Additional Analyses of a Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 908-908 ◽  
Author(s):  
Mikkael A. Sekeres ◽  
Megan Othus ◽  
Alan F. List ◽  
Olatoyosi Odenike ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Response Duration ◽  
High Volume ◽  
Centers Of Excellence ◽  
Advisory Committees ◽  
Data Safety ◽  
Randomized Phase Ii

Abstract Background: The few therapies available to treat higher-risk MDS and CMML have limited impact on outcome. We previously reported initial results of S1117, which compared overall response rates (ORRs) of azacitidine (AZA) monotherapy to AZA combined with the histone deacetylase inhibitor vorinostat (VOR), or the immunomodulator lenalidomide (LEN)( ASH 2014 LBA-5). We now report updated response data and overall survival (OS), subgroup analyses, impact of cytogenetics, and effect of treatment center volume/centers of excellence on outcome. Methods: This randomized, Phase II study (ClinTrials.gov # NCT01522976) enrolled higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High and/or bone marrow blasts ≥5%) and CMML adult patients (pts) with <20% blasts from 3/12-6/14 to receive AZA (75 mg/m2/d on d1-7 of a 28d cycle), AZA + LEN (10 mg/d on d1-21), or AZA + VOR (300 mg BID on d3-9). Pts continued treatment until treatment failure, defined as disease progression, relapse, significant or unresolved toxicity, or lack of response. Dose reductions occurred for grade ≥3 adverse events (per NCI CTCAE) or delayed count recovery. Cytogenetic risk groups were defined per IPSS-R. The primary endpoint was improvement in ORR, by intention to treat and reviewed centrally, of one of the combination arms vs. AZA per 2006 International Working Group MDS response criteria (complete response (CR) + partial response (PR) + hematologic improvement (HI)). OS was from study entry. MDS Centers of Excellence (MCE) were defined per MDS Foundation; center volume was defined as low (1-4 pts enrolled) or high (5-17 pts). Results: Of 277 pts, 92 received AZA, 93 AZA+LEN, and 92 AZA+VOR. Baseline characteristics, previously reported, were similar across arms. Pts received a median of 22 weeks of therapy and were followed for a median of 10 months (range: 0-30). Non-protocol defined dose modification and protocol discontinuation due to toxicity occurred more frequently in combination arms vs. AZA (p=.0014 and p=.018, respectively). Responses are now assessable in all pts (Table 1). ORR was statistically similar for combination arms vs. AZA, with a trend for longer response duration (p=.083) for combinations. Within HI, AZA+LEN pts had higher HI-n than AZA pts (16% vs. 5%, p=.031). ORR for CMML pts was significantly higher for LEN+AZA vs. AZA (63% vs. 29%, p=.04), with a trend for longer response duration for combinations (p=.06); no differences in ORR were seen for therapy-related MDS, IPSS subgroups, or transfusion-dependent pts. Allogeneic transplantation rates were similar. Median OS (Figure) for AZA:AZA+LEN:AZA+VOR was 15:18 (p=.38):17 (p=.17) months; p=.19 for combination arms vs. AZA. Median OS after failure was 7:9 (p=.6):9 (p=.05) months; p=.15 for combination arms after failure vs. AZA. For pts on therapy >6 months, there was a trend (p=.08) for higher ORR for AZA+LEN vs. AZA, though response duration was similar; median OS was 18:21 (p=.44 vs. AZA):21 months (p=.45 vs. AZA). Cytogenetic risk category distribution and ORR was similar across arms. OS (compared to Very Good/Good) was worse for Poor (HR 2.07, p=.022) and Very poor (HR 4.41, p<.001), without significant modification by treatment arm (Table 2). Compared to pts without identified cytogenetic abnormalities (abn), ORR across arms was better for pts with Chr 5 abn (OR 2.38, p=.004); OS was better for normal (HR .42, p<.001) and worse for Chr 5 abn (HR 3.1, p<.001), -7 (HR 2.69, p<.001), and 17p (HR 2.61, p<.001). While small numbers prevented definitive conclusions for treatment arm effect, combinations trended towards improving OS in Normal and Chr 5 abn only. The outcome of all pts and pts on discrete study arms treated at MCE (n=75) or high volume (n=138) sites were similar to non-MCE or low-volume sites for ORR, non-protocol defined dose modifications, dose adjustment in first 4 cycles, time to off-protocol (HR 1.2, p=.21 and HR .94, p=.64), and OS (HR .81, p=.3 and HR .77, p=.12). Conclusions: In higher-risk MDS pts, ORR and OS was similar for AZA monotherapy compared to combination arms, while for CMML pts, ORR was significantly higher with AZA+LEN. For cytogenetic subgroups, OS was worse for Chr 5 abn, -7, and 17p, and may be improved by combinations in normal or Chr 5 abn. MCE or treatment at a high volume site did not impact these effects or outcomes. Figure 1. Responses Figure 1. Responses Figure 2. Cytogenetics Figure 2. Cytogenetics Figure 3. Figure 3. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. List:Celgene Corporation: Honoraria, Research Funding. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stone:Merck: Consultancy; Celgene: Consultancy. Gore:Celgene: Consultancy, Honoraria, Research Funding. Buckstein:Celgene: Honoraria, Research Funding. Fang:Affymetrix: Research Funding. Attar:Agios Pharmaceuticals: Employment. Erba:Ariad: Consultancy; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Ariad: Consultancy; Celgene: Consultancy, Speakers Bureau; GlycoMimetics: Other: Data Safety and Monitoring Committees; Seattle Genetics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Millennium/Takeda: Research Funding; Celator: Research Funding; Celator: Research Funding; Astellas: Research Funding; Astellas: Research Funding; Sunesis: Consultancy; Daiichi Sankyo: Consultancy; GlycoMimetics: Other: Data Safety and Monitoring Committees; Jannsen (J&J): Other: Data Safety and Monitoring Committees.

