Combination Chemotherapy With or Without Bevacizumab in Treating Patients With Previously Untreated Stomach Cancer or Gastroesophageal Junction Cancer That Can Be Removed by Surgery

Condition(s) targeted: Gastric Cancer

Intervention: bevacizumab (Drug); capecitabine (Drug); cisplatin (Drug); epirubicin hydrochloride (Drug); adjuvant therapy (Procedure); conventional surgery (Procedure); neoadjuvant therapy (Procedure)

Phase: Phase 2/Phase 3

Status: Recruiting

Sponsored by: Medical Research Council

Official(s) and/or principal investigator(s):
David Cunningham, MD, Study Chair, Affiliation: Royal Marsden - Surrey

RATIONALE: Drugs used in chemotherapy, such as epirubicin, cisplatin, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving combination chemotherapy together with bevacizumab may kill more tumor cells.

PURPOSE: This randomized phase II/III trial is studying the side effects and how well giving combination chemotherapy together with bevacizumab works compared with combination chemotherapy alone in treating patients with previously untreated stomach cancer or gastroesophageal junction cancer that can be removed by surgery.

Official title: A Randomized Controlled Phase II/III Trial of Peri-Operative Chemotherapy With or Without Bevacizumab in Operable Adenocarcinoma of the Stomach and Gastro Oesophageal Junction

Study design: Treatment, Randomized, Open Label, Active Control

Primary outcome:

Safety

Efficacy

Overall survival

Secondary outcome:

Feasibility

Treatment-related morbidity

Response rates to pre-operative treatment

Surgical resection rates

Disease-free survival

Quality of life

Cost-effectiveness

Detailed description: OBJECTIVES:

Primary

- Assess the safety and efficacy of neoadjuvant and adjuvant chemotherapy comprising

epirubicin hydrochloride, cisplatin, and capecitabine with or without bevacizumab in patients with previously untreated, resectable gastric or gastroesophageal junction cancer.

OUTLINE: This is a multicenter, randomized, open-label, controlled study. Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive epirubicin hydrochloride IV and cisplatin IV over 4 hours on day

1 and capecitabine orally twice daily on days 1-21. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo surgery 5-6 weeks after completion of chemotherapy. Patients then receive 3 additional courses of chemotherapy beginning 6-10 weeks after surgery.

- Arm II: Patients receive bevacizumab IV over 30-90 minutes, epirubicin hydrochloride IV,

and cisplatin IV over 4 hours on day 1 and capecitabine orally twice daily on days 1-21. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo surgery 5-8 weeks after completion of chemotherapy. Patients then receive 3 additional courses of chemotherapy and bevacizumab beginning 6-10 weeks after surgery. Patients then receive maintenance therapy comprising bevacizumab IV over 30-90 minutes on day 1. Maintenance therapy repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, during treatment, and during the follow-up period.

After completion of study treatment, patients are followed at 9, 18, and 27 weeks after the start of course 4, 1 year post surgery, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 1,100 patients will be accrued for this study.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Histologically confirmed gastric or type III gastroesophageal junction adenocarcinoma

- Stage IB (T1, N1 or T2a/b, N0), II, III (with no evidence of distant metastases),

or IV (T4, N1 or N2, M0) disease

- Resectable disease

- Previously untreated disease

PATIENT CHARACTERISTICS:

- WHO performance status 0 or 1

- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 9 g/dL (can be post transfusion)

- WBC ≥ 3,000/mm^3

- Glomerular filtration rate ≥ 60 mL/min

- Proteinuria ≤ 1 g by 24-hour urine collection

- Bilirubin ≤ 1. 5 times upper limit of normal (ULN)

- ALT and AST ≤ 2. 5 times ULN

- Alkaline phosphatase ≤ 3 times ULN (in the absence of liver metastases)

- INR ≤ 1. 5

- PTT ≤ 1. 5 times ULN

- FEV_1 ≥ 1. 5 L

- Cardiac ejection fraction ≥ 50% by MUGA scan or echocardiogram

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Must be fit enough to receive protocol treatment

- No other malignancies within the past 5 years except for curatively treated basal cell

carcinoma of the skin and/or in situ carcinoma of the cervix

- No prior or concurrent significant medical conditions, including any of the

following:

- Cerebrovascular disease (including transient ischemic attack and stroke) within

the past year

- Cardiovascular disease, including the following:

- Myocardial infarction within the past year

- Uncontrolled hypertension while receiving chronic medication

- Unstable angina

- New York Heart Association class II-IV congestive heart failure

- Serious cardiac arrhythmia requiring medication

- Major trauma within the past 28 days

- Serious nonhealing wound, ulcer, or bone fracture

- Evidence of bleeding diathesis or coagulopathy

- Recent history of any active gastrointestinal inflammatory condition (e. g.,

peptic ulcer disease, diverticulitis, or inflammatory bowel disease)

- If patients have a known diagnosis of any of the above, evidence of disease

control is required by negative endoscopy within the past 28 days

- No severe tinnitus

- No lack of physical integrity of the upper gastrointestinal tract, malabsorption

syndrome, or inability to take oral medication

- No known peripheral neuropathy ≥ 1 (absence of deep tendon reflexes as the sole

neurological abnormality does not render the patient ineligible)

- No known dihydropyrimidine dehydrogenase deficiency

- No known allergy to any of the following:

- Chinese hamster ovary cell proteins

- Other recombinant human or humanized antibodies

- Any excipients of bevacizumab formulation or platinum compounds

- Any other components of the study drugs

PRIOR CONCURRENT THERAPY:

- No prior anthracycline

- More than 28 days since prior major surgery or open biopsy

- More than 10 days since prior thrombolytic therapy

- No concurrent thrombolytic therapy

- No concurrent dipyridamole or allopurinol

- No concurrent capecitabine or sorivudine (or sorivudine analogues [e. g., brivudine])

- No chronic, daily high-dose acetylsalicylic acid (> 325 mg/day) or nonsteroidal

anti-inflammatory drugs

- No chronic corticosteroids (≥ 10 mg/day methylprednisolone equivalent)

- Inhaled steroids allowed

- No other concurrent cytotoxic agents

- No other concurrent investigational drugs

- No concurrent radiotherapy

- Low molecular weight heparin allowed

Northern Centre for Cancer Treatment at Newcastle General Hospital, Newcastle-Upon-Tyne, England NE4 6BE, United Kingdom; Recruiting
Kate Sumpter, MD, Phone: 44-191-219-4200

Royal Marsden - Surrey, Sutton, England SM2 5PT, United Kingdom; Recruiting
David Cunningham, MD, Phone: 44-20-8661-3279, Email: david.cunningham@rmh.nhs.uk

Velindre Cancer Center at Velindre Hospital, Cardiff, Wales CF14 2TL, United Kingdom; Recruiting
Tom Crosby, MD, Phone: 44-29-2031-6292

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: October 2007
Last updated: July 23, 2008