Bevacizumab, Fluorouracil, Leucovorin Calcium, and Oxaliplatin Before Surgery in Treating Patients With Stage II-III Rectal Cancer

Sponsor

University of Southern California (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01871571

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

118.7

Anticipated Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II trial studies how well bevacizumab, fluorouracil, leucovorin calcium, and oxaliplatin before surgery works in treating patients with stage II-III rectal cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as fluorouracil, leucovorin calcium, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with fluorouracil, leucovorin calcium, and oxaliplatin may be an effective treatment for rectal cancer.

Condition or Disease	Intervention/Treatment	Phase
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	Biological: bevacizumab Drug: oxaliplatin Drug: leucovorin calcium Drug: fluorouracil Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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

TERTIARY OBJECTIVES:

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.

Prediction of surgical resection margin by pretreatment magnetic resonance imaging (MRI).

OUTLINE:

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

17 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Aug 2, 2013

Actual Primary Completion Date :

Jun 24, 2022

Anticipated Study Completion Date :

Jun 24, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (bevacizumab, mFOLFOX7) Patients receive bevacizumab 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.	Biological: bevacizumab Given IV Other Names: anti-VEGF humanized monoclonal antibody anti-VEGF monoclonal antibody Avastin rhuMAb VEGF Drug: oxaliplatin Given IV Other Names: 1-OHP Dacotin Dacplat Eloxatin L-OHP Drug: leucovorin calcium Given IV Other Names: CF CFR LV Drug: fluorouracil Given IV Other Names: 5-fluorouracil 5-Fluracil 5-FU Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Treatment (bevacizumab, mFOLFOX7)

Patients receive bevacizumab 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.

Biological: bevacizumab

Given IV

Other Names:

anti-VEGF humanized monoclonal antibody

anti-VEGF monoclonal antibody

Avastin

rhuMAb VEGF

Drug: oxaliplatin

Given IV

Other Names:

1-OHP

Dacotin

Dacplat

Eloxatin

L-OHP

Drug: leucovorin calcium

Given IV

Other Names:

CFR

Drug: fluorouracil

Given IV

Other Names:

5-fluorouracil

5-Fluracil

5-FU

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

Rate of CPR in the pathology specimen [Up to 3 years]

Secondary Outcome Measures

Tumor regression on mesorectal margins (pathologic stage lower than clinical stage) [Up to 3 years]
Rate of locoregional recurrence [Up to 3 years]
Incidence and nature of adverse events (AEs) according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 ( v4) [Up to 3 years]
Incidence and nature of serious AEs (SAEs) according to NCI CTCAE v4.0 [Up to 3 years]
Incidence and nature of AEs of special interest for bevacizumab (grades) according to NCI CTCAE v4.0 [Up to 3 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 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

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 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