The Improved Efficacy of Bortezomib Containing Induction Regimens (BCIR) Versus Non-Bortezomib Containing Induction Regimens (NBCIR) in Transplant-Eligible Patients with Multiple Myeloma (MM): Meta-Analysis of Phase III Randomized Controlled Trials (RCTs),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3994-3994
Author(s):  
Ajay K. Nooka ◽  
Jonathan L. Kaufman ◽  
Madhusmita Behera ◽  
Charise Gleason ◽  
Amelia Langston ◽  
...  
Keyword(s):  
Research Funding ◽  
Mixed Model ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Response Rates ◽  
Phase Iii ◽  
P Value ◽  
Cell Transplant ◽  
Odds Ratios ◽  
Grade 3

Abstract Abstract 3994 Introduction: Patients with MM undergoing autologous stem cell transplant (ASCT) achieving complete response (CR) or very good partial response (VGPR) have prolonged progression free survival (PFS) and overall survival (OS) compared to the patients that achieve <VGPR prior to ASCT (Lahuerta JJ et al., 2008; Moreau P et al., 2011). Therefore it is of profound significance to attain the best response with induction therapies to obtain the better long-term outcomes. The response rates have significantly improved since the introduction of bortezomib, a proteasome inhibitor, in the induction therapies for myeloma. We performed a meta-analysis to evaluate the efficacy of the addition of bortezomib to the existing regimens used in induction therapy. Methods: We searched Medline, Embase, Cochrane databases and ASH, ASCO conference proceedings from 01/2000 through 08/2011 for publications and abstracts to identify the phase III RCTs comparing BCIR vs. NBCIR in transplant-eligible patients with myeloma. A meta-analysis was performed using both the fixed (Mantel-Haenszel) and random (DerSimonain and Laird) models to calculate the risk difference with the comparator arm to evaluate the rates of CR, ≥VGPR, ORR, PFS, OS and toxicities. Altogether, we identified 4 RCTs (two published articles and unpublished data from two RCTs including 2086 patients). The consistency of results (effect sizes) among studies was investigated by means of two heterogeneity tests, the χ 2-based Cochran's Q test, and the I2 Statistic. We considered that heterogeneity was present when the P value of the Cochran's Q test was <.1 and I 2 statistic was > 50%. Results: Q-statistic for ORR (P =0.338; df =3; I2 = 11.1); ≥VGPR (P =0.175; df =3; I2 = 39.53); CR (P =0.677; df =3; I2 = 0) suggests homogeneity across studies. Pooled odds ratios of overall response rates (ORR), ≥VGPR, CR with BCIR vs. NBCIR were 2.619 (P <0.000; 95% CI: 2.103–3.261); 3.558 (P <0.000; 95% CI: 2.908–4.354); 2.739 (P <0.000; 95% CI: 2.072–3.621) respectively indicating BCIR result in improved efficacy. Similar results were translated post-ASCT demonstrating the superiority of BCIR over NBCIR. Post-ASCT ORR (p =0.141; df =3; I2 = 45.03); ≥VGPR (P =0.442; df =3; I2 = 0); CR (P =1.00; df =3; I2 = 0) suggest homogeneity. Pooled odds ratios of ORR, ≥VGPR, CR post-ASCT for BCIR vs. NBCIR were 1.907 (P <0.000; 95% CI: 1.431–2.639); 2.43 (P <0.000; 95% CI: 2.025–2.914); 2.406 (P <0.000; 95% CI: 1.966–2.945) respectively. The pooled hazard ratios (HR) for 3 year PFS and OS were HR 0.723 (95% CI 0.620–0.844; P =0.000); 3 year OS HR 0.789 (95% CI 0.651–0.957; P =0.016) respectively in favor of BCIR. The relative risk (RR) of selected ≥grade 3 toxicities was higher with BCIR. RR of peripheral neuropathy (PN) was 2.469 (95% CI 1.848–3.297; P =0.000) and infection with herpes-zoster virus (HZV) was 2.197 (95% CI 1.368–3.529; P =0.001). The RR of a thromboembolic event (TEE) with BCIR was 0.8 (95% CI 0.56–1.15; P =0.206). Conclusion: Our mixed model meta-analysis demonstrates that the addition of bortezomib to the induction regimens in the transplant-eligible patients with MM results in improved ORR, ≥VGPR, CR, PFS and OS compared with the NBCIR. Known bortezomib related grade 3 toxicities are higher with BCIR recommending appropriate PN monitoring and HZV prophylaxis. The pooled estimates of response and survival strongly favor inclusion of bortezomib in the induction regimens. Disclosures: Kaufman: Millenium, Onyx, Novartis, Keryx: Consultancy; Merck, Celgene: Research Funding. Gleason:Celgene, Merck, Millenium: Consultancy. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Lonial:Millennium: Consultancy; Novartis: Consultancy; Celgene: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy.

Efficacy and Safety of Triplet Versus Doublet Salvage Therapies Among Patients with Multiple Myeloma (MM) Experiencing Early Relapse: Meta-Analysis of Phase III Randomized Controlled Trials (RCTs)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5344-5344 ◽  
Author(s):  
Ajay K. Nooka ◽  
Jonathan L. Kaufman ◽  
Madhusmita Behera ◽  
Charise Gleason ◽  
Hannah Collins ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Mixed Model ◽  
Meta Analysis ◽  
Phase Iii ◽  
P Value ◽  
Serious Adverse Events ◽  
Early Relapse ◽  
The Impact ◽  
Relapsed Myeloma

