scholarly journals Randomized Phase II/III Trial Assessing Gemcitabine/Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer Who Are Unfit for Cisplatin-Based Chemotherapy: EORTC Study 30986

2012 ◽  
Vol 30 (2) ◽  
pp. 191-199 ◽  
Author(s):  
Maria De Santis ◽  
Joaquim Bellmunt ◽  
Graham Mead ◽  
J. Martijn Kerst ◽  
Michael Leahy ◽  
...  
Keyword(s):  
Phase Ii ◽  
Urothelial Cancer ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Error Rates ◽  
Phase Iii ◽  
Rank Test ◽  
Treatment Groups ◽  
Randomized Phase Ii ◽  
Grade 3

Purpose This is the first randomized phase II/III trial comparing two carboplatin-based chemotherapy regimens in patients with urothelial cancer who are ineligible (“unfit”) for cisplatin chemotherapy. Patients and Methods The primary objective of the phase III part of this study was to compare the overall survival (OS) of chemotherapy-naive patients with measurable disease and an impaired renal function (glomerular filtration rate < 60 but > 30 mL/min) and/or performance score of 2 who were randomly assigned to receive either gemcitabine/carboplatin (GC) or methotrexate/carboplatin/vinblastine (M-CAVI). To detect an increase of 50% in median survival with GC compared with M-CAVI (13.5 v 9 months) based on a two-sided log-rank test at error rates α = .05 and β = .20, 225 patients were required. Secondary end points were overall response rate (ORR), progression-free survival (PFS), toxicity, and quality of life. Results In all, 238 patients were randomly assigned by 29 institutions over a period of 7 years. The median follow-up was 4.5 years. Best ORRs were 41.2% (36.1% confirmed response) for patients receiving GC versus 30.3% (21.0% confirmed response) for patients receiving M-CAVI (P = .08). Median OS was 9.3 months in the GC arm and 8.1 months in the M-CAVI arm (P = .64). There was no difference in PFS (P = .78) between the two arms. Severe acute toxicity (death, grade 4 thrombocytopenia with bleeding, grade 3 or 4 renal toxicity, neutropenic fever, or mucositis) was observed in 9.3% of patients receiving GC and 21.2% of patients receiving M-CAVI. Conclusion There were no significant differences in efficacy between the two treatment groups. The incidence of severe acute toxicities was higher for those receiving M-CAVI.

Randomized phase II/III trial comparing gemcitabine/carboplatin (GC) and methotrexate/carboplatin/vinblastine (M-CAVI) in patients (pts) with advanced urothelial cancer (UC) unfit for cisplatin-based chemotherapy (CHT): Phase III results of EORTC study 30986.

2010 ◽  
Vol 28 (18_suppl) ◽  
pp. LBA4519-LBA4519 ◽  
Author(s):  
M. De Santis ◽  
J. Bellmunt ◽  
G. Mead ◽  
J. M. Kerst ◽  
M. G. Leahy ◽  
...  
Keyword(s):  
Renal Function ◽  
Phase Ii ◽  
Impaired Renal Function ◽  
Performance Status ◽  
Primary Objective ◽  
Error Rates ◽  
Phase Iii ◽  
Logrank Test ◽  
Randomized Phase Ii ◽  
Grade 3

