IMpower150: Exploratory analysis of brain metastases development.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9587-9587 ◽  
Author(s):  
Federico Cappuzzo ◽  
Martin Reck ◽  
Mark A. Socinski ◽  
Tony S. K. Mok ◽  
Robert M. Jotte ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Brain Lesion ◽  
Population Data ◽  
Brain Lesions ◽  
Exploratory Analysis ◽  
Phase Iii ◽  
Lesion Development ◽  
Brain Scans ◽  
Intention To Treat ◽  
Grade 3

9587 Background: In the global phase III IMpower150 study (NCT02366143), atezolizumab (atezo) + bevacizumab (bev) + chemo (carboplatin + paclitaxel [CP] (ABCP) showed significant improvements in PFS and OS vs BCP in patients with chemotherapy-naive metastatic NSCLC (Socinski et al. N Engl J Med 2018). Because bev has been shown to delay or prevent brain metastases progression in NSCLC (Fu et al. J Chemother 2016; Ilhan-Mutlu et al. Mol Can Ther 2016), exploratory analyses were conducted to assess the development of brain metastases in patients treated with ABCP, BCP and atezo + CP (ACP) in IMpower150. Methods: A total of 1202 patients (intention-to-treat [ITT] population) were randomized 1:1:1 to receive ABCP, ACP or BCP. Doses were given every 3 weeks: atezo 1200 mg, bev 15 mg/kg, carboplatin AUC 6 mg/mL/min and paclitaxel 200 mg/m2. Co-primary endpoints were investigator-assessed PFS and OS in ITT–wild-type (no EGFR or ALK alterations) patients. Exploratory analyses included the rate and time to development (TTD) of new brain metastases in the ITT population, regardless of the presence of baseline brain metastases, as well as safety. Brain scans were performed as clinically indicated, and analyses were based on investigator assessments. Results: With a minimum follow-up of 32.4 months in the ITT population (data cutoff: September 13, 2019), 100 patients had developed brain metastases, with the highest rate of new brain lesions seen in the ACP (11.9%) vs the ABCP (7.0%) and BCP (6.0%) arms (table). Median TTD was not reached in any arm; a trend toward delayed TTD was seen in the ABCP vs BCP arm (HR, 0.68 [95% CI: 0.39, 1.19]). Among patients with and without brain metastases, 17 (35.4%) and 155 (44.0%) in the ACP arm, 18 (64.3%) and 207 (56.7%) in the ABCP arm and 10 (41.7%) and 183 (49.5%) in the BCP arm had Grade 3-4 treatment-related adverse events, respectively. Conclusions: The ACP arm had the highest rate of new brain lesions, whereas the ABCP and BCP arms had similar, lower rates. Taken together with the trend toward delayed development of new brain lesions with ABCP, the data suggest that adding atezo to BCP may not reduce the rate of new brain lesion development but may delay the time to new lesion development. No new safety signals were observed in this exploratory analysis. Clinical trial information: NCT02366143 . [Table: see text]

A randomized comparison of carboplatin/vinorelbine versus carboplatin/gemcitabine in advanced non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7033-7033
Author(s):  
N. Helbekkmo ◽  
S. H. Sundtroem ◽  
U. Aaseboe ◽  
P. F. Brunsvig ◽  
C. L. Von Plessen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Performance Status ◽  
Stage Iiib ◽  
Phase Iii ◽  
Ecog Performance Status ◽  
Intention To Treat ◽  
Primary Endpoints ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
One Year

