Phase III, Double-Blind, Controlled Trial of Atamestane Plus Toremifene Compared With Letrozole in Postmenopausal Women With Advanced Receptor-Positive Breast Cancer

2007 ◽  
Vol 25 (31) ◽  
pp. 4961-4966 ◽  
Author(s):  
Paul Goss ◽  
Igor N. Bondarenko ◽  
Georgiy N. Manikhas ◽  
Kelly B. Pendergrass ◽  
Wilson H. Miller ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Controlled Trial ◽  
Objective Response ◽  
The United States ◽  
Phase Iii ◽  
Double Blind ◽  
Estrogen Receptor Modulators ◽  
Hazard Ratios ◽  
Baseline Characteristics ◽  
Receptor Modulators

Purpose To compare time to progression (TTP) with a steroidal aromatase inhibitor (AI) atamestane (ATA) combined with toremifene (TOR; complete estrogen blockade) versus letrozole (LET) in receptor-positive advanced breast cancer (ABC). Patients and Methods Eligibility included postmenopausal receptor-positive ABC and adjuvant hormonal therapy completed more than 12 months prior to study entry. Participants received daily ATA 500 mg with TOR 60 mg (ATA + TOR), or letrozole 2.5 mg (LET). The primary end point was TTP, whereas secondary objectives included objective response (OR), overall survival (OS), and time to treatment failure (TTF). The study had 80% power to detect a 25% increase in TTP assuming a TTP of 9.4 months in the LET population. Results A total of 865 patients were randomly assigned (434 to ATA + TOR and 431 to LET) in 60 centers in the United States, Canada, Russia, and Ukraine. Baseline characteristics were balanced. Median TTP was identical in the two arms at 11.2 months (P < .92). Median TTF was similar at 9.24 months (ATA + TOR) versus 10.44 months (LET). The hazard ratios (LET/ATA + TOR) were 1.00 (95% CI, 0.92 to 1.08) for TTP, 0.99 (95% CI, 0.92 to 1.06) for TTF, and 0.98 (95% CI, 0.87 to 1.11) for OS. OR occurred in 30% of patients receiving ATA + TOR and in 36% of patients receiving LET (P < .1). Adverse events (AEs) were similar for patients receiving ATA + TOR versus LET, and serious AEs were 10% v 11%, respectively. Conclusion TTP for patients receiving ATA + TOR was identical to that for patients receiving LET, representing the first endocrine therapy comparable to LET in ABC. Unlike in the Anastrozole, Tamoxifen, and Combined trial, addition of an antiestrogen did not decrease efficacy of the AI. Future studies of AIs in combination with more effective selective estrogen receptor modulators or selective receptor downregulators is warranted.

Brivanib in Patients With Advanced Hepatocellular Carcinoma Who Were Intolerant to Sorafenib or for Whom Sorafenib Failed: Results From the Randomized Phase III BRISK-PS Study

2013 ◽  
Vol 31 (28) ◽  
pp. 3509-3516 ◽  
Author(s):  
Josep M. Llovet ◽  
Thomas Decaens ◽  
Jean-Luc Raoul ◽  
Eveline Boucher ◽  
Masatoshi Kudo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Controlled Trial ◽  
Objective Response ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Time To Progression ◽  
Fibroblast Growth Factor Receptors ◽  
Double Blind ◽  
Dual Inhibitor

Purpose Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib. Patients and Methods In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety. Results Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%). Conclusion In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.

scholarly journals Circulating Tumor DNA Markers for Early Progression on Fulvestrant With or Without Palbociclib in ER+ Advanced Breast Cancer

2020 ◽  
Author(s):  
Ben O’Leary ◽  
Rosalind J Cutts ◽  
Xin Huang ◽  
Sarah Hrebien ◽  
Yuan Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Statistical Tests ◽  
Controlled Trial ◽  
Multivariable Analysis ◽  
Circulating Tumor Dna ◽  
Phase Iii ◽  
Genomic Alteration ◽  
Double Blind ◽  
Early Progression ◽  
Tumor Dna

