Final Results of Phase III SYMMETRY Study: Randomized, Double-Blind Trial of Elesclomol Plus Paclitaxel Versus Paclitaxel Alone As Treatment for Chemotherapy-Naive Patients With Advanced Melanoma

2013 ◽  
Vol 31 (9) ◽  
pp. 1211-1218 ◽  
Author(s):  
Steven J. O'Day ◽  
Alexander M.M. Eggermont ◽  
Vanna Chiarion-Sileni ◽  
Richard Kefford ◽  
Jean Jacques Grob ◽  
...  
Keyword(s):  
Survival Data ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Phase Iii ◽  
Double Blind ◽  
Free Survival ◽  
End Point ◽  
Phase Iii Study ◽  
Induced Apoptosis

Purpose Elesclomol, an investigational first-in-class compound, induces oxidative stress, triggers mitochondrial-induced apoptosis in cancer cells, and shows synergy with taxanes in tumor models. Following completion of a phase II trial of elesclomol in combination with paclitaxel that met its primary end point of progression-free survival (PFS), this randomized, double-blind, controlled phase III study was conducted to confirm the efficacy and tolerability of elesclomol in combination with paclitaxel versus paclitaxel alone in patients with advanced melanoma. Patients and Methods Patients with stage IV chemotherapy-naive melanoma (n = 651) were randomly assigned 1:1 to paclitaxel 80 mg/m2 either alone or in combination with elesclomol 213 mg/m2 administered weekly for 3 weeks of a 4-week cycle. Patients were stratified by prior systemic treatment, M1 subclass, and baseline lactate dehydrogenase (LDH) levels. The primary end point was PFS. Results The study did not achieve its PFS end point (hazard ratio, 0.89; P = .23). The study was stopped when an early overall survival data analysis indicated an imbalance in total deaths favoring paclitaxel, predominantly in patients with high LDH levels. A prospectively defined subgroup analysis revealed a statistically significant improvement in median PFS for the combination in patients with normal baseline LDH. Conclusion The addition of elesclomol to paclitaxel did not significantly improve PFS in unselected patients with advanced melanoma. The association between baseline LDH and clinical outcomes suggests that LDH may be a predictive factor for treatment with this combination, consistent with recent findings on the association between elesclomol anticancer activity and cellular metabolic state.

AMEERA-5: A randomized, double-blind phase III study of amcenestrant (SAR439859) + palbociclib versus letrozole + palbociclib for previously untreated ER+/HER2- advanced breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1104-TPS1104
Author(s):  
Aditya Bardia ◽  
Javier Cortes ◽  
Sara A. Hurvitz ◽  
Suzette Delaloge ◽  
Hiroji Iwata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Phase I ◽  
Advanced Breast Cancer ◽  
Progression Free Survival ◽  
Advanced Breast ◽  
Phase Iii ◽  
Double Blind ◽  
Free Survival ◽  
Phase Iii Study

TPS1104 Background: Selective estrogen receptor degraders (SERDs) block estrogen receptor (ER) associated signaling and have created interest for treating patients (pts) with advanced ER+ breast cancer (BC). Fulvestrant is currently the only SERD available for advanced BC but requires intramuscular administration, limiting the applied dose, exposure and receptor engagement. Amcenestrant (SAR439859) is an oral SERD that binds with high affinity to both wild-type and mutant ER, blocking estradiol binding and promoting up to 98% ER degradation in preclinical studies. In the phase I AMEERA-1 study of pretreated pts with ER+/HER2- advanced BC, amcenestrant 150–600 mg once daily (QD) showed a mean ER occupancy of 94% with plasma concentrations > 100 ng/mL and a favorable safety profile (Bardia, 2019; data on file). Combination therapy with amcenestrant + palbociclib (palbo) was also evaluated as part of this ongoing phase I study. CDK 4/6 inhibitors (CDK4/6i) combined with an aromatase inhibitor (AI), the gold standard for first line treatment for advanced breast cancer, prolong progression free survival (PFS) in pts with no prior treatment for ER+/HER2- advanced BC, but OS benefit has not been shown yet in postmenopausal pts. There remains a clinical need for more effective treatments in this setting. Methods: AMEERA-5 (NCT04478266) is an ongoing, prospective, randomized, double-blind phase III study comparing the efficacy and safety of amcenestrant + palbo with that of letrozole + palbo in pts with advanced, locoregional recurrent or metastatic ER+/HER2- BC who have not received prior systemic therapy for advanced disease. The study includes men, pre/peri-menopausal (with goserelin) and post-menopausal women. Pts with progression during or within 12 months of (neo)adjuvant endocrine therapy using any of the following agents are excluded: AI, selective estrogen receptor modulators, CDK4/6i. Pts are randomized 1:1 to either continuous amcenestrant 200 mg or letrozole 2.5 mg QD orally with matching placebos; both combined with palbo 125 mg QD orally (d1–21 every 28-d cycle). Randomization is stratified according to disease type (de novo metastatic vs recurrent disease), the presence of visceral metastasis, and menopausal status. The primary endpoint is investigator assessed progression free survival (PFS) (RECIST v1.1). Secondary endpoints are overall survival, PFS2, objective response rate, duration of response, clinical benefit rate, pharmacokinetics of amcenestrant and palbo, health-related quality of life, time to chemotherapy, and safety. Biomarkers will be measured in paired tumor biopsies and cell free deoxyribonucleic acid (cfDNA) over time. Target enrolment = 1066 pts; enrolment as of 1/2021 = 33 pts. Bardia A, et al., J Clin Oncol. 2019; 37 (15 suppl):1054 Clinical trial information: NCT04478266 .