LBA4519 Background: About 50% of pts with advanced UC are not eligible for cisplatin based CHT (“unfit”) due to impaired renal function, performance status (PS) or comorbidity. This is the first randomized phase II/III trial comparing two chemotherapy regimens in this pts group. Methods: The primary objective of the phase III part of this study was to compare the overall survival (OS) of CHT naïve pts with measurable disease and an impaired renal function (GFR<60 but >30 ml/min) and/or PS 2 who were randomized to receive either GC (G 1000 mg/m2 d1 and 8 and C AUC 4.5) q21 days or M-CAVI (M 30 mg/m2 d1 and 15 and 22, C AUC 4.5 d1 and VI 3 mg/m2 d1 and 15 and 22) q28 days. In order to detect an increase of 50% in median survival on GC compared to M-CAVI (13.5 versus 9 months) based on a two sided logrank test at error rates alpha=0.05 and beta=0.20, 225 pts were required. Secondary endpoints were overall response rate (ORR) and progression free survival (PFS). Results: 238 pts, 119 in each arm, were randomized between January 2001 and March 2008 by 29 institutions. The median follow-up is 4.5 years. Two pts were ineligible and two other pts never started treatment. Best ORRs (CR + PR) were 41.2% (36.1% confirmed response) on GC versus 30.3% (21.0% confirmed response) on M-CAVI (p = 0.08). Median OS was 9.3 months on GC and 8.1 months on M-CAVI (p = 0.64). There was no difference in PFS between the two arms (p = 0.78). OS, PFS and ORR were similar in each of the risk groups (reason unfit for cisplatin and Bajorin risk group). Severe acute toxicity (SAT) (death, grade 4 thrombocytopenia with bleeding, or grade 3/4 renal toxicity, neutropenic fever or mucositis) was observed in 9.3% of pts on GC (2 toxic deaths) and 21.2% on M-CAVI (4 toxic deaths). The most common grade 3/4 toxicities were leucopenia (44.9%, 46.6%), neutropenia (52.5%, 63.5%), febrile neutropenia (4.2%, 14.4%), thrombocytopenia (48.3%, 19.4%), and infection (11.8%, 12.7%) on GC and M-CAVI, respectively. Conclusions: There were no significant differences in efficacy between the two treatment groups. The incidence of SATs was slightly higher on M-CAVI. [Table: see text]

Randomized phase II trial of the multi-kinase inhibitor sorafenib versus interferon (IFN) in treatment-naïve patients with metastatic renal cell carcinoma (mRCC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4501-4501 ◽  
Author(s):  
B. Escudier ◽  
C. Szczylik ◽  
T. Demkow ◽  
M. Staehler ◽  
F. Rolland ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Trial ◽  
Prognostic Score ◽  
Primary Objective ◽  
Phase Iii ◽  
First Line ◽  
First Line Therapy ◽  
Randomized Phase Ii ◽  
Grade 3

4501 Background: Sorafenib, an oral multi-kinase inhibitor that targets tumor growth and vascularization, significantly prolonged PFS in a Phase III trial with previously treated mRCC patients. This randomized Phase II trial investigated the efficacy and tolerability of sorafenib compared with IFN in first-line therapy of patients with clear-cell RCC. Methods: Untreated patients with mRCC were stratified by MSKCC prognostic score and randomized to receive continuous oral sorafenib 400 mg bid or IFN 9 million units tiw, with an option of dose escalation (600 mg bid sorafenib) or crossover from IFN to sorafenib upon disease progression. The study assessed PFS at 99 events as primary objective, best response (RECIST), overall survival, health-related quality of life, and adverse events (AEs). Results: Baseline characteristics of 188 patients (sorafenib n=97; IFN n = 91) were: median age 62.0 years; MSKCC score: 57% low, 41% intermediate, 1% high; prior nephrectomy: 82%; ECOG 0:1, 55.3%:44.7%. As of January 6, 2006, PFS events have been reported for 64 (34%) patients. Preliminary data showed drug-related AEs of any severity (sorafenib vs IFN) in 50.5% vs 51.6% of patients (≥grade 3: 8.2% vs 11.0%), including diarrhea (24.7% vs 5.5%), fatigue (14.4% vs 20.9%), fever (2.1% vs 18.7%), hypertension (13.4% vs 0%), nausea (5.2% vs 13.2%), flu-like syndrome (1.0% vs 6.6%), hand-foot skin reaction (6.2% vs 0%), and rash/desquamation (4.1% vs 0%). Drug-related metabolic/laboratory abnormalities at grade 3 (no grade 4) comprised hypophosphatemia (21.7% vs. 0%), lipase elevation (5.6% vs. 11.1%), anemia (0% vs. 5.3%) and hypoalbuminemia (0% vs. 3.6%). Five patients receiving IFN withdrew from treatment due to AEs, whereas only one patient withdrew from sorafenib. Conclusions: Sorafenib was generally well tolerated in RCC patients in the first-line setting, with relatively infrequent drug-related AEs ≥grade 3. Full PFS data will be presented at the meeting. [Table: see text]

