakers Bureau; Takeda: Speakers Bureau. Kwei:Pharmacyclics LLC, an AbbVie Company: Employment. Chang:Pharmacyclics LLC, an AbbVie Company: Employment. Graef:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Bilotti:Pharmacyclics LLC, an AbbVie Company: Employment. McDonagh:Pharmacyclics LLC, an AbbVie Company: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Karyopharm: Research Funding.

Bendamustine in Combination with Thalidomide and Prednisolone (BPT) in Patients with Refractory or Relapsed Multiple Myeloma after Conventional Chemotherapy: Final Results of a Phase I Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5154-5154
Author(s):  
Wolfram Poenisch ◽  
Marta Rozanski ◽  
Sabine Leiblein ◽  
Hartmut Goldschmidt ◽  
Franz A. Hoffmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Side Effects ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Phase Iii ◽  
Fixed Dose ◽  
Hematological Toxicity ◽  
Conventional Chemotherapy ◽  
Who Grade

Abstract Thalidomide is a remarkably active agent in patients with advanced relapsed or refractory multiple myeloma (MM), but with a significant co morbidity due to side-effects such as neuropathy. We investigated whether lower doses of thalidomide in combination with weekly doses of bendamustine and prednisolone might be a more effective regimen with fewer side-effects especially in relation to neurotoxicity. Clinical studies in patients with newly diagnosed and relapsed MM have shown that bendamustine is effective as single agent as well as in combination with prednisolone. In a phase III study, overall response rate for bendamustine and prednisone was 75% as first line therapy. The purpose of this phase I study was the assessment of toxicity of the combination bendamustine, prednisolone, and thalidomide (BPT) in patients with advanced MM. The treatment consisted of a fixed dose of bendamustine (60 mg/qm) i.v. days 1, 8, and 15 and prednisolone (100 mg) p.o. days 1, 8, 15, and 22. Thalidomide was given to patient cohorts at escalating doses, starting with 50 mg up to a maximum of 200 mg daily. Four patients were enrolled at each dose level. If one dose limiting toxicity (DLT) occurred, additional two patients would be enrolled at that dose level. Cycles were repeated every 28 days for a minimum of 2 and a maximum of 10 cycles until maximum response, DLT, or progressive disease. Fourteen patients (4 in the first thalidomide dose level with 50 mg, 4 in the second dose level with 100 mg, and 6 patients in the third dose level with 200 mg) were enrolled. Median age was 69 years (range 61 - 78). The number of prior treatment regimens was 2 or more in all patients. Six younger patients were included who had failed VAD-like induction therapy (n=5) or stem cell mobilization (n=1). Six patients had been refractory to the last treatment. Results: All patients completed 2 cycles of BPT (1 completed 7 cycles, 4 completed 6 cycles, 3 completed 5 cycles, 3 completed 4 cycles, 2 completed 3 cycles, and 1 completed 2 cycles). Response was assessed using EBMT criteria modified to include near complete remission (nCR) and very good partial remission (VGPR). After at least 2 cycles of chemotherapy, 12 of 14 patients responded with 2 CR, 2 VGPR, 7 PR, and 1 MR (ORR 85%). Two patients had a stable disease. No DLT was observed at any dose level. Most common side-effects were constipation (7 patients WHO grade 1; 6 patients WHO grade 2), somnolence (4 patients WHO grade 1), and peripheral neuropathy (2 patients WHO grade 1; 2 patients WHO grade 2). None of the 14 patients developed dose-limiting hematological toxicity as defined by an ANC < 1,0 x 109/l for > 7 days or an ANC < 0,5 x 109/l for > 3 days or platelet count < 25 x 109/l. Neutropenia was reported in 4 patients (WHO grade 4) but no thrombocytopenia was observed. No grade 3 or 4 non-hematological toxicity was encountered and no dose modification was required. BPT with daily thalidomide between 50 mg and 200 mg is well tolerated in patients with relapsed or refractory MM after conventional chemotherapy.

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