Oxaliplatin, Capecitabine and Avastin for Metastatic Esophagogastric Adenocarcinoma

NCT ID: NCT00447330

Last Updated: 2015-02-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-02-28
• Study Completion Date: 2014-07-31

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.

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 .

Conditions

Esophageal Neoplasms; Stomach Neoplasms; Neoplasm Metastasis

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

1

Group Type: EXPERIMENTAL

capecitabine (Xeloda), oxaliplatin and bevacizumab (Avastin)

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Eligibility Criteria

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%

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: collaborator

Sanofi

INDUSTRY

Sponsor Role: collaborator

Genentech, Inc.

INDUSTRY

Sponsor Role: collaborator

Duke University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hope E Uronis, MD

Role: PRINCIPAL_INVESTIGATOR

Duke University

Locations

Duke University Medical Center

Durham, North Carolina, United States

University of Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, United States

Countries

United States

References

Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ. Cancer statistics, 2005. CA Cancer J Clin. 2005 Jan-Feb;55(1):10-30. doi: 10.3322/canjclin.55.1.10.

Reference Type: BACKGROUND

PMID: 15661684 (View on PubMed)

Bollschweiler E, Wolfgarten E, Gutschow C, Holscher AH. Demographic variations in the rising incidence of esophageal adenocarcinoma in white males. Cancer. 2001 Aug 1;92(3):549-55. doi: 10.1002/1097-0142(20010801)92:33.0.co;2-l.

Reference Type: BACKGROUND

PMID: 11505399 (View on PubMed)

Wijnhoven BP, Siersema PD, Hop WC, van Dekken H, Tilanus HW. Adenocarcinomas of the distal oesophagus and gastric cardia are one clinical entity. Rotterdam Oesophageal Tumour Study Group. Br J Surg. 1999 Apr;86(4):529-35. doi: 10.1046/j.1365-2168.1999.01082.x.

Reference Type: BACKGROUND

PMID: 10215831 (View on PubMed)

Glimelius B, Ekstrom K, Hoffman K, Graf W, Sjoden PO, Haglund U, Svensson C, Enander LK, Linne T, Sellstrom H, Heuman R. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol. 1997 Feb;8(2):163-8. doi: 10.1023/a:1008243606668.

Reference Type: BACKGROUND

PMID: 9093725 (View on PubMed)

Hsu CH, Yeh KH, Chen LT, Liu JM, Jan CM, Lin JT, Chen YC, Cheng AL. Weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin in the treatment of advanced gastric cancers. An effective and low-toxic regimen for patients with poor general condition. Oncology. 1997 Jul-Aug;54(4):275-80. doi: 10.1159/000227702.

Reference Type: BACKGROUND

PMID: 9216850 (View on PubMed)

Leichman L, McDonald B, Dindogru A, Samson M, Vaitkevicius VK. Cisplatin. An active drug in the treatment of disseminated gastric cancer. Cancer. 1984 Jan 1;53(1):18-22. doi: 10.1002/1097-0142(19840101)53:13.0.co;2-j.

Reference Type: BACKGROUND

PMID: 6317158 (View on PubMed)

Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Mansi J, Findlay M, Hill A, Oates J, Nicolson M, Hickish T, O'Brien M, Iveson T, Watson M, Underhill C, Wardley A, Meehan M. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol. 1997 Jan;15(1):261-7. doi: 10.1200/JCO.1997.15.1.261.

Reference Type: BACKGROUND

PMID: 8996151 (View on PubMed)

Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, Shimma N, Umeda I, Ishitsuka H. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer. 1998 Jul;34(8):1274-81. doi: 10.1016/s0959-8049(98)00058-6.

Reference Type: BACKGROUND

PMID: 9849491 (View on PubMed)

Schuller J, Cassidy J, Dumont E, Roos B, Durston S, Banken L, Utoh M, Mori K, Weidekamm E, Reigner B. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol. 2000;45(4):291-7. doi: 10.1007/s002800050043.

Reference Type: BACKGROUND

PMID: 10755317 (View on PubMed)

Hong YS, Song SY, Lee SI, Chung HC, Choi SH, Noh SH, Park JN, Han JY, Kang JH, Lee KS, Cho JY. A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol. 2004 Sep;15(9):1344-7. doi: 10.1093/annonc/mdh343.