Results of a Phase III, Randomized, Placebo-Controlled Study of Sorafenib in Combination With Carboplatin and Paclitaxel As Second-Line Treatment in Patients With Unresectable Stage III or Stage IV Melanoma

2009 ◽  
Vol 27 (17) ◽  
pp. 2823-2830 ◽  
Author(s):  
Axel Hauschild ◽  
Sanjiv S. Agarwala ◽  
Uwe Trefzer ◽  
David Hogg ◽  
Caroline Robert ◽  
...  
Keyword(s):  
Stage Iv ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Phase Iii ◽  
Controlled Study ◽  
Rank Test ◽  
Line Treatment ◽  
Second Line ◽  
Double Blind ◽  
End Points

PurposeThis phase III, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of sorafenib with carboplatin and paclitaxel (CP) in patients with advanced melanoma who had progressed on a dacarbazine- or temozolomide-containing regimen.Patients and MethodsA total of 270 patients were randomly assigned to receive intravenous paclitaxel 225 mg/m2plus intravenous carboplatin at area under curve 6 (AUC 6) on day 1 of a 21-day cycle followed by either placebo (n = 135) or oral sorafenib 400 mg (n = 135) twice daily on days 2 to 19. The primary efficacy end point was progression-free survival (PFS); secondary and tertiary end points included overall survival and incidence of best response, respectively.ResultsThe median PFS was 17.9 weeks for the placebo plus CP arm and 17.4 weeks for the sorafenib plus CP arm (hazard ratio, 0.91; 99% CI, 0.63 to 1.31; two-sided log-rank test P = .49). Response rate was 11% with placebo versus 12% with sorafenib. Dermatologic events, grade 3 thrombocytopenia, diarrhea, and fatigue were more common in patients treated with sorafenib plus CP versus placebo plus CP.ConclusionIn this study, the addition of sorafenib to CP did not improve any of the end points over placebo plus CP and cannot be recommended in the second-line setting for patients with advanced melanoma. Both regimens had clinically acceptable toxicity profiles with no unexpected adverse events. A trial of similar design for the first-line treatment of patients with advanced melanoma (intergroup trial E2603) is currently ongoing.

scholarly journals Gemcitabine Plus Cisplatin Versus Fluorouracil Plus Cisplatin as First-Line Therapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: Final Overall Survival Analysis of GEM20110714 Phase III Study

2021 ◽  
pp. JCO.21.00396
Author(s):  
Shaodong Hong ◽  
Yaxiong Zhang ◽  
Gengsheng Yu ◽  
Peijian Peng ◽  
Jiewen Peng ◽  
...  
Keyword(s):  
Overall Survival ◽  
Nasopharyngeal Carcinoma ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Once Daily ◽  
Free Survival ◽  
End Point ◽  
Metastatic Nasopharyngeal Carcinoma ◽  
Phase Iii Study