Randomized, open-label, phase III study of pemetrexed plus carboplatin (PemC) followed by maintenance pemetrexed versus paclitaxel/carboplatin/bevacizumab (PCB) followed by maintenance bevacizumab in patients with advanced nonsquamous (NS) non-small cell lung cancer (NSCLC).

2013 ◽  
Vol 31 (18_suppl) ◽  
pp. LBA8003-LBA8003 ◽  
Author(s):  
Ralph Zinner ◽  
Helen J. Ross ◽  
Robert Weaver ◽  
Ramaswamy Govindan ◽  
Viran R. Holden ◽  
...  
Keyword(s):  
Safety Data ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Drug Regimen ◽  
Primary Objective ◽  
Phase Iii ◽  
Rank Test ◽  
Type I ◽  
Open Label ◽  
Grade 3

LBA8003 Background: PemC and PCB are regimens used for first-line treatment of advanced NS-NSCLC. The primary objective was to compare progression-free survival without Grade 4 toxicity (G4PFS) between two vs three drug regimen arms. Methods: Patients ≥18 years, Stage IV NS NSCLC, AJCC (v7.0), and ECOG PS 0/1 were enrolled. Patients were randomized (1:1); received 4 cycles of induction (PemC: Pem, 500 mg/m2 and C, AUC = 6; PCB: P, 200 mg/m2, C, AUC = 6, and B, 15 mg/kg) followed by Pem (PemC Arm) or B (PCB Arm) maintenance therapy in the absence of progressive disease or discontinuation. Secondary endpoints were PFS, overall survival (OS), overall response rate (ORR), and disease control rate (DCR). The study was powered for G4PFS; assuming hazard ratio (HR) of 0.75; there was 80% power to detect superiority of PemC over PCB with a 2-sided type I error of 0.10. Efficacy data were analyzed by intent-to-treat principle using the log-rank test for time-to-event variables, and an exact test for ORR and DCR. Safety data were evaluated using CTCAE v3 for patients who received ≥1 dose of study treatment. Results: Patients were randomized to PemC (N = 182) or PCB (N = 179). Baseline factors were balanced between arms: median age 66/66 years; % female 42/42; % PS=0, 47/47; % stage IV M1a 29/30; for PemC vs PCB, median G4PFS (months) was 3.91/2.86 (HR = 0.85, 90% CI 0.7, 1.04, p = 0.176); PFS and OS had HR = 1.06 (95% CI 0.84, 1.35), p = 0.610, and HR = 1.07 (95% CI 0.83, 1.36), p = 0.616, respectively. The ORR (%) 23.6/ 27.4 and DCR (%) 59.9/57.0 were for PemC vs PCB, respectively. Significantly more drug-related grade 3/4 anemia (18.7% vs 5.4%), and thrombocytopenia (24.0% vs 9.6%) were seen on PemC; significantly more grade 3/4 neutropenia (48.8% vs 24.6%) and grade 1/2 alopecia (28.3 % vs 8.2%) were seen on PCB. Conclusions: PemC was not superior to PCB in G4PFS; no difference in PFS or OS was observed for the two- vs three-drug regimens. There were no unexpected toxicities; the toxicity profiles demonstrated distinctions by arm, and both regimens demonstrated tolerability. Clinical trial information: NCT00948675.