Reference Type: BACKGROUND

PMID: 15319239 (View on PubMed)

Koizumi W, Saigenji K, Ujiie S, Terashima M, Sakata Y, Taguchi T; Clinical Study Group of Capecitabine. A pilot phase II study of capecitabine in advanced or recurrent gastric cancer. Oncology. 2003;64(3):232-6. doi: 10.1159/000069313.

Reference Type: BACKGROUND

PMID: 12697963 (View on PubMed)

Kim TW, Kang YK, Ahn JH, Chang HM, Yook JH, Oh ST, Kim BS, Lee JS. Phase II study of capecitabine plus cisplatin as first-line chemotherapy in advanced gastric cancer. Ann Oncol. 2002 Dec;13(12):1893-8. doi: 10.1093/annonc/mdf323.

Reference Type: BACKGROUND

PMID: 12453857 (View on PubMed)

Evans TR, Pentheroudakis G, Paul J, McInnes A, Blackie R, Raby N, Morrison R, Fullarton GM, Soukop M, McDonald AC. A phase I and pharmacokinetic study of capecitabine in combination with epirubicin and cisplatin in patients with inoperable oesophago-gastric adenocarcinoma. Ann Oncol. 2002 Sep;13(9):1469-78. doi: 10.1093/annonc/mdf243.

Reference Type: BACKGROUND

PMID: 12196374 (View on PubMed)

Al-Batran SE, Atmaca A, Hegewisch-Becker S, Jaeger D, Hahnfeld S, Rummel MJ, Seipelt G, Rost A, Orth J, Knuth A, Jaeger E. Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer. J Clin Oncol. 2004 Feb 15;22(4):658-63. doi: 10.1200/JCO.2004.07.042.

Reference Type: BACKGROUND

PMID: 14966088 (View on PubMed)

Louvet C, Andre T, Tigaud JM, Gamelin E, Douillard JY, Brunet R, Francois E, Jacob JH, Levoir D, Taamma A, Rougier P, Cvitkovic E, de Gramont A. Phase II study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients. J Clin Oncol. 2002 Dec 1;20(23):4543-8. doi: 10.1200/JCO.2002.02.021.

Reference Type: BACKGROUND

PMID: 12454110 (View on PubMed)

Diaz-Rubio E, Evans TR, Tabemero J, Cassidy J, Sastre J, Eatock M, Bisset D, Regueiro P, Baselga J. Capecitabine (Xeloda) in combination with oxaliplatin: a phase I, dose-escalation study in patients with advanced or metastatic solid tumors. Ann Oncol. 2002 Apr;13(4):558-65. doi: 10.1093/annonc/mdf065.

Reference Type: BACKGROUND

PMID: 12056706 (View on PubMed)

Cassidy J, Tabernero J, Twelves C, Brunet R, Butts C, Conroy T, Debraud F, Figer A, Grossmann J, Sawada N, Schoffski P, Sobrero A, Van Cutsem E, Diaz-Rubio E. XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol. 2004 Jun 1;22(11):2084-91. doi: 10.1200/JCO.2004.11.069.

Reference Type: BACKGROUND

PMID: 15169795 (View on PubMed)

Shields AF, Zalupski MM, Marshall JL, Meropol NJ. Treatment of advanced colorectal carcinoma with oxaliplatin and capecitabine: a phase II trial. Cancer. 2004 Feb 1;100(3):531-7. doi: 10.1002/cncr.11925.

Reference Type: BACKGROUND

PMID: 14745869 (View on PubMed)

de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. doi: 10.1200/JCO.2000.18.16.2938.

Reference Type: BACKGROUND

PMID: 10944126 (View on PubMed)

Sumpter, K., et al. Randomised, mulitcenter phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer: confirmation of dose escalation. in Proc Am Soc Clin Onocol. 2003.

Reference Type: BACKGROUND

Chong G, Cunningham D. Can cisplatin and infused 5-fluorouracil be replaced by oxaliplatin and capecitabine in the treatment of advanced oesophagogastric cancer? The REAL 2 trial. Clin Oncol (R Coll Radiol). 2005 Apr;17(2):79-80. doi: 10.1016/j.clon.2004.12.004. No abstract available.