Abstract Background There are no established molecular biomarkers for patients with breast cancer receiving combination endocrine and CDK4/6 inhibitor (CDK4/6i). We aimed to determine whether genomic markers in circulating tumor DNA (ctDNA) can identify patients at higher risk of early progression on fulvestrant therapy with or without palbociclib, a CDK4/6i. Methods PALOMA-3 was a phase III, multicenter, double-blind randomized controlled trial of palbociclib plus fulvestrant (n = 347) vs placebo plus fulvestrant (n = 174) in patients with endocrine-pretreated estrogen receptor–positive (ER+) breast cancer. Pretreatment plasma samples from 459 patients were analyzed for mutations in 17 genes, copy number in 14 genes, and circulating tumor fraction. Progression-free survival (PFS) was compared in patients with circulating tumor fraction above or below a prespecified cutoff of 10% and with or without a specific genomic alteration. All statistical tests were 2-sided. Results Patients with high ctDNA fraction had worse PFS on both palbociclib plus fulvestrant (hazard ratio [HR] = 1.62, 95% confidence interval [CI] = 1.17 to 2.24; P = .004) and placebo plus fulvestrant (HR = 1.77, 95% CI = 1.21 to 2.59; P = .004). In multivariable analysis, high-circulating tumor fraction was associated with worse PFS (HR = 1.20 per 10% increase in tumor fraction, 95% CI = 1.09 to 1.32; P &lt; .001), as was TP53 mutation (HR = 1.84, 95% CI = 1.27 to 2.65; P = .001) and FGFR1 amplification (HR = 2.91, 95% CI = 1.61 to 5.25; P &lt; .001). No interaction with treatment randomization was observed. Conclusions Pretreatment ctDNA identified a group of high-risk patients with poor clinical outcome despite the addition of CDK4/6 inhibition. These patients might benefit from inclusion in future trials of escalating treatment, with therapies that may be active in these genomic contexts.

RILOMET-1: An international phase III multicenter, randomized, double-blind, placebo-controlled trial of rilotumumab plus epirubicin, cisplatin, and capecitabine (ECX) as first-line therapy in patients with advanced MET-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS4153-TPS4153 ◽  
Author(s):  
David Cunningham ◽  
Salah-Eddin Al-Batran ◽  
Irina Davidenko ◽  
David H. Ilson ◽  
André M. Murad ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Human Monoclonal Antibody ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
Data Monitoring Committee ◽  
Phase Iii ◽  
Double Blind ◽  
Disease Extent

TPS4153 Background: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor that inhibits signaling through the MET receptor. In a randomized phase II study in patients with advanced G/GEJ adenocarcinoma, addition of rilotumumab every 3 weeks (Q3W) to ECX showed trends toward improved overall survival (OS) and progression-free survival (PFS) compared with ECX alone. In patients with high tumor MET expression and high rilotumumab exposure, the treatment effect of rilotumumab combined with ECX was significantly enhanced. Methods: In this phase III study, patients (planned N=450) are randomized 1:1 to ECX (intravenous [IV] epirubicin 50 mg/m2 on day 1, IV cisplatin 60 mg/m2 on day 1, and oral capecitabine 625 mg/m2 twice daily on days 1−21) plus double-blind rilotumumab 15 mg/kg or placebo IV Q3W. Randomization is stratified by disease extent (locally advanced vs metastatic) and Eastern Cooperative Oncology Group (ECOG) score (0 vs 1). Key eligibility criteria include previously untreated, pathologically confirmed unresectable locally advanced or metastatic G/GEJ adenocarcinoma; ECOG score 0 or 1; ≥18 years old; MET-positive by centralized immunohistochemistry; HER2-negative; adequate organ function; and ≥6 months since neoadjuvant/adjuvant therapy. The primary endpoint is OS. Key secondary endpoints include PFS, 12-month survival rate, objective response, OS in MET expression tertiles, safety, and pharmacokinetics. An exploratory objective is to assess associations between outcomes and tumor and circulating biomarkers. Enrollment began in November 2012, and the trial continues to accrue. An independent data monitoring committee will conduct planned interim reviews for safety and efficacy. Status: recruiting participants. Sponsored by Amgen Inc. Clinical trial information: NCT01697072.

