RAMucirumab in combination with TAS102 versus TAS102 monotherapy in metastatic colorectal cancer: Safety results from the phase IIb part of the RAMTAS phase II/III trial of the German AIO (AIO-KRK-0316).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3566-3566
Author(s):  
Stefan Kasper ◽  
Thorsten Oliver Goetze ◽  
Sebastian Stintzing ◽  
Ralf Dieter Hofheinz ◽  
Marianne Sinn ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Fatal Outcome ◽  
Safety Analysis ◽  
Phase Iii ◽  
Open Label ◽  
Efficient Treatment ◽  
Phase Iii Study ◽  
Trial Endpoints ◽  
Grade 3 ◽  
A Minor

3566 Background: Patients (pts) with mCRC progressing on standard chemotherapy have limited therapeutic options. Trifluridine/tipiracil (TAS102) significantly improved survival in patients with refractory mCRC. Ramucirumab (ram) is approved in combination with FOLFIRI for second-line treatment. There is a strong rationale to evaluate the efficacy and safety of ram in combination with TAS102 in pts with refractory mCRC. Methods: This is a randomized, open-label, multicenter, starting as phase IIb and extended to a phase III study in pts with advanced mCRC. Eligible pts were randomized to receive either ram (8 mg/kg on d1+15, q4w) and TAS102 (35 mg/m² on d1-5 and d8-12, q4w, arm A) or TAS102 alone (arm B). The primary endpoint is overall survival. A total of 145 pts were enrolled into phase IIb. Here, we present the data from an interim safety analysis comprising the first 80 treated pts. The trial was extended to phase III including a total of 426 pts. Enrolment of additional 281 pts started in Dec 2020. The trial endpoints remained unchanged. Results: Pts (40 arm A, 40 arm B) received a median of 2.5 treatment cycles in arm A and 2 cycles in arm B; 31 pts in treatment arm A and 32 pts in arm B discontinued participation prematurely, mainly due to cancer progression. Most patients developed adverse events (AEs): grade 3 AEs were observed in 28 pts (70%) in arm A (24 treatment-related) and 27 pts (67%, 17 treatment-related) in arm B. More grade 4 AEs were seen in arm A (13 pts, 32.5%) than in arm B (5 pts, 12.5%). In total, 46 Serious AEs (SAEs) occurred, 27 in arm A (10 treatment-related) and 19 in Arm B (2 treatment-related). Five SAEs (3 in arm A, 2 in arm B) had a fatal outcome (one in arm A treatment-related). Within the analyzed population, no SUSAR occurred. Conclusions: This safety analysis demonstrates a minor increase in AEs in the experimental arm but no unexpected events. There were no excessive toxicity or unacceptable risks. In summary, a favorable risk-benefit-profile was confirmed. Based on these safety results and the ongoing need for efficient treatment in the tested population, the trial was extended to phase III. Clinical trial information: NCT03520946.

Open-Label, Multicenter, Randomized, Phase III Study Comparing Oral Topotecan/Cisplatin Versus Etoposide/Cisplatin As Treatment for Chemotherapy-Naive Patients With Extensive-Disease Small-Cell Lung Cancer

2006 ◽  
Vol 24 (13) ◽  
pp. 2044-2051 ◽  
Author(s):  
John R. Eckardt ◽  
Joachim von Pawel ◽  
Zsolt Papai ◽  
Antoaneta Tomova ◽  
Valentina Tzekova ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Open Label ◽  
Extensive Disease ◽  
Phase Iii Study ◽  
Grade 3 ◽  
Oral Topotecan