7033 Background: Carboplatin/vinorelbine (CV) and carboplatin/gemcitabine (CG) are novel 2-drug combinations in the treatment of NSCLC. In a randomized national multicenter phase III study in stage IIIB and IV patients (pts), we compared these regimens with respect to efficacy, toxicity and quality of life (QoL). Methods: Chemonaive pts with histologically or cytologically proven NSCLC, stage IIIB or IV and ECOG performance status (PS) 0–2 were eligible. There was no upper age limit. Pts received vinorelbine 25 mg/m2 or gemcitabine 1000 mg/m2, both administered on day 1 and 8, in combination with carboplatin (Chatelut AUC 4) at day 1. Three courses were administered in 3-week cycles. QoL questionnaires were completed at baseline, before each cycle and then every 8 weeks up to one year. Primary endpoints were survival and QoL and secondary endpoints toxicity and time to progression (TTP). Stratification was done for age, stage and PS, and the planned sample size per arm was minimum 200. The analyses were performed on an intention-to-treat basis Results: From Oct 2003 through Dec 2004, 433 pts from 33 institutions were randomized to CV (n=218) or CG (n=215). Follow-up was minimum one year. There was no difference in overall survival between the two arms (p=0.89). Median survival was 7.3 vs. 6.5 months and 1-year survival 28% and 31% in the CV and CG arm respectively. TTP was significantly longer in the CG arm (p=0.006) with median TTP 4.2 vs. 3.9 months. There was significantly more grade 3–4 anemia and thrombocytopenia in the CG arm (p<0.001) and more grade 3–4 leucopenia in the CV arm (p= 0.001). More pts in the CG arm needed transfusions of blood (p=0.003) or platelets (p=0.001). There was no difference between the arms with respect to neutropenic infections (p=0.87). QoL data are still being analyzed and will be presented at ASCO. Conclusions: Overall survival was similar in the two treatment arms. In the CG arm, the median TTP was longer, but grade 3–4 toxicity requiring interventions, was more frequent when compared to the VC arm. No significant financial relationships to disclose.

International randomized phase III study of capecitabine (Cap), bevacizumab (Bev), and mitomycin C (MMC) in first-line metastatic colorectal cancer (mCRC): Final results of the AGITG MAX trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4023-4023
Author(s):  
N. C. Tebbutt ◽  
V. Gebski ◽  
K. Wilson ◽  
M. Cummins ◽  
Y. Chua ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Phase Iii ◽  
First Line ◽  
Treatment Regimens ◽  
Intention To Treat ◽  
Common Grade ◽  
Secondary Endpoints ◽  
Phase Iii Study ◽  
Low Toxicity ◽  
Grade 3

4023 Background: The addition of Bev to oxaliplatin or irinotecan based doublet chemotherapy has shown benefit in mCRC. Cap± MMC are alternate chemotherapy regimens suitable for patients (pts) who are either unfit for or who do not require initial oxaliplatin/irinotecan. This phase III study compared Cap with Cap Bev and Cap Bev MMC. The aim was to develop a low toxicity regimen suitable for a broad population of pts with mCRC. Methods: Previously untreated pts with unresectable mCRC considered suitable for Cap monotherapy were randomised to arm A Cap (Cap 2000mg/m2/d or 2500mg/m2 d1–14 q21d), arm B Cap Bev (Bev 7.5mg/kg q3w) or arm C Cap Bev MMC (MMC 7mg/m2 q6w). Primary endpoint: PFS, secondary endpoints: RR, toxicity, OS, QoL . Randomisation was stratified by age, PS, centre and Cap dose. Response was assessed every 6w. The study was designed to detect an increase in the median PFS from 5.5m (arm A) to 8m (arm B or C) at p<0.025 with 80% power. Results: A total of 471 pts were randomised from July 2005-June 2007. Outcomes were evaluated on an intention to treat basis and included 15 ineligible pts. Baseline demographics were well balanced between arms with median age 67y (range 31–86y). Toxicity was reported: ASCO 2008 abstr 4029. The most common grade 3/4 toxicities were PPE (16%, 26%, 28%) and diarrhoea (11%, 17%, 16%) for arms (A,B,C). However, adjusted rates per cycle were similar as arms B & C received more cycles of Cap (A8.3, B10.8, C10.5). Other toxicity rates were generally <10%. The study achieved its primary endpoint with a highly significant improvement in PFS for arms B & C. RR and OS are summarized ( Table ). Conclusions: All treatment regimens were well tolerated in a relatively elderly patient cohort. The addition of Bev±MMC to Cap significantly improved PFS without significant additional toxicity. OS was similar for all arms. Cap Bev±MMC is an active, low toxicity regimen that may be considered as a treatment option for pts with mCRC. [Table: see text] [Table: see text]

Whole brain radiation therapy (WBRT) with or without oral topotecan (TPT) in patients (pts) with non-small cell lung cancer (NSCLC) with brain metastases: Final analysis of an open-label phase III study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2031-2031 ◽  
Author(s):  
Rodryg Ramlau ◽  
Jacek Jassem ◽  
Zsolt Papai-Szekely ◽  
Pierre Chabot ◽  
Philippe Legenne ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Population Analysis ◽  
Brain Lesion ◽  
Signs And Symptoms ◽  
Final Analysis ◽  
Primary Objective ◽  
Phase Iii ◽  
Smoking History ◽  
Hematologic Toxicity ◽  
Open Label