NETTER-1 phase III: Progression-free survival, radiographic response, and preliminary overall survival results in patients with midgut neuroendocrine tumors treated with 177-Lu-Dotatate.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 194-194 ◽  
Author(s):  
Jonathan R. Strosberg ◽  
Edward M. Wolin ◽  
Beth Chasen ◽  
Matthew H. Kulke ◽  
David L Bushnell ◽  
...  
Keyword(s):  
Overall Survival ◽  
Neuroendocrine Tumors ◽  
Controlled Trial ◽  
Somatostatin Receptor ◽  
Objective Response ◽  
Progression Free Survival ◽  
The United States ◽  
Phase Iii ◽  
Octreotide Lar ◽  
Related Quality

194 Background: Currently, there are limited therapeutic options for patients with advanced midgut neuroendocrine tumors progressing on first-line somatostatin analog therapy. Methods: NETTER-1 is the first Phase III multicentric, randomized, controlled trial evaluating 177Lu-DOTA0-Tyr3-Octreotate (Lutathera) in patients with inoperable, progressive, somatostatin receptor positive midgut NETs. 230 patients with Grade 1-2 metastatic midgut NETs were randomized to receive Lutathera 7.4 GBq every 8 weeks (x4 administrations) versus Octreotide LAR 60 mg every 4-weeks. The primary endpoint was PFS per RECIST 1.1 criteria, with objective tumor assessment performed by an independent reading center every 12 weeks. Secondary objectives included objective response rate, overall survival, toxicity, and health-related quality of life. Results: Enrolment was completed in February 2015, with a target of 230 patients randomized (1:1) in 36 European and 15 sites in the United States. At the time of statistical analysis, the number of centrally confirmed disease progressions or deaths was 23 in the Lutathera group and 67 in the Octreotide LAR 60 mg group. The median PFS was not reached for Lutathera and was 8.4 months with 60 mg Octreotide LAR [95% CI: 5.8-11.0 months], p < 0.0001, with a hazard ratio of 0.21 [95% CI: 0.13-0.34]. Within the current evaluable patient dataset for tumor responses (n = 201), the number of CR+PR was 19 (18.8%) in the Lutathera group and 3 (3.0%) in the Octreotide LAR 60 mg group (p < 0.0004). Although the OS data were not mature enough for a definitive analysis, the number of deaths was 13 in the Lutathera group and 22 in the Octreotide LAR 60 mg group (p < 0.019 at interim analysis) which suggests an improvement in overall survival. Conclusions: The Phase III NETTER-1 trial provides evidence for a clinically meaningful and statistically significant increase in PFS and ORR, and also suggests a survival benefit in patients with advanced midgut NETs treated with Lutathera. Clinical trial information: NCT01578239.

SWOG S0715: Randomized placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy during adjuvant breast cancer therapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9018-9018 ◽  
Author(s):  
Dawn L. Hershman ◽  
Joseph M Unger ◽  
Katherine D. Crew ◽  
Carol Moinpour ◽  
Lori M. Minasian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Positive Impact ◽  
Controlled Trial ◽  
Performance Status ◽  
Primary Objective ◽  
Phase Iii ◽  
Unexpected Finding ◽  
Double Blind ◽  
Phase Ii Studies ◽  
The Mean

9018 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect of taxanes that leads to suboptimal treatment and diminished quality of life. Acetyl-L-Carnitine (ALC) is a natural compound involved in tubulin acetylation and neuronal protection. Pre-clinical and phase II studies suggest ALC may be effective for the prevention and treatment of CIPN. Methods: A randomized, double-blind, multi-center, phase III trial comparing ALC (1000 mg TID) vs placebo for 24 wks in women with stage I-III breast cancer undergoing adjuvant taxane therapy was conducted. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the FACT-Taxane scale (low score = worse NTX) at 12 wks. Secondary objectives included change at 24 wks, change in the Trial Outcome Index (TOI), fatigue (FACIT Fatigue) and NTX grade. Patients were stratified by planned treatment, and age (<60, ≥60). Results: 409 patients were evaluable (208 ALC, 201 placebo). No imbalances were observed by age, ethnicity, race, planned taxane treatment, performance status, or stage. The mean FACT-NTX score was 5.2 points lower at 12 wks on ALC and 4.5 points lower on placebo. In a linear regression adjusting for baseline score, planned treatment and age, wk 12 scores were 0.9 points lower on ALC than placebo (95% CI: -2.2 to 0.4, p=.17). At 24 wks, the mean observed FACT-NTX score was lower for ALC (5.3 vs. 3.6). In the multivariate model, wk 24 scores were 1.8 points lower on ALC (95% CI: -3.2 to -0.4, p=.01), representing more self-reported NTX. Grade 3/4 NTX was more frequent in the ALC arm (p=.04). Also at 24 wks, 38% on ALC had >5 point decrease score compared to 28% on placebo (OR=1.57, p=.05), and FACT-TOI scores were 3.5 points lower on ALC (95% CI: -6.5 to -0.4, p=.03). No differences between arms were observed for the FACIT-Fatigue scale or for other toxicities. Conclusions: There is no evidence that ALC has a positive impact on CIPN at 12 wks. However, ALC increases CIPN by 24 wks. Correlative studies are ongoing to explain this unexpected finding. Patients should be discouraged from using ALC and other supplements without proven efficacy.

