Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer

2015 ◽  
Vol 33 (33) ◽  
pp. 3858-3865 ◽  
Author(s):  
Yung-Jue Bang ◽  
Seock-Ah Im ◽  
Keun-Wook Lee ◽  
Jae Yong Cho ◽  
Eun-Kee Song ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Phase Iii ◽  
Double Blind Study ◽  
Double Blind ◽  
Gastric Cancer Cell Lines ◽  
Study Population ◽  
Atm Protein

Purpose Gastric cancer cell lines, particularly those with low levels of ataxia telangiectasia mutated (ATM), a key activator of DNA damage response, are sensitive to the poly (ADP-ribose) polymerase inhibitor olaparib. We compared the efficacy of olaparib plus paclitaxel (olaparib/paclitaxel) with paclitaxel alone in patients with recurrent or metastatic gastric cancer and assessed whether low ATM expression is predictive of improved clinical outcome for olaparib/paclitaxel. Patients and Methods In this phase II, double-blind study (Study 39; NCT01063517), patients were randomly assigned to oral olaparib 100 mg twice per day (tablets) plus paclitaxel (80 mg/m2 per day intravenously on days 1, 8, and 15 of every 28-day cycle) or placebo plus paclitaxel (placebo/paclitaxel), followed by maintenance monotherapy with olaparib (200 mg twice per day) or placebo. The study population was enriched to 50% for patients with low or undetectable ATM levels (ATMlow). Primary end point was progression-free survival (PFS). Results One hundred twenty-three of 124 randomly assigned patients received treatment (olaparib/paclitaxel, n = 61; placebo/paclitaxel, n = 62). The screening prevalence of ATMlow patients was 14%. Olaparib/paclitaxel did not lead to a significant improvement in PFS versus placebo/paclitaxel (overall population: hazard ratio [HR], 0.80; median PFS, 3.91 v 3.55 months, respectively; ATMlow population: HR, 0.74; median PFS, 5.29 v 3.68 months, respectively). However, olaparib/paclitaxel significantly improved overall survival (OS) versus placebo/paclitaxel in both the overall population (HR, 0.56; 80% CI, 0.41 to 0.75; P = .005; median OS, 13.1 v 8.3 months, respectively) and the ATMlow population (HR, 0.35; 80% CI, 0.22 to 0.56; P = .002; median OS, not reached v 8.2 months, respectively). Olaparib/paclitaxel was generally well tolerated, with no unexpected safety findings. Conclusion Olaparib/paclitaxel is active in the treatment of patients with metastatic gastric cancer, with a greater OS benefit in ATMlow patients. A phase III trial in this setting is under way.

Olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer: A randomized, double-blind phase II study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4013-4013 ◽  
Author(s):  
Yung-Jue Bang ◽  
Seock-Ah Im ◽  
Keun-Wook Lee ◽  
Jae Yong Cho ◽  
Eun-Kee Song ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Double Blind ◽  
Protein Levels ◽  
Common Grade ◽  
Atm Protein ◽  
Grade 3

4013 Background: Our multicenter study compared the efficacy of the oral PARP inhibitor olaparib plus paclitaxel (O/P) vs paclitaxel alone (P) as second-line therapy in pts with recurrent/metastatic gastric cancer (GC) (NCT01063517). As initial preclinical data suggested that responsiveness of GC cell lines to olaparib was associated with low ATM protein levels, our study was enriched for pts with low ATM tumors (ATM–) by IHC (50% randomized vs 14% screening prevalence). Methods: Eligible pts were randomized 1:1 (stratified by ATM status) to receiveolaparib 100 mg bid (tablet form) plus paclitaxel (80 mg/m2 iv on days 1, 8, 15 per 28-day cycle) or placebo plus paclitaxel until progression or investigator decision. After combination therapy, pts could take olaparib 200 mg bid monotherapy or placebo until progression. Co-primary endpoints: progression-free survival (PFS; RECIST v1.1) in all pts and ATM– pts. Secondary endpoints: overall survival (OS), objective response rate (ORR), safety. Results: 123/124 randomized pts were treated (O/P=61; P=62). Baseline characteristics were generally well balanced. Use of post-progression therapy was similar in both arms (O/P=48.4%; P=43.5%) as was median paclitaxel duration (O/P=17 wks; P=16 wks); 18 pts received monotherapy (O/P=11; P=7). More pts in the O/P than P arm had delays (79 vs 63%) and reductions (41 vs 27%) in paclitaxel dosing. The most common grade ≥3 AEs in the O/P and P arms were neutropenia (56 vs 39%) and anemia (11 vs 11%). Conclusions: Olaparib plus paclitaxel was well tolerated and led to a statistically significant improvement in OS, but not PFS, vs paclitaxel alone in both all pts and ATM– pts, with a larger benefit in ATM– pts. Clinical trial information: NCT01063517. [Table: see text]