2031 Background: Brain metastases from NSCLC occur in ~ 20% of pts and if untreated are associated with a 1 to 2 month overall survival (OS). Pre-clinical studies show that TPT added to radiation results in a radiotherapy enhancement ratio of 1.4 to 1.6. This trial was designed to test the effect of TPT co-administered with WBRT on OS. Methods: Pts with NSCLC and at least one measurable brain lesion were eligible. 472 pts were randomized to WBRT (3 Gy/day x 10 days) or WBRT and TPT 1.1 mg/m2/day for 10 days. Stratification factors: number of brain metastases and recursive partitioning analysis (RPA) class. Two weeks following WBRT, systemic anti-cancer therapy could be restarted at the treating physician’s discretion. Results: 468 pts were in the modified ITT population; 235 pts (WBRT + TPT) and 233 pts (WBRT+ best supportive care [BSC]). Of the 235 pts administered WBRT + TPT, 91 also received TPT after WBRT. The treatment arms were balanced for gender, age and smoking history. Median daily TPT dose was 2.25 mg. The median OS in the TPT arm was not better than in the BSC alone arm; 4.0 months (95%CI 3.4,4.8) vs.3.6 months (95%CI 3.0, 4.0), respectively; HR 0.88 (0.73, 1.07), P=0.1862. In the ITT population analysis by stratification variables, RPA class (I vs. II/III) was significantly different (HR 0.59) whereas baseline brain lesions (1 vs >1) were not (HR 0.97). Complete response and overall response rates in the WBRT+ TPT were 10% and 27%, and with BSC 5% and 26%, respectively. There were no differences in time to response or neurologic signs and symptoms. All adverse events (AEs) were more frequent in the TPT arm (87% vs. 64%) as were AEs related to study treatment (57% vs. 21%), serious AEs (41% vs. 18%) and fatal AEs (5% vs. 0%). The AEs more frequently seen in the TPT arm were typical for TPT (hematologic toxicity, febrile neutropenia and diarrhea). Conclusions: The study did not achieve its primary objective. There was no difference in OS achieved by the addition of TPT to WBRT. AEs were more common in the TPT arm. Clinical trial information: NCT00390806.

Motexafin gadolinium (MGd) combined with prompt whole brain radiation therapy (RT) prolongs time to neurologic progression in non-small cell lung cancer (NSCLC) patients with brain metastases: Results of a phase III trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7014-7014 ◽  
Author(s):  
M. P. Mehta ◽  
R. Gervais ◽  
P. Chabot ◽  
W. R. Shapiro ◽  
R. A. Patchell ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Randomized Study ◽  
Phase Iii ◽  
Phase 3 ◽  
Motexafin Gadolinium ◽  
Whole Brain Radiation ◽  
Significant Prolongation ◽  
Clinically Significant ◽  
Grade 3 ◽  
Nsclc Patients

7014 Background: In a previous randomized study, RT plus MGd prolonged time to neurologic progression (TNP) in NSCLC patients (pts) with brain metastases (BM) (p=0.048). Methods: This Phase 3 trial randomized pts with BM from NSCLC and KPS ≥70 to RT (30 Gy) or RT+MGd, 5 mg/kg qd x 10. A sample size of 550 was based on α=0.001, β=0.8, hazard ratio (HR)=0.65, with a primary endpoint of TNP determined by a blinded events review committee. Results: 554 pts received RT (N=275) or RT+MGd (N=279), 348 in North America (NA), 206 in Europe and Australia (EA). Treatment arms were balanced for factors of known prognostic importance. Most pts had multiple BM (81%), extracranial metastases (51%) and presented with neurologic deficits (84%). Treatment with MGd was well tolerated, with >92% of intended doses administered. Most common MGd-related grade 3+ adverse events were hypertension (4%), ALT increase (3%), and fatigue (3%). TNP improved from 10 months (mo) for RT to 15.4 mo for RT+MGd, p=0.12, HR=0.78. Time to neurocognitive progression was also improved, p=0.089, HR=0.79. More RT pts required salvage brain surgery or radiosurgery than RT+MGd pts (41 RT, 19 RT+MGd). In NA pts, statistically significant prolongation of both TNP, from 8.8 mo for RT to 24.2 mo for RT+MGd, p=0.004, HR=0.53, and time to neurocognitive progression, p=0.04, HR=0.69, were observed. In NA, RT was started sooner after the diagnosis of BM than in EA (median/mean 1.6/2.2 weeks NA vs. 3.0/6.5 weeks EA). There was a significant interaction between earlier RT and MGd benefit, p=0.017. When RT was initiated within 3 weeks of BM diagnosis, regardless of region, TNP was significantly prolonged by addition of MGd (N=378, p=0.006, HR=0.59). When initiation of RT was delayed beyond 3 weeks after BM diagnosis (N=176, 21% of NA pts, 50% of EA pts), MGd benefit was lost. A major reason for RT delay was use of chemotherapy as initial treatment for BM in 41 pts, 17% NA, 83% EA. Conclusions: MGd significantly prolonged TNP in NSCLC patients with BM receiving prompt RT in this randomized Phase 3 trial. The majority of patients in NA received prompt RT (79%), leading to a statistically and clinically significant benefit when combined with MGd. [Table: see text]