MERiDiAN: A phase III, randomized, double-blind study of the efficacy, safety, and associated biomarkers of bevacizumab plus paclitaxel compared with paclitaxel plus placebo, as first-line treatment of patients with HER2-negative metastatic breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS1142-TPS1142 ◽  
Author(s):  
David Miles ◽  
Leonardo Faoro ◽  
Yan V. Wang ◽  
Joyce O'Shaughnessy
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Metastatic Breast Cancer ◽  
Objective Response ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Double Blind Study ◽  
Clinical Trial Registry ◽  
Double Blind ◽  
Treatment Benefit

TPS1142^ Background: Bevacizumab (BV), a humanized monoclonal antibody targeting the angiogenic VEGF, has demonstrated activity in patients with metastatic breast cancer (MBC). Plasma VEGF-A levels ([VEGF-A]p) appear to positively correlate with the effect of BV on progression-free survival (PFS) in MBC, metastatic pancreatic, and advanced gastric cancers. The MERiDiAN study will prospectively investigate (1) whether baseline [VEGF-A]ppredict treatment benefit with BV, (2) efficacy of BV with weekly paclitaxel (P), based on previously observed differences in the magnitude of benefit compared with BV + non-P chemotherapies. Methods: MERiDiAN is a global, randomized, double-blind, phase III study enrolling patients with HER2-negative MBC (first patient was enrolled in August 2012). The co-primary endpoints are PFS by investigator assessment in the intent-to-treat (ITT) population, and PFS in the subgroup with high baseline [VEGF-A]p. Secondary endpoints are overall survival (OS), 1-year survival, objective response rate and duration, and safety. Exploratory objectives include assessing the predictive or prognostic potential of blood, DNA and tumor tissue markers, and genetic variants involved in angiogenesis and tumorigenesis, with regard to BV efficacy and safety.Patients will be randomized 1:1 to either P 90 mg/m2 IV weekly (qw) for 3 weeks followed by a 1-week rest and BV 10 mg/kg every 2 weeks (q2w) until disease progression (PD); or P 90 mg/m2IV qw for 3 weeks followed by a 1-week rest and placebo 10 mg/kg q2w until PD. An interim analysis of OS will be performed at the time of the primary PFS analysis. Clinical Trial Registry Number NCT01663727. Clinical trial information: NCT01663727.

Efficacy and safety of gemcitabine in combination with TH-302 compared with gemcitabine in combination with placebo in previously untreated patients with metastatic or locally advanced unresectable pancreatic adenocarcinoma: The MAESTRO trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS4148-TPS4148 ◽  
Author(s):  
Eric Van Cutsem ◽  
Robert J. Fram ◽  
Michael Schlichting ◽  
David P. Ryan
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Controlled Trial ◽  
Performance Status ◽  
Objective Response ◽  
Locally Advanced ◽  
Predictive Biomarkers ◽  
Treatment Discontinuation ◽  
Phase Iii ◽  
Ecog Performance Status ◽  
Double Blind

TPS4148 Background: Tumors often consist of highly hypoxic subregions that are resistant to chemotherapy and radiotherapy. The investigational hypoxia-targeted drug TH-302 is reduced at its nitroimidazole group, and under hypoxic conditions releases the DNA alkylator bromo-isophosphoramide mustard (Br-IPM). A randomized Phase IIb trial of TH-302 in pts with metastatic or locally advanced unresectable pancreatic adenocarcinoma (PDAC) confirmed a significant PFS improvement (p=0.008) in pts treated with TH-302 at 340 mg/m2+ gemcitabine compared with gemcitabine alone (Borad et al, ESMO 2012). Skin and mucosal toxicities, mainly Grade 1/2, and myelosuppression (thrombocytopenia, neutropenia and anemia) were the most common AEs related to TH-302 and did not lead to increases in treatment discontinuation. Grade 3/4 myelosuppression was more frequent in the TH-302 + gemcitabine arm. AEs leading to treatment discontinuation as well as non-hematological serious AEs were balanced across arms. Methods: This is a Phase III, randomized, double-blind, placebo-controlled trial (NCT01746979) of gemcitabine + TH-302 compared with gemcitabine + placebo in pts with locally advanced unresectable or metastatic PDAC. The study is designed to detect a 25% risk reduction of death with 90% power and two-sided alpha of 5%. A total of 660 pts are planned to be randomized 1:1. Key eligibility criteria include histologically or cytologically confirmed disease, no prior chemotherapy or systemic therapy (except as specified in the protocol), ECOG performance status 0 – 1, and bilirubin ≤ 1.5x upper limit of normal. Randomized pts receive TH-302 + gemcitabine or gemcitabine + placebo in 4-week cycles until progressive disease, intolerable toxicity, or pt withdrawal. The primary objective is to evaluate OS. Secondary objectives include PFS, objective response, and disease control; safety and tolerability; pt-reported QoL and pain; CA 19-9 levels and PK of TH-302; exploratory pharmacogenomic markers and potential predictive biomarkers. Enrollment to the study is ongoing. Clinical trial information: NCT01746979.