Lapatinib in combination with ECF/x in EGFR1 positive first-line metastatic gastric cancer (GC): A phase II randomized placebo controlled trial (EORTC 40071).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4140-TPS4140
Author(s):  
Markus Hermann Moehler ◽  
Arno Schad ◽  
Murielle E. Mauer ◽  
Michel Praet ◽  
Francisco J. Sapunar ◽  
...  
Keyword(s):  
Phase Ii ◽  
Controlled Trial ◽  
Cohort Analysis ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Phase Iii ◽  
Her2 Status ◽  
Clinical Activity ◽  
Curative Surgery ◽  
Double Blind

TPS4140 Background: Survival of HER2+ metastatic GC is prolonged by trastuzumab when administered with CF/X (VanCutsem, ASCO 2009). Lapatinib inhibits both EGFR1 and HER2, is active in HER2+ GC lines, and has shown clinical activity in uncontrolled phase II GC trials. A phase III trial of lapatinib with X + oxaliplatin in HER2+ (FISH) GC is closed to recruitment. Additional unaddressed questions include the efficacy and safety of lapatinib with ECF/X (epirubicin + cisplatin + 5-FU or capecitabine (X), which is a preferred chemotherapy (CT) regimen in GC), and its activity in patients (pts) with discordant FISH or IHC HER2 status or EGFR1+. Methods: This is a phase II, randomized, double- blind, placebo controlled, multicenter trial sponsored by the EORTC. About 480 pts with adenocarcinoma of the stomach or esophagogastric junction not amenable to curative surgery and without prior palliative CT are screened centrally for HER2/EGFR1 by FISH and IHC. Patients are enrolled into one of two strata: 1) HER2 FISH- and IHC 2/3+, or 2) HER2 IHC 0/+ and EGFR1 FISH+ or IHC 2/3+. Pts HER2 FISH+/IHC 2/3+ and pts without HER2/EGFR1 by FISH/IHC will be excluded. 168 pts are anticipated to be randomized to lapatinib 1,250 mg cont. until progression or placebo, administered 6 cycles of ECF or ECX (72/96 in stratum 1/2, respectively).The primary endpoint is progression-free survival (PFS) in stratum 2 and 77 events are needed for 80% power to detect an increase in PFS from 4 to 6.5 months with lapatinib (HR=0.615, one-sided alpha 10%). Secondary endpoints include PFS, toxicity, response rate, overall survival, and correlation of HER2/EGFR1 status with response. Currently, half of all screened patients (19/38) have been randomized. So far, 8/38 (21%) pts were HER2+ according TOGA criteria. By FISH or IHC, 14/38 were EGFR1+, with 4/14 pts double HER2/EGFR+. Enrolment continues in 5 centers with about 4-10 patients per month. A safety cohort analysis will be performed in the first 15 pts receiving lapatinib. Conclusions: This is the first trial to analyze prospectively and separately the role of lapatinib combined with chemotherapy in EGFR1+ GC pts stratified by FISH/ IHC.

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.