Atezolizumab (atezo) monotherapy versus chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma (mUC): Clinical outcomes by PD-L1 status in cisplatin (cis)-ineligible pts from the phase III IMvigor130 study.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 434-434
Author(s):  
Matt D. Galsky ◽  
Aristotelis Bamias ◽  
Jose Angel Arranz Arija ◽  
Ian D. Davis ◽  
Maria De Santis ◽  
...  
Keyword(s):  
Single Agent ◽  
Locally Advanced ◽  
Exploratory Analysis ◽  
Phase Iii ◽  
Primary Analysis ◽  
Fixed Sequence ◽  
Safety Population ◽  
Metastatic Urothelial Carcinoma ◽  
Grade 3 ◽  
In Cis

434 Background: Atezo (anti–PD-L1) monotherapy is approved for cis-ineligible pts who have locally advanced or mUC with PD-L1–expressing immune cells on ≥ 5% of the tumor area (IC2/3 per VENTANA SP142 IHC assay). The IMvigor130 primary analysis demonstrated a significant PFS benefit with atezo + platinum/gemcitabine (plt/gem) (arm A) vs placebo (pbo) + plt/gem (arm C) as 1L treatment for mUC (Galsky Lancet 2020); at that time, interim OS data for arm A vs C were encouraging but immature. OS with atezo monotherapy (arm B) could not be formally tested, but favorable efficacy was seen in IC2/3 pts. In this exploratory analysis, we assess outcomes by PD-L1 status in cis-ineligible pts. Methods: Pts were randomized 1:1:1 to arms A, B or C (Galsky Lancet 2020). Evaluation of OS (co-primary EP) was performed via a hierarchical fixed sequence procedure: arm A vs C ITT pts; then, arm B vs C ITT and IC2/3 pts. No formal testing was performed in this exploratory subgroup analyses; OS and RECIST 1.1 ORR (per investigator [secondary EP]) were descriptively evaluated. Results: Efficacy data suggested OS and ORR benefit in atezo-treated cis-ineligible IC2/3 pts (Table). In the overall safety population, all-grade treatment-related AEs (TRAEs) had occurred in 60% and 96% of arm B and C pts, respectively; grade 3-4 TRAEs occurred in 15% and 81%, respectively. Biomarker data evaluating PD-L1 biology (assessed by SP142) and associated transcriptome analysis in arms B vs C will be presented. Conclusions: This exploratory analysis of IMvigor130 pts with 1L cis–ineligible IC2/3 mUC provides additional evidence for clinical benefit with single-agent atezo, a well-tolerated treatment with a distinct safety profile vs chemo. Analyses with longer OS follow-up are warranted. Clinical trial information: NCT02807636 . Research Sponsor: F. Hoffmann-La Roche Ltd[Table: see text]

SWOG S1216: A phase III randomized trial comparing androgen deprivation therapy (ADT) plus TAK-700 with ADT plus bicalutamide in patients (pts) with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) (NCT01809691).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5001-5001
Author(s):  
Neeraj Agarwal ◽  
Catherine Tangen ◽  
Maha H. A. Hussain ◽  
Shilpa Gupta ◽  
Melissa Plets ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Performance Status ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Meaningful Improvement ◽  
Intention To Treat ◽  
Grade 3