PURPOSE GEM20110714 (ClinicalTrials.gov identifier: NCT01528618 ), the first randomized, phase III study of systemic chemotherapy in recurrent or metastatic nasopharyngeal carcinoma (NPC), reported significant progression-free survival improvement with gemcitabine plus cisplatin (GP) versus fluorouracil plus cisplatin (FP; hazard ratio, 0.55; 95% CI, 0.44 to 0.68; P < .001). Data from the final analysis of overall survival (OS) are presented here. METHODS From February 2012 to October 2015, 362 patients were randomly assigned to receive either GP (gemcitabine 1 g/m2 once daily on days 1 and 8 and cisplatin 80 mg/m2 once daily on day 1; n = 181) or FP (fluorouracil 4 g/m2 in continuous intravenous infusion over 96 hours and cisplatin 80 mg/m2 once daily on day 1; n = 181) once every 21 days. The primary end point was progression-free survival, which has been previously reported; OS was a secondary end point. RESULTS After a median follow-up time of 69.5 months with GP and 69.7 months with FP, 148 (81.8%) and 166 (91.7%) deaths occurred in the GP and FP arms, respectively. The estimated hazard ratio for OS was 0.72 (95% CI, 0.58 to 0.90; two-sided P = .004). The median OS was 22.1 months (95% CI, 19.2 to 25.0 months) with GP versus 18.6 months (95% CI, 15.4 to 21.7 months) with FP. The OS probabilities at 1, 3, and 5 years were 79.9% versus 71.8%, 31.0% versus 20.4%, and 19.2% versus 7.8%, respectively. Poststudy therapy was administered in 51.9% and 55.2% of patients in the GP and FP arms, respectively. CONCLUSION Among patients with previously untreated advanced nasopharyngeal carcinoma, those who receive GP have longer OS than those receive FP. Gemcitabine plus cisplatin should be considered a preferred front-line option for these patients.

366 A randomized double-blind placebo-controlled phase III study evaluating perioperative toripalimab combined with platinum-based doublet chemotherapy in resectable stage III NSCLC

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A391-A391
Author(s):  
Wenxiang Wang ◽  
Lin Wu ◽  
Wei Zhang ◽  
Shun Lu ◽  
Haohui Fang ◽  
...  
Keyword(s):  
Small Cell ◽  
Pathological Response ◽  
Phase Iii ◽  
Stage Iii ◽  
Small Cell Lung ◽  
Double Blind ◽  
Free Survival ◽  
Phase Iii Study ◽  
Stage Iii Nsclc ◽  
Doublet Chemotherapy

BackgroundSurgery remains the mainstay of treatment for resectable stage III non-small cell lung cancer (NSCLC). The preliminary results from some pilot trials have shown that neoadjuvant immunotherapy in NSCLC is safe and tolerable.1 2Hypothesizing that neoadjuvant toripalimab (a humanized anti-PD-1 antibody) plus chemotherapy can improve the outcome in resectable NSCLC, we are conducting a randomized, double-blind, placebo-controlled, phase III study to evaluate the efficacy and safety of toripalimab plus platinum-based doublet chemotherapy as neoadjuvant/adjuvant therapy for patients with resectable stage III NSCLC.MethodsThis ongoing study enrolls patients aged 18–70 years with treatment-naïve, histopathologically confirmed resectable stage III NSCLC without EGFR mutation or ALK translocation, ECOG PS 0–1, and adequate organ function. Eligible subjects are randomized (1:1) into experimental or control group, to receive perioperative toripalimab 240 mg or placebo combined with chemotherapy for 4 cycle in total (Docetaxel 60–75 mg/m2 or Paclitaxel 175 mg/m2 with platinum [squamous histology] or Pemetrexed 500 mg/m2 with platinum [non-squamous histology]) every 3 weeks for three cycles followed by surgery, and one more cycle after surgery, then monotherapy of toripalimab 240 mg or placebo every 3 weeks up to 13 cycles is delivered. Adjuvant radiotherapy is allowed. Randomization is stratified by tumor stage(IIIA vs IIIB), pathological type (squamous vs non-squamous), PD-L1 expression (PD-L1≥1% vs <1% or not evaluable) and planned surgical procedure (pneumonectomy vs lobectomy). Radiographic response is assessed within 4–6 weeks after last dose of neoadjuvant therapy, at 30 days after surgery and every 12 weeks thereafter. Primary endpoints are major pathologic response (MPR) rate evaluated by blind independent central pathology review (BIPR-MPR) and event-free survival evaluated by investigator (INV-EFS). Secondary endpoints include pathologic complete response (pCR) rate evaluated by BIPR and investigators (BIPR-pCR and INV-pCR), disease-free survival (DFS), 2–3 years OS rate, OS, safety, and feasibility of surgery. Exploratory endpoints are potential correlations between biomarkers and efficacy. A stratified Cochran Mantel Haenszel method will be used to assess binary endpoints. A Kaplan-Meier method, a stratified log-rank test and a stratified Cox proportional hazards model will be used to assess survival endpoints.Planned enrollment is 406 patients. The study is actively enrolling at 52 Chinese sites.ResultsN/AConclusionsN/AAcknowledgementsN/ATrial RegistrationThe Clinical trials. gov no NCT04158440Ethics ApprovalThis study was approved by the Ethics Board of all the involved sites; Approval number of Shanghai Chest Hospital: LS1936ConsentN/AReferencesForde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer N Engl J Med 2018;378:1976–1986Hellmann MD, Chaft JE, William WN Jr, et al. Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint. Lancet oncol 2014;15:e42–50.