Phase II Trial of 4′-Epi-Doxorubicin in Locally Advanced or Metastatic Gastric Cancer

1988 ◽  
Vol 74 (3) ◽  
pp. 313-315 ◽  
Author(s):  
Eduardo Cazap ◽  
Roberto Estevez ◽  
Mario Bruno ◽  
Daniel Levy ◽  
Carlos Algamiz ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastric Adenocarcinoma ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Metastatic Gastric Cancer ◽  
Phase Iii ◽  
Future Studies ◽  
Phase Iii Trials

Patients with locally advanced or metastatic gastric adenocarcinoma received an i.v. bolus of 4′-epi-doxorubicin, 75/mg/m2/cycle, every 21 days. Partial responses were observed in 5 of 23 evaluable patients (21.7%). Treatment was generally well tolerated and toxicity was mild. The response rate to epirubicin appears to be very similar to that reported for doxorubicin. Larger doses of epirubicin could be safely used in future studies, and further evaluation of epirubicin in phase III trials is indicated.

Randomized Multicenter Phase II Trial of a Biweekly Regimen of Fluorouracil and Leucovorin (LV5FU2), LV5FU2 Plus Cisplatin, or LV5FU2 Plus Irinotecan in Patients With Previously Untreated Metastatic Gastric Cancer: A Fédération Francophone de Cancérologie Digestive Group Study—FFCD 9803

2004 ◽  
Vol 22 (21) ◽  
pp. 4319-4328 ◽  
Author(s):  
Olivier Bouché ◽  
Jean Luc Raoul ◽  
Franck Bonnetain ◽  
Marc Giovannini ◽  
Pierre Luc Etienne ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Phase Iii ◽  
Survival Times ◽  
Multicenter Phase ◽  
Independent Expert ◽  
Phase Iii Study ◽  
Cancérologie Digestive

Purpose To determine the efficacy and safety of a biweekly regimen of leucovorin (LV) plus fluorouracil (FU) alone or in combination with cisplatin or irinotecan in patients with previously untreated metastatic gastric adenocarcinoma and to select the best arm for a phase III study. Patients and Methods One hundred thirty-six patients (two were ineligible) were enrolled onto the randomized multicenter phase II trial. Patients received LV 200 mg/m2 (2-hour infusion) followed by FU 400 mg/m2 (bolus) and FU 600 mg/m2 (22-hour continuous infusion) on days 1 and 2 every 14 days (LV5FU2; arm A), LV5FU2 plus cisplatin 50 mg/m2 (1-hour infusion) on day 1 or 2 (arm B), or LV5FU2 plus irinotecan 180 mg/m2 (2-hour infusion) on day 1 (arm C). Results The overall response rates, which were confirmed by an independent expert panel, were 13% (95% CI, 3.4% to 23.3%), 27% (95% CI, 14.1% to 40.4%), and 40% (95% CI, 25.7% to 54.3%) for arms A, B, and C, respectively. Median progression-free survival and overall survival times were 3.2 months (95% CI, 1.8 to 4.6 months) and 6.8 months (95% CI, 2.6 to 11.1 months) with LV5FU2, respectively; 4.9 months (95% CI, 3.5 to 6.3 months) and 9.5 months (95% CI, 6.9 to 12.2 months) with LV5FU2-cisplatin, respectively; and 6.9 months (95% CI, 5.5 to 8.3 months) and 11.3 months (95% CI, 9.3 to 13.3 months) with LV5FU2-irinotecan, respectively. Conclusion Of the three regimens tested, the combination of LV5FU2-irinotecan is the most promising and will be assessed in a phase III trial.

scholarly journals A Review of Docetaxel: Its Use in the Treatment of Gastric Cancer

2010 ◽  
Vol 2 ◽  
pp. CMT.S5191
Author(s):  
Alessandro Inno ◽  
Michele Basso ◽  
Alessandra Cassano ◽  
Carlo Barone
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Poor Performance ◽  
Phase Iii ◽  
Poor Performance Status ◽  
Phase Ii Studies ◽  
Combination Regimens

