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Overall Survival of Inoperable Gastric/GastroOesophageal Cancer Subjects on Treating With LMWH + Chemotherapy(CT) Versus Standard CT (GASTRANOX)
This study is currently recruiting participants.
Verified by Thrombosis Research Institute, August 2008
First Received: July 16, 2008   Last Updated: August 11, 2008   History of Changes
Sponsored by: Thrombosis Research Institute
Information provided by: Thrombosis Research Institute
ClinicalTrials.gov Identifier: NCT00718354
  Purpose

Due to evidence available both in terms of efficacy and safety of low molecular weight heparin, its use for the prevention of thromboembolic disease in cancer patients undergoing surgical intervention, and its extended use in higher doses for the prevention of recurrent thromboembolism in cancer patients with established thrombosis, with a view that the potential benefits for survival in cancer patients from low molecular weight heparin therapy comes because of a biological activity, the dose of 1mg/Kg (50% of the full treatment dose) for a period of 6 months coincident with 6 cycles of chemotherapy, has been chosen for this study.


Condition Intervention Phase
Gastric Cancer
Gastroesophageal Cancer
Drug: Enoxaparin
Drug: Standard Chemotherapy
Phase III

MedlinePlus related topics: Blood Thinners Cancer Stomach Cancer
Drug Information available for: Cisplatin Epirubicin hydrochloride Epirubicin Capecitabine Enoxaparin Sodium
U.S. FDA Resources
Study Type: Interventional
Study Design: Supportive Care, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study
Official Title: Randomized, Phase III-b, Multi-Centre, Open-Label, Parallel Study of Enoxaparin (Low Molecular Weight Heparin) Given Concomitantly With Chemotherapy vs Chemotherapy Alone in Patients With Inoperable Gastric and Gastro-Oesophageal Cancer

Further study details as provided by Thrombosis Research Institute:

Primary Outcome Measures:
  • Event Free Survival (EFS) - Composite endpoint of overall survival plus free of symptomatic VTE . [ Time Frame: up to 1 year from start of treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Incidence of SVTE Overall survival Major and minor haemorrhages during chemotherapy and / or up to 30 days after last dose is provided. Serious adverse events, All reported adverse events HIT [ Time Frame: upto 1 year from the start of treatment ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 740
Study Start Date: July 2008
Estimated Study Completion Date: April 2010
Estimated Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
B: Active Comparator
Standard Chemotherapy (upto 6 cycles)
Drug: Standard Chemotherapy
Investigator's discretion
A: Experimental
Enoxaparin: 1 mg/kg once daily in addition to standard chemotherapy up to 6 months
Drug: Enoxaparin
Once daily dose of 1mg/Kg of body weight for 6 months

Detailed Description:

In the GASTRANOX study, patients will have inoperable (locally advanced) or metastatic newly diagnosed gastric or gastro oesophageal cancer. These patients carry a definite thrombosis risk. Patients will be scheduled to have at least 6 months of palliative chemotherapy. During this period symptomatic thromboembolism will be common but currently no routine prophylaxis is provided.

The dose of Enoxaparin to be evaluated in this study is 1mg/kg. This represents half of the full treatment dose. For an average weight individual this will represent between 60 and 70 mg a day of Enoxaparin. The prophylactic dose for high-risk surgical patients in the United States is 60mg total daily dosing of Enoxaparin per day. This high-risk dose has been shown to be safe and effective in preventing thromboembolic disease in high-risk populations such as those undergoing major elective orthopaedic surgery. An alternative for high-risk dose is 40mg given once a day. This dose is also effective and safe. Thus the dose to be provided in the GASTRANOX study is not markedly different from the high-risk doses already in routine clinical practice either in North America (30mg twice a day - 60mg total daily dosing) or 40mg once a day in Europe. It is also half of the full treatment dose which has been shown to be effective and safe in the treatment of venous thromboembolism.

Since cancer patients are recognised to have bleeding risk it was felt inappropriate to provide the full treatment dose of Enoxaparin. Thus half the full treatment doses provided. On the other hand the biological effect of low molecular weight heparins in cancer suggests that higher doses be given to enhance the potential survival benefit.

The study is intended to evaluate the safety and efficacy of the study drug compared to best normal practice. The standard methodology for such a comparison is to conduct a randomized, comparative study. Multi-centre: It is anticipated that a single centre will be unable to recruit sufficient subjects, in 1 year, to conduct the assessment and therefore multiple centres will be recruited to conduct the study. Open Label: All patients will receive standard care at their site. It would not be feasible to expect placebo parenteral administration for six months.

All VTE events will be adjudicated. Mortality is an objective end-point. Standard treatment control: subjects will be treated according to best practice with half also receiving the study treatment.