Pomalidomide, Cyclophosphamide, and Dexamethasone Is Superior to Pomalidomide and Dexamethasone in Relapsed and Refractory Myeloma: Results of a Multicenter Randomized Phase II Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 303-303 ◽  
Author(s):  
Rachid Baz ◽  
Thomas G. Martin ◽  
Melissa Alsina ◽  
Kenneth H. Shain ◽  
Hearn J. Cho ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Advisory Committees ◽  
Overall Response ◽  
Best Response ◽  
Randomized Phase Ii ◽  
Grade 3

Abstract Background: Pomalidomide-dexamethasone results in an overall response rate of 33% and median PFS of 4.2 months in patients with prior lenalidomide and bortezomib (Richardson et al. Blood 2014). In this randomized phase II trial, we compared pomalidomide-dexamethasone (arm B) versus the addition of oral weekly cyclophosphamide to pomalidomide-dexamethasone (arm C) in patients with lenalidomide-refractory multiple myeloma (MM). We have previously reported that the recommended phase II dose of cyclophosphamide with standard-dose pomalidomide + dexamethasone was 400 mg PO D1, 8, 15. Patients and Methods: Eligible patients had relapsed and refractory MM after at least 2 prior therapies and were lenalidomide refractory. Patients had a platelet count ≥ 50,000/mm3 and ANC ≥ 1,000/mm3 (patients with ≥50% bone marrow plasmacytosis were allowed if platelet count was ≥ 30,000/mm3and ANC could be supported with GCSF during screening and therapy). Patients were randomized (1:1) to receive pomalidomide 4 mg PO D1-21 and dexamethasone 40 mg PO D1, 8, 15, 22 (20 mg if older than 75 years) (arm B) with or without oral cyclophosphamide 400 mg PO D1, 8, 15 of a 28-day cycle (arm C). Patients randomized to arm B were allowed to cross over to arm C in the event of disease progression. Thromboprophylaxis was mandated with aspirin, warfarin, or LMWH. The primary endpoint was overall response rate using IMWG criteria. Secondary endpoints included an evaluation of PFS, OS and safety of the two arms. Results: Between 7/2012 and 3/2014, 36 patients were randomized to arm B and 34 to arm C. Patients characteristics were not different between the 2 arms (table below). The median number of prior therapies was 4 (2-12). All patients were lenalidomide refractory and none received prior pomalidomide. After a median follow up of 15 months, the overall response rate (partial response or better) was 39% and 65% (p=0.03) for arm B and C, respectively. The clinical benefit rate (minimal response or better) was 64% and 79% (p=0.2) for arm B and C, respectively. The median PFS was 4.4 months (95% CI 2.3-5.9) for arm B and 9.2 months (95% CI 4.6-16) for arm C (log rank p=0.04). As of July 2014, 28 patients had died (16 arm B, 12 arm C) with median overall survival of 10.5 versus 16.4 months (p=0.08) for arm B and C, respectively. Hematologic grade 3/4 adverse events were more frequent in arm C, although this was not statistically significant (see table). Thirteen patients crossed over and oral weekly cyclophosphamide was added to their tolerated dose of pomalidomide dexamethasone. For those patients, the best response was as follows: 2 PR, 2 MR, and 6 SD, 3 PD. Conclusions: Pomalidomide-dexamethasone in combination with oral weekly cyclophosphamide resulted in a superior response rate and PFS compared to pomalidomide-dexamethasone alone in patients with relapsed and refractory MM. The increased hematologic toxicities, as a result of the addition of oral cyclophosphamide, were manageable. Table Arm B (N=36) Arm C (N=34) P value Age, years, median (range) 63 (50-78) 64 (47-80) 0.7 Male, n (%) 23 (64) 18 (53) 0.3 Number of prior therapies, median (range) 4 (2-12) 4 (2-9) 0.5 Bortezomib refractory, n (%) 28 (78) 24 (71) 0.3 Carfilzomib refractory, n (%) 16 (44) 13 (38) 0.5 Prior high-dose therapy, n (%) 27 (75) 28 (82) 0.6 Prior alkylating agent, n (%) 32 (89) 32 (94) 1 B2-microglobulin, median (range) 3.2 (1.6-10) 3.6 (1.5-13.9) 0.5 Serum creatinine, median (range) 1 (0.5-2.3) 0.9 (0.6-2.1) 0.6 High-risk cytogenetics, n (%) 5 (24) 6 (28) 0.8 Deletion 17p, n (%) 3 (14) 4 (20) 0.8 t(4;14), n (%) 3 (14) 3 (14) 0.9 Trisomy or tetrasomy 1q, n (%) 11 (55) 6 (33) 0.4 Best response (partial response or better), n (%) 14 (39) 22 (65) 0.03 Clinical benefit rate (MR or better), n (%) 23 (64) 27 (79) 0.2 Grade 3/4 neutropenia, n (%) 12 (33) 17 (50) 0.2 Grade 3/4 febrile neutropenia, n (%) 4 (11) 6 (18) 0.5 Grade 3/4 thrombocytopenia, n (%) 2 (5) 5 (15) 0.2 Grade 3/4 anemia, n (%) 3 (8) 7 (20) 0.2 Grade 3/4 pneumonia, n (%) 4 (11) 3 (9) 1 Grade 3/4 fatigue, n (%) 2 (5) 4 (12) 0.4 Number of serious adverse events 17 20 Disclosures Baz: Celgene: Research Funding; Millenium: Research Funding; Bristol-Myers Squibb: Research Funding; Karypharm: Research Funding; Sanofi: Research Funding. Off Label Use: Pomalidomide cyclophosphamide dexamethasone in relapsed refractory myeloma. Martin:Sanofi: Research Funding; Novartis: Speakers Bureau. Alsina:Triphase: Research Funding; Millenium: Research Funding. Shain:Onyx / Amgen: Research Funding; Treshold: Research Funding. Chari:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Membership on an entity's Board of Directors or advisory committees. Jagannath:Celgene: Honoraria; Millennium: Honoraria; Sanofi: Honoraria.