HALT MBC: HER2 suppression with the addition of lapatinib to trastuzumab in HER2-positive metastatic breast cancer (LPT112515).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS658-TPS658
Author(s):  
Nancy U. Lin ◽  
Michael A. Danso ◽  
Alice K. David ◽  
Joseph J. Muscato ◽  
Daniel Rayson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Objective Response ◽  
Pathologic Complete Response ◽  
The United States ◽  
Phase Iii ◽  
Type I ◽  
Preoperative Treatment ◽  
Line Treatment ◽  
Second Line ◽  
Her2 Positive

TPS658 Background: Dual blockade of HER2 with the combination of trastuzumab (T) and lapatinib (L) enhances antitumor activity in HER2-positive breast cancer (BC) preclinical models due to the complementary mechanisms of action of the 2 agents. In patients (pts) with T-treated HER2-positive metastatic BC (MBC), treatment with the combination was associated with longer progression-free (PFS) and overall survival (OS) compared with L alone. In pts with stage II/III BC, preoperative treatment with the combination plus paclitaxel (P) resulted in significantly higher pathologic complete response rates compared with P combined with either agent alone. This evidence supports the concept of dual HER2 blockade as a treatment strategy for HER2-positive MBC. The present study is designed to evaluate whether the addition of L improves PFS among women with HER2-positive MBC receiving T as maintenance therapy. Methods: In this open-label, Phase III study, 280 pts will be stratified by line of treatment (first/second) and hormone receptor status (positive/negative), then randomized 1:1 to receive maintenance treatment with either L (1000 mg qd, continuously) in combination with T (6 mg/kg once every 3 weeks [q3w]) or T (6 mg/kg q3w) alone. Pts will receive study treatment until disease progression, death, discontinuation due to adverse events, or other reasons. The primary endpoint is PFS; secondary endpoints are OS, clinical benefit rate, and safety. Key eligibility criteria include pts with HER2-positive MBC who have completed 12 to 24 weeks of first- or second-line treatment with T plus chemotherapy with an objective response or stable disease at time of chemotherapy discontinuation. Pts with stable brain metastases are eligible if entering the study on second-line treatment. Efficacy endpoints will be analyzed in the ITT population. A total of 193 PFS events is required to detect a 50% increase in median PFS (hazard ratio=0.67) for L plus T compared with T alone (median PFS 27 vs 18 weeks, respectively). The hypothesis will be tested using a 1-sided test with 80% power and a type I error of 0.025. The trial is currently open for accrual in the United States and Canada.

Pertuzumab (P) with trastuzumab (T) and chemotherapy (CTX) in patients (pts) with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer: An international phase III study (JACOB).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS4150-TPS4150 ◽  
Author(s):  
Josep Tabernero ◽  
Paulo Marcelo Hoff ◽  
Lin Shen ◽  
Atsushi Ohtsu ◽  
Ron Yu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Her2 Positive ◽  
Double Blind ◽  
Patient Reported ◽  
Phase Iii Study ◽  
Unacceptable Toxicity