Abstract Introduction: Controversy exists regarding the choice of triplet versus doublet salvage therapy among patients with multiple myeloma (MM) experiencing early relapse. Triplet therapies produce deeper responses (CR, ≥VGPR, ORR) and result in prolonged progression free survival (PFS) while doublet therapies demonstrate an improved toxicity profile. We performed a meta-analysis of the RCTs comparing triplet to doublet salvage regimens in early relapsed myeloma patients (1-3 prior lines of therapy). The objective is to test the hypothesis that triplet regimens are tolerable, improve CR, ≥VGPR, ORR rates and would translate to an improved PFS. Methods: We searched Pubmed, Cochrane databases and ASH, ASCO conference proceedings from 01/2000 through 07/2015 for publications and abstracts to identify the phase III RCTs comparing triplet vs. doublet salvage therapies among patients with relapsed myeloma. A meta-analysis of 4 RCTs (PANORAMA1, MMVAR/IFM 2005-04, ASPIRE, ELOQUENT2 consisting of 2475 patients) was performed using the fixed (Mantel-Haenszel) and random (DerSimonain and Laird) models to calculate the impact of triplets versus doublets (table 1) by evaluating the CR, ≥VGPR, ORR, PFS and toxicities. Mature OS data was not available for the RCTs, hence not included in meta-analysis. The consistency of results (effect sizes) among studies was investigated by means of 2 heterogeneity tests: the χ 2-based Cochran's Q test, and the I2 Statistic. We considered that heterogeneity was present when the P-value of the Cochran's Q test was <.1 and the I2 statistic was > 50%. Results: The pooled odds ratios of ORR, ≥VGPR and CR with triplets vs. doublets were 1.935 (P <0.000; 95% CI: 1.614-2.321); 2.185 (P <0.000; 95% CI: 1.832-2.606); 2.461 (P <0.000; 95% CI: 1.888-3.207) respectively, indicating that the odds of achieving higher quality responses are improved with triplet regimens compared to the use of a doublet regimens. The pooled hazard ratio (HR) for PFS was 0.661 (95% CI 0.596-0.734; P =0.000) in favor of triplet regimens (Figure 1). The Q-statistic for PFS (P =0.725; df =3; I2 = 0.00) suggests homogeneity across studies. Though the relative risk of selected ≥grade 3 serious adverse events (G3 SAE) was higher with triplet regimens (diarrhea, fatigue, thrombocytopenia 2.288 (95% CI 1.637-3.197; P =0.000), 1.654 (95% CI 1.263-2.166; P =0.000), 2.434 (95% CI 1.934-3.063; P =0.000), respectively), the overall G3 SAE were comparable with RR 1.498 (95% CI 1.176-1.908; P =0.001) favoring doublets. Conclusion: Our mixed model meta-analysis demonstrates that triplet regimens in early relapsed myeloma patients result in improved ORR, ≥VGPR, CR and PFS compared to doublets. G3 SAEs are higher with triplet regimens, however this appears to be influenced by the regimen-related toxicity from the PANORAMA1 trial. Appropriate dose modifications or use of selective HDAC inhibitors in future may mitigate the toxicities of the regimen. The pooled estimates ofresponse and survival strongly favor triplets in the early relapsed setting. Table 1. Triplet vs. doublet regimens in RCTs Trial Triplet regimen Doublet regimen PANORAMA1 Panobinostat, bortezomib, dexamethasone Placebo, bortezomib, dexamethasone MMVAR/IFM 2005-04 Bortezomib, thalidomide, Dexamethasone Thalidomide, Dexamethasone ASPIRE Carfilzomib, lenalidomide, Dexamethasone Lenalidomide, Dexamethasone ELOQUENT 2 Elotuzumab, lenalidomide, Dexamethasone Lenalidomide, Dexamethasone Figure 1. VGPR rates and PFS with triplet vs. doublet regimens Figure 1. VGPR rates and PFS with triplet vs. doublet regimens Disclosures Nooka: Spectrum Pharmaceuticals: Consultancy; Onyx Pharmaceuticals: Consultancy. Kaufman:Onyx: Consultancy; Celgene: Consultancy; Novartis: Research Funding; Onyx: Research Funding; Merck: Research Funding; Janssen: Consultancy; Spectrum: Consultancy; Novartis: Consultancy. Gleason:Onyx: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Lonial:Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Lenalidomide Maintenance Therapy In Multiple Myeloma: A Meta-Analysis Of Randomized Trials

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 407-407 ◽  
Author(s):  
Preet Paul Singh ◽  
Shaji K Kumar ◽  
Betsy R. LaPlant ◽  
Morie A Gertz ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Meta Analysis ◽  
Phase Iii ◽  
Controlled Trials ◽  
Cell Transplant ◽  
Grade 3 ◽  
Substantial Heterogeneity

