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Phase II Trial Of Neoadjuvant Bevacizumab With Modified FOLFOX7 In Patients With Stage II And III Rectal Cancer

Phase 2
18 Years
Not Enrolling
Mucinous Adenocarcinoma of the Rectum, Signet Ring Adenocarcinoma of the Rectum, Stage IIA Rectal Cancer, Stage IIB Rectal Cancer, Stage IIC Rectal Cancer, Stage IIIA Rectal Cancer, Stage IIIB Rectal Cancer, Stage IIIC Rectal Cancer

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Trial Information

Phase II Trial Of Neoadjuvant Bevacizumab With Modified FOLFOX7 In Patients With Stage II And III Rectal Cancer


I. To determine if six cycles of modified fluorouracil, leucovorin calcium, and oxaliplatin
(mFOLFOX7) plus bevacizumab (Avastin) will yield complete pathologic response (cPR) of 25%
or more in the primary tumor of patients with stage II and III rectal cancer.


I. To assess the rate of tumor regression (pathologic stage lower than clinical stage) after
6 cycles of mFOLFOX7 and bevacizumab in the primary rectal cancer.

II. To assess local recurrence rate over 3 years after 6 cycles of mFOLFOX7 and bevacizumab.


I. Correlation of the following marker with response (defined as CPR or down staging):

- Intratumoral Gene expression and germline polymorphism of genes involved in the
vascular endothelial growth factor (VEGF) and VEGF independent pathways (VEGF, vascular
endothelial growth factor receptor 1 [VEGFR1], VEGFR2, interleukin-8 [IL8], chemokine
(C-X-C motif) receptor 2 [CXCR2], intercellular adhesion molecule [ICAM], VEGFR1 and
VEGFR2, neuropilin 1 or 2 [NRP1,2], cluster of differentiation [CD] 44, aldehyde
dehydrogenase [ALDH], leucine-rich repeats and immunoglobulin-like [LRIG].

- Circulating tumor cells (CTC) and VEGF-factor A (A) on the CTC.

II. Prediction of surgical resection margin by pretreatment magnetic resonance imaging


Patients receive bevacizumab intravenously (IV) over 30-90 minutes, oxaliplatin IV over 2
hours, leucovorin calcium IV, and fluorouracil IV continuously over 46-48 hours on day 1.
Treatment repeats every 14 days for 6 courses in the absence of disease progression or
unacceptable toxicity. Within 6-8 weeks after treatment, patients undergo surgery.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion 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

- 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

- 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

Exclusion Criteria:

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Rate of CPR in the pathology specimen

Outcome Time Frame:

Up to 3 years

Safety Issue:


Principal Investigator

Afsaneh Barzi

Investigator Role:

Principal Investigator

Investigator Affiliation:

USC/Norris Comprehensive Cancer Center


United States: Institutional Review Board

Study ID:




Start Date:

July 2013

Completion Date:

July 2016

Related Keywords:

  • Mucinous Adenocarcinoma of the Rectum
  • Signet Ring Adenocarcinoma of the Rectum
  • Stage IIA Rectal Cancer
  • Stage IIB Rectal Cancer
  • Stage IIC Rectal Cancer
  • Stage IIIA Rectal Cancer
  • Stage IIIB Rectal Cancer
  • Stage IIIC Rectal Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Rectal Neoplasms
  • Cystadenocarcinoma



USC Norris Comprehensive Cancer CenterLos Angeles, California  90089