Pre- versus postoperative CAPOX plus bevacizumab (CAPOX-Bev) for resectable liver metastases from colorectal cancer (CLM): A randomized phase II/III trial (HiSCO-01).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4021-4021 ◽  
Author(s):  
Yuji Takakura ◽  
Katsunori Shinozaki ◽  
Satoshi Ikeda ◽  
Hiroyuki Egi ◽  
Yuzo Hirata ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Phase Ii ◽  
Radical Surgery ◽  
Progression Free Survival ◽  
Gastrointestinal Disorder ◽  
Biliary Fistula ◽  
Completion Rate ◽  
Phase Iii ◽  
Randomized Phase Ii ◽  
Grade 3

4021 Background: The role of neoadjuvant chemotherapy, particularly for those with initially resectable CLM, is controversial. And the optimal regimen and duration to be used in the neoadjuvant setting is not established. We conducted prospective, multicenter, randomized phase II/III study to assess pre-operative 8 cycles of CAPOX-Bev (arm A) plus radical surgery compared with post-operative 8 cycles of CAPOX-Bev (arm B) for patients (pts) with resectable CLM. Methods: The primary endpoint in the Phase II was completion rate of protocol treatment (more than 6 cycles of CAPOX-Bev plus R0 surgical resection) and PFS in the Phase III. The secondary endpoints were OS, ORR (arm A), liver damage (arm A), safety. The Phase III part was terminated due to slow enrollment. Results: 81 pts were enrolled from 10 centers between November 2010 and November 2017. The full analysis set consisted of 76 pts who started protocol treatment (arm A 37 vs. arm B 39). 76 pts had the following characteristics: median age 66 (27-80), median number of liver metastases 2 (1-14), 69.7% male, 67.1% synchronous and 94.7% primary resected. Completion rate of protocol treatment was 89.2% in arm A and 71.8% in arm B (p = .06). ORR was 63.9%, including 2 pts who had pathologically complete response (5.6%). Only 1 pts in arm A could not undergo surgery due to progression of disease. In the chemotherapy safety population, arm B was associated with more grade 3 neutropenia and grade 3 gastrointestinal disorder than arm A. The most frequent surgical adverse event was biliary fistula, with an incidence of 0% in arm A and 10.3% in arm B (p = .02). No patient died from treatment-related adverse events. The median follow-up time was 40 months. The rate of PFS at 3 years was 32.2% in arm A versus 38.5% in arm B (p = .99). Conclusions: Pre-operative 8 cycles of CAPOX-Bev is compatible with radical surgery, but may have no impact on progression-free survival compared with post-operative chemotherapy. Clinical trial information: UMIN000003783 .

scholarly journals Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer

2015 ◽  
Vol 33 (13) ◽  
pp. 1475-1481 ◽  
Author(s):  
Mitesh J. Borad ◽  
Shantan G. Reddy ◽  
Nathan Bahary ◽  
Hope E. Uronis ◽  
Darren Sigal ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Metastatic Disease ◽  
Tumor Response ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Randomized Phase Ii ◽  
Grade 3

Purpose TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer. Patients and Methods Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m2), gemcitabine plus TH-302 240 mg/m2 (G+T240), or gemcitabine plus TH-302 340 mg/m2 (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety. Results Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (−5,398 v −549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302–related AEs but were not associated with treatment discontinuation. Conclusion PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979).

scholarly journals Phase II Trial of Cetuximab With or Without Paclitaxel in Patients With Advanced Urothelial Tract Carcinoma

2012 ◽  
Vol 30 (28) ◽  
pp. 3545-3551 ◽  
Author(s):  
Yu-Ning Wong ◽  
Samuel Litwin ◽  
David Vaughn ◽  
Seth Cohen ◽  
Elizabeth R. Plimack ◽  
...  
Keyword(s):  
Phase Ii ◽  
Urothelial Cancer ◽  
Single Agent ◽  
Progression Free Survival ◽  
Salvage Chemotherapy ◽  
Free Survival ◽  
Metastatic Urothelial Cancer ◽  
Metastatic Setting ◽  
Previously Treated ◽  
Grade 3