scholarly journals A Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. LBA-5-LBA-5 ◽  
Author(s):  
Mikkael A. Sekeres ◽  
Megan Othus ◽  
Alan F. List ◽  
Olatoyosi Odenike ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Combination Therapy ◽  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
International Prognostic Scoring System ◽  
Advisory Committees ◽  
N Rates

Abstract Background: Higher-risk MDS and CMML comprise a spectrum of disorders associated with cytopenias, high risk of transformation to acute myeloid leukemia (AML), and truncated survival. Initial treatment with a hypomethylating agent such as azacitidine (AZA) is considered standard of care. Whether addition of the histone deacetylase inhibitor vorinostat (VOR), which acts synergistically with AZA to reactivate epigenetically silenced genes, or addition of lenalidomide (LEN), which impacts the bone marrow microenvironment, improves response rates compared to AZA monotherapy is unknown. Methods: This Phase II study (ClinTrials.gov # NCT01522976) randomized higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High and/or bone marrow blasts >5%) and CMML patients (pts) with <20% blasts to receive AZA (75 mg/m2/d on d1-7 of a 28d cycle), AZA + LEN (10 mg/d on d1-21), or AZA + VOR (300 mg BID on d3-9). Eligibility criteria included: >18 years (yrs), no previous allogeneic transplant, no prior treatment with any of the study drugs, and adequate organ function; therapy-related (t)MDS was allowed. Pts continued treatment until disease progression, relapse, unacceptable toxicity, or lack of response. Dose reductions occurred for unresolved grade >3 adverse events (per NCI CTCAE) or delayed count recovery. The primary endpoint was improvement in overall response rate (ORR), by intention to treat and reviewed centrally, of one of the combination arms vs. AZA monotherapy per 2006 International Working Group MDS response criteria (complete response (CR) + partial response (PR) + hematologic improvement (HI)). Relapse-free survival (RFS) was from time of response. The study had 81% power to detect a 20% improvement in ORR from 35% to 55%. Results: Of 282 pts enrolled from 3/12–6/14, 276 are included in analyses (6 ineligible pts excluded): 92 on the AZA arm, 93 on AZA+LEN, and 91 on AZA+VOR. Baseline characteristics were well-balanced across arms (Table). Pts received a median of 23 weeks of therapy: 25 of AZA; 24 of AZA+LEN; and 20 of AZA+VOR and were followed for a median of 9 months (range: 0-26). Numbers of pts with notable adverse events >grade 3 for AZA:AZA+LEN:AZA+VOR included febrile neutropenia (10:13:13); gastrointestinal disorders (4:11:23); infections (2:3:3); and rash (2:12:1). Responses were assessable in 260 pts (94%). ORR for the entire cohort was 33%: 19% CR, 1% PR, and 13% HI, with a median RFS of 7 months. ORR was similar across study arms: 36% for AZA, 37% for AZA+LEN (p=1.0 vs. AZA), and 22% for AZA+VOR (p=.07 vs. AZA). CR/PR/HI rates across arms were also similar: 23%/0%/13% for AZA; 18%/1%/17% for AZA+LEN (CR p=.47 vs. AZA); and 14%/1%/7% for AZA+VOR (CR p=.18 vs. AZA); rates of bone marrow exams to assess response were 76%, 67%, and 73%, respectively. HI-P/HI-E/HI-N rates were 21%/15%/5% for AZA, 26%/14%/15% for AZA+LEN, and 12%/8%/4% for AZA+VOR. HI-N rates were higher in AZA+LEN vs. AZA (p=.05) but otherwise were similar across arms. Median time to best response across arms was 15 weeks in AZA, 16 weeks in AZA+LEN, and 16 weeks in AZA+VOR. ORR did not vary significantly across arms in subgroup analyses for tMDS, baseline red blood cell (RBC) transfusion dependence, and by IPSS risk group. ORR for CMML pts for AZA:AZA+LEN:AZA+VOR was 33%:53%(p=.15 vs. AZA):12%(p=.41 vs. AZA). Allogeneic transplantation rates were: 7 pts on AZA, 6 on AZA+LEN, and 9 on AZA+VOR. For AZA:AZA+LEN:AZA+VOR, median RFS was: 6:8:11 months (log-rank p=.3 for combination arms vs. AZA, Figure); and for pts on therapy >6 months, it was 7:7.5:13 months (log-rank p=.11 for AZA+VOR, .74 for AZA+LEN vs. AZA). Conclusions: In higher-risk MDS pts, ORR was similar for AZA monotherapy compared to AZA-containing combination arms, though some subgroups may have benefitted from combination therapy. Differences in types of response may have resulted from differential rates of follow-up bone marrow assessments. While a non-significant signal of a DFS advantage for combination therapy was observed, longer-term outcome data are being assessed. Table Table. Figure Figure. Disclosures Sekeres: Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: lenalidomide, vorinostat for higher-risk MDS. List:Celgene Corporation: Consultancy. Gore:Celgene: Consultancy, Research Funding. Attar:Celgene: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau.