Purpose This open-label, randomized, multicenter phase III study compared oral topotecan/intravenous cisplatin (TC) with intravenous (IV) etoposide/cisplatin (PE) in patients with untreated extensive-disease small-cell lung cancer (ED-SCLC). Patients and Methods A total of 784 patients were randomly assigned to either oral topotecan 1.7 mg/m2/d × 5 with IV cisplatin 60 mg/m2 on day 5 (n = 389) or IV etoposide 100 mg/m2/d × 3 with IV cisplatin 80 mg/m2 on day 1 (n = 395) every 21 days. Results Overall survival (primary end point) was similar between groups (P = .48; median: TC, 39.3 weeks v PE, 40.3 weeks). One-year survival was 31% (95% CI, 27% to 36%) in both groups and the difference of −0.03 (95% CI, −6.53 to 6.47) met the predefined criteria of ≤ 10% absolute difference for noninferiority of TC relative to PE. Response rates were similar between groups (TC, 63% v PE, 69%). Time to progression was slightly but statistically longer with PE (log-rank P = .02; median: TC, 24.1 weeks v PE, 25.1 weeks). The regimens were similarly tolerable. Grade 3/4 neutropenia occurred more frequently with PE (84% v 59%), whereas grade 3/4 anemia and thrombocytopenia occurred more frequently with TC (38% v 21% and 38% v 23%, respectively). Lung Cancer Symptom Scale scores were statistically better with PE, but the differences were small and of debatable clinical significance. Conclusion Oral topotecan with cisplatin provides similar efficacy and tolerability to the standard (etoposide with cisplatin) in untreated ED-SCLC and may provide greater patient convenience compared with intravenous etoposide and cisplatin.

Phase III, randomized, open-label study of triweekly docetaxel versus biweekly docetaxel as treatments for advanced hormone-refractory prostate cancer: Findings from an interim safety analysis of the Finnish Uro-oncological Group Study 1-2003.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 129-129
Author(s):  
P. Hervonen ◽  
H. Joensuu ◽  
T. K. Joensuu ◽  
P. Nyandoto ◽  
M. Luukkaa ◽  
...  
Keyword(s):  
Adverse Events ◽  
Performance Status ◽  
Safety Analysis ◽  
Similar Efficacy ◽  
Multicenter Trial ◽  
Phase Iii ◽  
Open Label ◽  
Serious Adverse Events ◽  
Hormone Refractory ◽  
Grade 3

129 Background: Docetaxel (T) administered at every three weeks is standard treatment for advanced HRPC. We compared 2-weekly to 3-weekly T as first- or second-line chemotherapy of advanced HRPC in this prospective randomized multicenter trial. Methods: 360 pts were randomly allocated to receive T 75 mg/m2 i.v. d1 q3 wks (tT) or 50 mg/m2 i.v. d1 and d 14, q4 wks (bT) from March 2004 to May 2009. Prednisolon 10 mg/day was administered in both groups. The groups were well balanced according to the WHO performance status, mean age (70 vs. 68, range 45–87), and the median serum PSA level at study entry (109 vs. 98 μ g/L, range 11–1,490). The primary endpoint was TTF. Study identifier: NCT00255606 . Results: 158 pts (tT, 79; bT, 79) were included in this preplanned interim safety analysis. 567 and 487 cycles were administered in the tT and bT groups, respectively. The most common grade 3–4 adverse events (expressed as %/cycles) in tT /bT were neutropenia 20%/14%, infection with/without neutropenia 8%/3%, fatigue 3%/ 3%, febrile neutropenia 2%/1%, and bone pain 2%/1%. Serious adverse events occurred more frequently in tT (n=60, 10.6% of cycles) than in bT (n=29, 6.0%, p=0.012). One pt. died from coronary infarction and one was diagnosed with ALL (both in bT group). 30 pts (38%) in bT group and 22 pts (28%) in tT group were receiving treatment at 6 months. (p=0.176). Conclusions: Biweekly T has been better tolerated than the conventional triweekly T with fewer serious adverse events and may be associated with similar efficacy. [Table: see text]

Randomized, Open-Label, Phase III Study of a 28-Day Oral Regimen of Eniluracil Plus Fluorouracil Versus Intravenous Fluorouracil Plus Leucovorin as First-Line Therapy in Patients With Metastatic/Advanced Colorectal Cancer

