scholarly journals Bendamustine, Obinutuzumab and Venetoclax As Induction Therapy for Untreated Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Irl Brian Greenwell ◽  
Jeffrey M. Switchenko ◽  
Kami J. Maddocks ◽  
Brad S. Kahl ◽  
Alexander F. M. Craig ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
Advisory Committees ◽  
Tumor Lysis ◽  
Phase 2 Study ◽  
Mantle Cell ◽  
Grade 3 ◽  
Stage 1

Bendamustine-rituximab (BR) is a standard of care for patients with mantle cell lymphoma (MCL) with median progression free survival (PFS) of approximately 3 years. Venetoclax has proven activity both as a single agent and in combination with other targeted therapies in relapsed MCL. We developed a phase 2 study of bendamustine, obinutuzumab, and venetoclax (BOV) for untreated patients with MCL to determine the efficacy and toxicity of this combination (NCT03872180). Patients ≥ 18 years old with untreated MCL received up to six 28-day cycles of BOV, consisting of bendamustine (90mg/m2 on D1-2) and obinutuzumab (1000mg, C1: D 1,8,15 and C2-6: D1) with a venetoclax ramp up from 20mg to 200mg during the first cycle and then 400mg on days 1-10 of cycles 2-6. Post-induction therapy is determined by the treating physician and is not dictated by the study. The primary endpoint was CR rate at the end of induction, per Lugano criteria. We assumed a historical CR rate of 60% with BR, with a goal CR rate of 85% with the BOV regimen and plan to accrue 23 total patients to assess for this difference. This was a two-stage design that included 9 patients in stage 1 with a requirement of 7 CR's in the first 9 patients to justify continued accrual. Secondary and correlative endpoints include PFS/overall survival, toxicity (including frequency and severity of tumor lysis syndrome), and MRD negativity using both commercial IgHTS assays as well as CAPP-Seq. Supportive care included G-CSF, antimicrobial prophylaxis, and prescribed monitoring for and management of tumor lysis syndrome. 11 patients have initiated therapy. Median age is 70 years (45-80), with 7 males and 4 females. All 11 patients had marrow involvement. Five patients had Ki67 index ≥30%, and TP53/17p abnormalities were found in 2 patients. Eight patients have completed 6 cycles, one patient discontinued study therapy after 5 cycles due to thrombocytopenia and 2 patients remain on therapy after 5 cycles of treatment. Of 9 patients who have completed end of treatment restaging, the ORR was 100%, including 8 CR's (89%) and 1 PR. The two patients currently completing study therapy have completed their interim PET/CT's and both have achieved CR. Three patients experienced grade 3+ obinutuzumab infusion reactions on cycle 1 day 1, with both patients requiring admission but subsequently fully recovering. One of these patients chose to forgo additional obinutuzumab while a second patient safely completed 6 cycles of treatment. The third patient initiated treatment in the hospital and experienced atrial fibrillation requiring ICU transfer, as well as grade 2 hyperkalemia while receiving day 1 treatment. Cardiology did not feel AFib was a result of TLS. She was ultimately able to safely complete 6 cycles of obinutuzumab. Although this event was not clear clinical TLS, the protocol was subsequently amended to incorporate venetoclax administration beginning on day 8 of cycle 1 to prevent overlapping infusional and TLS toxicities from venetoclax and obinutuzumab on day 1. No other patients have had TLS to date. Grade 3/4 hematologic toxicities include neutropenia (n=4), anemia (n=1), thrombocytopenia (n=4) leukopenia (n=3), and lymphopenia (n=10). Grade 3/4 non-hematologic toxicities included rash (n=2), hypophosphatemia (n=2). One patient has experienced prolonged leukopenia 2 months after finishing 6 cycles of therapy and was unable to collect stem cells after cycle 4 for a planned post-induction autologous transplant. To date, 2 patients have relapsed at 7 and 8 months after completing therapy, and one patient died suddenly while in remission of unknown causes at 6 months post-treatment. Of the two relapses, one patient chose not to receive any obinutuzumab during treatment due to a grade 3 reaction during cycle 1, and both patients initially presented with aggressive leukemic phase disease with Ki67 > 30%. Here we report the pre-planned stage 1 of this phase 2 study, the BOV regimen has resulted in CRs in 8 of the first 9 patients, and accrual continues to stage 2. Expected hematologic and infusional toxicities have been manageable. One patient has discontinued therapy due to toxicity, and the prescribed venetoclax ramp-up has successfully avoided clinically significant tumor lysis syndrome. Accrual continues, and additional follow-up of currently treated patients will provide insights into response duration, OS, and rate of MRD negativity with this regimen. Disclosures Greenwell: Acrotech Biopharma LLC, Kyowa Kirin: Consultancy; Lymphoma Research Foundation: Research Funding. Maddocks:Karyopharm: Consultancy; ADC Therapeutics, AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Kahl:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy, Research Funding. Alizadeh:Janssen: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Chugai: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Roche: Consultancy; Pfizer: Research Funding. Allen:Curio Sciences: Honoraria; Bayer: Consultancy, Other; Clinical Care Options: Speakers Bureau; Research to Practice: Speakers Bureau; Imbrium: Consultancy, Other. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy.