5001 Background: Tak is an oral selective nonsteroidal 17, 20-lyase inhibitor that blocks the synthesis of gonadal and adrenal androgens. We evaluated the clinical benefit of Tak with ADT in pts with newly diagnosed mHSPC. Methods: Pts with mHSPC with a Zubrod performance status (PS) of 0-2 and a PSA of ≥ 2 ng/ml were randomized 1:1 to ADT+Tak (300 mg twice daily) or ADT+Bic (50 mg daily). Stratification factors included PS (0-1 vs ≥2), extent of disease (minimal vs extensive), and receipt of ADT prior to registration (yes vs no). The primary endpoint was overall survival (OS). Secondary endpoints were progression free survival (PFS; based on PSA, imaging or clinical progression), PSA at 7 months (≤0.2 vs 0.2 < PSA; ≤-4 vs. > 4 ng/ml) and adverse event (AE) profile. With 2.75 yrs to accrue 1,186 eligible pts and 3 additional yrs of follow-up, we would have 90% power to determine a 33% improvement in OS from 54 to 72 mos (1-sided α = 0.025). A final analysis was pre-specified after 523 deaths using a 1-sided α = 0.022 to account for interim analyses. Results: Between 3/2013 and 7/2017, 1,313 pts were randomized and 1,279 were included in the intention-to-treat (ITT) analysis (32 pts were ineligible and 2 pts withdrew consent). Median age was 68 yrs and 10% of subjects were Black. Median PSA was 30 ng/mL (range 2-6710) and 49% of pts had extensive disease. After a median follow-up of 4.9 yrs, PFS and PSA response were significantly improved with Tak over Bic but no significant improvement in OS was observed (Table). More grade 3/4 AEs occurred in Tak vs. Bic arms (43% vs. 14%), and included hypertension (20% vs. 5%) and fatigue (5% vs. 2%). Five pts in Tak and 1 pt in the Bic arm had grade 5 AE. Conclusions: Despite clinically meaningful improvement in various outcome measures with Tak+ADT over Bic+ADT in this representative population of mHSPC, the improvement in OS did not meet the pre-specified criteria for statistical significance. The median OS of 70 mos in the control arm (standard ADT) was higher than that reported in contemporary phase 3 trials in this setting, and 16 mos higher than originally estimated. This trial sets a new landmark for survival estimates when pts with mHSPC have access to multiple approved subsequent life-prolonging therapies. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820; U10CA180821; and in part by Millennium Pharmaceuticals, Inc. (Takeda Pharmaceutical Company LTD) Clinical trial information: NCT01809691. [Table: see text]

A Prospective Randomized Study of Rituximab and Dexamethasone vs Dexamethasone Alone in ITP.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 567-567 ◽  
Author(s):  
Francesco Zaja ◽  
Patrizio Mazza ◽  
Nicola Vianelli ◽  
Marzia De Fina ◽  
Vincenzo Liso ◽  
...  
Keyword(s):  
Demographic Data ◽  
Randomized Study ◽  
Complete Response ◽  
Primary Objective ◽  
Sustained Response ◽  
Phase Iii ◽  
Final Report ◽  
Entire Study ◽  
Intention To Treat ◽  
Grade 3

Abstract Previous uncontrolled studies have highlighted the potential activity of Rituximab in patients with idiopathic thrombocytopenic purpura (ITP) relapsed or refractory to standard treatments. To better address this effect, a prospective randomized, multicenter, phase III study comparing treatment with Dexamethasone alone (arm A) vs Dexamethasone plus Rituximab (arm B) was started in July 2005 for adult patients with ITP according to the ASH guidelines. Main inclusion criteria were: age ≥ 18 years, untreated ITP, platelet (PLT) count ≤ 20 x109/L, HIV- HCV-HbsAg negativity, informed consent. Patients randomized to arm A received a single course of Dexamethasone 40 mg po on days +1, +2, +3, +4, while patients randomized to arm B received Dexamethasone (as in arm A) in association with Rituximab 375 mg/m2 iv on days +7, +14, +21, +28. Patients in arm A who failed to achieve a sustained response (SR) could be rescued with arm B treatment. The primary objective of the study was to compare SR, i.e. PLT ≥ 50 x 109/L at month + 6 of treatment. The secondary objectives were: the initial overall (OR= PLT ≥ 50 x109/L) and complete response (CR= PLT ≥ 100 x 109/L) by day 30 after starting treatment, respectively; the toxic profile. The statistical plan considered three interim analyses, after the first 50, 100 and 150 enrolled patients, with an estimated sample size of 198 patients (99 per arm). Table 1 summarizes the main demographic data and the results of efficacy and toxicity according to an intention to treat analysis of the first interim analysis. The toxic profile was characterized by only grade 3 adverse events (AE); no patient died during the study period. 16 patients of arm A were rescued with arm B. For this group SR was 81% and no patient experienced SAE or ≥ grade 3 AE. In accordance with the initial statistical plan of the study, which stated that patients’ recruitment would ceased if a ≥ 50% difference in sustained response was demonstrated, enrolment has been stopped in June 2007 with a total number of 103 randomized patients. This preliminary report indicates a significantly higher SR for arm B of treatment with no difference in toxicity profile. A final report will be prepared when the results on the entire study group will be available. Table 1 Therapy Arm A Arm B Statistics Patients 24 26 Male/female 11/13 10/16 p = NS Age (median ± SD) 54.54 ± 18.78 48.65 ± 15.10 p = NS Initial OR 15 (62.5%) 18 (69%) p = NS Initial CR 10 (42%) 16 (61%) p = NS SR 7 (29%) 21 (81%) p = 0.0001 SAE or grade 3 AE 3 (12.5%) 2 (8%) p = NS