Reference Type: BACKGROUND

PMID: 15830568 (View on PubMed)

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. doi: 10.1056/NEJMoa032691.

Reference Type: BACKGROUND

PMID: 15175435 (View on PubMed)

Giantonio, B., et al. High-dose bevacizumab in combination with FOLFOX4 improves survival in patients with previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. in Proc Am Soc Clin Oncol. 2005.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

Takimoto CH, Remick SC, Sharma S, Mani S, Ramanathan RK, Doroshow J, Hamilton A, Mulkerin D, Graham M, Lockwood GF, Ivy P, Egorin M, Schuler B, Greenslade D, Goetz A, Knight R, Thomas R, Monahan BP, Dahut W, Grem JL; National Cancer Institute Organ Dysfunction Working Group Study. Dose-escalating and pharmacological study of oxaliplatin in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study. J Clin Oncol. 2003 Jul 15;21(14):2664-72. doi: 10.1200/JCO.2003.11.015.

Reference Type: BACKGROUND

PMID: 12860942 (View on PubMed)

Xeloda Investigator Drug Brochure (Ro 09-1978), in Version 6. January 2002.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

Poon RT, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol. 2001 Feb 15;19(4):1207-25. doi: 10.1200/JCO.2001.19.4.1207.

Reference Type: BACKGROUND

PMID: 11181687 (View on PubMed)

Lockhart AC, Braun RD, Yu D, Ross JR, Dewhirst MW, Klitzman B, Yuan F, Grichnik JM, Proia AD, Conway DA, Mann G, Hurwitz HI. A clinical model of dermal wound angiogenesis. Wound Repair Regen. 2003 Jul-Aug;11(4):306-13. doi: 10.1046/j.1524-475x.2003.11411.x.

Reference Type: BACKGROUND

PMID: 12846919 (View on PubMed)

Lockhart AC, Braun RD, Yu D, Ross JR, Dewhirst MW, Humphrey JS, Thompson S, Williams KM, Klitzman B, Yuan F, Grichnik JM, Proia AD, Conway DA, Hurwitz HI. Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor. Clin Cancer Res. 2003 Feb;9(2):586-93.

Reference Type: BACKGROUND

PMID: 12576422 (View on PubMed)

Holden SN, Eckhardt SG, Basser R, de Boer R, Rischin D, Green M, Rosenthal MA, Wheeler C, Barge A, Hurwitz HI. Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors. Ann Oncol. 2005 Aug;16(8):1391-7. doi: 10.1093/annonc/mdi247. Epub 2005 May 19.

Reference Type: BACKGROUND

PMID: 15905307 (View on PubMed)

Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K, Chi JT, van de Rijn M, Botstein D, Brown PO. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol. 2004 Feb;2(2):E7. doi: 10.1371/journal.pbio.0020007. Epub 2004 Jan 13.

Reference Type: BACKGROUND

PMID: 14737219 (View on PubMed)

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.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

Gerber HP, Kowalski J, Sherman D, Eberhard DA, Ferrara N. Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res. 2000 Nov 15;60(22):6253-8.

Reference Type: BACKGROUND

PMID: 11103779 (View on PubMed)

Kim ES, Serur A, Huang J, Manley CA, McCrudden KW, Frischer JS, Soffer SZ, Ring L, New T, Zabski S, Rudge JS, Holash J, Yancopoulos GD, Kandel JJ, Yamashiro DJ. Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11399-404. doi: 10.1073/pnas.172398399. Epub 2002 Aug 12.

Reference Type: BACKGROUND

PMID: 12177446 (View on PubMed)

Brookmeyer, R. and J.J. Crowley, A confidence interval for the median survival time. Biometrics, 1982. 38: p. 29-41.

Reference Type: BACKGROUND

Other Identifiers

11100

Identifier Type: OTHER

Identifier Source: secondary_id

8797

Identifier Type: OTHER

Identifier Source: secondary_id

Pro00008710

Identifier Type: -

Identifier Source: org_study_id