Alternating Courses of 3x CHOP and 3x DHAP Plus Rituximab Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation (ASCT) Is Superior to 6 Courses CHOP Plus Rituximab Followed by Myeloablative Radiochemotherapy and ASCT In Mantle Cell Lymphoma: Results of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 110-110 ◽  
Author(s):  
Olivier Hermine ◽  
Eva Hoster ◽  
Jan Walewski ◽  
Vincent Ribrag ◽  
Nicole Brousse ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
High Dose ◽  
Advisory Committees ◽  
Overall Response ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 110 Background: Mantle Cell Lymphoma (MCL) has been characterized by poor long term prognosis with a median survival of only 3 to 4 years. However, outcome has improved during the last decades. In its first randomized trial, the MCL net demonstrated that myeloablative consolidation followed by ASCT resulted in a significant prolongation of PFS in advanced stage MCL (Dreyling et al Blood 2005). Recent phase II studies suggested that the addition of rituximab to CHOP like chemotherapy and/or high dose ARA-C may significantly improve remission rates and PFS. A French phase II trial using sequential R-CHOP/R-DHAP followed by ASCT showed an overall response rate of 95% with a CR rate of 61% translating into a median EFS of 83 months and a 75% survival rate at 5 years (Delarue et al ASH 2008). Methods: To evaluate the potential superiority of a high dose ARA-C containing regimen, the MCL net initiated a randomized trial comparing 6 courses of CHOP plus Rituximab followed by myeloablative radiochemotherapy (12 Gray TBI, 2×60mg/kg Cyclophosphamide) and ASCT (control arm A) versus alternating courses of 3x CHOP and 3x DHAP plus Rituximab followed by a high dose ARA-C containing myeloablative regimen (10 Gray TBI, 4×1,5 g/m2 Ara-C, 140mg/m2 melphalan) and ASCT (experimental arm B). Patient eligibility criteria included previously untreated MCL stage II-IV up to the age of 65 years. Histological diagnosis was confirmed by a central pathology review board. The primary end point time to treatment failure (TTF) was monitored continuously by a sequential procedure based on a one sided triangular test. Stable disease after induction, progression or death from any causes, were considered as treatment failure. Sample size was calculated to detect a hazard ratio of 52% for arm B with a power of 95%. Randomization was stopped as soon as a significant difference was observed between the two arms. Results: From July 2004 to May 2010, 497 patients were randomized in 4 countries (Germany, France, Poland, Belgium). The 391 patients evaluable for the primary analysis (19 no MCL, 87 not yet documented) displayed similar characteristics in both treatment arms: median age 55 vs 56 years, male 78% vs 79%, stage IV 85% vs 79%, B symptoms 43% vs 33%, ECOG >2 5% vs 5%, elevated LDH 37% vs 38%, and MIPI low/int/high risk 61%/25%/14% vs 62%/23%/15%, respectively. After induction overall response was similarly high in both arms (A: 90% vs B: 94%; p=0.19) and CR rate and combined CR/CRu rate were significantly higher in arm B (26% vs 39%; p=0.012 and 41% vs 60%; p=0.0003). The number of patients transplanted was similar in both arms (72% vs 73%) and after transplantation overall response and CR rates were comparable in both arms (97% vs 97% and 63% vs 65%, respectively). After a median follow up of 27 months, patients in arm B experienced a significantly longer TTF (49 months vs NR; p=0.0384, hazard ratio 0.68) mainly due to a lower number of relapses after CR/CRu/PR (20% vs 10%), whereas the rate of ASCT-related deaths in remission was similar in both arms (3% vs 4%). Although CR rate after ASCT was comparable in both arms, remission duration (RD) after ASCT was superior in Arm B (48m vs NR; p=0.047). Interestingly, for patients in CR after ASCT, RD after ASCT was also presumably superior in arm B (51 months vs NR; p=0.077). At the time of analysis overall survival was similar in both arms with medians not reached and 79% vs. 80% survival rates at 3 years (p=0.74). Safety after induction was comparable in both arms except for an increased grade 3/4 hematological toxicity (Hb 8% vs 28%, WBC 48% vs 75%, platelets 9% vs 74%, respectively), an excess of renal toxicity (creatinine grade 1/2: 8% vs 38%, grade 3/4: none vs 2%), and more frequent grade 1/2 nausea and vomiting in arm B. Toxicities of both conditioning regimen were similar, except for higher grade 3/4 mucositis (43% vs. 61%) in Arm B, and higher grade 1/2 liver toxicity and constipation in Arm A. Conclusions: High dose ARA-C in addition to R-CHOP+ASCT increases significantly complete response rates and TTF without clinically relevant increase of toxicity. Therefore, induction regimen containing high dose ARA-C followed by ASCT should become the new standard of care of MCL patients up to 65 years. Disclosures: Walewski: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stilgenbauer:Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Feugier:roche: Consultancy, Honoraria. Bosly:Roche: Membership on an entity's Board of Directors or advisory committees. Gisselbrecht:Roche: Research Funding.

Phase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-Cell Neoplasms - Update of the “Bolus” Infusion Schedule of Alvocidib.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2959-2959
Author(s):  
Beata Holkova ◽  
Edward B. Perkins ◽  
Prithviraj Bose ◽  
Daniel M Sullivan ◽  
Rachid Baz ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Research Funding ◽  
Phase I Trial ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
Tumor Lysis ◽  
Mantle Cell ◽  
Infusion Schedule ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 2959 Preclinical studies suggest that neoplastic cells may be particularly sensitive to simultaneous interruption of cell cycle and survival signaling pathways. We have previously reported that the cyclin-dependent kinase inhibitor alvocidib interacts with bortezomib, a proteasome inhibitor, to induce mitochondrial injury and apoptosis in human leukemia, myeloma, and lymphoma cells (Dai et al, Oncogene 22:7108, 2003; Dai et al, Blood 104:509, 2004). These actions were associated with inhibition of NF-κB DNA binding, increased expression of pJNK, and down-regulation of XIAP and Mcl-1. Based on these findings, a phase I trial was initiated in which bortezomib was administered in conjunction with alvocidib on the same days, according to 2 separate schedules: a “hybrid” infusion schedule (half the dose over 30 minutes and half over a 4-hour infusion); and a bolus infusion schedule in which alvocidib was administered over 1 hour. Results of the hybrid infusion schedule have recently been reported (Holkova et al, Clin Cancer Res 17:3388, 2011). The primary objective was to identify the maximum tolerated doses (MTDs) for the combination in the treatment of recurrent or refractory indolent B-cell neoplasms. Eligible patients included those with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL), with recurrent or refractory disease following at least 1 prior systemic therapy. To date, 43 patients have been treated at 9 dose levels. Patients with the following disease types have been treated: MM n=25 (Waldenstrom's macroglobulinemia n=2), NHL n=18 (mantle cell lymphoma n=5). The male:female ratio was n = 31 (72%):12 (28%); the median age was 65 (range: 40–79) years; ECOG performance scores ranged from 0–1; and the median number of prior therapies was 3 (range: 1–10). The schedule of administration was bortezomib via intravenous push over 3–5 seconds followed by alvocidib via intravenous 1-hour infusion on days 1, 4, 8, and 11; on a 21-day cycle, with indefinite continuation for responding patients and those with stable disease. Adverse events (AEs) were evaluated using CTCAE version 4. Dose limiting toxicities (DLTs) observed to date are shown in Table 1. Grade 3 and 4 AEs possibly, probably, or definitely related to study treatment tht occurred in ≥ 5% of patients were dehydration (7%), diarrhea (19%), fatigue (16%), febrile neutropenia (5%), leukopenia (37%), lymphopenia (28%), neutropenia (58%), peripheral neuropathy (12%), and thrombocytopenia (44%). No grade 5 events were observed. One patient developed tumor lysis syndrome and required hospitalization for 48 hours with complete recovery. Common grade 2 AEs possibly, probably or definitely related to treatment were anemia (30%), anorexia (28%), diarrhea (47%), fatigue (60%), leukopenia (47%), lymphopenia (28%), and thrombocytopenia (56%). Of the 43 patients treated, 38 have been evaluable for response. Patient responses are shown in Table 2. Correlative studies examining expression of pJNK, Mcl-1, XIAP, PARP, and NFκB are being collected for processing at the end of the study. Collectively, these findings indicate that the combination of bortezomib and alvocidib, the latter administered as a 1-hour infusion, is tolerable. The regimen appears active in patients with relapsed and/or refractory MM or NHL, justifying phase II studies to determine the activity of this regimen more definitively. The MTD has not yet been reached. Table 1. Dose levels and DLTs Dose Level Bortezomib (mg/m2) Alvocidib (mg/m2) Patients treated/# DLTs DLT 1 1.0 15 3/0 2 1.3 15 5/0 3 1.3 22 3/0 4 1.3 30 3/0 5 1.3 40 7/1 Grade 3 back pain 6* 1.3 50 5/1 Grade 3 fatigue 7** 1.3 60 8/2 Grade 3 febrile neutropenia Grade 3 tumor lysis syndrome 8** 1.3 75 6/2 Grade 3 diarrhea Grade 3 esophagitis/oral mucositis 9** 1.3 90 3/2 Grade 3 febrile neutropenia Grade 4 absolute neutrophil count decrease * Study is currently enrolling to dose level 6 ** Exceeded MTD Table 2. Response by diagnosis NHL MM Total (n = 15) (n = 23) (n = 38) Complete Remission 2b,c 1a 3 Partial Remission 3 7d,e 10 Complete + Partial Remission N(%) 5 (33) 8 (35) 13 (34) a Includes 1 patient with prior bortezomib b Includes 1 patient with prior autologous SCT c Includes 1 patient with mantle cell lymphoma d Includes 1 patient with Waldenstrom's macroglobulinemia e Includes 1 patient still under active treatment Disclosures: Baz: Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding.