Thalidomide/Dexamethasone (TD) Vs. Bortezomib(Velcade®)/Thalidomide/Dexamethasone (VTD) Vs. VBMCP/VBAD/Velcade® As Induction Regimens Prior Autologous Stem Cell Transplantation (ASCT) in Younger Patients with Multiple Myeloma (MM): First Results of a Prospective Phase III PETHEMA/Gem Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 654-654 ◽  
Author(s):  
Laura Rosinol ◽  
M. Teresa Cibeira ◽  
Joaquin Martinez ◽  
Maria Victoria Mateos ◽  
Ma José Terol ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Induction Therapy ◽  
Statistical Significance ◽  
Phase Iii ◽  
Induction Phase ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Intention To Treat ◽  
The Difference ◽  
Grade 3

Abstract The benefit of ASCT in MM is associated with the degree of tumour decrease with the initial induction chemotherapy. In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing TD vs. VTD vs. VBMCP/VBAD/Velcade® in patients 65 years-old or younger with newly diagnosed symptomatic MM, followed by ASCT with MEL-200. The primary end points were response rate after induction and after ASCT and time to progression. TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1–4 and 9–12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus Velcade 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus Velcade® consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of Velcade® (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. Two-hundred and seventy-five out of the 390 planned patients have been included so far. As of February 15, 2008, 190 patients (median age: 57 yrs., M:96, F:94; IgG:107, IgA:50, light chain:25, others:9) entered the study. 32 (17%) patients had soft-tissue extramedullary plasmacytomas (EMP) and the stage according to the ISS classification was I in 38%, II in 41%, III in 20% and unknown in 1%. The prognostic factors, including cytogenetics, were similar in the 3 arms. The prognostic factors, including cytogenetics, were similar in the three arms. 173 patients (TD:61, VTD:54 and VBMCP/VBAD/Velcade:58) were already evaluable for response and toxicity to induction therapy. Efficacy and toxicity were assessed on an intention-to-treat basis. The ≥PR rate was 62%, 77% and 70% with TD, VTD and VBMCP/VBAD/Velcade®, respectively (p=NS). The IF negative CR rate was significantly higher with VTD (31%) and with VBMCP/VBAD/Velcade® (22%) compared to TD (6%) (p< 0.01). Progressive disease was significantly higher in patients with EMP (31% vs. 12%, p=0.01). This higher PD rate in patients with EMP was similar in the three arms. The incidence of grade 3 and 4 adverse events (AEs) was 38%, 54% and 50% with TD, VTD, and VBMCP/VBAD/Velcade® respectively. The total number of AEs for TD, VTD and VBMCP/VBAD/Velcade® were 37, 36 and 44, respectively. 13% of patients receiving TD developed ≥ grade 3 thrombotic events while 16% of patients in the VTD arm had grade ≥3 peripheral neuropathy. Treatment discontinuation due to toxicity was required in 8 patients (TD: 1; VTD: 5, VBMCP/VBAD: 2). 5 patients died during the induction phase (TD:3, VTD:0, VBMCP/VBAD/Velcade:2). 72 patients were evaluable for response after ASCT. The post-ASCT CR rate were higher with VTD (50%) and with VBMCP/VBAD/Velcade® (39%) compared to the TD arm (26%), although the difference did not reach statistical significance. Our preliminary analysis shows that VTD and VBCMP/VBAD plus Velcade® result in a higher CR rate than TD both before and after ASCT and that the toxicity in the three arms is not significantly different. Longer follow-up is needed to establish whether or not this higher tumour reduction is translated into a significant better long-term outcome. Updated results will be presented at the meeting.