Phase II Study of Daratumumab in Combination with Azacitidine and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients Previously Treated with Daratumumab: Darazadex

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Swetha Kambhampati ◽  
Sandy W. Wong ◽  
Thomas Martin ◽  
Jeffrey L. Wolf ◽  
Priya Choudhry ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma ◽  
Duration Of Response ◽  
Previously Treated ◽  
Dose Modifications

Background: Daratumumab, a human anti-CD38 monoclonal antibody, is approved in many countries for use as monotherapy in relapsed/refractory multiple myeloma (RRMM), and in combination with standard-of-care regimens in RRMM. The phase 2 DARAZADEX study will evaluate the efficacy and safety of daratumumab plus azacitidine and dexamethasone in RRMM patients previously treated with daratumumab. Pre-clinical data from our laboratory has demonstrated that azacitidine induces a 1.2 - 2.4 increase in CD38 median fluorescent intensity (MFI) in a dose-dependent manner across four different MM cell lines. (Figure 1A) Using an immortalized transgenic natural killer (NK) cell line to mediate lysis, we observed a significant increase in antibody-dependent cell-mediated cytotoxicity (ADCC) in the azacitidine-treated MM cells as opposed to control. Importantly, this increase in ADCC correlated with CD38 MFI upregulation. (Figure 1B). Based on this data we hypothesize that azacitidine, by upregulating the expression of CD38, can potentially increase the ADCC and efficacy of daratumumab on multiple myeloma cells and help reverse daratumumab resistance. Methods: In this single-arm, 2-stage, phase II study, approximately 23 RRMM patients in the United States will be treated with combination of daratumumab, azacitidine, and dexamethasone. Eligible patients must have progressed on ≥2 lines of prior therapy, including an immunomodulatory drug (IMiD) and proteasome inhibitor, and have previously been treated with daratumumab with most recent daratumumab treatment being at least 6 months prior to enrollment to allow for CD38 normalization. Patients who were previously primary refractory to daratumumab will be excluded from the study. Patients will receive azacitidine at the standard 75 mg/m2 dose 5 days consecutively every 4 weeks starting day -7 to day -3 of Cycle 1 and then Day 22-26 of Cycle 1-3, and subsequently Day 1-5 of Cycle 5 and thereafter until disease progression or intolerance, with dose modifications for toxicities. Daratumumab will be administered intravenously at the standard dose of 16 mg/kg, with first dose administered on day 1. Daratumumab will be dosed in standard fashion: weekly for 8 doses (induction phase), every two weeks for 8 doses (consolidation phase), and then every 4 weeks thereafter (maintenance phase). Daratumumab will be switched to the subcutaneous formulation at a later timepoint. There will be no dose modifications for daratumumab. Dexamethasone at a dose of 40 mg PO (or IV if PO is not available) will be given weekly for Cycle 1 and 2, after which the pre-infusion medication dose can be reduced to 20 mg and non-pre-infusion dose can be reduced or stopped based on investigator's discretion. Bone marrow biopsies will be done within 14 days prior to Cycle 1 day -7 (first azacitidine dose) and on Cycle 1 day 1 prior to first daratumumab infusion (or after completion of first 5 days of azacitidine and prior to first daratumumab infusion), for correlative studies. (Figure 1C) Simon's minimax two-stage design will be used with a safety lead-in cohort of 6 patients. In the first stage, a total of 13 patients will be enrolled (including the safety cohort), and if there is ≥2 responses in 13 patients the study will enroll an additional 10 patients; if there is ≤ 1 responses in 13 patients the study will be stopped. Primary objective is to evaluate the efficacy, as determined by the overall response rate (ORR) of this combination. Secondary objectives include duration of response per international myeloma working group (IMWG) criteria, safety and toxicity, and the 1-year OS and PFS of this combination. An additional secondary objective is to evaluate the changes in CD38 expression on plasma cells induced by azacitidine in patients with RRMM and identify any correlation of this change with depth and duration of response. The exploratory objective will be to evaluate the tumor microenvironment changes induced by azacitidine via mass cytometry (CyTOF). NCT04407442. Figure 1 Disclosures Wong: Bristol Myers Squibb: Research Funding; GSK: Research Funding; Janssen: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Roche: Research Funding; Fortis: Research Funding. Martin:Janssen: Research Funding; GSK: Consultancy; Seattle Genetics: Research Funding; Sanofi: Research Funding; AMGEN: Research Funding. Wolf:Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. OffLabel Disclosure: Azactidine is being used off-label in multiple myeloma

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.