2002 ◽  
Vol 20 (6) ◽  
pp. 1519-1526 ◽  
Author(s):  
Richard L. Schilsky ◽  
Jeremey Levin ◽  
William H. West ◽  
Alfred Wong ◽  
Bruce Colwell ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Phase Iii ◽  
First Line ◽  
Open Label ◽  
First Line Therapy ◽  
Line Therapy ◽  
Open Label Phase ◽  
Phase Iii Study ◽  
Grade 3

PURPOSE: To compare the efficacy and tolerability of eniluracil (EU)/fluorouracil (5-FU) with that of 5-FU/leucovorin (LV) as first-line therapy for patients with metastatic/advanced colorectal cancer. PATIENTS AND METHODS: This multicenter, randomized, open-label, phase III study (FUMA3008) conducted in the United States and Canada compared the safety and efficacy of EU/5-FU (11.5 mg/m2/1.15 mg/m2 twice daily for 28 days every 35 days) with that of intravenous 5-FU/LV (425 mg/m2/20 mg/m2 once daily for 5 days every 28 days) in patients with previously untreated metastatic colorectal cancer. Overall survival (OS) was the primary end point. RESULTS: A total of 981 patients were randomized and 964 patients received treatment (485 EU/5FU, 479 5FU/LV). Survival for EU/5-FU was not statistically equivalent (but not statistically inferior) to that for 5-FU/LV (hazard ratio, 0.880; 95% confidence interval [CI], 0.75 to 1.03). Median duration of survival was 13.3 months in the EU/5-FU group and 14.5 months in the 5-FU/LV group. Median duration of progression-free survival for EU/5-FU was statistically inferior to that of the control group (20.0 weeks [95% CI, 19.1 to 20.9 weeks] v 22.7 weeks [95% CI, 18.3 to 24.6 weeks]; P = .01). Both treatments were well tolerated. Diarrhea was the most common nonhematologic toxicity in both groups; treatment-related grade 3 or 4 diarrhea occurred in 19% of patients treated with EU/5-FU and 16% of patients receiving 5-FU/LV (P = .354). Grade 3 or 4 granulocytopenia occurred in 5% of EU/5-FU patients and 47% of 5-FU/LV patients. CONCLUSION: Safety profiles of both treatments were acceptable. Although antitumor activity was observed, EU/5-FU did not meet the protocol-specified statistical criteria for equivalence to 5-FU/LV in terms of OS.

Randomized Phase III Study of Irinotecan Plus Cisplatin Versus Etoposide Plus Cisplatin for Completely Resected High-Grade Neuroendocrine Carcinoma of the Lung: JCOG1205/1206

2020 ◽  
Vol 38 (36) ◽  
pp. 4292-4301
Author(s):  
Hirotsugu Kenmotsu ◽  
Seiji Niho ◽  
Masahiro Tsuboi ◽  
Masashi Wakabayashi ◽  
Genichiro Ishii ◽  
...  
Keyword(s):  
Neuroendocrine Carcinoma ◽  
Stage I ◽  
Phase Iii ◽  
High Grade ◽  
Open Label ◽  
Intention To Treat ◽  
Open Label Phase ◽  
Phase Iii Study ◽  
Grade 3 ◽  
Resected Stage

PURPOSE To verify the superiority of irinotecan plus cisplatin over etoposide plus cisplatin as postoperative adjuvant chemotherapy for patients with pathologic stage I-IIIA, completely resected, high-grade neuroendocrine carcinoma (HGNEC) of the lung. METHODS This was a randomized, open-label, phase III study on patients with completely resected stage I-IIIA HGNEC of the lung. They were randomly assigned to receive either etoposide (100 mg/m2, days 1-3) plus cisplatin (80 mg/m2, day 1) or irinotecan (60 mg/m2, days 1, 8, 15) plus cisplatin (60 mg/m2, day 1) up to four cycles. The primary end point was relapse-free survival (RFS) in the intention-to-treat population. This trial was registered with the Japan Registry of Clinical Trials (jRCTs031180216). RESULTS Between April 2013 and October 2018, 221 patients were enrolled (etoposide plus cisplatin arm, 111 patients; irinotecan plus cisplatin arm, 110 patients). In the second interim analysis, early termination of the trial was recommended because of futility. At a median follow-up of 24.1 months, the 3-year RFS was 65.4% for etoposide plus cisplatin and 69.0% for irinotecan plus cisplatin, with a hazard ratio of 1.076 (95% CI, 0.666 to 1.738; one-sided log-rank P = .619). Grade 3-4 adverse events were more frequent in the etoposide plus cisplatin arm, with febrile neutropenia (20% of 109 patients v 4% of 107 patients) and neutropenia (97% v 36%) being the most common. Meanwhile, grade 3-4 anorexia (6% v 11%) and diarrhea (1% v 8%) were more frequently observed in the irinotecan plus cisplatin arm. CONCLUSION Irinotecan plus cisplatin is not superior to etoposide plus cisplatin for improving RFS in patients with completely resected HGNEC; thus, etoposide plus cisplatin remains the standard treatment.