Abstract Background Conflicting results have emerged, especially with respect to the impact on overall survival (OS), from trials evaluating lenalidomide maintenance (LM) therapy after induction therapy alone or post-autologous stem cell transplant (ASCT) in multiple myeloma (MM). We performed a systematic review and meta-analysis of existing outcome data from LM trials to evaluate role of lenalidomide as maintenance strategy in MM. Patients and methods A comprehensive search of electronic databases and abstracts through June 2013 was performed to identify randomized controlled trials (RCTs) that compared LM vs. placebo/no maintenance. Single arm studies were excluded. Pooled hazard ratio (HR) or odds ratio (OR) estimates with 95% confidence intervals (CIs) were calculated using the random-effects model for clinical endpoints of progression free survival (PFS), OS, response rate (RR) and adverse events (AEs), including second primary malignancies (SPMs). Analyses were performed using Comprehensive Meta-Analysis Software Version 2. We assessed between-study heterogeneity with the Cochran Q test and quantified its extent with the I2 statistic. Results Overall, five RCTs, with data extractable from four phase III trials (3 publications and 1 abstract) were identified (n= 1935). All studies were RCTs with an adequate randomization. MRC MM XI study was excluded from analyses as survival data are not available. Two placebo controlled trials (IFM 05-02, CALGB 100104) addressed the role of LM post-ASCT, one placebo-controlled trial (MM-015) studied LM therapy in the non-transplant setting and the remaining trial (RV-MM-PI209) had a 2 X 2 design comprising of both ASCT and non-transplant randomized arms followed by a second randomization of LM versus no maintenance. There was no heterogeneity for estimate of PFS results (Cochran Q, p=0.68; I2=0%), but considerable heterogeneity for estimate of OS (Cochran Q, p=0.09; I2= 55%), among the studies. There was significant prolongation of both PFS (HR 0.49, 95% CI, 0.41–0.58, p<0.001) and OS (HR 0.77, 95% CI, 0.62–0.95, p=0.013) with LM vs. placebo/no maintenance (Figure 1). Best response during maintenance was reported only in 2 studies and odds of responding (very good partial response or better) were not significantly different with LM (OR 1.28, p=0.3). Grade 3-4 AEs data were available from 3 trials for calculation of pooled OR with LM compared with placebo. We observed a nearly two-fold increase in the risk of SPMs with LM (OR 1.99; 95% CI, 1.31–3.04; p=0.001). Patients on LM were more likely to have grade 3-4 AEs than placebo: neutropenia (OR 4.9, p<0.001), thrombocytopenia (OR 2.7, p<0.001), fatigue (OR 2.3, p=0.01) and venous thromboembolism (OR 3.2, p=0.02). Odds of discontinuing treatment were also significantly higher in patients on lenalidomide (OR 2.9, p<0.001). Conclusions Meta-analysis of RCTs demonstrates significant improvement in PFS and modest improvement in OS with LM. There is an increased risk of grade 3-4 adverse effects, including SPMs with LM. Substantial heterogeneity for estimate of OS among protocols is a limitation of this analysis. Lack of uniform access to lenalidomide upon disease progression in the placebo/no maintenance arms of the constituent studies should be taken into account while interpreting aggregate effect estimates for OS in this meta-analysis. OS: Cochran Q p=0.09, I2=55%, substantial heterogeneity PFS: Cochran Q p=0.68, I2=0%, minimal heterogeneity Disclosures: Off Label Use: Lenalidomide for maintenance therapy in multiple myeloma. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Novartis: Research Funding; Genzyme: Research Funding. Dispenzieri:Celgene, Millenium, Jansenn, Pfizer: Research Funding. Bergsagel:Onyx: Consultancy. Lacy:Celgene Corporation: Research Funding.

scholarly journals Long Term Outcome of Lenalidomide-Dexamethasone (Rd) Vs Melphalan-Lenalidomide-Prednisone (MPR) Vs Cyclophosphamide-Prednisone-Lenalidomide (CPR) As Induction Followed By Lenalidomide-Prednisone (RP) Vs Lenalidomide (R) As Maintenance in a Community-Based Newly Diagnosed Myeloma Population: Updated Analysis of EMN01 Phase III Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 901-901
Author(s):  
Sara Bringhen ◽  
Massimo Offidani ◽  
Pellegrino Musto ◽  
Anna Marina Liberati ◽  
Giulia Benevolo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Community Based ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Grade 3 ◽  
To Receive

Abstract Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those &gt;75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in &gt;75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in &gt;75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p&lt;0.0001). Grade ≥3 non hematologic AEs were similar among arms. At the end of induction, 402 pts were eligible for maintenance, 198 in the RP and 204 in the R groups. PFS from start of maintenance was 22.2 months in the RP group and 17.6 in the R group, with 20% reduced the risk of death/progression for pts receiving RP maintenance (HR 0.81, p=0.07; Figure 1). A subgroup analysis was performed to determine the consistency of RP vs R treatment effect in different subgroups using interaction terms between treatment and cytogenetic abnormalities, ISS, age, sex, induction treatment and response before maintenance (Figure 1). No difference in OS was observed (HR 1.02, p=0.93) but the OS analysis was limited by the low number of events. Median duration of maintenance was 23.0 months in RP pts and 20.5 months in R pts, 14% and 13% of pts discontinued due to AEs, in RP and R groups, respectively. Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: 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. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Meta Analysis of Grade 3 and/or 4 Toxicities in Low-Grade Non-Hodgkin Lymphoma (LG-NHL) Patients Receiving Maintenance Rituximab (MR) Therapy: Impact of Schedule on Toxicity

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2704-2704
Author(s):  
Chadi Nabhan ◽  
Dana Villines ◽  
Tina V. Valdez ◽  
Michele Ghielmini ◽  
Shu-Fang Hsu Schmitz ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Research Funding ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Comparative Trial ◽  
Progression Free Survival ◽  
Low Grade ◽  
Front Line ◽  
Grade 3 ◽  
The Impact