Docetaxel, a member of the taxane family, promotes cell death by binding β-tubulin and has demonstrated activity against several human malignancies, both as a single agent and in combination therapy. It has been approved in Europe and the US as front-line treatment for advanced gastric cancer in combination with cisplatin and fluorouracil (DCF regimen). This approval was based on the results of a pivotal study (V325) which demonstrated that the addition of docetaxel to the reference regimen of cisplatin and fluorouracil improves overall survival and progression-free survival with a better quality of life despite increased toxicity (mainly haematological). Modifications of DCF regimen have been successfully investigated as a means of making the treatment more tolerable and suitable also for elderly patients or patients with poor performance status. Emerging data from several phase II studies suggest that other docetaxel-based combination regimens with anthracyclines or irinotecan have interesting activity with acceptable toxicity profiles, but the true efficacy of these regimens needs to be assessed in large randomized phase III studies. Thus, the best docetaxel-containing regimen has yet to be identified. Docetaxel also represents a good candidate for combination with novel molecular target agents. In light of the high response rates observed in phase II-III studies, a docetaxel-based chemotherapy regimen might also be considered a treatment option as perioperative or adjuvant therapy in potentially curable gastric cancer and further studies with or without biological agents are eagerly awaited in this setting.

Docetaxel, oxaliplatin, and capecitabine (TEX regimen) for patients with metastatic gastric cancer: Interim results from a phase II trial by the German AIO Group

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4554-4554 ◽  
Author(s):  
M. H. Moehler ◽  
P. Thuss-Patience ◽  
D. Arnold ◽  
W. Grothe ◽  
A. Stein ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Distant Metastases ◽  
Response Assessment ◽  
Metastatic Gastric Cancer ◽  
Phase Ii Trials ◽  
Grade 3 ◽  
Ecog Ps

4554 Background: Combination regimens of 3 drugs have shown promising activity as treatment for patients (pts) with metastatic gastric cancer (GC). Docetaxel combined with cisplatin and 5-FU (CF) improved overall survival and response rates when compared to standard CF. However, the identification of less toxic and more convenient variants of this regimen is still important. We have previously established a regimen with docetaxel (T) combined with oxaliplatin (E) and capecitabine (X) in a phase I trial [Grothe et al., Proc. ASCO 2006]. Results of a preplanned interim analysis of subsequent multicenter phase II trials of the TEX regimen are presented here. Methods: Pts with metastatic or locally advanced GC, adequate organ function, ECOG PS 0–2, and no prior chemotherapy for advanced disease (adjuvant allowed) were enrolled. TEX regimen was administered as defined: T 35 mg/m2 and E 70 mg/m2 on days (d) 1 and 8, with X 800 mg/m2 bid on d1–14 every 22 days Toxicity assessment was done 3-weekly while CT scans were repeated 9-weekly. Results: 35 of 48 pts were enrolled until 06/08: 28 male / 7 female, median age 59 (36–81) years, ECOG PS 0/1/2 69%/31%/0%, gastric / gastroesophageal cancer 60%/40%, distant metastases 96%, tumor in situ 37%. The most common toxicities reported were (CTC grade [gr] 3/4): diarrhea 20%/3%, vomiting 11%/3%, asthenia and neurotoxicity each 9%/0%. Mucositis and hand-foot-syndrome were observed in (grade 1+2 / grade 3) 29%/0% and 26%/3%, respectively. Hematoxicity was mild with grade 3 anemia in 10% and no other grade 3/4 toxicity except one episode of febrile neutropenia . Of 25 pts evaluable so far, first tumor response assessment revealed (RECIST criteria) partial response in 36% and stable disease in 40% of patients. Conclusions: TEX is a safe and tolerable regimen for patients with metastatic gastric cancer. Preliminary efficacy results indicate promising activity. Mature data including progression free survival will be presented at the meeting. [Table: see text]

Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial.

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA10008-LBA10008 ◽  
Author(s):  
George D. Demetri ◽  
Peter Reichardt ◽  
Yoon-Koo Kang ◽  
Jean-Yves Blay ◽  
Heikki Joensuu ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Controlled Trial ◽  
Performance Status ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Double Blind Study ◽  
Open Label ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Multikinase Inhibitor