Phase II Randomized, Multicenter Study of Lenalidomide Vs Best Investigator’s Choice in Relapsed/Refractory Mantle Cell Lymphoma: Results of the MCL-002 (SPRINT) Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 626-626 ◽  
Author(s):  
Marek Trneny ◽  
Thierry Lamy ◽  
Jan Walewski ◽  
Wojciech Jurczak ◽  
David Belada ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Tumor Burden ◽  
Advisory Committees ◽  
First Response ◽  
Mantle Cell ◽  
Grade 3 ◽  
Prognostic Profile

Abstract Introduction: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin’s lymphoma with poor outcome, especially after failure of first-line treatment. Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, has shown activity in single-arm phase II studies of patients with relapsed/refractory (R/R) MCL. The present controlled randomized study compared the efficacy and safety of lenalidomide vs investigator’s choice (IC) in patients with R/R MCL. Methods: MCL-002 (SPRINT), a European multicenter, open-label, phase II study enrolled patients with up to 3 relapses or who failed prior therapy and were ineligible for intensified treatment or stem cell transplantation (NCT00875667). Oral lenalidomide was given at 25 mg/day on days 1-21 of each 28-day cycle until progressive disease (PD) or intolerability. The IC treatment consisted of single-agent therapy with cytarabine, rituximab, gemcitabine, fludarabine, or chlorambucil. Patients who progressed on IC per investigator judgment were allowed to crossover to lenalidomide. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), time to first response, duration of response (DOR), overall survival (OS), and safety. Response assessments were centrally reviewed using the modified IWG criteria. Results: 254 patients with R/R MCL were randomized 2:1 to lenalidomide (n=170) or IC (n=84). Patients had median age 68.5 years, were predominantly male (73%), and had received a median of 2 prior therapies. 91% had stage III/IV disease at diagnosis, with 34% high-risk MIPI, 43% high tumor burden, and 20% bulky disease at baseline. Overall, patients on the lenalidomide arm had a worse prognostic profile than the IC arm due to higher tumor burden and disease risk (>5 percentage points for a number of parameters). After a median time of 2.9 months, 39 patients (46%) from the IC arm crossed over to lenalidomide due to PD. Overall, 84 patients remain on lenalidomide (15 having crossed over from IC) and 11 patients on IC without PD. At a median follow-up time on study of 15.9 months, the risk reduction for PFS was 39% (HR=0.61 [95% CI, 0.44-0.84]; P=0.004; Table) in favor of lenalidomide (median PFS: 8.7 months lenalidomide vs 5.2 months IC). ORR was significantly improved for lenalidomide vs IC (40% vs 11%; CR/CRu 5% vs 0%). Median time to first response was 4.3 months for lenalidomide (not reached for IC). Median DOR (16.1 vs 10.4 months) and OS on mature data (27.9 vs 21.2 months) were longer for lenalidomide vs IC. Efficacy results were consistent among subgroups. Safety data in 250 patients receiving ≥1 dose showed more dose reductions in lenalidomide-treated patients (41%) vs IC (17%), due in part to a longer median duration of lenalidomide treatment vs IC, and to strict dose modification rules for lenalidomide. The most common grade 3/4 adverse events (AEs) were neutropenia (lenalidomide 44% vs IC 34% [without increased risk of infection]), thrombocytopenia (18% vs 28%), and leukopenia (8% vs 11%). Tumor flare reaction occurred in lenalidomide patients only (10%; 2% grade ≥3); 1 patient in each arm experienced tumor lysis syndrome. Invasive second primary malignancies were identified in 4% and 5% of lenalidomide and IC treated patients, respectively. Conclusions: The MCL-002 study demonstrated a statistically significant and clinically meaningful improvement in PFS for lenalidomide over best IC monotherapy in patients with advanced R/R MCL despite a worse prognostic profile in the lenalidomide arm at baseline. In addition, ORR and CR rates, TTR, DOR, and OS were improved for lenalidomide over IC. The DOR has been remarkably consistent in various studies with lenalidomide in MCL patients. The safety profile for lenalidomide was as expected and no new safety signals were identified. The results of this first randomized, controlled study of lenalidomide showed superior efficacy compared to IC in patients with R/R MCL with a manageable toxicity profile. Table Efficacy of lenalidomide vs IC in R/R MCL Efficacy Lenalidomide (n=170) IC (n=84) P PFS (Lenalidomide vs IC)  Median PFS, mo (95% CI) 8.7 (5.54-12.14) 5.2 (3.67-6.95)  Sequential HR (95% CI) 0.61 (0.44-0.84)  Sequential log-rank test p-value 0.004 ORR, n (%) 68 (40) 9 (11) <0.001 CR/CRu, n (%) 8 (5) 0 (0) 0.043 Median DOR, mo 16.1 10.4 0.421 Median OS, mo 27.9 21.2 0.52 Disclosures Trneny: Celgene, Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Walewski:Celgene: Consultancy, Other, Research Funding; Janssen-Cilag: Consultancy; Mundipharma : Consultancy, Research Funding; Roche: Consultancy, Honoraria, Other, Research Funding. Jurczak:Celgene, Eisai, Gilead, Janssen, Pharmacyclics, Pfizer, Roche, Novartis, Spectrum, Takeda, Teva: Research Funding. Belada:Celgene: Research Funding. Mayer:Janssen Research & Development: Research Funding; Roche: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding. Biyukov:Celgene: Employment. Patturajan:Celgene: Employment. Casadebaig Bravo:Celgene: Employment. Arcaini:Celgene, Roche, Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Carfilzomib Combined with Thalidomide and Dexamethasone (CARTHADEX) As Induction Treatment Prior to High-Dose Melphalan (HDM) in Newly Diagnosed Patients with Multiple Myeloma (MM). A Trial of the European Myeloma Network EMN