A Phase III PETHEMA/GEM Study of Induction Therapy Prior Autologous Stem Cell Transplantation (ASCT) In Multiple Myeloma: Superiority of VTD (Bortezomib/Thalidomide/Dexamethasone) Over TD and VBMCP/VBAD Plus Bortezomib

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 307-307 ◽  
Author(s):  
Laura Rosiñol ◽  
María Teresa Cibeira ◽  
Maria Victoria Mateos ◽  
Joaquin Martinez ◽  
Albert Oriol ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Therapy ◽  
Research Funding ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Advisory Committees ◽  
Intention To Treat ◽  
Grade 3

Abstract Abstract 307 Introduction: In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing TD vs. VTD vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM followed by ASCT with MEL-200. Primary end points: response rate after induction and after ASCT and time to progression. Patients and Method: TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1–4 and 9–12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus bortezomib 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus bortezomib consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of bortezomib (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. From April 6, 2006 to August 5, 2009 the 390 planned patients entered the study. Four patients failed the eligibility criteria. 386 patients (median age: 56 yrs; M: 207, F: 179; IgG: 233, IgA: 85, light chain: 57, IgD: 9, Ig M: 2) were analyzed. The stage according to the ISS was I in 147 patients, II in 160, III in 75 and unknown in 4 and 66 patients (17%) had extramedullary soft-tissue plasmacytomas (EMP). Seventy out of the 330 patients (21%) with cytogenetic studies had high-risk cytogenetics (t(4;14), t(14;16), and/or 17p deletion). One-hundred and thirty patients were allocated to VTD, 127 to TD and 129 to VBMCP/VBAD/B. Prognostic factors, including cytogenetics, were similar in the 3 arms. Response, survival and toxicity were evaluated on an intention-to-treat basis. Responses reported by investigators were centrally reassessed. Result: The IFE negative CR rate was significantly higher with VTD (35%) compared to TD (14%) and VBMCP/VBAD/B (22%) (p=0.0001 and p=0.01, respectively). The progressive disease (PD) rate during induction was significantly lower with VTD than with TD (7% vs. 23%, p=0.001). In patiens with high-risk cytogenetics, the CR rate was significantly greater with VTD when compared with TD (35% vs. 0%, p=0.002) and with VBMCP/VBAD/B (35% vs. 22%, p=0.02). The CR rate to VTD in patients with 17p deletion was 58% while none of the patients with this cytogenetic abnormality responded to TD or to VBMVP/VBAD/B (p=0.03 and p=0.02, respectively). Of interest, the CR rate in patients with t(11;14) was significantly lower than in patients lacking this abnormality (11% vs. 27%, p=0.01). This low CR rate in patients with t(11;14) was similar in the 3 arms. In the overall series, PD was significantly higher in patients with EMP (24% vs. 11%, p=0.01) with a significantly higher PD rate for TD as compared to VTD (40% vs. 12%, p=0.02). The incidence of thrombotic events was 2%, 6% and 5% for VTD, TD and VBMCP/VBAD/B, respectively (p=NS). The frequency of grade ≥ 3 peripheral neuropathy was 12% with VTD compared to 1% in both the TD and the VBMCP/VBAD/B arms (p= 0.0002). Treatment was discontinued due to toxicity en 16 patients (VTD:9, TD:4, VBMCP/VBAD/B:3). Nine patients died during the induction period (3 in each arm). On an intention to treat basis, the post-ASCT CR rate was higher in the VTD arm compared with TD (46% vs. 24%, p=0.004) and VBMCP/VBAD/B (46% vs. 38%, p=0.1). The estimated overall survival (OS) at 4 years was 76% with no significant differences among the 3 arms. After a median follow-up of 27 months, the progression-free survival (PFS) was not reached with VTD while it was 27 and 38 months with TD and VBMCP/VBAD/B, respectively (p=0.006). In the overall series, patients with high-risk cytogenetics had a significantly shorter OS (p=0.00007) and PFS (p=0.004). In addition, when compared with the good-risk group, patients with high-risk cytogenetics showed a trend towards a shorter PFS either after induction with VTD (median not reached vs. 17 months, p=0.05) and with TD (median 28 vs. 15 months, p=0.09). Conclusion: Induction with VTD resulted in a significantly higher CR rate in both the overall series and in patients with high-risk cytogenetics. The post-ASCT CR rate was also significantly higher with VTD than with TD and there was a trend when compared with VBMCP/VBAD/B. Finally, VTD resulted in a significantly longer PFS. However, longer follow-up is required to establish whether or not VTD will overcome the poor prognosis of patients with high-risk cytogenetics. Disclosures: Rosiñol: Janssen-Cilag: Honoraria; Celgene: Honoraria. Off Label Use: Bortezomib and Thalidomide are not approve for first line in Spain. Cibeira:Janssen-Cilag: Honoraria; Celgene: Honoraria. Mateos:Janssen-Cilag: Honoraria; Celgene: Honoraria. Oriol:Janssen-Cilag: Honoraria; Celgene: Honoraria. García-Laraña:Janssen-Cilag: Honoraria; Celgene: Honoraria. De La Rubia:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sureda:Janssen-Cilag: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen-Cilag: Honoraria. Alegre:Janssen-Cilag: Honoraria; Celgene: Honoraria. Lahuerta:Janssen-Cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria, Speakers Bureau. Blade:Janssen-Cilag: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