Abstract Abstract 2704 Background: MR has improved the outcome and progression-free survival (PFS) in patients with follicular lymphoma (FL) in front-line and relapsed settings. However, maintenance schedules have been empirically designed based on either B-cell depletion kinetics or rituximab levels, with no consensus on the optimal regimen. Overall, toxicities have been predictable and tolerable but the impact of MR schedule on toxicities has not been previously reported and could influence selection of maintenance regimens. Methods: Using PubMed, prospective clinical trials employing MR were identified. Data presented in abstract form or at meetings were deemed incomplete and thus excluded. Data were analyzed from published manuscripts as percentages of subjects experiencing an adverse event (AE). Percentages were considered as the unit of analysis as this adjusted for the uneven sample sizes. Data were collected for overall Grade 3 and/or Grade 4 toxicity (AE reported at any phase of treatment) and was further categorized as AE occurring during initial treatment or during MR. Grade 1 and 2 toxicities were excluded from meta-analysis, given lack of consistent reporting. No grade 5 toxicities were reported. The incidence, severity, and type of toxicity was analyzed by type of induction (Rituximab (R) vs. R plus chemotherapy), histology (FL vs. FL plus other LG-NHL), setting (front-line vs. relapsed), and MR schedule (one dose every 2 months vs. one dose every 3 months vs. 4 doses every 6 months). Results: Nine clinical trials involving 1,928 patients were included in this Meta analysis (4 of which were randomized controlled in the MR phase). Of those, 1,004 patients received MR. The mean percentage of Grade 3/4 toxicities during any phase of treatment was 26% (95% CI = 0.12–51.88) but when restricted to the MR phase; it was 12.88% (95% CI = 6.50–19.26). Toxicities were numerically higher in patients receiving R induction plus chemotherapy versus R induction alone and in patients receiving MR for relapsed disease versus newly diagnosed patients, but did not reach statistical significance (P = 0.661 and 0.517, respectively). However, patients receiving MR every 2 months were significantly more likely to develop grade 3 and 4 toxicities compared to patients receiving MR every 6 months (P = 0.005). No statistical differences were demonstrated between the 2 vs. 3 months schedules or when comparing the 3 vs. 6 months schedules (P = 0.342 and 0.267, respectively) (Table 1). Statistically significant differences were also found in studies restricted to FL versus others allowing non-FL histologies (P = 0.025) with the FL patients experiencing more toxicity than others. The most frequently reported toxicities were neutropenia and infections. There were no treatment-related deaths in any of the arms. Conclusions: Approximately 13% of patients receiving MR experience grade 3 and/or 4 toxicities, mainly consisting of neutropenia and infections. MR given every 6 months appears to provide the least grade 3 and 4 toxicities. There is a suggestion of increased toxicity in FL histologies. It is important to note that this meta-analysis did not address efficacy and only a true comparative trial can definitively establish the relative risk/benefit ratios amongst MR schedules. Disclosures: Nabhan: Genentech: Research Funding, Speakers Bureau. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Smith:Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Cyclophosphamide, Adriamycin, Vincristine and Prednisone Plus Rituximab (CHOP-R) in Fludarabine (F) Refractory Chronic Lymphocytic Leukemia (CLL) or CLL with Autoimmune Cytopenia (AIC) or Richter's Transformation (RT): Final Analysis of a Phase II Study of the German CLL Study Group

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2860-2860
Author(s):  
Petra Jenke ◽  
Barbara Eichhorst ◽  
Raymonde Busch ◽  
Nadine Anheier ◽  
Ulrich Duehrsen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Research Funding ◽  
Progression Free Survival ◽  
Response Rates ◽  
Median Number ◽  
Response Evaluation ◽  
Free Survival ◽  
Richter's Transformation ◽  
Grade 3

Abstract Abstract 2860 Introduction: In the last decade, important progress has been achieved in the treatment of CLL through the use of purine analog-based chemoimmunotherapies. Several conditions remain a challenge, often with a poor outcome. Amongst these therapeutic problems are Richter's transformation (RT), refractoriness to F-based therapies (Fref), and the occurrence of AIC, which are sometimes induced by F. Fref and RT pts have a very poor prognosis with an estimated overall survival (OS) of only 10 and 8 months (mos), respectively. Therefore, therapeutic alternatives are urgently warranted. CHOP-R has improved the outcome of pts with aggressive non-Hodgkin's lymphoma. To test the efficacy and tolerability of the CHOP-R regimen in CLL patients with RT, Fref, or AIC, the GCLLSG initiated a prospective phase II trial. Material and Methods: 62 patients were included in the study. Due to protocol violations, 2 patients were excluded. Within the group of Fref pts, the medical review detected 11 patients who had received pre-treatment with F (Fpret), but were not refractory according to the updated guidelines (Hallek et al., Blood 2008). Thus, 26 pts were classified as Fref/pret, 19 pts as AIC and 15 pts as RT. All patients received CHOP every 3 weeks (cyclophosphamide 750mg/m2, adriamycin 50mg/m2 and vincristine 1, 4mg/m2 d1; prednisone 100mg/m2 d1–5). Rituximab was added starting with the 2nd cycle (375mg/m2 on each d0, and 21 days after the last CHOP-R). RT pts received up to 8, Fref/pret and AIC up to 6 courses of CHOP-R. In case of PD after 3 cycles, pts went off-study. The primary endpoints were remission rate, quality and duration of response. Results: 79%, 73%, and 40% of AIC, Fref/pret, and RT pts were male, respectively. The median age was 65 years (y) for Fref/pret-pts, 66y in the AIC and 69y in the RT group. Binet stages for Fref/pret pts were: A: 8%; B: 27% C: 65 %. All but 3 AIC pts were at Binet stage C. Initial RT stages according to Ann Arbor were: II: 13%, III: 13%, IV 73%. The median number of previous therapies were 3 for Fref/pret, 2 for AIC and 2 for RT. A total of 314 cycles were administered, with a median number of 3 cycles for AIC and Fref pts and a median number of 4 cycles for the RT group. Due to toxicity 73% of cycles in the Fref/pret group, 66% in the AIC and 87% in the RT group were dose-reduced. 69% of Fref/pret-pts and 58% of AIC-pts received full 6 cycles of therapy and only 40% of RT-pts completed 8 cycles of therapy. Treatment was stopped in 6 pts because of PD. Due to treatment related toxicity treatment was stopped in 16 pts (27%). Treatment related mortality was 3% (2 pts). Treatment toxicity was reported according to NCI common toxicity criteria (CTC) version 2.0. Adverse events grade 3 or 4 for anemia, neutropenia and thrombocytopenia were documented in 75%, 55% and 65% of patients, respectively. Infections were the most common non-hematologic toxicity and occurred in 67%; severe infections CTC grade 3 or 4 occurred in 28%. All 26 Fref/pret-pts were available for response evaluation. CHOP-R achieved 54% PR, 35% SD and 12% PD. The median progression-free survival (PFS) and median treatment-free survival (TFS) were 11 and 14 mos. OS was 27 mos with a significant difference concerning F-ref (n=15) and F-pret (n=11) pts (17 vs. 35m; p=0.05). We evaluated the response of all 15 RT-pts with 60% PR, 7% CR, 13% SD and 20% PD. The PFS was 15 mos, TFS was 17 mos and OS 27 mos. 17 AIC pts were available for response evaluation with 82% PR, 6% SD and 12% PD. The PFS and TFS were only 14 and 16 mos. The OS was 50 mos. The population had a high incidence of unfavourable genetic markers: deletion of chromosome 17p [del(17p)] was detected in 24%, del(11q) in 34% and unmutated IGHV in 70%. 85% had high levels of serum thymidine kinase (sTK > 10 U/l), and 49% had high levels of ß2-microglobulin (ß2M > 3.5 mg/l). Patients with del(17p) had an unfavourable response rate and achieved significant less a PR or CR (36% vs. 76%; p=0.03). Multivariate analyses showed that del(17p) and ECOG performance status had a negative prognostic impact on OS (p<0.0001). Moreover the presence of a del(17p) predicted a short PFS (6 vs. 16.9 mos; p=0.001). Conclusion: CHOP-R achieves promising response rates in CLL patients with Fref and RT and very good response rates in patients with AIC. However, the progression-free survival and overall survival remain unsatisfactory. Therefore, CHOP-R might be used as induction therapy prior to allogeneic stem cell transplantation in physically fit patients. Disclosures: Eichhorst: Hoffmann La Roche: Honoraria, Research Funding, Travel Grants; Mundipharma: Research Funding, Travel Grants; Gilead: Consultancy. Dreyling:Roche: Research Funding, Scientific advisory board, Speakers Bureau. Bergmann:Celgene: Honoraria. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Fink:Hoffmann La Roche: travel grants. Fischer:Hoffmann La Roche:. Wendtner:Hofmann-La Roche: Consultancy, Honoraria, Research Funding. Hallek:Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Honoraria.

