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3R-12-2 Phase II Trial Of Neoadjuvant Bevacizumab With Modified FOLFOX7 In Patients With Stage II And III Rectal Cancer


There were about 40,000 cases of rectal cancer in the United States in 2011. The standard treatment is surgery, but the cancer recurs in 10-20% of cases. To decrease recurrence, chemotherapy and radiation are given before surgery. However, radiation with chemotherapy has not been shown to improve overall survival, so chemotherapy is also given for 3-4 months after surgery. Radiation is also associated with short and long term side effects and has differing effects on survival depending on the stage of disease, but the degree of tumor response after radiation with chemotherapy is associated with survival. Thus, tumor response or complete pathologic response (CPR) appears to be a good indicator for long term outcomes. A previous study has shown that chemotherapy without radiation using FOLFOX (Oxaliplatin, Leukovorin and Fluororacil) and Bevacizumab yields a CPR rate of 27% and does not compromise the removal of the tumor with surgery. This Phase II study will attempt to validate the results of that study using FOLFOX and Bevacizumab without radiation in patients with rectal cancer that has not spread and can be removed surgically. This study will also assess the rate that the tumor recurs and assess specific biomarkers that may be associated with tumor response.Once participants sign the informed consent and are deemed eligible for the study, participants will receive a modified FOLFOX regimen, called mFOLFOX7, with Bevacizumab through a vein in the arm every 2 weeks. Every 2 weeks is called a cycle. During the study, participants will have the following procedures done during each cycle: a physical exam, vital signs, blood tests, performance status, assessment of side effects, review of medications, and tumor assessments with ultrasound and radiographic scans at the end of study treatment before surgery. All participants will stop taking study drug(s) if their disease worsens, they will not have surgery, they have another illness which prevents them from taking the study drug(s), they cannot tolerate the side effects, they withdraw from the study, or their study doctor thinks that being on the study is no longer in their best interest. All participants will be followed every 3 months after stopping the study drug(s) for the first 2 years, and then every 6 months for 3 years.The primary endpoint of this study is complete pathologic response. A two-stage Simon design was used to calculate sample size. All subjects will be analyzed as intent to treat. Biomarkers will be analyzed using a contingency table, bar plots, Fisher's exact test, scatterplots, and two-sample Wilcoxon or t-test. An optimal cut-off value of the continuous biomarker will be chosen to separate patients into 2 groups in term of probability of CPR using the maximal chi-square approach. P value for the associations will be adjusted using bootstrap like simulations.


Phase 2 - takes the treatment one step further, assessing the activity of a particular therapy in a disease, often building upon leads from the Phase I trial. While patients are generally required to be previously untreated, participation in a Phase II trial doesn't usually preclude the patient from getting the standard treatment after they've received the investigational agent. At best they are allowed to get a new drug they wouldn't be able to get otherwise that may turn out to be better for their disease.

Inclusion and Exclusion Criteria

  • Histologically confirmed adenocarcinoma of the rectum in patients with no prior therapy who are candidate for surgical resection
  • Tumor lesion is 5-15 cm from anal verge
  • cT2 N+ or cT3-T4 N0 or N+ as assessed by endorectal ultrasound scan (US)
  • No evidence of distant metastatic disease
  • Signed informed consent prior to initiation of any study-specific procedure or treatment
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Able to comply with the protocol, including tissue sampling, imaging studies and surgical intervention
  • Life expectancy more than 12 weeks
  • Absolute neutrophil count >= 1500 per mm^3
  • Platelet count >= 100,000 per mm^3
  • Hemoglobin >= 9 g/dL (may be transfused to maintain or exceed this level)
  • Total bilirubin < 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase and alanine aminotransferase < 2.5 x ULN
  • Calculated creatinine clearance according to Cockroft and Gault formula >= 50 mL/min
  • Urine for proteinuria should be < 2 +; patients discovered to have >= 2 + proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate < 1 g of protein in 24 hours
  • International normalized ratio =< 1.5 and activated prothrombin time =< 1.5 x ULN within 7 days prior to enrollment; the use of full-dose oral or parenteral anticoagulants is permitted as long as the international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least two weeks prior to the first study treatment
  • Female patients should not be pregnant or breast-feeding. Female patients, if not postmenopausal (< 12 months of amenorrhea) or surgically sterile, should agree to use effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) during the study and for a period of at least 6 months following the last administration of study drugs. Female patients with an intact uterus (unless amenorrheic for the last 24 months) must have a negative serum pregnancy test within 7 days prior to randomization into the study
  • Fertile male patients must agree to use a highly effective contraceptive method (i.e., with a failure rate of < 1 % per year, such as vasectomy, sexual abstinence, or female partner's use of hormonal implants or combined oral contraceptives) during the trial and for a period of at least 6 months after the last dose of study drug
  • Archival tumor tissue sample must be requested and available prior to study entry; a copy of the local pathology report must be submitted along with the specimens; patients without available archival tissue are excluded

  • Prior chemotherapy or radiotherapy for colorectal cancer
  • Clinical evidence of bleeding diathesis or coagulopathy
  • Pregnancy or lactation
  • Sensory peripheral neuropathy >= grade 2
  • Known positivity for human immunodeficiency virus (HIV)
  • Malignancies other than rectal cancer within 5 years prior to randomization, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, and ductal carcinoma in situ treated surgically with curative intent
  • Radiotherapy to any site for any reason within 28 days prior to study entry
  • Treatment with any other investigational agent, or participation in another investigational drug trial within 28 days prior to randomization
  • Evidence of any other disease, neurological or metabolic dysfunction, physical examination finding, or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of bevacizumab or puts the patient at high risk for treatment-related complications
  • Surgery (including open biopsy), significant traumatic injury within 28 days prior to randomization, minor surgery, including insertion of an indwelling catheter, within 24 hours prior to the first bevacizumab infusion is allowed
  • Current or recent (within 10 days prior to first dose of bevacizumab) use of aspirin (> 325 mg/day)
  • History or evidence of inherited bleeding diathesis or coagulopathy with a risk of bleeding
  • Inadequately controlled hypertension (blood pressure: systolic > 150 mmHg and/or diastolic > 100 mmHg)
  • Clinically significant (i.e., active) cardiovascular disease (e.g., cerebrovascular accident or myocardial infarction within 6 months prior to randomization), unstable angina, congestive heart failure (New York Heart Association Class >= II) or serious cardiac arrhythmia that is uncontrolled by medication or may interfere with administration of study treatment
  • Serious non-healing wound, active peptic ulcer, or untreated bone fracture
  • History of abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months of randomization
  • Known hypersensitivity to bevacizumab or any of its excipients or any other study drug


  • California

    • USC Norris Comprehensive Cancer Center, Los Angeles, California, 90033
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