Final Results of the Phase I/II Study of Chemosensitization Using the CXCR4 Inhibitor Plerixafor in Combination with Bortezomib in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4256-4256 ◽  
Author(s):  
Irene M. Ghobrial ◽  
Kenneth H. Shain ◽  
Jacob Laubach ◽  
Patrick Henrick ◽  
James Vredenburg ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Plasma Cells ◽  
Response Rate ◽  
Phase Ii Study ◽  
Median Number ◽  
Recommended Dose ◽  
Advisory Committees

Abstract PURPOSE: This study aimed to determine activity and safety of the CXCR4 inhibitor plerixafor in combination with bortezomib and dexamethasone in patients with relapsed or refractory Multiple Myeloma (MM). This was based on our preclinical studies showing that plerixafor (Mozobil, Sanofi Corporation) induces de-adhesion of MM cells and sensitization to bortezomib in preclinical animal models. PATIENTS AND METHODS: Theprimary endpoint of the phase I study was the maximum tolerated dose (MTD) and for the phase II study, the safety and response rate of the combination. Eligibility criteria included patients with relapsed or relapsed/refractory MM with 1-5 prior lines of therapy including bortezomib (unless patients were refractory to bortezomib). The phase I included 8 cohorts with different doses and two treatment schedules. In cohorts 1-5, patients received plerixafor at the recommended dose sq on days 1-6 of each cycle and bortezomib at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. In cohort 5b-6, plerixafor was given at the recommended dose sq on days 1, 3, 6, 10, and 13 and bortezomib was given at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. For the phase II portion patients received plerixafor at the MTD established in phase I of trial, 320 mcg/kg sq on days 1, 2, 3, 6, 10, and 13. Bortezomib was given 1.3 mg/m2 IV or sq twice a week on days 3, 6, 10, 13, every 21 days. Dexamethasone was given at 40mg on days of Bortezomib. RESULTS: A total of 58 patients were enrolled on this study from June 2009 to March 2015, with 25 on the phase I and 33 on the phase II study. In the phase I study, the median age was 60 years (range, 43-85), the median number of prior therapies was 2 (range, 1-4), with all but 3 patients receiving prior bortezomib. The median number of cycles on therapy was 4 (1-12). Dose limiting toxicities including insomnia, restlessness, and psychosis were observed in two patients at dose level 6 (plerixafor 0.40 mg/kg and bortezomib 1.3 mg/m2). Therefore, 3 additional patients were enrolled at dose level 5b (plerixafor 0.32 mg/kg and bortezomib 1.3 mg/m2). There were no grade 4 toxicities. Grade 3 toxicities included lymphopenia (40%), hypophosphatemia (20%), anemia (10%), hyponatremia (10%), hypercalcemia (10%), and bone fracture due to myeloma bone disease (10%). Twenty-three patients were evaluable for response, including 1 (4%) complete response (CR), 1 (4%) very good partial response (VGPR), 1 partial remission (PR) and 2 (9%) MR, and 15 (65%) having stable disease with only 3 (13%) progressive disease (PD). In the phase II study, the median age was 63 (46-83). The median number of prior therapies was 2 (1-5), with 22 (66%) who have received prior bortezomib. The median number of cycles on therapy is 5 (1-24). The response rate included 5 VGPR (16%), 11 PR (35%) with an overall response rate of 51% and another 11 (35%) stable disease. Grade 3/4 toxicities included thrombocytopenia (68%), lymphopenia (6%), hypophosphatemia (2%), anemia (4%), infections (4%), hyponatremia (2%), hypercalcemia (2%) and neurological toxicity (2%). We also examined in vivo mobilization of plasma cells, CD34+ hematopoietic stem cells and other accessory bone marrow cells. Analysis of these samples showed rapid mobilization of plasma cells at 2 hours post-plerixafor with a rapid return to normal levels at 4 and 24 hours post plerixafor. CONCLUSIONS: The combination of plerixafor and bortezomib is generally well tolerated with minimal neuropathy or other toxicities seen to date. The responses observed are strongly encouraging with 51% ORR in this relapsed and refractory population. This study was supported by R01CA133799-01, and by Sanofi and Takeda Corporations. Disclosures Off Label Use: Plerixafor in myeloma. Azab:Verastem: Research Funding; Selexys: Research Funding; Karyopharm: Research Funding; Cell Works: Research Funding; Targeted Therapeutics LLC: Other: Founder and owner . Schlossman:Millennium: Consultancy. Richardson:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees.

Final Results of Phase I/II Trial of the Oral mTOR Inhibitor Everolimus (RAD001) in Combination with Bortezomib and Rituximab (RVR) in Relapsed or Refractory Waldenstrom Macroglobulinemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3081-3081 ◽  
Author(s):  
Irene M. Ghobrial ◽  
Robert Allyn Redd ◽  
Jeffrey Matous ◽  
Philippe Armand ◽  
Erica N Boswell ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Phase I ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Advisory Board ◽  
Advisory Committees