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 633-633 ◽  
Author(s):  
Pieter Sonneveld ◽  
Emilie Hacker ◽  
Sonja Zweegman ◽  
Marie Jose Kersten ◽  
Edo Vellenga ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Tumor Lysis Syndrome ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Tumor Lysis ◽  
Grade 3 ◽  
Cell Harvest

Abstract Abstract 633 Introduction: This independent phase 2 trial was designed to evaluate carfilzomib (C) combined with thalidomide and dexamethasone during induction and consolidation for feasibility, response and progression-free survival (PFS) in patients with newly diagnosed symptomatic MM, who were candidates for high-dose therapy. Patients with symptomatic MM and measurable disease, age 15 to 65 and no significant co-morbidity were eligible. At diagnosis Fluorescent in situ Hybridization (FISH) was performed of recurrent translocations, trisomy 9, del(17p), del (13q) and add(1q) Patients received 4 cycles of carfilzomib at 20 mg/m2 on days 1 & 2 followed by 27mg/m2 on days 8,9,15,16 of cycle 1 and on days 1,2, 8, 9, 15 & 16 of all subsequent 28-day cycles, thalidomide 200 mg days 1 – 28 of a 28 day cycle and dexamethasone 40 mg days 1, 8, 15 & 22 of a 28 day cycle. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Following HDM (200 mg/m2) and autologous stem cell transplantation (ASCT), consolidation therapy consisted of 4 cycles of carfilzomib 27 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle, thalidomide 50 mg days 1–28 of a 28 day cycle and dexamethasone 20 mg days 1, 8, 15, 22 of a 28 day cycle. The primary endpoint was response, other endpoints were complete response (CR) according to IMWG criteria, immunofixation-negative CR (sCR), VGPR all pre-and post HDM, PFS and overall survival (OS). An interim analysis was planned after 20 evaluable patients, primarily to guard against excessive toxicity and/or lack of response. Results: While recruitment is still ongoing, 34 patients have been included, of which the first 20 patients were are evaluated for response and toxicity, with a median follow-up of 5 months. One patient was excluded because unavailability of data. Median age was 60 yr and ISS stages I/II/III were 8/6/5, respectively. Four patients went off treatment because of intolerance to thalidomide (n=1), tumor lysis syndrome with renal failure (n=1) or respiratory infections (n=2). Adverse events CTC grade 3+4 included tumor lysis syndrome (n=2), metabolic disorders (n=4), cardiovascular including DVT (n=5), gastrointestinal (n=2), skin rash (n=2) and reversible renal failure (n=3). Peripheral polyneuropathy grades 1+ 2 was observed in 7 (35%) of patients, but no grade 3 or higher. Responses after cycle 1 were CR + sCR 5%, VGPR 32%, PR 47%, SD 10%, NE 5% and after induction overall CR + sCR 21%, VGPR 47%, PR 16%, SD 10%, NE 5%. Median time to maximum response was 1 cycle. Secondary analysis revealed that responses occurred across cytogenetic subgroups as determined by FISH, i.e. add (1q) (n=2), t(4;14) (n=2), del(17p) (n=1) and del(13q) (n=5). Stem cell harvest was accomplished with standard CD34+ yield in all patients and HDM/ASCT was performed with complete hematologic recovery in 4/4 patients. Conclusion: Carfilzomib combined with thalidomide and dexamethasone during induction and consolidation is feasible and effective. The complete data including response after consolidation will be reported at the ASH meeting. This EMN trial was registered as NTR2422. Carfilzomib and an unrestricted grant was provided by ONYX Pharmaceuticals. Disclosures: Sonneveld: Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Zweegman:Celgene: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Amgen: Honoraria.