LBA10008 Background: Oral multikinase inhibitor regorafenib (REG) demonstrated substantial activity in a phase II trial in pts with GIST after failure of both IM and SU (J Clin Oncol. 2011; 29:606s; abstr 10007). This phase III, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of REG for this unmet clinical need. Methods: Eligible pts had metastatic and/or unresectable GIST, objective failure of both prior IM and SU (progressive disease [PD] on, or intolerance to, IM and PD on SU), ≥1 measurable lesion, ECOG performance status 0 or 1. Pts were randomized 2:1 to receive best supportive care plus either REG 160 mg po once daily (3 wks on/1 wk off) or placebo (PL). The primary endpoint was progression-free survival (PFS) (modified RECIST 1.1, independent central review). Secondary endpoints included overall survival (OS), disease control rate (DCR, defined as rate of partial response [PR] plus stable disease [SD] lasting for ≥12 wks), response rate and duration, safety and correlative genotype analyses. At time of PD, pts were eligible for unblinding and crossover to open-label REG. Results: Between Jan and Aug of 2011, 234 pts were screened; 199 were randomized (REG: 133, PL: 66). Pts were stratified at randomization according to number of prior systemic therapies and geographical region. Baseline characteristics were balanced between the two arms. The primary endpoint was met: median PFS was 4.8 months for REG vs. 0.9 months for PL. Hazard ratio for PFS was 0.27 (95% CI, 0.18-0.39), p<0.0001. PFS rates at 3 and 6 months were 60% and 38% for REG vs. 11% and 0% for PL. DCR was 53% (REG) vs. 9% (PL).The HR for OS was 0.77 (p=0.20) with 85% PL pts having crossed over to REG. The most common > grade 3 treatment-emergent AEs in the REG arm during double-blind study were hypertension (28%), hand-foot skin reaction (21%), and diarrhea (8%). Conclusions: This randomized trial demonstrated that REG significantly improved PFS and DCR in pts with advanced GIST after failure of at least prior IM and SU. REG was well tolerated, with AEs as expected for this class and manageable with dose modifications.

INTEGRATE: A randomized phase II double-blind placebo-controlled study of regorafenib in refractory advanced oesophagogastric cancer (AOGC)—A study by the Australasian Gastrointestinal Trials Group (AGITG), first results.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 9-9 ◽  
Author(s):  
Nick Pavlakis ◽  
Katrin Marie Sjoquist ◽  
Eric Tsobanis ◽  
Andrew Martin ◽  
Yoon-Koo Kang ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Secondary Analysis ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Prognostic Indicators ◽  
Controlled Study ◽  
Primary Analysis ◽  
Double Blind

9 Background: Advanced Oesophago-Gastric Carcinoma (AOGC) has limited options following failure of first or second line chemotherapy (CT). Regorafenib (REG) is an oral multi-kinase inhibitor of kinases involved in angiogenesis, tumor microenvironment, and oncogenesis. This study examined whether REG has sufficient activity and safety for further evaluation. Methods: International (Australia & New Zealand (ANZ), Korea, Canada (NCIC CTG)) randomised phase II trial with 2:1 randomisation and stratification by: (1) Lines of prior CT for advanced disease (1 vs. 2) and (2) Region. Eligible patients received best supportive care plus 160mg REG or matching PBO orally on days 1-21 each 28-day cycle until disease progression or prohibitive adverse events. Primary endpoint was progression free survival (PFS) in the REG arm, assuming median 8 weeks (wks) in PBO arm, aiming for 13.2 wks with REG to be of interest. Results: From Nov 2012 to Feb 2014, 152 patients were enrolled, 147 evaluable [pre-specified primary analysis population]: (REG n=97: PBO n=50); well matched for key baseline prognostic indicators; male:female (118:29); primary location: OG Junction (56), stomach (85); lines of prior therapy: 1 (63), 2 (84); ECOG 0 (62): 1 (85). Time on treatment: Median: 7.9 (REG) v 4 (PBO) wks. In the evaluable population median PFS was 11.1 wks (95% CI: 7.7 - 12.3) (REG) and 3.9 wks (95% CI: 3.7 - 4.0) (PBO), log-rank p <0.0001; HR 0.41 (95% CI: 0.28 to 0.59). PFS results were maintained for secondary analysis including all randomized patients (n = 152). REG was well tolerated, with the spectrum of toxicity in keeping with previous reports. Conclusions: PFS was clearly significantly longer with REG than PBO, though PBO PFS was less than anticipated. The pre-specified exploratory comparisons provide compelling evidence that REG has sufficient activity with acceptable tolerability in refractory AOGC to warrant phase III evaluation. Mature OS results will be presented at the meeting. Clinical trial information: 12612000239864.

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