scholarly journals Bevacizumab use in the frontline, maintenance and recurrent settings for ovarian cancer

2020 ◽  
Vol 16 (7) ◽  
pp. 225-246 ◽  
Author(s):  
Carolyn E Haunschild ◽  
Krishnansu S Tewari
Keyword(s):  
Ovarian Cancer ◽  
Gynecologic Oncology ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Gynecologic Oncology Group ◽  
Double Blind ◽  
Free Survival ◽  
Platinum Sensitive ◽  
The Us ◽  
Us Fda

On 13 June 2018, Genentech, Inc. issued a press release announcing that the US FDA had approved the antiangiogenesis drug, bevacizumab, in combination with chemotherapy for frontline and maintenance therapy for women with newly diagnosed ovarian cancer. Regulatory approval was based on the National Cancer Institute-sponsored Gynecologic Oncology Group (GOG) protocol 0218, the Phase III, randomized, placebo-controlled, double-blind, multi-center and multi-national clinical trial that met its primary end point, progression-free survival. Bevacizumab is now approved in the frontline, platinum-sensitive recurrent and platinum-resistant recurrent settings for epithelial ovarian cancer. This review will address the broad range of clinical trials addressing the efficacy of bevacizumab use in ovarian cancer.

Phase III Trial of Infusional Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan (FOLFOXIRI) Compared With Infusional Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) As First-Line Treatment for Metastatic Colorectal Cancer: The Gruppo Oncologico Nord Ovest

2007 ◽  
Vol 25 (13) ◽  
pp. 1670-1676 ◽  
Author(s):  
Alfredo Falcone ◽  
Sergio Ricci ◽  
Isa Brunetti ◽  
Elisabetta Pfanner ◽  
Giacomo Allegrini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Peripheral Neurotoxicity ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Secondary Resection ◽  
Phase Iii Study ◽  
Grade 3

Purpose The Gruppo Oncologico Nord Ovest (GONO) conducted a phase III study comparing fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI [irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin 200 mg/m2 day 1, fluorouracil 3,200 mg/m2 48-hour continuous infusion starting on day 1, every 2 weeks]) with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI). Methods Selection criteria included unresectable metastatic colorectal cancer, age 18 to 75 years, and no prior chemotherapy for advanced disease. The primary end point was response rate (RR). Results A total of 244 patients were randomly assigned. An increase of grade 2 to 3 peripheral neurotoxicity (0% v 19%; P < .001), and grade 3 to 4 neutropenia (28% v 50%; P < .001) were observed in the FOLFOXIRI arm. The incidence of febrile neutropenia (3% v 5%) and grade 3 to 4 diarrhea (12% v 20%) were not significantly different. Responses, as assessed by investigators, were, for FOLFIRI and FOLFOXIRI, respectively, complete, 6% and 8%; and partial, 35% and 58%, (RR, 41% v 66%; P = .0002). RR confirmed by an external panel was 34% versus 60% (P < .0001). The R0 secondary resection rate of metastases was greater in the FOLFOXIRI arm (6% v 15%; P = .033, among all 244 patients; and 12% v 36%; P = .017 among patients with liver metastases only). Progression-free survival (PFS) and overall survival (OS) were both significantly improved in the FOLFOXIRI arm (median PFS, 6.9 v 9.8 months; hazard ratio [HR], 0.63; P = .0006; median OS, 16.7 v 22.6 months; HR, 0.70; P = .032). Conclusion The FOLFOXIRI regimen improves RR, PFS, and OS compared with FOLFIRI, with an increased, but manageable, toxicity in patients with metastatic colorectal cancer with favorable prognostic characteristics. Further studies of FOLFOXIRI in combination with targeted agents and in the neoadjuvant setting are warranted.