A randomized, double-blind phase III study (VEG105192) of pazopanib (paz) versus placebo (pbo) in patients with advanced/metastatic renal cell carcinoma (mRCC): Updated safety results.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 313-313 ◽  
Author(s):  
C. N. Sternberg ◽  
R. E. Hawkins ◽  
C. Szczylik ◽  
I. D. Davis ◽  
J. Wagstaff ◽  
...  
Keyword(s):  
Failure Time ◽  
Myocardial Dysfunction ◽  
Safety Data ◽  
Phase Iii ◽  
Cumulative Exposure ◽  
Open Label ◽  
Double Blind ◽  
Hand Foot Syndrome ◽  
Phase Iii Study ◽  
Grade 3

313 Background: This study evaluated the efficacy and safety of paz in 435 pts with mRCC. The primary endpoint of PFS with paz vs pbo was met with a median PFS of 9.2 vs. 4.2 mo (HR 0.46; p<0.0001) respectively. Final OS was 22.9 mos in paz arm vs. 20.5 mos in pbo (HR 0.91; p=0.224); however, OS was confounded by extensive crossover of pbo pts to paz and other therapies. Two independent analyses to adjust for crossover, IPCW (Inverse Probability of Censoring Weighted) and RPSFT (Rank Preserving Structural Failure Time) suggest an OS benefit with paz;HR 0.504; p=0.002 by IPCW and HR 0.43; p=0.172 by RPFST. At the final OS analysis, pts on the paz arm had a 30% increase or in absolute terms 70 yrs (303.7 yrs from 233.5 yrs) in cumulative exposure since analysis 2 yrs ago (Sternberg; JCO 2010). Updated safety data is reported. Methods: Pts with clear cell mRCC and measurable disease with no prior treatment or 1 prior cytokine-based trt were randomized (2:1) to paz 800 mg QD or pbo and treated until progression (PD), death, or unacceptable toxicity. Upon PD, pts on the pbo arm could receive paz through a parallel open-label study. Results: Median exposure duration was nearly doubled in the paz arm vs. pbo (7.4 mo vs. 3.8 mo). In the paz arm, 32% of subjects remained on treatment > than 12 mos, 15% for > 24 mos and 8% for > 36 mos. The mean daily dose of paz was 679 mg. ALT elevations >3xULN occurred in 54 pts; upon interruption of paz, or with continuation (adaptation), 85% of pts had documented recovery, 9% no recovery data and 6% not recovered. Further details regarding these and less frequent class effect AEs such as hand-foot syndrome (6%), myocardial dysfunction (<1%) will be reported. Conclusions: This safety update reflects a 30% increase in the cumulative exposure to paz since the previous clinical cutoff. There are no significant changes to the type, frequency or severity of AEs and no differences in grade 3, 4, or 5 AEs. No new safety signals have been detected. [Table: see text] [Table: see text]

scholarly journals Randomized, open-label, multicenter, phase III study of eribulin versus dacarbazine in patients (pts) with leiomyosarcoma (LMS) and adipocytic sarcoma (ADI).

