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Oxaliplatin, Capecitabine and Avastin for Metastatic Esophagogastric Adenocarcinoma (XAGastric)

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ClinicalTrials.gov Identifier: NCT00447330
Recruitment Status : Completed
First Posted : March 14, 2007
Results First Posted : January 28, 2015
Last Update Posted : February 13, 2015
Hoffmann-La Roche
Genentech, Inc.
Information provided by (Responsible Party):
Duke University

Brief Summary:
The purpose of this study is to evaluate the progression free survival of capecitabine (Xeloda), oxaliplatin and bevacizumab (Avastin) in previously untreated metastatic esophagogastric adenocarcinomas.

Condition or disease Intervention/treatment Phase
Esophageal Neoplasms Stomach Neoplasms Neoplasm Metastasis Drug: capecitabine (Xeloda), oxaliplatin and bevacizumab (Avastin) Phase 2

Detailed Description:

The number of new cases of esophageal and gastric cancers in the United States in 2005 is 14520 for esophageal cancer and 21860 for gastric cancer. Unfortunately, esophageal and gastric cancers will also account for 13570 and 11550 deaths, respectively, in 2005. The 5 year survival rates for metastatic gastroesophageal, GE junctional, and gastric cancers are less than 5%. The major current treatment modality for patients with advanced esophageal, GE junctional, and gastric adenocarcinomas is systemic chemotherapy.

We seek to investigate the efficacy of capecitabine and oxaliplatin in combination with bevacizumab as first line treatment for metastatic esophagogastric cancers. The choice of capecitabine and oxaliplatin is made to develop a user-friendly biologically-based regimen, offering patients oral capecitabine in place of continuous 5FU infusion pumps. Since capecitabine can be given crushed this regimen may both be active and user-friendly. Preliminary data in colorectal cancer suggest that the regimen of capecitabine, oxaliplatin, and bevacizumab has comparable activity to FOLFOX-bevacizumab. The goal of the proposed regimen is to define a capecitabine and oxaliplatin-based regimen that optimizes biological approaches over cytotoxic approaches. The addition of bevacizumab to chemotherapy regimens for metastatic colorectal cancer, metastatic non-small cell lung cancer, and metastatic breast cancer has shown to improve response rates and overall survival. If active, this regimen could serve as a first line comparator to the capecitabine, oxaliplatin, and epirubicin combination. This approach will also help to simplify regimen development across gastrointestinal cancers.

In addition to the primary efficacy endpoint of this protocol, several correlative endpoints will also be examined in an exploratory manner. The importance of developing blood-based and tumor biomarkers has been extensively reviewed. However, the role of such predictive markers has not been well studied for XELOX-A. This information is important since it may help define which populations are most likely to benefit and most likely to suffer significant toxicity from this important GI cancer regimen. This biomarker approach may also help understand and define mechanisms of sensitivity, resistance, and toxicity that may be used to guide future hypothesis-driven studies designed to improve the efficacy and safety of this regimen. The correlative biomarker endpoints include serum, plasma and urine biomarkers (e.g. VEGF and bFGF), a wound healing model of angiogenesis, and tumor biopsy studies .

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase ll Study of Oxaliplatin, Capecitabine, and Bevacizumab in the Treatment of Metastatic Esophagogastric Adenocarcinomas
Study Start Date : February 2007
Primary Completion Date : January 2014
Study Completion Date : July 2014

Arm Intervention/treatment
Experimental: 1 Drug: capecitabine (Xeloda), oxaliplatin and bevacizumab (Avastin)

Capecitabine will be administered orally at a twice daily dose of 850 mg/m2 (equivalent to a total daily dose of 1700 mg/m2) given days 1-14 of the three week cycle.

Oxaliplatin will be administered at the dose of 130 mg/m2 given as a 2-hour intravenous infusion on day 1 of a three week cycle.

Bevacizumab will be administered at a dose of 15 mg/kg given as a 30-90 minute intravenous infusion on day 1 of a three week cycle following the administration of oxaliplatin.

Primary Outcome Measures :
  1. Median Progression-Free Survival (PFS) [ Time Frame: 5 years from study start date ]
    Time in months from the start of study treatment to the date of first progression (PD) according to the RECIST criteria, or death due to any cause. PER RECIST, a PD is indicated when there is at least a 20% increase in the sum of the longest diameters from target lesions relative to the smallest sum recorded since treatment is initiated. Median PFS was estimated using a Kaplan-Meier curve, and is the time at which 50% of patients remain alive without disease progression.

Secondary Outcome Measures :
  1. To Assess the Safety and Tolerability of the Combination of Bevacizumab, Oxaliplatin and Capecitabine in Patients With Previously Untreated Metastatic Esophagogastric Adenocarcinoma [ Time Frame: Every 21 days ]
    Number of subjects who experienced an adverse event

  2. Response Rate [ Time Frame: Every 9 weeks for up to 1 year ]
    The proportion of patients for whom the best overall response is complete response (CR) or partial response (PR). A CR occurs when all lesions disappear; whereas, a PR is indicated when there is at least a 30% decrease in the sum of the longest diameters (LD) of the target lesion. A PD (progressive disese) occurs when there is at least a 20% increase in the sum of the LD relative to the smallest sum LD recorded since treatment is initiated. Disease is considered stable if there is no response and no PD. All patients were assigned a best response for inclusion in this calculation in accordance with the protocol.