Purpose The benefit of salvage chemotherapy is modest in metastatic urothelial cancer. We conducted a randomized, noncomparative phase II study to measure the efficacy of cetuximab with or without paclitaxel in patients with previously treated urothelial cancer. Patients and Methods Patients with metastatic urothelial cancer who received one line of chemotherapy in the perioperative or metastatic setting were randomly assigned to 4-week cycles of cetuximab 250 mg/m2 with or without paclitaxel 80 mg/m2 per week. We used early progression as an indicator of futility. Either arm would close if seven of the initial 15 patients in that arm progressed at the first disease evaluation at 8 weeks. Results We enrolled 39 evaluable patients. The single-agent cetuximab arm closed after nine of the first 11 patients progressed by 8 weeks. The combination arm completed the full accrual of 28 patients, of whom 22 patients (78.5%) had visceral disease. Twelve of 28 patients had progression-free survival greater than 16 weeks. The overall response rate was 25% (95% CI, 11% to 45%; three complete responses and four partial responses). The median progression-free survival was 16.4 weeks (95% CI, 12 to 25.1 weeks), and the median overall survival was 42 weeks (95% CI, 30.4 to 78 weeks). Treatment-related grade 3 and 4 adverse events that occurred in at least two patients were rash (six cases), fatigue (five cases), and low magnesium (three cases). Conclusion Although it had limited activity as a single agent, cetuximab appears to augment the antitumor activity of paclitaxel in previously treated urothelial cancers. The cetuximab and paclitaxel combination merits additional study to establish its role in the treatment of urothelial cancers.

Design Issues of Randomized Phase II Trials and a Proposal for Phase II Screening Trials

2005 ◽  
Vol 23 (28) ◽  
pp. 7199-7206 ◽  
Author(s):  
Lawrence V. Rubinstein ◽  
Edward L. Korn ◽  
Boris Freidlin ◽  
Sally Hunsberger ◽  
S. Percy Ivy ◽  
...  
Keyword(s):  
Phase Ii ◽  
False Positive ◽  
Standard Treatment ◽  
False Negative ◽  
Error Rates ◽  
Targeted Treatment ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Treatment Control ◽  
Randomized Phase Ii

Future progress in improving cancer therapy can be expedited by better prioritization of new treatments for phase III evaluation. Historically, phase II trials have been key components in the prioritization process. There has been a long-standing interest in using phase II trials with randomization against a standard-treatment control arm or an additional experimental arm to provide greater assurance than afforded by comparison to historic controls that the new agent or regimen is promising and warrants further evaluation. Relevant trial designs that have been developed and utilized include phase II selection designs, randomized phase II designs that include a reference standard-treatment control arm, and phase II/III designs. We present our own explorations into the possibilities of developing “phase II screening trials,” in which preliminary and nondefinitive randomized comparisons of experimental regimens to standard treatments are made (preferably using an intermediate end point) by carefully adjusting the false-positive error rates (α or type I error) and false-negative error rates (β or type II error), so that the targeted treatment benefit may be appropriate while the sample size remains restricted. If the ability to conduct a definitive phase III trial can be protected, and if investigators feel that by judicious choice of false-positive probability and false-negative probability and magnitude of targeted treatment effect they can appropriately balance the conflicting demands of screening out useless regimens versus reliably detecting useful ones, the phase II screening trial design may be appropriate to apply.

