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A Randomised Phase II/III Trial of Peri-Operative Chemotherapy With or Without Bevacizumab in Operable Oesophagogastric Adenocarcinoma and A Feasibility Study Evaluating Lapatinib in HER-2 Positive Oesophagogastric Adenocarcinomas


Phase 2/Phase 3
18 Years
N/A
Open (Enrolling)
Both
Oesophagogastric Cancer

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Trial Information

A Randomised Phase II/III Trial of Peri-Operative Chemotherapy With or Without Bevacizumab in Operable Oesophagogastric Adenocarcinoma and A Feasibility Study Evaluating Lapatinib in HER-2 Positive Oesophagogastric Adenocarcinomas


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, gastroesophageal junction or
lower oesophageal cancer.

- Assess the safety of neoadjuvant and adjuvant chemotherapy comprising epirubicin
hydrochloride, cisplatin, and capecitabine with or without lapatinib in patients with
HER-2 positive previously untreated, resectable gastric, gastroesophageal junction or
lower oesophageal cancer.

OUTLINE: This is a multicenter, randomized, open-label, controlled study. Patients are
randomized to 1 of 4 treatment arms.

- Arm I and II: 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.

- Arm IV: Patients receive lapatinib orally once daily, 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 lapatinib beginning 6-10 weeks after surgery.
Patients then receive maintenance therapy comprising lapatinib orally once daily on days
1-21. 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 and 40 patients
with HER-2 positive tumours recruited into the ST03 feasibility study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed gastric or type I, II or III gastroesophageal junction
adenocarcinoma or lower oesophageal

Gastric and Type III junctional tumours should be Stage Ib (T1 N1, T2a/b N0), II, III or
stage IV (T4 N1 or N2) with no evidence of distant metastases (M0)

Lower oesophageal and Type I and II junctional tumours should be Stage II to Stage IVa (T1
N1, T2 N1, T3 N0-1, but not T2N0). T4 (N0 or N1) tumours are also eligible providing that
they involve only the crura OR invade only the mediastinal pleura. Patients with nodal
disease affecting the origin of the left gastric and splenic artery or coeliac axis
(staged as M1a) are also eligible.

- 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 history of interstitial lung disease or radiological evidence of lung fibrosis

- 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

Due to an increase in perforations associated with self-expandable metal stents in
patients with colorectal cancer receiving bevacizumab, patients with an oesophageal or
gastric stent (metal or biodegradable) in situ are ineligible for the study.

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

- 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

- More than 7 days since prior CYP3A4 inhibitor therapy

- More than 14 days since prior CYP3A4 inducer therapy

- More than 6 months since prior amiodarone therapy

- More than 14 days since prior St John's Wort, modafinil, ginkgo biloba, kava, grape
seed, valerian, ginseng, echinacea and evening primrose oil

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety

Outcome Time Frame:

at the end of phase II and phase III

Safety Issue:

Yes

Principal Investigator

David Cunningham, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Royal Marsden NHS Foundation Trust

Authority:

United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:

CDR0000536013

NCT ID:

NCT00450203

Start Date:

October 2007

Completion Date:

December 2016

Related Keywords:

  • Oesophagogastric Cancer
  • adenocarcinoma of the stomach
  • adenocarcinoma of the gastro oesophageal junction
  • adenocarcinoma of the lower oesophagus
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous

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