Quadruplet Vs Sequential Triplet Induction Therapy Approaches to Maximise Response for Newly Diagnosed, Transplant Eligible, Myeloma Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 189-189 ◽  
Author(s):  
Charlotte Pawlyn ◽  
Faith E Davies ◽  
David A Cairns ◽  
Corinne Collett ◽  
Anna Chalmers ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Initial Response ◽  
Response Rates ◽  
Phase Iii ◽  
Induction Treatment ◽  
Cell Transplant ◽  
Medical Sciences ◽  
Advisory Committees ◽  
Sequential Strategy

Abstract Background: Maximising response in myeloma (MM) patients with effective induction regimens prior to autologous stem cell transplant (ASCT) improves progression-free and overall survival. Triplet regimens combining an immunomodulatory agent (IMiD) and/or proteasome inhibitor (PI) are standard of care, however a more personalised approach is achieved by sequential triplet combinations based on an individual's response. Alternatively, quadruplet regimens may be more effective and new generation PIs such as carfilzomib, with less off-target activity, provide the opportunity to investigate this whilst minimising the risk of increased toxicity. The UK NCRI Myeloma XI trial is a large, phase III study aiming to answer these questions in transplant eligible (TE) patients comparing the quadruplet carfilzomib, cyclophosphamide, lenalidomide and dexamethasone to the sequential strategy of triplet IMiD combinations (with thalidomide or lenalidomide) followed by additional PI triplet therapy for those with a suboptimal response (<VGPR) prior to ASCT. Methods: In 2013, the TE pathway was amended to include KCRD: carfilzomib 36mg/m2 IV d1-2,8-9,15-16 (20mg/m2 #1d1-2), cyclophosphamide (cyclo) 500mg PO d1,8, lenalidomide (len) 25mg PO d1-21, dexamethasone (dex) 40mg PO d1-4,8-9,15-16). Patients are randomised to this up-front quadruplet or the sequential strategy of CRD: cyclo 500mg PO d1,8, len 25mg PO d1-21 PO daily, dex 40mg PO d1-4, 12-15 or CTD: cyclo 500mg PO d1,8,15 thalidomide 100-200mg PO daily, dex 40mg PO d1-4,12-15 given to max. response - patients with VGPR/CR proceed straight to ASCT, PR/MR are randomised to sequential CVD: cyclo 500mg d1,8,15, bortezomib 1.3mg/m2 IV/SC d1,4,8,11, dex 20mg PO d1,2,4,5,8,9,11,12 or nothing and SD/PD all receive sequential CVD. All treatments are given to max. response prior to ASCT, after which there is a maintenance randomisation. Patients: 1512 patients entered the TE pathway prior to amendment (756 CRD, 756 CTD). Of these, 201 patients with a suboptimal initial response went on to receive CVD, 142 following randomisation (initial response PR/MR) and 59 with NC/PD. 788 (of target n=1036) patients have been randomised post-amendment to date (394 KCRD, 197 CRD, 197 CTD). Results: TE patients receiving treatment prior to the amendment had response rates ≥VGPR: CRD 58% vs CTD 52%. For patients receiving the sequential triplet CVD due to a suboptimal response this was upgraded to ≥VGPR in 49% of those with initial MR/PR, 27% with NC/PD. This suggests the overall ≥VGPR rate to this treatment approach prior to ASCT would be approx. 75%. This now needs to be compared to the alternative approach of an upfront quadruplet. Comparing patients contemporaneously randomised to initial induction the patients receiving KCRD have completed a median 4 cycles (range 1-7), CRD 5 (range 1-10) and CTD 6 (range 1-9). Dose modifications have been required in 62% of patients receiving KCRD (56% to carfilzomib, 42% to lenalidomide) 44% CRD (40% to lenalidomide) and 65% CTD (59% to thalidomide). Data for study drug related toxicity in patients who have completed at least one cycle of initial induction are shown in table 1. Serious adverse events suspected to be due to trial medications have occurred in 37% on KCRD, 32% CRD and 35% CTD. Updated toxicity and preliminary response analysis on 23/09/15 will be presented at the meeting. This will include a response comparison at the end of initial induction regimen i.e. KCRD vs CRD vs CTD for an anticipated 700 contemporaneous patients who will have completed treatment. Updated response to the sequencing approach (with 250 patients having received sequential CVD) will also be presented and compared. Conclusions: In our study KCRD, an outpatient delivered 4-drug regimen combining second generation IMiD and PI drugs, is well-tolerated in TE NDMM patients, comparable to 3-drug regimens. Data will be presented at the meeting to compare the response rates achieved with the different regimens and treatment approaches. On behalf of the NCRI Haemato-oncology CSG Table 1. Comparative toxicities KCRD n=261 CRD n=143 CTD n=142 % (no. of patients) Peripheral neuropathy Sensory Gr II-IV 1.9 (5) 1.4 (2) 8.5 (12) Motor Gr II-IV 3.1 (8) 1 (1) 5.6 (8) VTE all grades 4.2 (11) 4.9 (7) 5.6 (8) Anaemia Gr III-IV 9.2 (24) 4.2 (6) 5.6 (8) Neutropenia Gr III-IV 14.9 (39) 16.1 (22) 13.3 (19) Thrombocytopenia Gr III-IV 8.4 (22) 1.4 (2) 1.4 (2) Infusion reaction Gr III-IV 0.4 (1) - - Disclosures Pawlyn: Celgene: Honoraria, Other: Travel support; The Institute of Cancer Research: Employment. Off Label Use: Carfilzomib as induction treatment for myeloma Lenalidomide and vorinostat as maintenance treatments for myeloma. Davies:University of Arkansas for Medical Sciences: Employment; Celgene: Honoraria; Onyx-Amgen: Honoraria; Takeda-Milenium: Honoraria. Jones:Celgene: Other: Travel support, Research Funding. Kaiser:Janssen: Honoraria; Chugai: Consultancy; Amgen: Consultancy, Honoraria; BristolMyerSquibb: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Jenner:Takeda: Honoraria; Amgen: Honoraria. Cook:Jazz Pharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Chugai: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Russell:Therakos: Other: shares. Owen:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Gregory:Janssen: Honoraria; Celgene: Honoraria. Jackson:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Morgan:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; CancerNet: Honoraria; Weisman Institute: Honoraria; MMRF: Honoraria; MMRF: Honoraria; University of Arkansas for Medical Sciences: Employment; Weisman Institute: Honoraria; CancerNet: Honoraria.