Pillar-1: Multicenter Phase 2 Study of Everolimus for Patients with Mantle Cell Lymphoma Who Are Refractory or Intolerant to Bortezomib.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2751-2751
Author(s):  
Michael Wang ◽  
Leslie Popplewell ◽  
Robert H. Collins ◽  
Jane N. Winter ◽  
Andre Goy ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Median Duration ◽  
Mtor Inhibitor ◽  
Cell Lymphoma ◽  
Phase 2 ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 2751 Background: Mantle cell lymphoma (MCL) is a rare, often aggressive form of B-cell lymphoma. In relapsed MCL, bortezomib is associated with an overall response rate (ORR) of 32% and a median time to progression of 6.7 months (Ann Oncol 2009;20:520-5). The mammalian target of rapamycin (mTOR) pathway is frequently dysregulated in hematologic malignancies. In a phase 2 study of relapsed/refractory lymphomas, including MCL, reported by Witzig et al, the oral mTOR inhibitor everolimus showed antitumor efficacy and acceptable tolerability (Leukemia 2011;25:341-7). PILLAR-1 (PIvotaL Lymphoma triAls of RAD001-1) was a phase 2 study conducted to determine the efficacy and safety of everolimus monotherapy in patients with previously treated MCL refractory or intolerant to bortezomib. Methods: PILLAR-1 was a US, multicenter, open-label, 2-stage, single-arm, phase 2 study of oral everolimus 10 mg/day for adults with pathologically confirmed MCL who were refractory or intolerant to bortezomib and received ≥1 other antineoplastic therapy. Patients were considered refractory to bortezomib if they had documented radiological progression on or within 12 months of the last bortezomib dose when given alone or on or within 12 months of the last dose of the last component of a combination therapy that included bortezomib. Patients were considered intolerant to bortezomib if they discontinued bortezomib for toxicity (documentation was required). Primary endpoint was ORR assessed by the investigator according to the modified response criteria for malignant lymphoma. To declare a positive study, ≥8 responders out of 57 patients were required. Secondary endpoints included progression-free and overall survival (PFS and OS, respectively), duration of response (DOR), and safety. Results: Fifty-eight patients were enrolled between August 2008 and January 2011. Median age was 68 years (range, 50 to 83 years), 77.6% were male, 19.0% and 67.2% had stage III and IV disease, respectively, 20.7% received autologous stem cell transplant, 74.1% received ≥3 prior treatment regimens, 84.5% were bortezomib refractory, and 13.8% were bortezomib intolerant; 1 patient (1.7%) was considered neither bortezomib refractory nor intolerant as disease progression occurred >12 months after the last bortezomib dose. Median duration of follow-up was 23.2 months. As of April 20, 2012, all patients discontinued study treatment, most commonly due to disease progression (51.7%) or adverse events (AEs) (39.7%). Median duration of everolimus exposure was 2.9 months (range, 0.4 to 16.9 months). The study did not meet its primary objective as only 5 objective responses per local review (all partial responses [PR]) were observed, resulting in an ORR of 8.6% (90% confidence interval [CI], 3.5% to 17.3%). The DOR ranged from 21 to 338+ days. Per local review, 35 patients (60.3%) experienced stable disease (SD). The median duration of disease control in the 40 patients with PR or SD was 5.7 months (range, 1.7+ to 16.7+ months). Median PFS per local review was 4.4 months (95% CI, 3.5 to 6.1 months). In a sensitivity analysis based on central radiology review, 6 patients experienced PR (ORR, 10.3%; 90% CI, 4.6% to 19.4%), the DOR ranged from 49+ to 401+ days, 30 patients experienced SD (51.7%), and median PFS was 5.2 months (95% CI, 4.0 to 7.1 months). Median OS was 16.9 months (95% CI, 14.4 to 29.9 months). Four patients proceeded to stem cell transplantation. Grade 3/4 nonhematologic AEs were experienced by 70.7% of patients; those that occurred in ≥5% of patients were abdominal pain (8.6%), pneumonia (8.6%), fatigue (6.9%), hyperglycemia (6.9%), asthenia (5.2%), diarrhea (5.2%), dyspnea (5.2%), hyponatremia (5.2%), and pneumonitis (5.2%). Based on laboratory values, grade 3/4 thrombocytopenia and neutropenia occurred in 13.8% of patients each, and anemia occurred in 8.6%. Conclusions: In this phase 2 study, everolimus monotherapy demonstrated modest activity in heavily pretreated patients with bortezomib-refractory MCL. Future studies exploring everolimus as monotherapy in a less refractory population or in combination with other targeted therapies in refractory MCL are warranted. Disclosures: Wang: Novartis: Research Funding. Off Label Use: Everolimus is an mTOR inhibitor indicated in the US for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with letrozole after failure of letrozole or anastrozole; adults with progressive pancreatic neuroendocrine tumors that are unresectable, locally advanced, or metastatic; adults with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib; adults with renal angiomyolipoma and tuberous sclerosis complex not requiring immediate surgery; and adults and children aged 3 years or greater with subependymal giant cell astrocytoma associated with tuberous sclerosis complex who require therapeutic intervention but are not candidates for curative surgical resection. Winter:Seattle Genetics: Consultancy; Talon: Consultancy; BMS: Consultancy; Sanofi-Aventis: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Caremark/CVS: Consultancy; Eisai: Consultancy; Novartis: Consultancy; TG Therapeutics: Consultancy; Spectrum: Consultancy; Teva: Consultancy; Medalis: Consultancy. Goy:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Robeva:Novartis: Employment. Pirotta:Novartis: Employment. Fan:Novartis: Employment. Klimovsky:Novartis: Employment.

scholarly journals Rituximab, Bendamustine and Cytarabine (RBAC500) As Induction Therapy in Elderly Patients with Mantle Cell Lymphoma: Final Results of a Phase 2 Study from the Fondazione Italiana Linfomi

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 472-472 ◽  
Author(s):  
Carlo Visco ◽  
Annalisa Chiappella ◽  
Luca Nassi ◽  
Caterina Patti ◽  
Simone Ferrero ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Board Of Directors ◽  
Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Phase 2 ◽  
Advisory Committees ◽  
Ki 67 ◽  
Phase 2 Study ◽  
Mantle Cell ◽  
Grade 3

Abstract Background: The combination of rituximab (R, 375 mg/m2 intravenously [IV], day 1), bendamustine (B, 70 mg/m2IV, days 2 and 3), and cytarabine (800 mg/m2, IV on days 2 to 4) was highly active in patients with mantle-cell lymphoma (MCL) in a phase 2 study [R-BAC; Visco et al, JCO 2013]. This regimen was well tolerated, but hematologic toxicity was quite relevant, especially in terms of transient grade 3 to 4 thrombocytopenia (76% of cycles). Aiming at reducing hematologic toxicity, the Fondazione Italiana Linfomi (FIL) designed a phase 2 trial adopting the R-BAC schedule, but lowering cytarabine dose to 500 mg/m2 (RBAC500). Materials and Methods: Patients with newly diagnosed MCL, aged 61 to 80 years, not eligible for autologous transplant and fit according to the comprehensive geriatric assessment, were enrolled. Patients presenting with non-nodal leukemic disease were excluded. The primary endpoints were complete remission rate (CR) measured by FDG-PET according to Cheson criteria 2007, and safety. Secondary endpoints included rate of molecular response (MR) by nested-PCR using patient specific IGH or BCL1 based targets, progression-free (PFS) and overall survival (OS). The study was conducted according to the Bryant and Day two-stage design. Results: From May 2012 to February 2014, 57 patients with MCL from 29 centers were recruited and treated. Central pathology revision was performed in 87% of cases. Median age was 71 years (range 61-79), 75% were males, and 91% had Ann Arbor stage III/IV disease. Mantle Cell International Prognostic Index (MIPI) was low in 15%, intermediate in 40%, high in 45%, Ki-67 was ≥30% in 31%, and 9% had the blastoid cytological variant. Overall, 53 patients (91%) received at least 4 cycles, while 36 (63%) had 6 cycles (median 5.3 cycles per patient). Fifteen patients (26%) discontinued treatment before reaching cycle 6 because of toxicity/adverse events, that mainly consisted of prolonged hemato-toxicity between cycles. Only one patient discontinued due to progressive disease. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 49% and 52% of administered cycles, respectively. Febrile neutropenia occurred in 6% of cycles. Extra-hematologic toxicity was mainly cardiac (5%). Overall response rate was 96%, and CR was 93%. The MR rate at the end of treatment was 76% on peripheral blood and 55% on bone marrow (BM) samples. With a median follow-up of 34 months (28-52), the 2-years PFS (± confidence interval) was 81%±5% and the OS 85%±4%. Elevated Ki-67 (≥30%), and the blastoid variant were the strongest independent predictors of adverse PFS. Patients with either of these two features (33%), had a significantly inferior PFS (41% vs 97% after 34 months) compared to patients with classical/pleomorphic variants and low proliferative index (p<0.0001, Figure 1). Conclusions: The R-BAC500 regimen can be safely administered as first line therapy to elderly patients with MCL. Hematologic toxicity is substantially reduced compared to our previous experience. With 93% of FDG-PET negative CR, and a 2-years PFS of 81% without maintenance therapy, the R-BAC500 regimen is a highly effective treatment for patients with MCL, and compares favourably with previously reported regimens in this patient population, including R-bendamustine. Figure 1 Figure 1. Disclosures Visco: Gilead: Speakers Bureau; Lundbeck: Consultancy; Mundipharma: Research Funding; Celgene: Speakers Bureau. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Di Rocco:Celgene: Honoraria. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Honoraria; Celgene: Honoraria.