2015 ◽  
Vol 33 (18_suppl) ◽  
pp. LBA10502-LBA10502 ◽  
Author(s):  
Patrick Schöffski ◽  
Robert G. Maki ◽  
Antoine Italiano ◽  
Hans Gelderblom ◽  
Giovanni Grignani ◽  
...  
Keyword(s):  
Sensory Neuropathy ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Phase Iii ◽  
Open Label ◽  
Treatment Regimens ◽  
Secondary Endpoints ◽  
Phase Iii Study ◽  
Grade 3 ◽  
Peripheral Sensory

LBA10502 Background: In a phase II study of pts with advanced soft tissue sarcoma, 32% and 47% of pts with LMS and ADI respectively, treated with the microtubule dynamics inhibitor eribulin achieved progression-free survival (PFS) at the 12 wk timepoint (Schöffski et al. Lancet Oncol. 2011; NCT00413192). Based on these findings, this phase III study (NCT01327885) compared overall survival (OS) in pts with advanced LMS and ADI treated with eribulin or dacarbazine. Methods: Pts aged ≥ 18 yrs with advanced high/intermediate grade LMS or dedifferentiated, myxoid, round cell or pleomorphic variants of ADI incurable by surgery and/or radiotherapy were enrolled. Pts had ECOG status ≤ 2 and had received ≥ 2 standard systemic treatment regimens including an anthracycline. Pts were randomized 1:1 to eribulin (1.4 mg/m2, IV on D1 and D8) or dacarbazine (850–1200 mg/m2, IV on D1) every 21 days until disease progression. Primary endpoint was OS. Secondary endpoints included PFS, PFS rate at Wk 12 and safety. Results: Overall, 452 pts (67% female; 79% < 65 yrs) were randomized (228 eribulin; 224 dacarbazine). Median OS for eribulin and dacarbazine was 13.5 and 11.5 months, respectively (HR = 0.768, 95% CI 0.618–0.954; P= 0.017). PFS was 2.6 months in both arms (HR = 0.877, 95% CI 0.710–1.085; P= 0.229). PFS rate at Wk 12 was 33% and 29% for eribulin and dacarbazine, respectively. In eribulin and dacarbazine arms, respectively, 26% and 14% of pts required dose reductions and 8% and 5% discontinued due to treatment-emergent adverse events (TEAEs). TEAEs were more frequent in eribulin than dacarbazine arm, including neutropenia (44% vs 24%), pyrexia (28% vs 14%), peripheral sensory neuropathy (20% vs 4%) and alopecia (35% vs. 3%); as were TEAEs of grade 3 (63% vs 53%), grade 4 (26% vs 20%), and fatal TEAEs (4% vs 1%). Thrombocytopenia was more frequent in dacarbazine than eribulin arm (28% vs 6%). Conclusions: This phase III trial of eribulin trial met its primary objective of OS benefit in pretreated pts with advanced LMS or ADI. Eribulin had a toxicity profile consistent with prior experience, with no unexpected or new safety findings. Funding Source: Eisai Inc. Clinical trial information: NCT01327885.

Safety, Efficacy, and Pharmacokinetic Profiles of Intravenous Rigosertib in Japanese Patients with Recurrent/Relapsed or Refractory Myelodysplastic Syndromes: A Multicenter, Open-Label Phase I Clinical Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5549-5549
Author(s):  
Michinori Ogura ◽  
Yukio Kobayashi ◽  
Shiro Kubonishi ◽  
Michihiro Hidaka ◽  
Toshiki Uchida ◽  
...  
Keyword(s):  
Phase I ◽  
Research Funding ◽  
Japanese Patients ◽  
Cytogenetic Response ◽  
Phase Iii ◽  
Open Label ◽  
Open Label Phase ◽  
Phase Iii Study ◽  
Grade 3 ◽  
The U.S