Regorafenib (REG) in progressive metastatic colorectal cancer (mCRC): Analysis of age subgroups in the phase III CORRECT trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3636-3636 ◽  
Author(s):  
Eric van Cutsem ◽  
Alberto Sobrero ◽  
Salvatore Siena ◽  
Alfredo Falcone ◽  
Marc Ychou ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
P Value ◽  
Correct Trial ◽  
Multikinase Inhibitor ◽  
Once Daily ◽  
Grade 3 ◽  
Dose Modifications ◽  
The Impact ◽  
To Receive

3636 Background: In the CORRECT phase III trial, the multikinase inhibitor REG demonstrated significant improvement in overall survival (OS) and progression-free survival vs placebo (Pla) in patients (pts) with mCRC whose disease progressed on other standard therapies. The most frequent REG-related grade ≥3 adverse events (AEs) of interest were hand–foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash/desquamation. We explored whether the impact of REG in pts aged ≥65 years differed from that in younger patients. Methods: Pts with mCRC progressing following all other available therapies were randomized 2:1 to receive REG 160 mg once daily (n=505) or Pla (n=255) for the first 3 weeks of each 4-week cycle. The dose could be modified to manage AEs. The primary endpoint was OS. We report efficacy, safety, and dosing data from REG recipients by age. Results: The REG treatment group included 309 pts <65 years (307 evaluable for safety) and 196 pts ≥65 years (193 evaluable for safety). The OS hazard ratio (REG/Pla) was 0.72 (95% confidence interval [CI] 0.56–0.91) in pts <65 years and 0.86 (95% CI 0.61–1.19) in pts ≥65 years (interaction p-value = 0.405). Median OS was 6.7 vs 5 months for REG vs Pla in pts <65 years, and 6.0 vs 5.6 months, respectively, in pts ≥65 years. Most pts experienced drug-related AEs (<65 years: 93.8%; ≥65 years: 91.7%). The rates of grade ≥3 REG-related AEs of interest and dose modifications are shown in the Table. In pts <65 years vs ≥65 years, median (interquartile range [IQR]) duration of REG was 7.6 weeks (6.6–15.4) vs 7.1 weeks (5.1–17.2), median (IQR) daily REG dose was 160.0 mg (134.6–160.0) vs 160.0 mg (137.5–160.0), and median (IQR) proportion of planned REG dose was 83.3% (65.7–100.0) vs 78.6% (66.7–100.0), respectively. Conclusions: In the CORRECT trial, REG demonstrated an OS benefit in pts <65 years and ≥65 years. Safety and tolerability of REG appeared to be similar in both age subgroups. Clinical trial information: NCT01103323. [Table: see text]

scholarly journals Safety Analysis of Intra-Patient Dose- Study of Crenolanib Maintenance Therapy in Patients with FLT3 Mutant AML Following Allogeneic Hematopoietic Stem Cell Transplant