Quadruplet regimen with capecitabine, irinotecan, oxaliplatin, and bevacizumab in chemo-naive patients with metastatic colorectal cancer: Results from the safety lead-in of QUATTRO-II study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 57-57
Author(s):  
Hideaki Bando ◽  
Daisuke Kotani ◽  
Masahito Kotaka ◽  
Akihito Kawazoe ◽  
Toshiki Masuishi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Braf V600e ◽  
Phase Iii ◽  
Fixed Dose ◽  
Wild Type ◽  
Randomized Phase Ii ◽  
Level 1 ◽  
Grade 3

57 Background: FOLFOXIRI plus bevacizumab (BEV) is regarded as the standard of care for selected patients (pts) with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea. The AXEPT phase III study showed that the modified capecitabine (CAP) + irinotecan (IRI) + BEV (CAPIRI+BEV) [CAP 1600 mg/m2, IRI 200 mg/m2, and BEV 7.5 mg/kg q3wk] treatment was non-inferior to FOLFIRI+BEV, with a lower incidence of hematologic toxicity. We hypothesized that the modified CAPIRI combined with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) would be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods: The QUATTRO-II study is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses (RD) of OX and IRI were investigated as a safety lead-in. In Step 2, pts are randomized to either the RD of CAPOXIRI+BEV or FOLFOXIRI+BEV. In Step 1, four dose levels of CAPOXIRI (fixed dose of CAP 1600 mg/m2 and BEV 7.5 mg/kg plus escalated or de-escalated doses of OX and IRI, q3wk) were investigated in a 3+3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results: A total of 9 pts (3 at Level 0, 6 at Level 1) were included in Step 1. The baseline characteristics were as follows: the median age was 62 years; 6 were male; 6 presented with a left-sided tumor; 8 had a performance status of 0; all wild type/ RAS mutant/ BRAF V600E mutant were 8/1/0; and UGT1A1 wild type/*6 single hetero/*28 single hetero were 7/0/2. In Level 0 (IRI 200 mg/m2, OX 100 mg/m2), one grade 4 neutropenia and one grade 3 anorexia were observed, but without DLT. In Level 1 (IRI 200 mg/m2, OX 130 mg/m2), two grade 4 neutropenia and one grade 3 colitis were observed, with 1 DLT (febrile neutropenia) case, fully recovered without G-CSF administration. No treatment-related deaths were observed. Although dose modifications were needed in 4 of the 6 pts, no further safety concerns related to treatment continuity were observed in the 2nd or subsequent cycles. Thus, we determined that the dose administered in Level 1 is the RD for Step 2. According to the preliminary efficacy results at 8 weeks after initiating study treatment, 6 pts achieved a partial response (2 in Level 0 and 4 in Level 1). Conclusions: The RD of CAPOXIRI+BEV was 200 mg/m2 IRI, 130 mg/m2 OX, 1600 mg/m2 CAP, and 7.5mg/kg BEV. The randomized phase II Step (Step 2) of QUATTRO-II is ongoing. Clinical trial information: NCT04097444.

TRYHARD, a randomized phase II trial (RTOG Foundation 3501) of concurrent accelerated radiation plus cisplatin (cis) with or without lapatinib (Lap) for stage III- IV Non-HPV head and neck carcinoma (HNC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6014-6014
Author(s):  
Stuart J. Wong ◽  
Pedro A. Torres-Saavedra ◽  
Nabil F. Saba ◽  
George Shenouda ◽  
Jeffrey Bumpous ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Stage Iii ◽  
Adverse Event Rate ◽  
Rank Test ◽  
Days Of Therapy ◽  
Grade 3