A Phase III PETHEMA/GEM Randomized Trial of Postransplant (ASCT) Maintenance in Multiple Myeloma: Superiority of Bortezomib/Thalidomide Compared with Thalidomide and Alfa-2b Interferon,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3962-3962 ◽  
Author(s):  
Laura Rosiñol ◽  
María Teresa Cibeira ◽  
Maria Victoria Mateos ◽  
Joaquin Martinez ◽  
Albert Oriol ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Single Agent ◽  
Phase Iii ◽  
Hematological Toxicity ◽  
Advisory Committees ◽  
Intention To Treat ◽  
Maintenance Program ◽  
Response Status ◽  
Grade 3

Abstract Abstract 3962 Introduction: In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing induction with TD vs. VTD vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM and ASCT with MEL-200 followed by maintenance with thalidomide/bortezomib (TV) vs. thalidomide (T) vs. alfa-2b-interferon (alfa2-IFN). Primary end points : response rate after induction and after ASCT and time to progression. Patients and Methods: The maintenance program consisted of TV (thalidomide 100 mg daily plus one cycle of bortezomib-1.3 mg/m2 on days 1, 4, 8 and 11 every 3 months) versus T (single agent thalidomide at a dose of 100 mg daily) versus alfa2-IFN (subcutaneous alfa2b-IFN at a dose of 3 MU three times per week). The planned maintenance duration was three years or until disease progression or toxicity. From February 1, 2007 to January 27, 2011 266 patients were randomized to maintenance therapy (TV:90; T: 89, alfa2-IFN: 87). Response and survival were evaluated on an intention-to-treat basis. Responses and progressions reported by the investigators were centrally reassessed. Results: the patient's characteristics at diagnosis such as age, ISS stage, cytogenetics and presence of extramedullary plasmacytomas as well as induction regimen (VTD, TD and VBMCP/VBAD/Bortezomib) and diagnosis-randomization interval were similarly distributed among the 3 arms. The response status at the time of randomization after ASCT was CR: 51%, VGPR: 23%, PR: 24% and SD: 2% and was well balanced in the three groups. The CR rate with maintenance was improved by 23% with TV, 11% with T and 19% with alfa2-IFN (p=NS). After a median follow-up of 24 months, the PFS was significantly longer with TV compared with T and alfa2-IFN (PFS at 2 yrs: 78% vs. 63% vs. 49%, p=0.01). However, OS was not significantly different among the 3 arms. Grade 3 and 4 hematological toxicity was similar (22.2% vs. 16% vs. 21.8%). No peripheral neuropathy (PN) was observed with alfa2-IFN being its frequency similar with TV (12.2%) and T (10.1%). No grade IV PN was observed. Dose reductions for TV, T and alfa2-IFN were required in 33.3%, 33.7% and 19.5% of the patients, respectively. The discontinuation rate due to toxicity was significantly higher with thalidomide compared with TV (30.3% vs. 15.6%, p= 0.08) and with alfa2-IFN (30.3% vs. 18.3%, p= 0.17). Conclusion: the addition of bortezomib to thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide alone or with IFN with no increased toxicity. Disclosures: Rosiñol: Janssen: Honoraria; Celgene: Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria. Martinez:Janssen: Honoraria; Celgene: Honoraria. de la Rubia:Janssen: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Blade:Janssen: Honoraria; Celgene: Honoraria.

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