Abstract Background: Waldenstrom Macroglobulinemia is a distinct lymphoplasmacytic lymphoma. Several clinical trials have shown high rates of response in patients with relapsed WM using bortezomib and rituximab combinations. In addition, the TORC1 inhibitor everolimus has previously shown a high response rate of 70% in this patient population. In this trial, we aimed to examine the safety and activity of the combination of everolimus with bortezomib and rituximab (RVR) and to determine whether a deep response can be achieved with a triple combination of targeted therapeutic agents in WM. Methods: The phase I portion of the study evaluated the maximum tolerated dose of everolimus, rituximab combination or RVR combination, while the phase II portion evaluated the depth of responses to the RVR combination. Patients were eligible for this trial if they had relapsed or refractory WM. There was no limit on the number of prior therapies. Patients were required to be ≥18 years old and have measurable and symptomatic disease. For the phase I, patients were assigned to a dose level in the order of study entry. In the dose-escalation scheme, everolimus was given at 5 or 10 mg PO with rituximab, or with bortezomib at 1.3 or 1.6 mg/m2 and rituximab. Rituximab was given at a fixed dose of 375 mg/m2 IV. In the phase II, patients received everolimus 10 mg flat dose PO daily, Bortezomib IV 1.6mg/m2 weekly on days 1, 8, 15 q 28 days and rituximab IV 375 mg/ m2 weekly on days 1, 8, 15 22 q 28 days on cycles 1 and 4 only. Treatment was daily and 4 weeks (28 days) was considered one cycle. Patients received a total of 6 cycles followed by maintenance therapy with everolimus 10 mg PO daily until progression. Dexamethasone was not permitted. Patients were assessed every cycle while on combination therapy, and every 3 months while on maintenance therapy. Patients with stable disease (SD) or responding disease could continue therapy until progression. Results: From April 2010 to July 2013, a total of 46 patients were enrolled on this trial; of these, 23 patients were in the phase I study and 23 patients in the phase II study. The median number of prior treatments was 2 (range 1-9) Prior therapies received included bortezomib-based therapy (26, 56%) and rituximab (45, 98%). Median treatment duration was 10 months (range, 3 weeks to 41 months) for all patients. There were no DLTs observed and no deaths occurred on this study. The most common toxicities in all patients on study were fatigue (29 patients, 63%); anemia and leukopenia (each in 24 patients, 52%); neutropenia (22, 48%); diarrhea (20, 43%); and neuropathy, pneumonitis/pulmonary infiltrates (each in 19 patients, 41%). The overall response rate (ORR) which includes patients with minor response (MR) or better in the phase II study (N=23) was 91% (95% CI, 72-99%) with 1 CR, 1 VGPR, 16 PR, and 3 MR. When all 36 patients on the phase I and phase II studies who received full dose of RVR were combined, the ORR was 89% (95% CI 74 – 97%), with 2 CR, 3 VGPR, 21 PR, and 6 MR. Conclusions: The RVR regimen is safe and well tolerated. RVR led to an overall response rate of 89% with PR or better achieved in 72% making this a highly effective regimen even in patients previously treated with bortezomib and/or rituximab. This study represents one of the first combination efforts of novel agents targeting the PI3K signaling pathway with a proteasome inhibitor. Disclosures Ghobrial: Sanofi: Research Funding; Noxxon: Research Funding; BMS: Advisory board, Advisory board Other, Research Funding; Onyx: Advisory board Other; Millennium: 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. Off Label Use: Bortezomib and everolimus are not approved for WM. Laubach:Novartis: Research Funding; Onyx Pharmaceuticals: Research Funding. Anderson:Celgene: Consultancy; Sanofi-Aventis: Consultancy; Onyx: Consultancy; Acetylon: Scientific Founder, Scientific Founder Other; Oncoprep: Scientific Founder Other; Gilead Sciences: Consultancy.

A Lysa Phase II Study of Oral JAK1/2 Inhibitor Ruxolitinib in Advanced Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4160-4160 ◽  
Author(s):  
Eric W Van Den Neste ◽  
Marc Andre ◽  
Thomas Gastinne ◽  
Aspasia Stamatoullas ◽  
Corinne Haioun ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Study Drug ◽  
Median Number ◽  
Primary Objective ◽  
Additional Treatment ◽  
Advisory Committees ◽  
Grade 3

Abstract Background: JAK2 constitutive activation/overexpression is frequent in classical HL tumor cells and many autocrine/paracrine cytokines stimulate HL cells by recognizing JAK1- or JAK2-bound receptors. Thus, JAKs blockade may be of therapeutic value in HL. Methods: A phase II study (HIJAK study)was conducted to evaluate safety and efficacy of ruxolitinib, an oral JAK1/2 inhibitor, in R/R HL, given at 20 mg bid for 6 cycles of 28 days. Dosage at 15 mg bid was planned for patients with platelets comprised between 75 and 200 x 109/L at inclusion. Patients with platelets < 75 x 109/L, neutrophils < 1000 x 109/L were excluded. Maintenance beyond 6 cycles was permitted if disease control. The primary objective was overall response rate (ORR, Cheson 2007) at 6 cycles. Secondary objectives were safety, B symptoms relief, best ORR, response duration, PFS and OS. To be evaluable for response and survivals, patients had to receive at least one cycle of the study drug. The safety set included all patients who received at least one dose of ruxolitinib. Median follow-up was 27.1 months (95% CI: 14.4-27.1). Results: 33 patients were included between Jul 2013 and Dec 2014 in 10 LYSA centers in France and Belgium: M/F, 21/12; median age 37 (range 19-80) years; stage III/IV, 75.8%; B symptoms, 51.5%; median number of prior lines, 5 (range 1-16); prior transplantation, 60.6%; prior radiotherapy, 54,5%; prior brentuximab vedotin (BV), 82%; refractory to last therapy, 81.8%. Overall, median number of ruxolitinib cycles was 4. Nine (27.3%) patients received at least 6 cycles and 6 (18.2%) maintenance. ORR at the end of induction was 3/32 (9.4%) patients, all PRs. Best ORR at any time during study was 18.8% (6/32) with five PRs and 1 patient who converted into CR beyond 6 cycles. Transient stable disease was noted in 11 patients. Rapid and durable alleviation of B-symptoms (pruritus, fever, sweating) was frequently noted, especially pruritus which was present in 35.5% of patients before treatment and 6.6% of them after one cycle of ruxolitinib. Median duration of response was 7.7 months (95% CI: 1.8-NA). Two patients remain on therapy. Median PFS was 3.5 months (95%CI: 1.9-4.6) and median OS was 27.1 months (95%CI: 14.4-27.1). Using bead-based immunoassays, plasma levels of 27 cytokines related to the immune system were measured at baseline and after cycle 1. Before ruxolitinib, there was no difference in cytokine levels between responders and non-responders. In responders, the only cytokine that significantly decreased was CX-CL10 (P.01). In patients presenting with pruritus (n=11), PDGF-BB, IL-5, IL-10, IL-12, IL-13, IL-17, eotaxin, FGF basic, MIP1b, rantes, and VEGF were significantly increased. In the latter patients, ruxolitinib treatment significanlty decreased PDGF-BB, IL-10, IL-12, IL-13, IL-17, FGF basic and VEGF. Among patients who were analyzable for JAK2 amplification in RS cells (n=12), polysomy was detected in all of them and specific JAK2 amplification in one. Further analysis of Jak2 targets by IHC will be performed. 40 adverse events (AEs) were reported in 14/33 patients (42.4%), of which 18 were related to ruxolitinib and 18 were grade ≥ 3. One AE led to permanent treatment discontinuation. No AE leading to death was reported. 87.5% of AEs recovered without sequelae. Eight SAEs (infection, 3; anemia, 1; diarrhea, 1; subdural hematoma, 1; bone pain, 1; pulmonary embolism, 1) were reported in 4 patients (12.1%), of which 2 were related to ruxolitinib. No grade 4 neutropenia and 1 grade 3/4 thrombocytopenia was observed. Five patients had grade 3 anemia. Twelve patients died due to lymphoma (83.3%) or toxicity of additional treatment (8.3%) or other reason (8.3%). Among 30 patients who progressed (initial site in 97% and/or new site in 60%), 25 (83.3%) were retreated: with chemotherapy in 19 (comprising bendamustine in 10) and/or immunotherapy in 9 (rituximab, n=4; BV, n=3; nivolumab, n=2). Transplantation was eventually performed in 5/25 (4 allogenic, 1 autologous). In the 25 patients who were retreated, CR/PR rates were 10/15%, respectively. Conclusions: Ruxolitinib shows hints of activity beyond simple anti-inflammatory action in highly advanced, mostly refractory, HL patients, although most responses are short-lived. Toxicity was limited suggesting potential to be combined with other modalities. Further treatment, beyond ruxolitinib, was possible in most patients, even with chemotherapy. Disclosures Haioun: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Casasnovas:BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; ROCHE: Consultancy, Honoraria, Research Funding. Ghesquieres:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; Roche France: Research Funding. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria.