scholarly journals Final Results of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue Lymphoma: Improved Event-Free and Progression-Free Survival With Rituximab Plus Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy

2017 ◽  
Vol 35 (17) ◽  
pp. 1905-1912 ◽  
Author(s):  
Emanuele Zucca ◽  
Annarita Conconi ◽  
Giovanni Martinelli ◽  
Reda Bouabdallah ◽  
Alessandra Tucci ◽  
...  
Keyword(s):  
Overall Survival ◽  
Randomized Trial ◽  
Lymphoid Tissue ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Free Survival ◽  
Final Sample ◽  
Phase Iii Study ◽  
To Receive

Purpose There is no consensus on the optimal systemic treatment of patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The IELSG-19 phase III study, to our knowledge, was the first such study to address the question of first-line treatment in a randomized trial. Patients and Methods Eligible patients were initially randomly assigned (1:1 ratio) to receive either chlorambucil monotherapy (6 mg/m2/d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22) or a combination of chlorambucil (same schedule as above) and rituximab (375 mg/m2 intravenously on day 1 of weeks 1, 2, 3, 4, 9, 13, 17, and 21). After the planned enrollment of 252 patients, the protocol was amended to continue with a three-arm design (1:1:6 ratio), with a new arm that included rituximab alone (same schedule as the combination arm) and with a final sample size of 454 patients. The main end point was event-free survival (EFS). Analysis of chlorambucil versus the combination arm was performed and reported separately before any analysis of the third arm. Results At a median follow-up of 7.4 years, addition of rituximab to chlorambucil led to significantly better EFS (hazard ratio, 0.54; 95% CI, 0.38 to 0.77). EFS at 5 years was 51% (95% CI, 42 to 60) with chlorambucil alone, 50% (95% CI, 42 to 59) with rituximab alone, and 68% (95% CI, 60 to 76) with the combination ( P = .0009). Progression-free survival was also significantly better with the combination ( P = .0119). Five-year overall survival was approximately 90% in each arm. All treatments were well tolerated. No unexpected toxicities were recorded. Conclusion Rituximab in combination with chlorambucil demonstrated superior efficacy in mucosa-associated lymphoid tissue lymphoma; however, improvements in EFS and progression-free survival did not translate into longer overall survival.

Phase III Trial of Gemcitabine Plus Tipifarnib Compared With Gemcitabine Plus Placebo in Advanced Pancreatic Cancer

2004 ◽  
Vol 22 (8) ◽  
pp. 1430-1438 ◽  
Author(s):  
E. Van Cutsem ◽  
H. van de Velde ◽  
P. Karasek ◽  
H. Oettle ◽  
W.L. Vervenne ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Single Agent ◽  
Survival Rates ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Controlled Study ◽  
Double Blind ◽  
Free Survival

Purpose To determine whether addition of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777; Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium) to standard gemcitabine therapy improves overall survival in advanced pancreatic cancer. Patients and Methods This randomized, double-blind, placebo-controlled study compared gemcitabine + tipifarnib versus gemcitabine + placebo in patients with advanced pancreatic adenocarcinoma previously untreated with systemic therapy. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine was given at 1,000 mg/m2 intravenously weekly × 7 for 8 weeks, then weekly × 3 every 4 weeks. The primary end point was overall survival; secondary end points included 6-month and 1-year survival rates, progression-free survival, response rate, safety, and quality of life. Results Six hundred eighty-eight patients were enrolled. Baseline characteristics were well balanced between the two treatment arms. No statistically significant differences in survival parameters were observed. The median overall survival for the experimental arm was 193 v 182 days for the control arm (P = .75); 6-month and 1-year survival rates were 53% and 27% v 49% and 24% for the control arm, respectively; median progression-free survival was 112 v 109 days for the control arm. Ten drug-related deaths were reported for the experimental arm and seven for the control arm. Neutropenia and thrombocytopenia grade ≥ 3 were observed in 40% and 15% in the experimental arm versus 30% and 12% in the control arm. Incidences of nonhematologic adverse events were similar in two groups. Conclusion The combination of gemcitabine and tipifarnib has an acceptable toxicity profile but does not prolong overall survival in advanced pancreatic cancer compared with single-agent gemcitabine.

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