6014 Background: Chemoradiation (CRT) with cis or anti-EGFR Ab has been shown to improve survival of patients with stage III-IV HNC. Since Lap, a dual EGFR and HER2 inhibitor, has shown effectiveness with CRT in a pilot non-HPV HNC cohort, the RTOG Foundation launched a phase II trial to test the hypothesis that adding Lap to the RT-cis for frontline therapy of stage III-IV Non-HPV HNC improves progression-free survival (PFS). Methods: Patients with stage III-IV carcinoma of the oropharynx (p16-negative), larynx, and hypopharynx, having Zubrod performance of 0-1, and meeting predefined blood chemistry criteria were enrolled after providing consent. Patients were randomized (1:1) to 70 Gy (6 weeks) + 2 cycles of CDDP (q3 weeks) plus either Lap (1500 mg daily, Arm A) or placebo (Arm B) starting 1 week prior to RT and concurrent with RT and for 3 months post RT. PFS was the primary endpoint. The protocol specified 69 PFS events (142 patients) for the final analysis based on HR = 0.65, 80% power, 1-sided alpha 0.20, and one interim efficacy and futility analysis at 50% information. PFS rates between arms for all randomized patients were compared by 1-sided log-rank test (1-sided alpha 0.1803). Overall survival (OS) was a secondary endpoint. Results: From 10/’12 to 04/’17, 142 patients were enrolled, of whom 127 were randomized, 63 to Arm A and 64 to Arm B. Arms A vs B, respectively, were similar in baseline patient characteristics, radiation delivery, completing ≥ 70 Gy (85.7% vs. 82.8%) and cisplatin delivery, completing 200 (±5%) mg/m2 (65.1% vs 70.3%), but dissimilar in Lap/placebo delivery (median dose, 87000 mg vs. 125250 mg). Median follow-up was 4.1 years for surviving patients. The final analysis suggests no improvement in PFS of adding Lap to CRT (HR [A/B]: 0.91, 95% confidence interval CI 0.56-1.46; P= 0.34; 2-year rates: 50.6%, CI 37.5-63.7% vs. 56.2% CI 43.0-69.4%), or in OS (HR: 1.06, CI 0.61-1.86; P = 0.58; 2-year rates: 71.8% CI 60.1-83.5% vs. 76% CI 64.5-87.4%), death within 30 days of therapy (3.3% vs. 3.4%), and overall treatment-related grade 3-5 adverse event rate (86.7% vs. 84.7%). Grade 3-4 mucositis rates on Arm A and Arm B were 21.7% vs. 23.7%, all grade dysphagia and rash rates were 43.3% vs. 59.3%, and 13.3% vs. 6.8%, respectively. Conclusions: The addition of Lap to the radiation-cisplatin platform did not improve progression-free or overall survival in unselected non-HPV HN. Thus, dual EGFR, HER-2 inhibition does not appear to enhance the effects of chemoradiation. Although we showed that accrual to a non-HPV HN specific trial is feasible, new strategies must be investigated to improve the outcome for this poor prognosis HN population.

scholarly journals Anti-Angiogenic Agents in Management of Sarcoma Patients: Overview of Published Trials

2020 ◽  
Vol 10 ◽  
Author(s):  
Pierre-Yves Cren ◽  
Loïc Lebellec ◽  
Thomas Ryckewaert ◽  
Nicolas Penel
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Double Blind ◽  
Multikinase Inhibitors ◽  
Randomized Phase Ii ◽  
Phase Iii Trials

We reviewed all fully published clinical trials assessing anti-angiogenic agents in sarcoma patients (last issue, January 13, 2020). Anti-angiogenic macromolecules (e.g., bevacizumab or ombrabulin) provide disappointing results. Many multikinase inhibitors have been assessed with non-randomized phase II trials with limited samples and without stratification according to histological subtypes, therefore interpretation of such trials is very challenging. On the contrary, pazopanib, regorafenib, and sorafenib have been assessed using double-blind placebo-controlled randomized phase II or phase III trials. Compared to placebo, sorafenib demonstrates activity in desmoid-type fibromatosis patients. Based on results of phase 3 trial, pazopanib had obtained approval for treatment of pretreated non-adipocytic soft tissue sarcoma. Regorafenib is currently assessed in several clinical settings and provides significant improvement of progression-free survival in pre-treated non-adipocytic soft tissue sarcoma and in advanced pretreated osteosarcoma. Multikinase inhibitors are a breakthrough in sarcoma management. Many trials are ongoing. Nevertheless, predictive factors are still missing.

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