scholarly journals Clinical and Molecular Results of the Phase II Brb (Bendamustine, Rituximab and Bortezomib) Trial of the Fondazione Italiana Linfomi (FIL) for Relapsed/Refractory Waldenström Macroglobulinemia Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1607-1607 ◽  
Author(s):  
Giulia Benevolo ◽  
Simone Ferrero ◽  
Alessandro Andriani ◽  
Anna Castiglione ◽  
Anna Baraldi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Salvage Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Grade 3 ◽  
Line Of Therapy

Abstract BACKGROUND: Standard rituximab plus chemotherapy salvage treatment has shown moderate activity in patients with relapsed/refractory Waldenström's macroglobulinemia (RR-WM), with 18-months progression free survival (18-PFS) of about 50%. On behalf of the Fondazione Italiana Linfomi (F.I.L.) we designed a multicenter phase II study to assess the efficacy of a combination of bendamustine, rituximab and bortezomib (BRB) in improving these results. METHODS and PATIENTS: This single-arm phase II study tested the hypothesis that 18-PFS is at least 65%. The required sample size was 38 patients (alpha=0.10; beta=0.25; minimum follow up=24 months). Treatment plan was: rituximab 375 mg/m2 intravenously on day 1 followed by intravenously bendamustine 90 mg/m2 on day 1 and 2 and subcutaneous bortezomib 1.3 mg/m2 on day 1, 8, 15 and 22, every 28 days for 6 months. Patients with RR-WM after first line of therapy were enrolled in 18 F.I.L. centers, from October 2014 to November 2017. In the last 23 patients MYD88L265Pwas tested by the recently described droplet digital PCR (ddPCR) assay both on bone marrow (BM) and peripheral blood (PB) samples, both at baseline (as mutational screening) and at the end of treatment (for minimal residual disease purposes, MRD). RESULTS: At the time of analysis, 29 patients completed the six cycles of therapy, six patients stopped therapy for toxicity, two patients died and one had just finished therapy and was not yet evaluated. 18-PFS was 84% (95%CI: 61-94%), with two progressions and two deaths without evidence of progression (one cerebrovascular accident during the fifth cycle and one pulmonary embolism at three months follow up). On an intention-to-treat analysis (N=37), overall response rate was 70%, (N=26) including 4 (11%) complete, 11 (30%) very good partial, 10 (27%) partial responses and 1 (3%) minimal response according to IWM response criteria. Overall, treatment was well tolerated, the most common adverse events of any grade included 13 patients (34%) experiencing grade 3-4 neutropenia, especially in cycle 4 (leading in four cases to treatment discontinuation). Peripheral nervous system toxicity was observed in five patients (13%; 4 of grade 1-2 and 1 of grade 3-4), with no discontinuations. Serious adverse events were observed only in three patients, mainly rash, all resolved. All the 23 patients assessed for MYD88L265Pat baseline scored positive in BM, while only 18/23 (78%) in PB, prospectively confirming the risk of false negative results when only PB of rituximab pre-treated patients is analyzed. Among the 21 patients monitored for MRD after treatment 5 scored MRD negative in BM and 13 in PB, highlighting the deep activity of the BRB regimen in clearing the disease. CONCLUSIONS: Among patients with RR-WM after first line of therapy, BRB regimen is a well-tolerated salvage treatment, resulting in high rates of PFS at 18 months. Moreover, the deep anti-tumor activity of this regimen is highlighted by the promising rates of both clinical and molecular responses. More complete and mature results will be presented during the meeting. (ClinicalTrials.gov number: NCT02371148). Disclosures Gaidano: AbbVie: Consultancy, Honoraria; Morphosys: Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Vitolo:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Gilead: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: 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.