  3. Median Survival [ Time Frame: 5 years after study start date ]
    Time in months from the start of study treatment to date of death due to any cause. Median survival was estimated using a Kaplan-Meier curve and is the time point at which 50% of patients remain alive.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Primary Inclusion Criteria:

  • Histologically or cytologically documented and radiographically measurable adenocarcinoma of the esophagus or stomach that is metastatic/recurrent and not amenable to potentially curative treatment
  • No prior therapy for metastatic disease
  • Prior radiation therapy is permitted, provided it is completed > 28 days prior to day 1 of study drug
  • Normal organ and marrow function
  • Karnofsky Performance Status 70-100%

Primary Exclusion Criteria:

  • Unstable or poorly controlled hypertension > 150/100 mm Hg
  • Arterial thromboembolic events within 6 months
  • Clinically significant uncontrolled cardiac disease
  • Significant proteinuria at baseline
  • Grade 2 or greater peripheral neuropathy
  • History of abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00447330

United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
University of Wake Forest Baptist Medical Center
Winston Salem, North Carolina, United States, 27157-0001
Sponsors and Collaborators
Duke University
Hoffmann-La Roche
Genentech, Inc.
Principal Investigator: Hope E Uronis, MD Duke University

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Miller, K.D., et al. E2100: A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first line threapy for locally recurrent or metastatic breast cancer. in American Society for Clinical Oncology. 2005. Orlando, FL.
Shah, M.A., et al. A Multicenter Phase II Study of Irinotecan (CPT), Cisplatin (CIS), and Bevacizumab (BEV) in Patients with Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma. in Proc Am Soc Clin Oncol. 2005.
Goldberg, R.M., et al. N9741: oxaliplatin (Oxal) or CPT-11 + 5-fluorouracil (5FU)/leucovorin (LV) or oxal + CPT-11 in advanced colorectal cancer (CRC). Updated efficacy and quality of life (QOL) data from an intergroup study. in Proc Am Soc Clin Oncol. 2003.
Xeloda Investigator Drug Brochure (Ro 09-1978), in Version 6. January 2002.
Ishitsuka, H., T. Ishikawa, and Y. Fukase. Capecitabine and the dThdPase up-regulators IFN-gamma or taxol showed synergistic activity in human cancer xenografts. in Proc Am Assoc Cancer Res. 1996.
Giantonio, B.J., et al. Incorporating angiogenesis inhibition with bevacizumab (anti-VEGF) into frontline chemotherapy with irinotecan (CPT-11), fluorouracil and leucovorin (FU/LV) for advanced colorectal cancer (advCRC): a toxicity analysis of ECOG study E2200. in Proc Am Soc Clin Oncol. 2002.
Hochster, H., et al. Bevacizumab (B) with oxaliplatin (O)-based chemotherapy in the first-line therapy of metastatic colorectal cancer (mCRC): Preliminary results of the randomized モTREE-2ヤ trial. in Proc Am Soc Clin Oncol. 2005.
Hurwitz, H., S.N. Holden, and S.G. Eckhardt, Clinical evaluation of ZD6474, an orally active inhibitor of VEGF signaling in patients with solid tumors. Proceedings of the American Society of Clinical Oncology, 2002. 21: p. Abstract 325.
Hurwitz, H., et al. Wound healing/bleeding in metastatic colorectal cancer patients who undergo surgery during treatment with bevacizumab. in Proc Am Soc Clin Oncol. 2004.
Scappaticci, F., et al. Analysis of wound healing and bleeding post-surgery in metastatic colorectal cancer patients treated with bevacizumab. in Proc Am Soc Clin Oncol. 2004.
Hurwitz, H., et al. Clinical evaluation of ZD6474, an orally active inhibitor of VEGF signaling, in patients with solid tumors. in Proc Am Soc Clin Oncol. 2002.
Brookmeyer, R. and J.J. Crowley, A confidence interval for the median survival time. Biometrics, 1982. 38: p. 29-41.

Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT00447330     History of Changes
Other Study ID Numbers: Pro00008710
11100 ( Other Identifier: Old FDA IND Number )
8797 ( Other Identifier: Duke legacy protocol number )
First Posted: March 14, 2007    Key Record Dates
Results First Posted: January 28, 2015
Last Update Posted: February 13, 2015
Last Verified: July 2014

Keywords provided by Duke University:
metastatic esophagogastric adenocarcinomas

Additional relevant MeSH terms:
Neoplasm Metastasis
Stomach Neoplasms
Esophageal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplastic Processes
Pathologic Processes
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Head and Neck Neoplasms
Esophageal Diseases
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action