Parallel-group: due to the nature of the condition this is the only practical design.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Signed written informed consent
  • Male or Female of age 18-75 years
  • Histologically confirmed gastric or gastro-oesophageal carcinoma.
  • Adenocarcinoma of the stomach stage III or IV considered inoperable at presentation.
  • ECOG performance status ≤ 1
  • Criteria for chemotherapy fulfilled (haematological, hepatic, renal).
  • Ability to receive daily injection (self-injection or by patient relative).
  • Urine-Pregnancy test negative.
  • Consent to the use of Contraceptive for women of child bearing age group

Exclusion Criteria:

  • History of previous malignancy within the previous 5 years (except curatively treated carcinoma in situ of the uterine cervix, or basal cell carcinoma of the skin), or concomitant malignancy.
  • Prior treatment with chemotherapy or radiotherapy if relapse less than 6 months
  • Non-epithelial gastric tumours, borderline tumours.
  • Medically unstable patients, including but not limited to those with active infection, acute hepatitis, gastrointestinal bleeding, uncontrolled cardiac arrhythmias, interstitial lung disease, inflammatory bowel disease, uncontrolled angina, uncontrolled hypercalcaemia, uncompensated congestive heart failure, uncontrolled diabetes, persistent renal failure, dementia, seizures, superior vena cava syndrome.
  • Persistent renal failure (persistent value of the calculated creatinine clearance < 30 mL/min defined as a documented value < 30 mL/min on at least 2 occasions ≥ 3 days prior entry into the study).
  • Prosthetic heart valves.
  • Any evidence of active bleeding disorder or risk of bleeding identified on fibroscopy done as a routine investigation before the consent for the trial. Fibroscopy is not mandatory to be done for the trial
  • Current, objectively-verified DVT, PE or other clinically significant thrombosis.
  • Documented previous episode of heparin-induced thrombocytopenia and/or thrombosis (HIT, HAT, or HITTS).
  • Contraindications to anticoagulation
  • Coagulopathies (acquired or inherited)
  • Prior history of cerebral hemorrhage or neurosurgery within the previous month
  • Bacterial endocarditis
  • Uncontrolled arterial hypertension (systolic BP:200 mmHg or diastolic BP:110 mmHg) at 2 successive readings
  • Haemostatic abnormalities: circulating anticoagulant, baseline platelet count <50 000/mm3, activated partial thromboplastin time (aPTT) value 1.5 x the upper limit of normal, or International Normalized Ratio (INR) >1.5. The laboratory test valid would be no earlier than 14 days for this criterion.
  • Indication for thrombolytic therapy
  • Any long-term anticoagulant therapy for medical condition.
  • Immunocompromised subjects, such as subjects with known HIV and those who have either had an AIDS-defining condition (e.g. Kaposi's sarcoma, Pneumocystitis carinii pneumonia) or have CD4 + T-lymphocyte count < 200 /mm3.
  • Known hypersensitivity to heparin, or LMWH, or pork derived products.
  • Body weight >100 kg.
  • Pregnant or lactating women.
  • Women of childbearing potential not protected by effective contraceptive method of birth control and/or who are unwilling to be tested for pregnancy (pregnancy status should be checked by serum or urine pregnancy testing prior to exposure to the investigational product
  • Participation in another clinical trial (study medications / study devices) within the previous 30 days. (Surgical trials are allowed).
  • Psychiatric disorders of altered mentation that would preclude understanding of the informed consent process.
  • Psychological, familial, sociological, or geographical conditions, which do not permit treatment and/or medical follow-up required to comply with the study protocol.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00718354

Contacts
Contact: Janice M Maganji, MBBS 00447824836535 mmaganji@tri-london.ac.uk

Locations
India, West Bengal
Biswajit Sanyal Recruiting
Calcutta, West Bengal, India
Contact: Biswajit Sanyal, MD            
Principal Investigator: Biswajit Sanyal, MD            
Sponsors and Collaborators
Thrombosis Research Institute
Investigators
Principal Investigator: Ajay K Kakkar, PhD Thrombosis Research Institute
  More Information