Temsirolimus in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Report on An Ongoing Phase I/II Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2697-2697 ◽  
Author(s):  
Georg Hess ◽  
Ulrich Keller ◽  
Johannes Atta ◽  
Christian Buske ◽  
Peter Borchmann ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Response Rates ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Grade 3 ◽  
Entire Treatment ◽  
Ongoing Phase

Abstract Abstract 2697 Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas. Based on a phase III trial in relapsed MCL which proved superiority of temsirolimus to standard options, the drug is approved for this indication in the EU. Additionally, promising response rates could be observed in patients with follicular and diffuse large B-cell lymphoma (Smith et al, JCO 2010). Whereas combination to single agent rituximab seems feasible and with improved efficacy (Ansell et al, Lancet Oncology 2011), there is limited information on the feasibility and efficacy in combination with chemotherapy. Bendamustine has been shown to be effective in indolent lymphoma and has a beneficial side effect profile (Rummel et al, JCO, 2005). To evaluate the potential of the combination of temsirolimus with bendamustine and rituximab an ongoing phase I/II trial was initiated. Methods: This is a multicenter, national, prospective trial, approved by the centralized EC. Patients were eligible if they had histologically proven follicular (FL) or mantle cell lymphoma (MCL), the latter with Cyclin D1 positivity or detectable t(11;14), 1–3 prior treatment lines, no curative option available, no refractoriness to bendamustine, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. Treatment consisted of bendamustine 90mg/m2 day 1–2, rituximab 375mg/m2 day 1 and temsirolimus day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles. In the ongoing phase I part (3+3 design) the following dose cohorts for temsirolimus were planed: A 25mg, B 50mg, C 75mg. Currently cohort C is ongoing. Toxicity was evaluated throughout the treatment and analysis for DLT was performed after 2 cycles. An independent data safety monitoring board decided on the escalation to the next dose level. Results: Overall 9 patients have been included until now (6 pts cohort A, 3 patients cohort B) and 4 patients are in the prescreening period (cohort C). Median age 64; Histology: 8MCL/1FL; sex 2F/7M, median number of pretreatments 2 (1–3). Adverse events: overall the treatment was well tolerated. Toxicity was predominant hematologic with mostly leukopenia and thrombocytopenia. In 29 evaluable cycles of chemotherapy the following grade 3/4 toxicities were noted: Thrombocytopenia in 3 (all grade 3); leukopenia in 11 (9 grade 3; 2 grade 4), and increase in triglycerides, hyperglycemia and hypertension in one patient each (all grade 3). Importantly, one case of pneumonitis occurred, which resolved after steroid treatment and study treatment could be resumed w/o further problems. In addition, one reaction to contrast agent, an allergic reaction to berries and a transient parasthesia during the study phase were noted, leading to hospitalization. All of these events occurred several days after the last application of study drug and were considered not to be associated to the study treatment. As the episode of hypertension led to hospital admission, it was considered to be potentially a DLT, and cohort A was escalated to 6 patients w/o further DLT. In cohort B no DLT were observed in 3 patients and cohort C has been opened for inclusion. 5 patients have completed the entire treatment, in one patient treatment was stopped after cycle 3 due to delayed recovery of platelets, and treatment is ongoing in 3 patients. At interim staging all 9 patients evaluable achieved a partial remission (ORR 100%). After completion of the entire treatment ORR was 100% with 1 CR and 5 PR in 6 evaluable patients. Summary: In this ongoing phase I/II trial the combination of temsirolimus with bendamustine and Rituximab was feasible applying 3 weekly doses of up to 50mg temsirolimus in a 4 week cycle. Until now promising response rates have been noticed. Cohort C is currently recruiting patients (Temsirolimus 75mg), updated results of the phase I part of the trial will be presented at the meeting. If no dose limiting toxicities are observed, the extended phase II part of the trial will be initiated with patients stratified according to lymphoma subtype (30 patients each with FL and MCL). Disclosures: Hess: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria. Keller:Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Witzens-Harig:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy. Dreyling:Pfizer: Research Funding, Speakers Bureau, scientific advisory.

SAR245409 Monotherapy In Relapsed/Refractory Follicular Lymphoma: Preliminary Results From The Phase II ARD12130 Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 86-86 ◽  
Author(s):  
Jennifer R Brown ◽  
Mehdi Hamadani ◽  
Jon Arnason ◽  
Lionel Karlin ◽  
John Hayslip ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Objective Response ◽  
Advisory Committees ◽  
Grade 3 ◽  
General Physical ◽  
Stage 1 ◽  
Health Deterioration ◽  
General Physical Health