scholarly journals Ixazomib-Thalidomide-Low Dose Dexamethasone (ITd) Induction Followed By Maintenance Therapy with Ixazomib or Placebo in Newly Diagnosed Multiple Myeloma Patients Not Eligible for Autologous Stem Cell Transplantation; Results from the Randomized Phase II HOVON-126/Nmsg 21#13 Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 800-800 ◽  
Author(s):  
Sonja Zweegman ◽  
Fredrik H. Schjesvold ◽  
Bronno van der Holt ◽  
Mark-David Levin ◽  
Claudia A.M. Stege ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Board Of Directors ◽  
Phase Ii ◽  
Induction Therapy ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Induction Treatment ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Randomized Phase Ii

Abstract Introduction A triplet combination including a proteasome inhibitor (PI) and an IMiD has shown significant efficacy in newly diagnosed multiple myeloma (NDMM) patients. A role for maintenance therapy with the PI bortezomib has been suggested in non-head to head comparisons. Therefore, we investigated the efficacy and feasibility of an oral regimen including induction therapy with ixazomib in combination with thalidomide and dexamethasone, followed by a randomization between maintenance therapy with ixazomib or placebo in elderly non-transplant eligible (nte) NDMM. We here report the final analysis of induction therapy and preliminary results of the randomization phase of the study. This trial was registered at www.trialregister.nl as NTR4910. Methods In this prospective multicenter phase II trial nte-NDMM 143 patients were treated with 9 28 day-cycles consisting of ixazomib 4 mg (day 1, 8, 15), thalidomide 100 mg (day 1-28) and dexamethasone 40 mg (day 1, 8, 15, 22) followed by randomization between either ixazomib or placebo (both day 1, 8, 15/28 days) until progression. Primary objectives were comparison of progression free survival (PFS) between maintenance therapy with ixazomib or placebo (hypothesized hazard ratio (HR) 0.39) and to determine the overall response rate (ORR) of induction therapy. Frailty was assessed by a modification of the IMWG frailty index based on age, the Charlson Comorbidity Index and the WHO performance as a proxy for (instrumental) Activities of Daily Living (scoring WHO 0 as 0 points, WHO 1 as 1 point, and WHO 2-3 as 2 points). High risk cytogenetics was defined as del17p, t(4;14) and/or t(14;16). Results The median follow up (FU) from registration is 26.4 months (range 0.9-41.0 months). Patient characteristics are presented in table 1. Following induction treatment ORR (i.e. ≥PR) was 81% (95% confidence interval (CI) 74-87%), ≥ VGPR 47% (95% CI 38-55%) and ≥ CR 9% (95% CI 5-15%). Age ≥76 years, frailty (unfit or frail) or high cytogenetic risk did not affect the rate and quality of response. Median PFS from registration for all patients was 14.3 months (95%-CI 11.8-16.8). Frailty did not affect PFS. The median PFS for high risk and standard risk disease was comparable; 12.4 months (95%-CI 7.3-20.0) versus 14.6 months (95%-CI 11.5-17.4) respectively. The OS from registration at 18 months was 85% (95% CI 77-90). This was 90% (95% CI 72-97), 92% (95% CI 78-97) and 74% (95% CI 61-84) for fit, unfit and frail patients respectively. Seventy-eight patients (55%) were randomized. The reasons for not being randomized were toxicity (17% [24/143]), progressive disease (15% [21/143]), death (3% [5/143]) and other reasons (10% [15/143]). Median FU from randomization is 18.6 months (range 9.0-31.5 months). Baseline characteristics of randomized patients separately are presented in table 1. Upgrade of response occurred in 13% of patients receiving placebo and 10% of patients receiving ixazomib. The median PFS from randomization was 8.4 months (95%-CI 3.0-13.8) in the placebo arm and 10.1 months (95%-CI 5.6-24.1) in the ixazomib arm (p=0.47, figure 1). The OS from randomization at 18 months was 92% (95%-CI 77-97) in the placebo arm and 100% in the ixazomib arm (p=0.85). Toxicity is presented in table 2. The incidence of neuropathy was low; 8% grade 3 (mainly during thalidomide treatment; 5%) and no grade 4. There was no new onset neuropathy during ixazomib maintenance. During induction 24/143 (17%) patients discontinued therapy due to toxicity; 11 thalidomide-related neurotoxicity, 3 infection, 3 skin toxicity, 2 gastro-intestinal (GI) toxicity and 5 other. During maintenance 4/38 (11%) in the placebo (3 neurotoxicity and 1 other) versus 4/39 (10%) in the ixazomib arm (3 neurotoxicity and 1 GI) discontinued therapy due to toxicity. Discontinuation due to toxicity was comparable across age and frailty groups. Conclusion Induction treatment with 9 cycles of ITd in nte NDMM results in a high ORR of 81%, with 47% ≥ VGPR, independent of age, frailty status and cytogenetic risk. Our placebo controlled randomized phase II trial did not show an improvement in response and PFS with ixazomib maintenance therapy until progression. Ixazomib maintenance did not result in additional toxicity as compared to placebo. Disclosures Zweegman: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schjesvold:Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy; Bayer: Consultancy; Adaptive: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy; Abbvie: Honoraria; Novartis: Honoraria. Levin:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Sonneveld:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Abildgaard:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding.

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