Publications:
Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer. 2001 Oct;37 Suppl 8:S4-66. Review. No abstract available.
Lee YJ, Jy W, Horstman LL, Janania J, Reyes Y, Kelley RE, Ahn YS. Elevated platelet microparticles in transient ischemic attacks, lacunar infarcts, and multiinfarct dementias. Thromb Res. 1993 Nov 15;72(4):295-304.
Powell J, McConkey CC. The rising trend in oesophageal adenocarcinoma and gastric cardia. Eur J Cancer Prev. 1992 Apr;1(3):265-9.
Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin 2000; 50(1):7-33
Cohen AT, Wagner MB, Mohamed MS. Risk factors for bleeding in major abdominal surgery using heparin thromboprophylaxis. Am J Surg. 1997 Jul;174(1):1-5.
Ajani JA. Chemotherapy for gastric carcinoma: new and old options. Oncology (Williston Park). 1998 Oct;12(10 Suppl 7):44-7. Review.
Panzini I, Gianni L, Fattori PP, Tassinari D, Imola M, Fabbri P, Arcangeli V, Drudi G, Canuti D, Fochessati F, Ravaioli A. Adjuvant chemotherapy in gastric cancer: a meta-analysis of randomized trials and a comparison with previous meta-analyses. Tumori. 2002 Jan-Feb;88(1):21-7.
Petralia GA, Lemoine NR, Kakkar AK. Mechanisms of disease: the impact of antithrombotic therapy in cancer patients. Nat Clin Pract Oncol. 2005 Jul;2(7):356-63. Review.
Thodiyil PA, Kakkar AK. Variation in relative risk of venous thromboembolism in different cancers. Thromb Haemost. 2002 Jun;87(6):1076-7. No abstract available.
Mismetti P, Laporte S, Darmon JY, Buchmuller A, Decousus H. Meta-analysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery. Br J Surg. 2001 Jul;88(7):913-30.
Bergqvist D, Agnelli G, Cohen AT, Eldor A, Nilsson PE, Le Moigne-Amrani A, Dietrich-Neto F; ENOXACAN II Investigators. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med. 2002 Mar 28;346(13):975-80.
Rasmussen MS. Does prolonged thromboprophylaxis improve outcome in patients undergoing surgery? Cancer Treat Rev. 2003 Jun;29 Suppl 2:15-7.
Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK, Rustin G, Thomas M, Quigley M, Williamson RC. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol. 2004 May 15;22(10):1944-8.
Altinbas M, Coskun HS, Er O, Ozkan M, Eser B, Unal A, Cetin M, Soyuer S. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost. 2004 Aug;2(8):1266-71.
Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53.
Klerk CPW SS, Otten JMM, Buller HR, on behalf of the MALT Stusy Group. Malignancy and low molwcular weight heparin therapy: the MALT trial. Phathophysiology of Haemostasis and Thrombosis 2003; 33(Suppl 1):75.
von Tempelhoff GF, Harenberg J, Niemann F, Hommel G, Kirkpatrick CJ, Heilmann L. Effect of low molecular weight heparin (Certoparin) versus unfractionated heparin on cancer survival following breast and pelvic cancer surgery: A prospective randomized double-blind trial. Int J Oncol. 2000 Apr;16(4):815-24.
Lee AYY RF, Julian JA, Gent M, Baker RI, Bowden C, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of outsubjects with cancer and venous thromboembolism. Journal of Clinical Oncology 2005; 23(10):1-7.

Responsible Party: Thrombosis Research Institute ( Prof A K Kakkar )
Study ID Numbers: TRI0702
Study First Received: July 16, 2008
Last Updated: August 11, 2008
ClinicalTrials.gov Identifier: NCT00718354     History of Changes
Health Authority: India: Drugs Controller General of India

Keywords provided by Thrombosis Research Institute:
Bleeding events

Study placed in the following topic categories:
Antimetabolites
Gastrointestinal Diseases
Esophageal Neoplasms
Heparin, Low-Molecular-Weight
Fibrinolytic Agents
Hemorrhage
Calcium heparin
Body Weight
Anti-Bacterial Agents
Fibrin Modulating Agents
Oxaliplatin
Stomach Diseases
Cisplatin
Stomach Neoplasms
Heparin
Capecitabine
Anticoagulants
Digestive System Neoplasms
Esophageal Cancer
Cardiovascular Agents
Carboplatin
Epirubicin
Enoxaparin
Digestive System Diseases
Radiation-Sensitizing Agents
Esophageal Disorder
Fluorouracil
Gastrointestinal Neoplasms
Stomach Cancer
Esophageal Diseases

Additional relevant MeSH terms:
Antimetabolites
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Gastrointestinal Diseases
Antineoplastic Agents
Heparin, Low-Molecular-Weight
Physiological Effects of Drugs
Hematologic Agents
Fibrinolytic Agents
Antibiotics, Antineoplastic
Fibrin Modulating Agents
Stomach Diseases
Neoplasms by Site
Cisplatin
Stomach Neoplasms
Therapeutic Uses
Capecitabine
Digestive System Neoplasms
Anticoagulants
Cardiovascular Agents
Epirubicin
Pharmacologic Actions
Enoxaparin
Neoplasms
Digestive System Diseases
Radiation-Sensitizing Agents
Gastrointestinal Neoplasms

ClinicalTrials.gov processed this record on May 07, 2009