Pre-operative Chemotherapy Plus Bevacizumab With Early Salvage Therapy Based on PET Assessment of Response in Patients With Locally Advanced But Resectable Gastric and GEJ Adenocarcinoma
Condition: Esophageal Cancer; Gastric Cancer
MeSH terms: Adenocarcinoma
Intervention: epirubicin, cisplatin, capecitabine, bevacizumab, docetaxel and irinotecan
Intervention description: Patients with FDG avid locally advanced but resectable gastric or GEJ adenocarcinoma will receive preoperative therapy with epirubicin, cisplatin, capecitabine (ECX), and bevacizumab. Each cycle of therapy is 21 days. Near the completion of cycle 1 of therapy (eg during week 3, target days 18-21), patients will undergo a second FDG-PET/CT scan. Note, patients will hold capecitabine for 48 hours prior to the FDG-PET/CT scan.
Patients with a good metabolic response (eg. > 35% reduction in FDG uptake at the primary tumor on the week 3 PET scan as compared with baseline FDG uptake) will continue ECX for 2 additional cycles (cycle 2 and 3).
Cycle 2 will be administered with bevacizumab and cycle 3 will be administered without bevacizumab. Patients will then proceed to surgery approximately 4-6 weeks following the completion of cycle 3. There is a 10-12 week time interval (eg. 70-84 days) between the last bevacizumab treatment and surgery.
Intervention MeSH terms: Bevacizumab; Docetaxel; Capecitabine; Irinotecan; Epirubicin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: BEVACIZUMAB (AVASTIN); CAPECITABINE (ORAL); CISPLATIN; EPIRUBICIN; IRINOTECAN (CPT-11) CAMPTOSAR; TAXOTERE (DOCETAXEL); ESOPHAGUS; STOMACH; 08-081

Summary:

      This study is being done to find out how effective a new treatment strategy is on your
      cancer. In this strategy, the response your tumor has to the first cycle of therapy will help
      select the next treatments. We also will find out the effects, both good and/or bad, a drug
      called bevacizumab has on you and your tumor when given with chemotherapy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  All patients must have microscopically confirmed adenocarcinoma of the stomach or GE
             junction. Tumors involving the GE junction must have the bulk of their disease in the
             stomach; tumors of the distal esophagus that extend less than 2cm into the stomach are
             ineligible for this study.

          -  All patients must be considered candidates for surgical resection.

          -  Patients must have FDG-avid malignancies.

          -  FDG avid tumors are defined as primary tumors with an increased tracer uptake in the
             region of the tumor that has an SUV > or = to 3.5 or a tumor:liver ratio > or = to
             1.5, and felt to be "probably" or "definitely malignant" (i.e. likelihood score of 3
             or 4) by the reference nuclear medicine physician.

          -  All patients must have localized cancer potentially curable by surgery. The tumor
             stage should be T any N+ M0 or T3-T4a N any M0(AJCC 7th Edition), by staging that
             includes a CT scan and either laparoscopy or endoscopic ultrasound. Patients with T1-2
             N0M0 or patients with distant metastatic disease (i.e. M1) are ineligible. Any sites
             of suspected M1 disease by these criteria must be proven to be M0 prior to entrance
             into the neoadjuvant study.

          -  Patients may not have received prior chemotherapy or radiation for this disease.

          -  The patient is at least 18 years of age.

          -  If female and of child bearing potential, the patient has a negative serum pregnancy
             test within 14 days of starting therapy, and, if male or female and of child bearing
             potential, currently uses (and agree to continue to use throughout the study) an
             acceptable method of birth control (IUD, oral contraceptive, or barrier device). They
             should agree to continue to use these for three months after the study is completed.
             The patient also agrees to refrain from nursing during the duration of the study and
             for at least two months after the study is completed. Pregnant or lactating females
             are not included because the anti-proliferative effects of bevacizumab may be harmful
             to the fetus or developing infant.

        Karnofsky performance status > or = to 70%.