Abstract Background Dysregulation of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway signaling has been implicated in the pathogenesis of lymphoma. SAR245409 is a potent inhibitor of class I PI3K isoforms (α, β, γ and δ) and also inhibits mTORC1 and TORC2. In the phase 1 dose-expansion cohort of study TED11440 (NCT00485719), SAR245409 showed promise in several lymphoma subtypes: 1 complete response (CR) in a transformed lymphoma and 2 partial response (PR) [1 diffuse large B cell lymphoma (DLBCL) and 1 mantle cell lymphoma (MCL)] and 3 patients with stable disease (SD) longer than 3 months [1 follicular lymphoma (FL), 1 MCL and 1 Hodgkin Lymphoma] (Papadopoulos et al. ASH 2011). The Sanofi sponsored study ARD12130 (NCT01403636) is an ongoing multicenter, multinational, open-label, phase 2 study of SAR245409 in patients with lymphoproliferative malignancies enrolling on 4-arms: FL, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), MCL and DLBCL. Preliminary Stage 1 results from FL patients (pts) are reported. Methods Eligible pts for the FL arm had relapsed or refractory FL (Grade 1, 2, or 3a) with no clinical suspicion of transformation to an aggressive subtype and who had received ≥2 but ≤ 6 prior chemotherapy regimens. Pts were treated with SAR245409 at 50 mg twice daily orally until disease progression or withdrawal for other reasons including toxicity. Tumor response was based on modified International Working Group response criteria. A Simon 2-stage design was used to evaluate the primary efficacy endpoint of objective response rate (ORR) in the FL arm; if at least 6 of the first 24 evaluable patients in Stage 1 achieved an objective response (OR), the study would continue to Stage 2 with a total of 45 evaluable patients. If 14 or greater total patients among the 45 total evaluable achieved OR, the null hypothesis would be rejected. Results Twenty-eight FL patients were enrolled to stage 1. Median age was 62 years (range 38-87 years), 60% were males, 78% of pts had stage III/IV disease and 64% had received ≥ 3 prior lines of treatment. At data cutoff (end of March 2013), 15/28 (54%) pts had discontinued treatment: 10 due to disease progression, 2 due to adverse events (AEs) (grade 2 pneumococcal pneumonitis and grade 3 diarrhea), 2 due to consent withdrawal, and 1 due to non-compliance. Median treatment duration was 32 weeks (range 4-72 weeks). Among the first 24 evaluable patients in the per protocol primary efficacy population, the ORR was 50% (2 CR and 10 PR); 14 (58%) had progression free survival (PFS) ≥ 24 weeks and the median PFS has not yet been reached with a median follow-up of 8 mos. Eighty-three percent of pts experienced treatment emergent AEs (TEAEs), with the most common (≥ 10%) TEAEs regardless of relationship including diarrhea, pyrexia, fatigue, cough, decreased weight, vomiting, decreased appetite, nausea, anemia and headache. Fifty-five percent of pts presented with Grade 3/4 TEAES (any relationship) which included lymphopenia (13%) and the following TEAEs in less than 10% of pts: anemia, pneumonia, neutropenia, alanine aminotransferase elevation (ALT), diarrhea, hypokalemia, hyperglycemia, thrombocytopenia, decreased appetite and general physical health deterioration. Fifty-four percent of pts had serious adverse events but only the following events were reported as related to SAR245409: general physical health deterioration, diarrhea, hypophosphatemia, lung infection and cortical cataracts. The pre-specified criteria for the primary endpoint of ORR of at least 25% was achieved in Stage 1 and the FL arm has been expanded to enroll Stage 2. Conclusions Single agent SAR245409 exhibited clinical activity and an acceptable safety profile in patients with relapsed or refractory FL. Disclosures: Brown: Novartis: Consultancy; Avila: Consultancy; Vertex: Consultancy; Sanofi Aventis: Consultancy; Onyx: Consultancy; Emergent: Consultancy; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Consultancy; Genzyme: Research Funding. Off Label Use: The abstract shows scientific information on SAR245409 which is an investigational product developed by Sanofi. This investigational product is not approved by any health authority for any indication. Karlin:Celgene: Expert board Other, Honoraria; Janssen: Honoraria. Hayslip:Sanofi: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Celgene: Research Funding. Wagner-Johnston:Celgene: Research Funding. Cartron:Roche: Consultancy, Honoraria, Speakers Bureau; GSK: Honoraria; LFB: Honoraria. Ribrag:Servier: 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; Bayer: Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; J&J: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Opat:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Tilly:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Roche: Honoraria; Takeda: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; Janssen: Honoraria; Amgen: Research Funding. Janssens:Amgen: Speakers Bureau; Roche: Speakers Bureau; GSK: Speakers Bureau. Offner:Lilly: Membership on an entity’s Board of Directors or advisory committees. Ganguly:Sanofi: Research Funding. Millenson:Sanofi: My spouse was previously employed by Sanofi (within the past 24 months, ending April 2013) Other. Bron:Sanofi: Research Funding. Xu:Sanofi: Employment. Ruiz-Soto:Sanofi: Employment. Kersten:Sanofi: Honoraria, Member of steering committee for this study Other.