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3426-3426 ◽  
Author(s):  
Betul Oran ◽  
Stefan O. Ciurea ◽  
David Marin ◽  
Jessica M McCarty ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Stem Cell ◽  
Side Effects ◽  
Maintenance Therapy ◽  
Dose Escalation ◽  
Research Funding ◽  
Patient Dose ◽  
Phase Iii ◽  
Cell Transplant ◽  
Grade 3 ◽  
Active Disease

Abstract Background: FLT3 inhibitors (like sorafenib and midostaurin) have been administered as maintenance therapy post allogeneic stem cell transplantation (SCT) to reduce persistent relapse risks in FLT3-mutant AML patients. Reduced doses of both sorafenib and midostaurin have been found to be tolerable in the post-HSCT setting. Crenolanib is a highly potent and selective FLT3-targeted TKI that has activity as a single-agent and combined with chemotherapy in patients with FLT3-ITD and/or FLT3-TKD mutations. We here report the outcomes of safety and tolerability of crenolanib maintenance in FLT3 mutant AML patients after allo-HSCT (NCT02400255). Methods: To assess the tolerability of crenolanib maintenance in post-SCT AML patients and evaluate the appropriate dose for such patient population, a clinical trial of crenolanib maintenance therapy was performed in patients (age ≥ 18) with FLT3 mutant AML who had undergone SCT. Enrollment criteria included patients with FLT3-ITD, or FLT3-TKD positive disease at any point prior to SCT, having first SCT, with ≥ 50% T cell donor chimerism, adequate engraftment with complete remission (CR) at post-SCT evaluations. Patients needed to enroll between 42 and 90 days post-transplant without uncontrolled infection and graft versus host disease (GvHD). Initially, the study was designed for patients to be treated with crenolanib 80 mg TID (240 mg daily. Due to initial tolerability in the first patients (n=4), the design was changed to an intra-patient dose-escalation, in which patients received crenolanib starting at a dose of 60 mg BID for a month and then escalated to 80 mg BID and finally 80 mg TID as tolerated. As of July 2018, 24 patients, median age 53.5 years (range 31-74) have been enrolled and received crenolanib maintenance therapy. Disease status at SCT was CR (n=10, 42%), CR without count recovery (CRi, n=12, 50%), and active disease (n=2, 8%). The minimal residual disease (MRD) by multicolor flow cytometry was evaluable in 22 CR/CRi patients at SCT and was deemed to positive in 5 (23%). Conditioning regimen was myeloablative (20, 83%) or reduced intensity (4, 17%). Donors were matched related (n=11, 46%), matched unrelated (n=11, 46%) or haploidentical (n=2, 8%). After 4 patients enrolled, the trial design was altered to allow for intra-patient dose escalation. Ten patients were never able to escalate above 60mg BID, one patient stayed at 60 mg TID, 12 patients escalated to 80 mg BID, of those 12, 7 were able to escalate to 80 mg TID. The median days on crenolanib was 474 days (4-728 days) and median number of cycles was 17.5 cycles (1-26 cycles). Of the 21 patients no longer on study, 6 were due to relapse with median time to progression of 17 days (7-76 days) after first dose of crenolanib. Of the 6 relapses, four patients were positive for MRD prior to transplant and two had active disease. Two patients came off study due to noncompliance with study procedures, two were due to withdrawal of consent, 7 were patient decision due to side effects, one was due to suicidal ideation, and one was for insurance non-payment. Only one patient completed the planned 24 cycles of treatment with crenolanib 60 mg BID. Currently, four patients remain on study. Observed side effects were predominantly grade 1 and 2 with the most common (regardless of attribution) being nausea (62%), vomiting (38%), and diarrhea (33%), 13 adverse events that were grade 3 were reported likely attributable to crenolanib, no grade 4 side effects reported. There were two grade 2 GVHD-AEs, one grade 1 and one ungraded GVHD-AEs reported. One patient had a grade 3 rash that was confirmed as GVHD. Conclusion: These interim results suggest that crenolanib can be safely given at a dose of 160 mg to 240 mg total daily in the post-SCT setting. Two randomized phase III trials have been initiated to investigate the efficacy of crenolanib with chemotherapy vs chemotherapy alone in R/R FLT3 mutated AML as well as crenolanib vs midostaurin following chemotherapy in newly diagnosed FLT3 mutated AML (NCT03250338, EudraCT 2017-001600-29; NCT03258931). Post HSCT crenolanib maintenance will be offered at 100 mg BID (200 mg daily) in both trials. Disclosures Oran: AROG pharmaceuticals: Research Funding; ASTEX: Research Funding; Celgene: Consultancy, Research Funding. Shpall:Affirmed GmbH: Research Funding. Agrawal:Arog: Employment. Champlin:Sanofi: Research Funding; Otsuka: Research Funding.

scholarly journals 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 ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3930-3930
Author(s):  
Georg Hess ◽  
Ulrich Keller ◽  
Johannes Atta ◽  
Ulrich Bitz ◽  
Christian Lerchenmueller ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Response Rates ◽  
Phase Iii ◽  
Mtor Inhibition ◽  
Grade 3 ◽  
Ongoing Phase