          -  The patient has adequate hematopoietic function, defined as having a total neutrophil
             count (ANC) ≥ or = to 1500/mm3, a platelet count ≥ or = 100,000/mm3. The patient has
             adequate renal and hepatic function, defined as having a serum creatinine ≤ or = to
             2.5 mg/dl, urinalysis demonstrating < 2+ proteinuria and/or a urine protein/creatinine
             (UPC) ratio < 1.0. LFTs include a total serum bilirubin ≤ than or = to 2 x ULN, serum
             AST (SGOT)/ALT (SGPT) and ALK PHOS < than or = to 2.5 ULN.

          -  The patient has a PT (INR) < than or = to 1.5 and an PTT < than or = to 3 seconds
             above the upper limits of normal (i.e. at MSKCC PTT < than or = to 37.7 sec) if the
             patient is not on anticoagulation.

          -  If a patient is on full-dose anticoagulants, the following criteria should be met for
             enrollment

               1. If using warfarin, the subject must have an in-range INR (usually between 2 and
                  3) and on a stable dose of warfarin.

               2. The subject must not have active bleeding or pathological conditions that carry
                  high risk of bleeding (e.g. tumor involving major vessels, known varices).

          -  Ability to understand informed consent and signing of written informed consent
             document prior to the initiation of treatment.

        Exclusion Criteria:

          -  Any metastatic disease.

          -  Significant cardiac disease as defined as:

          -  New York Heart Association (NYHA) grade II or greater (see Appendix B for NYHA Class),

          -  congestive heart failure, or history of myocardial infarction or unstable angina
             within 12 months of study enrollment

          -  Any history of stroke or transient ischemic attack at any time.

          -  Pregnant (positive pregnancy test) or lactating women. A pregnancy test will be
             performed on sexually active women of childbearing potential prior to entry into the
             study. Treatment may not begin until the results of the pregnancy test are
             ascertained.

          -  Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg
             and/or diastolic blood pressure > 100 mmHg) on antihypertensive therapy.

          -  Any prior history of hypertensive crisis or hypertensive encephalopathy.

          -  Significant vascular disease (e.g. aortic aneurysm, aortic dissection)

          -  Symptomatic peripheral vascular disease (ie. grade 2 or higher).

          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to starting therapy (eg. day 0).

          -  Core biopsy or other minor surgical procedure, excluding placement of a vascular
             device, within 7 days of starting therapy.

          -  Evidence of bleeding diathesis or coagulopathy.

          -  Proteinuria at screening as demonstrated by either

               -  Urine protein:creatinine (UPC) ratio > 1.0 at screening, or

               -  Urine dipstick for proteinuria > or = to 2+ (patients discovered to have > or =
                  to 2+ proteinuria on dipstick urinalysis at baseline should undergo 24 hour urine
                  collection and must demonstrate < than or = to 1g of protein in 24 hours to be
                  eligible).

          -  Serious intercurrent infections, or nonmalignant medical illnesses that are
             uncontrolled or whose control may be jeopardized by the complications of this therapy.

          -  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
             within 6 months prior to study enrollment.

          -  Serious, non-healing wound, ulcer, or bone fracture.

          -  Grade 2 or greater pre-existing peripheral neuropathy.

          -  Psychiatric disorders rendering patients incapable of complying with the requirements
             of the protocol.

          -  Any concurrent active malignancy other than non-melanoma skin cancers, non-metastatic
             prostate cancer or carcinoma-in-situ of the uterine cervix. Patients with previous
             malignancies but without evidence of disease for > 5 years will be allowed to enter
             the trial.

          -  Clinically significant hearing loss.

          -  EKG evidence of acute ischemia or significant conduction abnormality, as determined by
             the treating physician.

          -  Known hypersensitivity to Chinese hamster ovary cell products, other recominant human
             antibodies, or to any component of bevacizumab.

          -  Patients with any other medical condition or reason that, in the investigator's
             opinion, makes the patient unsuitable to participate in a clinical trial.