Alternating Courses of 3x CHOP and 3x DHAP Plus Rituximab Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation (ASCT) Increases Overall Survival When Compared to 6 Courses of CHOP Plus Rituximab Followed by Myeloablative Radiochemotherapy and ASCT in Mantle Cell Lymphoma: Final Analysis of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 151-151 ◽  
Author(s):  
Olivier Hermine ◽  
Eva Hoster ◽  
Jan Walewski ◽  
Vincent Ribrag ◽  
Nicole Brousse ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Final Analysis ◽  
High Dose ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 151 Background MCL outcome has improved during the last decades. In its first randomized trial, the MCL net demonstrated that myeloablative consolidation followed by ASCT resulted in a significant prolongation of PFS in advanced stage MCL (Dreyling et al Blood 2005). Recent phase II studies suggest that the addition of rituximab and/or high dose ARA-C may significantly improve outcome. A phase II trial using sequential R-CHOP/R-DHAP followed by ASCT showed an ORR of 95% with a CR rate of 61%, a median EFS of 83m and a 75% survival rate at 5 years (Delarue et al Blood 20012). Two years ago we presented preliminary results of the the MCL randomized trial comparing 6 courses of CHOP plus Rituximab followed by myeloablative radiochemotherapy (12 Gray TBI, 2×60mg/kg Cyclophosphamide) and ASCT (control arm A) versus alternating courses of 3x CHOP and 3x DHAP plus Rituximab followed by a high dose ARA-C containing myeloablative regimen (10 Gray TBI, 4×1,5 g/m2 Ara-C, 140mg/m2 melphalan) and ASCT (experimental arm B) and have shown that after a follow up (FU) median of 27m patients of Arm B experienced a significantly better time to treatment failure (TTF) (49m vs NR; p=0.0384, HR 0.68), but no overall survival difference. Here, we present final results after a longer FU. Methods Patient eligibility criteria included previously untreated MCL stage II-IV up to the age of 65 years. Histological diagnosis was confirmed by a central pathology review board. The primary end point TTF was monitored continuously by a sequential procedure based on a one sided triangular test. Stable diseases after induction, progression or death from any causes were considered as treatment failure. Sample size was calculated to detect a relative risk of 52% for arm B with a power of 95%. Randomization was stopped as soon as a significant difference was observed between the two arms. Results From July 2004 to May 2010, 497 patients were randomized in 4 countries (Germany, France, Poland, Belgium). The 455 patients evaluable for the primary analysis (19 no MCL, 13 not yet documented, 7 lost of follow up, 2 stage 1, and 1 R bendamustine chemotherapy) displayed the following characteristics (A vs B): median age 54 vs 56 year, male 79% vs 79%, stage IV 82% vs 81%, B symptoms 43% vs 31%, ECOG >2 4% vs 4%, elevated LDH 39% vs 35%, and MIPI low/int/high risk 60%/25%/15% vs 64%/23%/13%, respectively. After induction overall response (OR) was similar in both arms (90% vs 95%; p=0.19) but CR and CR/CRu rates were significantly higher in arm B (25% vs 36%; p=0.012 and 40% vs 54%; p=0.0003). The number of patients transplanted was similar in both arms (72% vs 73%). After transplantation OR and CR rates were comparable in both arms (98% vs 97% and 63% vs 61%). After a median FU of 51 months, TTF was longer in Arm B (46m vs 88m; p=0.0382, HR 0.68) mainly due to a lower number of relapses after CR/CRu/PR (n= 81 vs 40). The rate of ASCT-related death in remission was similar in both arms (4% vs 4%). Although CR rate after ASCT was similar in both arms, remission duration (RD) after ASCT was superior in Arm B (49m vs 84m; p=0.0001). At the time of final analysis, OS was superior in Arm B (NR vs 82m, p=0.045). Safety after induction was comparable in both arms except for an increased grade 3/4 hematological toxicity (Hb 9% vs 30%, WBC 50% vs 75%, platelets 10% vs 74%), renal toxicity (creatinine grade 1/2: 10% vs 44%, grade 3/4: none vs 1%), and grade 1/2 nausea and vomiting in arm B. Toxicities of both conditioning regimen were similar. Conclusions With a longer FU, we confirmed that high dose ARA-C in addition to R-CHOP increases significantly complete response rates, TTF and in addition overall survival without clinically relevant increase of toxicity. Therefore, induction regimen containing high dose ARA-C followed by ASCT should become the new standard of care of MCL patients <65 y. Disclosures: Ribrag: Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; astrazeneca: Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees; bayer: Research Funding; sanofi: Research Funding. Gisselbrecht:roche: Consultancy, Research Funding; baxter: Research Funding.

scholarly journals Temsirolimus in Combination with Three Different Immuno-Chemotherapy Regimens in Relapse and Refractory Mantle Cell Lymphoma, Final Results of the T3 Phase IB Trial of the Lysa Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2987-2987 ◽  
Author(s):  
Steven Le Gouill ◽  
Krimo Bouabdallah ◽  
Barbara Burroni ◽  
Thierry Lamy ◽  
Remy Gressin ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Maximum Tolerated Dose ◽  
Advisory Committees ◽  
Phase Ib ◽  
Mantle Cell ◽  
Grade 3

Abstract Temsirolimus has shown clinical activity in heavily pretreated patients with mantle cell lymphoma (MCL) leading to evaluate tolerability and efficacy of combinations regimens. The T3 trial is a multicenter, Phase IB, dose escalation study (3+3) of Temsirolimus administered in combination with three chemotherapy regimens in relapse or refractory (R/R) mantle cell lymphoma (MCL) patients. The primary objective was to determine the maximum tolerated dose (MTD). DLT was assessed during the first two cycles. Study design: Temsirolimus was added for 6 cycles to R-CHOP (R-CHOP-T) administered every 3 weeks or to or R-FC (R-FC-T) and R plus high dose cytarabine and dexamethasone (R-DHA-T) administered every 4 weeks. Temsirolimus was administered IV at day 2, 8 and 15. Three dose levels of Temsirolimus was tested: 15 mg, 25 mg (starting dose) and 50 mg. Patients were treated with one of these 3 chemotherapy regimens according to the choice of local investigator and no randomization was performed. LYSARC was the sponsor and the trial was conducted with a financial support of Pfizer Results: forty-one patients (R-CHOP-T n=10; R-FC-T n=14 and R-DHA-T, n=17)were enrolled. At time of inclusion, median age of patients was 68y (56-79), 32 patients were male, median time from last therapy to inclusion was 23,1m (2-143), MIPI score was low in 8, intermediate in 13 and high in 19 cases (missing=1). Previous lines of treatment included autologous stem cell transplantation in 18 patients. Among patients treated in the R-CHOP-T arm, all patients (n=4) presented grade 3 toxicities at the 25mg dose level. At the 15mg dose level (n=6), one DLT occurs (Thrombopenia). Consequently, the maximum tolerated dose (MTD) of Temsirolimus in the R-CHOP-T was 15 mg. Among patients of the R-FC-T arm (n=14) and R-DHA-T, the recommended dose of Temsirolimus has not been found because of toxicities that occurred at all Temsirolimus doses (25 and 15mg). Hematologic grade 3/4 toxicities were the most frequent, mainly thrombocytopenia (n=28). In term of efficacy, ORR (CR/CRu/PR) during treatment period was 40% for R-CHOP-T including 2 patients who reached CR, 35,7% for R-FC-T including 3 patients who reached CR and 47,1% for R-DHA-T including 6 patients who reached CR. For all patients, mFU is 30.5 m (23-39). The mPFS and mOS according to treatment arms and for all patients (n=41) are as followed: 15,1m and not reached for R-CHOP-T (n= 10); 8.6m and 17.8 m for R-FC-T (n=14) ; 11.9m and 24.2m for R-DHA-T (n=17). In conclusion, the recommended dose of Temsirolimus for R-CHOP-T is 15mg D1,8,15. We are not able to recommend a dose of Temisrolimus for both R-DHA-T and R-FC-T. Hematologic toxicity was the main concern in all arms. A good efficacy in term of response rates PFS and OS was observed in all arms suggesting that Temsirolimus-based chemotherapy regimen should be further investigated in prospective trials but dose of Temsirolimus should be carefully investigated. Disclosures Cartron: Roche: Consultancy, Honoraria; Celgene: Honoraria; Gilead: Honoraria; Jansen: Honoraria. Thieblemont:Roche: Consultancy; Gilead: Consultancy; Janssen: Consultancy. 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:ROCHE: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Hermine:AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Celgene: Research Funding; Novartis: Research Funding; Alexion: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document