Abstract Background and Objectives: Rigosertib, a novel phosphoinositide 3/polo-like kinase pathway inhibitor, promotes G2/M arrest, selectively induces the apoptosis of cancer cells, and has no impact on normal cells. A Phase I/II study in the U.S. showed that rigosertib was safe and well tolerated in patients (pts) with myelodysplastic syndromes (MDS) or acute myeloid leukemia relapsed after or refractory to treatment with hypomethylating agents. A multicenter, open-label Phase I dose-finding study of rigosertib was conducted to evaluate the safety and preliminary efficacy, and to determine the recommended dose for a Phase II study in Japanese patients with recurrent/relapsed or refractory MDS. Patients and Methods: The key eligibility criteria were as follows: patients withrecurrent/relapsed or refractory MDS; FAB classifications (RA, RARS, RAEB, RABE-t, and CMML), excepting patients at IPSS low- or Int-1 risk with respect to RA; aged 20 years or older, ECOG PS of 0 to 2, no major organ dysfunctions, and written informed consent. Rigosertib (1,200 and 1,800 mg daily) was administered intravenously in one 14-day cycle that consisted of continuous intravenous administration for 72 hours followed by monitoring for 14 days. In principle, intravenous rigosertib was administered in up to cycle 8. The primary endpoint was the dose-limiting toxicity (DLT) in each cohort. The secondary endpoints were as follows: 1) safety as assessed with adverse events (AEs) and laboratory results; 2) the hematological remission rate, the hematological improvement rate, and the cytogenetic response rate¾all of which were assessed according to the International Working Group 2006 criteria; and 3) pharmacokinetics. Results: Between June 2012 and February 2015, a total of 9 pts with a median age of 70 (range: 63 to 84) years and with a 7/2 ratio of male/female were enrolled from 5 medical institutions in Japan, and 3 and 6 pts were eventually assigned to the 1,200 and 1,800 mg cohorts, respectively. According to the FAB classification, 6, 2, and 1 pts were categorized to RAEB, RAEB-t, and RA, respectively. There were 3 pts each in the IPSS Int-1, Int-2, and high-risk risk groups, with 1 and 2 pts in each risk group in the 1,200 and 1,800 mg cohorts, respectively. The median numbers of delivered cycles in the 1,200 and 1,800 mg cohorts were 4 (2 to 4) and 2 (1 to 8), respectively. The median relative dose intensity (RDI) in the 1,200 and 1,800 mg cohorts was 100% (98.2 to 100.0%) and 79% (55.6-100%), respectively; lower RDI in the 1,800 mg cohort was caused by dose delay in the next treatment due to toxicities. A total of 169 AEs developed. The most frequently observed grade 4 hematologic toxicities included neutropenia (3/9, 33%), thrombocytopenia (3/9, 33%), and leukopenia (3/9, 33%). Grade 3 or greater non-hematologic toxicities included grade 4 meningitis (1/9, 11%), grade 4 sepsis (1/9, 11%), grade 3 catheter-related infections (2/9, 22%), grade 3 hyponatremia (2/9, 22%), and grade 3 anorexia (2/9, 22%). DLT was not observed in the 1,200 mg cohort, while 2 pts in the 1,800 mg cohort had 5 DLTs (sepsis and meningitis in one pt, as well as hyponatremia, pustular rash, and hypochloremia in the other pt). Three serious AEs, including grade 4 meningitis, grade 4 sepsis, and grade 3 catheter-related infection, developed in the 1,800 mg cohort. No death occurred during the study period. Stable disease was obtained in 2 pts in the 1,800 mg cohort. Any hematological remission, hematological improvement, and cytogenetic response were not obtained in the two cohorts. In the 1,200 mg cohort, maximum plasma concentration (Cmax) was 5.99 ± 1.50 μg/mL (mean ± SD), and the area under the concentration-time curve (AUC0-∞) was 314.6 ± 142.7 μgŸ・hr/mL. In the 1,800 mg cohort, the Cmax was 6.74 ± 2.39 μg/mL, and the AUC0-∞ was 324.8 ± 83.9 μgŸ・hr/mL. The urinary excretion rates of rigosertib in the 1,200 and 1,800 mg cohorts were 12.7 ± 6.6% and 16.2 ± 4.7%, respectively. Conclusions: This Phase I study showed that intravenous rigosertib of 1,800 mg daily for 72 hours was well tolerated, although remarkable efficacy was not observed. The recommended dose for Japanese patients was determined to be 1,800 mg daily for 3 consecutive days as with a Phase III study in the U.S. Based on these data, Japanese MDS patients started to participate in a global randomized Phase III study to compare rigosertib vs. physicians' choice of treatment. Disclosures Ogura: SymBio Pharmaceuticals: Consultancy, Honoraria; Celltrion, Inc.: Consultancy, Honoraria. Kobayashi:Ariad: Research Funding; Ohtsuka Pharmaceutical: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; SymBio Pharmaceuticals: Research Funding. Kubonishi:SymBio Pharmaceuticals: Research Funding. Hidaka:SymBio Pharmaceuticals: Research Funding. Uchida:SymBio Pharmaceuticals: Research Funding. Takamatsu:SymBio Pharmaceuticals: Research Funding.

GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma.

2015 ◽  
Vol 33 (18_suppl) ◽  
pp. LBA8502-LBA8502 ◽  
Author(s):  
Laurie Helen Sehn ◽  
Neil Sun Chua ◽  
Jiri Mayer ◽  
Gregory Scott Dueck ◽  
Marek Trněný ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Response Duration ◽  
Observation Time ◽  
Phase Iii ◽  
Open Label ◽  
Open Label Study ◽  
Non Hodgkin Lymphoma ◽  
Phase Iii Study ◽  
Grade 3 ◽  
To Receive

LBA8502 Background: Treatments are limited and outcomes poor in rituximab-refractory (Rit-Ref) iNHL. Bendamustine (B) has a 9 mo median PFS and 10 mo response duration in ph II trials. Obinutuzumab (GA101/Gazyva [G]) is a glycoengineered type II aCD20 mAb with activity and acceptable safety in Rit-Ref NHL. Methods: GADOLIN (NCT01059630) is a ph III open label study in pts with CD20+ Rit-Ref iNHL. In the B arm, pts received B 120 mg/m2 (d1+2, c1–6) alone; GB arm pts received B 90 mg/m2 (d1+2, c1–6) with G 1000 mg (d1, 8, 15 c1, d1 c2–6) for up to six 28d cycles. Non-PD GB pts then received G monotherapy every 2 mo for up to 2 yrs. Primary endpoint was PFS assessed by an independent radiology facility (IRF), with 80% power to detect 43% improvement in median PFS. Results: In the protocol specified interim analysis, 396 pts were randomized to receive B (n = 202 [198 treated]) or GB (n = 194). The IDMC recommended to unblind the study as the primary endpoint had been reached (4 Feb 2015). Baseline characteristics were balanced between arms. Median age was 63 yrs and pts had a median of 2 prior therapies. Median observation time was 20 mo (B) and 22 mo (GB). IRF-assessed median PFS was 14.9 mo (B) and not reached (NR) for GB (HR 0.55, 95% CI 0.4–0.74; p = 0.00011). Median investigator-assessed PFS was 14 mo for B and 29 mo for GB (HR 0.52, 95% CI 0.39–0.70; p < 0.0001). There were no significant differences in IRF-assessed ORR (63.0% B vs 69.1% GB) or CR (12.2% B vs 11.2% GB) at end of induction, in IRF-assessed best overall response up to 12 mo from start of treatment (76.6% B vs 78.6% GB), or in preliminary OS (median OS NR in either arm). In the treatment period, there were fewer Grade ≥ 3 adverse events with B than GB (62.1% B vs 68% GB), notably neutropenia (26.3% B vs 33.0% GB) and infusion-related reactions (3.5% B vs 8.8% GB), but more Grade ≥ 3 thrombocytopenia (16.2% B vs 10.8% GB), anemia (10.1% B vs 7.7% GB) and pneumonia (5.6% B vs 2.6% GB). Conclusions: G combined with B (90 mg/m2) followed by G maintenance significantly improved PFS vs B alone (120 mg/m2) in Rit-Ref iNHL. The clinically meaningful PFS improvement with GB is the first randomized evidence of benefit for a novel aCD20 mAb in Rit-Ref iNHL. Clinical trial information: NCT01059630.

Sign in / Sign up

Export Citation Format

Share Document