TPS4150 Background: Human epidermal growth factor receptor 2 (HER2) is overexpressed in ~20% of gastric cancers. Specific targeting of HER2 by T in combination with CTX has demonstrated significantly improved overall survival (OS) vs CTX in pts with advanced gastric or GEJ cancer (Bang Lancet 2010). In HER2-positive 1L metastatic breast cancer the combination of T plus docetaxel with a second HER2-targeted antibody, P, demonstrated significant improvement of progression-free survival (PFS) and OS vs placebo+T+docetaxel (Baselga NEJM 2012; Swain SABCS 2012). Based on these positive findings with HER2-targeted therapies in gastric and breast cancer, JACOB, a double-blind, placebo-controlled, randomized Phase III study, is designed to evaluate efficacy and safety of P+T+CTX in pts with HER2-positive 1L metastatic gastric or GEJ cancer. Methods: Pts will be randomized 1:1 to receive P+T+cisplatin+fluoropyrimidine or the same regimen replacing P with placebo, q3w (P: 840 mg; T: 8 mg/kg first dose, then 6 mg/kg; cisplatin: 80 mg/m2; 5-fluorouracil: 800 mg/m2/24 h given continuously for 120 h or capecitabine: 1000 mg/m2 bid for 14 days). P/placebo+T will be given until progressive disease (PD) or unacceptable toxicity. On or before Cycle 6, CTX should only be discontinued for PD or unacceptable toxicity. Continuation of CTX after Cycle 6 is at the discretion of pt and physician. Randomization will be stratified by region (Japan vs North America/Western Europe/Australia vs Asia [excluding Japan] vs South America/Eastern Europe), prior gastrectomy, and HER2-positivity (IHC 3+ vs IHC 2+ and ISH+). Primary endpoint: OS; secondary endpoints include PFS, objective response rate, duration of response, clinical benefit rate, safety, pharmacokinetics of P, and patient-reported outcomes. Tumor and blood samples for biomarker evaluation will be collected. The study is estimated to have 80% power to detect a significant improvement in OS at a two-sided α-level of 5% (HR=0.777), with ~502 deaths required for the primary analysis. Target enrollment is 780 pts from ~200 sites and 35 countries; FPI is planned for April 2013. NCT01774786 Clinical trial information: NCT01774786.

An International, Randomized, Double-blind, Placebo-controlled, Phase III Trial of Pregabalin Monotherapy in Treatment of Patients with Fibromyalgia

2011 ◽  
Vol 38 (12) ◽  
pp. 2643-2652 ◽  
Author(s):  
LYNNE PAUER ◽  
ANDREAS WINKELMANN ◽  
PIERRE ARSENAULT ◽  
ANDERS JESPERSEN ◽  
LAURENCE WHELAN ◽  
...  
Keyword(s):  
Pain Relief ◽  
Global Assessment ◽  
Controlled Trial ◽  
Fibromyalgia Impact Questionnaire ◽  
The United States ◽  
Phase Iii ◽  
Clinical Trial Registry ◽  
Double Blind ◽  
Double Blind Placebo ◽  
And Function

Objective.To evaluate the efficacy and safety of pregabalin monotherapy versus placebo for symptomatic pain relief and improvement of patient global assessment in patients with fibromyalgia (FM) enrolled from countries outside the United States.Methods.This international, multicenter, double-blind, placebo-controlled trial randomly assigned 747 patients with FM to placebo or 300, 450, or 600 mg/day pregabalin twice daily for 14 weeks. Primary efficacy measures were endpoint mean pain scores and Patient Global Impression of Change (PGIC). Secondary outcomes included assessments of sleep and function.Results.Patients in the 450 mg/day pregabalin group showed significant improvements versus placebo in endpoint mean pain score (−0.56; p = 0.0132), PGIC (73% improved vs 56% placebo; p = 0.0017), and function [Fibromyalgia Impact Questionnaire (FIQ) total score −5.85; p = 0.0012]. PGIC was also significant for 600 mg/day pregabalin (69% improved; p = 0.0227). Results for these endpoints were nonsignificant for pregabalin at 300 mg/day and for pain and FIQ score at 600 mg/day. Early onset of pain relief was seen, with separation from placebo detected by Week 1 in all pregabalin groups. All pregabalin doses demonstrated superiority to placebo on the Medical Outcomes Study-Sleep Scale Sleep Disturbance subscale and the Sleep Quality diary. Dizziness and somnolence were the most frequently reported adverse events.Conclusion.Pregabalin demonstrated modest efficacy in pain, global assessment, and function in FM at 450 mg/day, and improved sleep across all dose levels, but it did not provide consistent evidence of benefit at 300 and 600 mg/day in this study. Pregabalin was generally well tolerated for the treatment of FM. (Clinical trial registryNCT00333866).

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