Abstract Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas. In relapsed MCL a phase III trial could prove superiority of Temsirolimus to standard options. Furthermore, in patients with follicular and diffuse large B-cell lymphoma, promising response rates could be observed (Smith et al, JCO 2010). Whereas combination to single agent Rituximab (R) improved efficacy (Ansell et al, Lancet Oncology 2011), there is limited information of the feasibility and efficacy in combination with chemotherapy. Bendamustine (B) has been shown to be effective in various lymphoma entities and has a beneficial side effect profile (Rummel et al, JCO, 2005). In the phase I of this trial, we have established that 50mg of Temsirolimus given 3 times weekly in a four week cycle could be safely added to BR (Hess, Leukemia, 2015). Here we report for the first time combined results of phase I and II of this trial. Methods: this is a multicenter, national, prospective trial. Inclusion criteria: patients were eligible if they had histologically proven FL or MCL, 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 50 mg day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles. Results: Overall 34 patients (pts) have been included until now (15 pts phase I, 19 pts phase II). Concerning clinical characteristics, median age was 71 years, with 25 MCL and 9FL, and a median number of 2 pretreatments (1-3). Overall the treatment was well tolerated, and toxicity was predominantly hematologic. In 118 evaluable cycles of chemotherapy the following hematologic grade 3 / 4 toxicities were noted: leukopenia (11 pts, 32%), neutropenia (8 pts, 24%), and thrombocytopenia (7 pts, 21%). Non-hematologic grade 3 / 4 observed in at least two patients were angioedema and decrease in blood potassium, infection, metabolic (4 events). AE's of special interest: pulmonary: rate of cough (4; 12%) and pneumonitis (1; 3%); gastrointestinal: diarrhea (6; 18%), nausea (13, 38%); general: fatigue (16; 47%), mucositis (13, 38%); bleeding: epistaxis (4; 12%), which all were predominantly grade 1 or 2. Response: currently, best responses were 8 CR (31%), 16 PR (62%) and 2 SD (8%) in 26 patients evaluable so far. Updated results will be presented at the meeting. Overall responses were 94% in MCL (7 CR, 10 PR, 1 SD) and 88% in FL (1 CR, 6 PR, 1 SD). After a median follow up of 13 months (mean: 21 months) median PFS is 18.6 months for the entire cohort, with 22 months for MCL and not reached in FL. Summary: In this ongoing phase II trial 50mg Temsirolimus (day 1,8,15) in combination with Bendamustine and Rituximab was well tolerated and feasible. A moderate dose of Temsirolimus to standard chemotherapy might be the optimal way to achieve the maximum efficacy with mTOR inhibitors; in fact excellent response rates suggest an additive effect of mTOR inhibition to BR. Even after the BTK inhibitor Ibrutinib has entered the clinical arena of MCL, this combined treatment represents a valuable additional option especially for patients with relapsed MCL Disclosures Hess: Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding; Janssen, Roche, , Celgene, Novartis: Consultancy. Keller:Roche: Consultancy, Honoraria; Pfizer: Consultancy. Witzens-Harig:Roche: Honoraria; Pfizer: Honoraria, Research Funding.

A randomized phase III trial of S-1/oxaliplatin (SOX) plus bevacizumab versus 5-FU/l-LV/oxaliplatin (mFOLFOX6) plus bevacizmab in patients with metastatic colorectal cancer: The SOFT study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3519-3519 ◽  
Author(s):  
Daisuke Takahari ◽  
Yasuhide Yamada ◽  
Hiroshi Matsumoto ◽  
Hideo Baba ◽  
Kazuhiro Yoshida ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
P Value ◽  
Open Label ◽  
Phase Iii Trial ◽  
Open Label Phase ◽  
Grade 3 ◽  
Ecog Ps

3519 Background: Several studies of oxaliplatin plus S-1 combination therapy (SOX) conducted in Asia have shown promising efficacy and safety for metastatic colorectal cancer (mCRC), suggesting the potential to replace mFOLFOX6. We performed a randomized phase III trial to determine whether SOX plus bevacizmab (SOX+Bev) is non-inferior to mFOLFOX6 plus bevacizmab (mFOLFOX6+Bev) in terms of progression-free survival (PFS). Methods: The SOFT study was a randomized, open-label, phase III trial. Chemotherapy-naïve patients (pts) with mCRC, an ECOG PS of 0-1, and adequate organ functions were randomized to receive either mFOLFOX6+Bev (5 mg/kg of bevacizumab, followed by 200 mg/m2 of l-leucovorin given simultaneously with 85 mg/m2 of oxaliplatin, followed by a 400 mg/m2 bolus of 5-FU on day 1 and then 2,400 mg/m2 of 5-FU over 46 h, every 2 weeks) or SOX+Bev (7.5 mg/kg of bevacizumab, 130 mg/m2 of oxaliplatin on day 1, and 40−60 mg of S-1 twice daily for 2 weeks, followed by a 1-week rest). The primary endpoint was PFS. A sample size of 225 pts per group was estimated to be necessary based on a median PFS of 10.0 months in each group and an 80% power to demonstrate non-inferiority of SOX+Bev with a 2.5-month margin (hazard ratio, HR = 1.33) and a 2-sided alpha of 0.05. Results: A total of 512 pts were enrolled from February 2009 to March 2011. Data were analyzed after confirming >388 events as planned. Demographic factors were well balanced. Pts received a median of 12 cycles (1 cycle = 2 weeks) of mFOLFOX6+Bev and 8 cycles (1 cycle = 3 weeks) of SOX+Bev (range: 1−16). Median PFS was 11.5 months (95% CI: 10.7−13.2) with mFOLFOX6+Bev and 11.7 months (95% CI: 10.7−12.9) with SOX+Bev. The adjusted HR for PFS was 1.043 (95% CI: 0.860−1.266), and the p value for non-inferiority was 0.0139. Response rate was 62.7% with mFOLFOX6+Bev and 61.5% with SOX+Bev. Grade 3/4 toxicities (%) with mFOLFOX6+Bev/SOX+Bev were leukopenia 8.4/2.4, neutropenia 33.7/8.8, anorexia 1.2/5.2, and diarrhea 2.8/9.2. Conclusions: SOX+Bev is non-inferior to mFOLFOX6+Bev with respect to PFS as 1st-line treatment for mCRC and thus can replace mFOLFOX6+Bev. Clinical trial information: JapicCTI-090699.

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