Combination Chemotherapy Plus Bevacizumab With or Without Oxaliplatin in Treating Older Patients With Metastatic Colorectal Cancer

NCT01279681 | Terminated Phase 3 Results DMC

• 4 other identifiers: N0949NCCTG-N0949CDR0000692257NCI-2011-02622
• Study Type: interventional
• Target: 32
• Locations: 0 countries
• Sites: N/A

Brief Summary

This randomized phase III trial studies how well combination chemotherapy plus bevacizumab with or without oxaliplatin works in treating older patients with colorectal cancer that has spread to other places in the body. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Monoclonal antibodies, such as bevacizumab, may block tumor growth in different ways by targeting certain cells. Bevacizumab may also stop the growth of cancer by blocking blood flow to the tumor. It is not yet known whether combination chemotherapy plus bevacizumab is more effective with or without oxaliplatin in treating colorectal cancer.

Conditions

Cognitive/Functional Effects; Colorectal Cancer; Neurotoxicity

Keywords

neurotoxicity; cognitive/functional effects; stage IVA colon cancer; stage IVA rectal cancer; stage IVB colon cancer; stage IVB rectal cancer; recurrent colon cancer; recurrent rectal cancer

Outcome Measures

Primary Outcomes (1)

• Progression-Free Survival

  Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Progression free survival was defined as the time (in months) from the date of randomization to the date of documented disease progression or death, whichever occurs first. Patients were followed until progression (and progression was declared) regardless of whether the patient was on the first line treatment or not. Patients who progress following a missed scan will have their date of progression back-dated to the date of missing scan. Patients without a progression who are still alive at the time of analysis will be censored at the date of last follow-up.

  Up to 5 years

Secondary Outcomes (3)

• Overall Survival

  Up to 5 years

• Response Rate, Defined as the Percentage of Patients in Each Arm Who Have an Objective Status of Complete Response or Partial Response, Confirmed by a Second Assessment Measured at Least 6 Weeks From the Initial Assessment

  Up to 5 years

• Number of Participants With Grade 3 Adverse Events At Least Possibly Related to Treatment

  Up to 42 days after treatment discontinuation

Other Outcomes (5)

• Change in Geriatric/Frailty Using the North Central Cancer Treatment Group (NCCTG) Brief Frailty Inventory and the Rockwood Frailty Index Physician and Patient-reported Items

  Baseline to 42 days after termination of study treatment

• Change in QOL Using the Fatigue/Uniscale Assessment, Linear Analog Self-Assessment (LASA), and the European Quality of Live Five Dimensions Questionnaire (EQ-5D)

  Baseline to up to 42 days after termination of study treatment

• Proportion of Patients Reporting Satisfaction Using the Was It Worth IT (WIWI) Questionnaire

  Baseline to up to 42 days after termination of study treatment

Study Arms (2)

Arm A [fluoropyrimidine + bevacizumab (BEV)]

ACTIVE COMPARATOR

Patients receive either 5FU/LV or Capecitabine, plus BEV. 5FU/LV + BEV is comprised of 5FU IV over 46-48 hours, LV calcium IV over 2 hours, and BEV IV over 10-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Capecitabine + BEV is comprised of capecitabine PO BID on days 1-14 and BEV IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Biological: bevacizumab; Drug: capecitabine; Drug: fluorouracil; Drug: leucovorin calcium

Arm B [fluoropyrimidine/oxaliplatin (OXAL) + BEV]

EXPERIMENTAL

Patients receive either mFOLFOX7 plus BEV, or Capecitabine + OXAL (XELOX) plus BEV. mFOLFOX7 + BEV is comprised of OXAL IV over 2 hours, LV calcium IV over 2 hours, and 5FU IV over 46-48 hours on day 1. Patients also receive BEV IV over 10-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. XELOX + BEV is comprised of OXAL IV over 2 hours on day 1 and capecitabine PO BID on days 1-14. Patients also receive BEV IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Biological: bevacizumab; Drug: capecitabine; Drug: fluorouracil; Drug: leucovorin calcium; Drug: oxaliplatin

Interventions

bevacizumab BIOLOGICAL

Given IV

Arm A [fluoropyrimidine + bevacizumab (BEV)]; Arm B [fluoropyrimidine/oxaliplatin (OXAL) + BEV]

capecitabine DRUG

Given PO

Arm A [fluoropyrimidine + bevacizumab (BEV)]; Arm B [fluoropyrimidine/oxaliplatin (OXAL) + BEV]

fluorouracil DRUG

Given IV

Arm A [fluoropyrimidine + bevacizumab (BEV)]; Arm B [fluoropyrimidine/oxaliplatin (OXAL) + BEV]

leucovorin calcium DRUG

Given IV

Arm A [fluoropyrimidine + bevacizumab (BEV)]; Arm B [fluoropyrimidine/oxaliplatin (OXAL) + BEV]

oxaliplatin DRUG

Given IV

Arm B [fluoropyrimidine/oxaliplatin (OXAL) + BEV]

Eligibility Criteria

• Age: 70 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• Patients must have metastatic colorectal cancer that has been histologically or cytologically confirmed; Note: histologic confirmation can be obtained from the primary tumor with appropriate imaging studies confirming metastatic spread
• Eastern Cooperative Oncology Group performance status (ECOG PS) 0, 1, or 2
• Absolute neutrophil count (ANC) \>= 1,500/mm\^3
• Peripheral platelet count (PLT) \>= 100,000/mm\^3
• Hemoglobin (HgB) \> 9.0 g/dL
• Total bilirubin =\< 1.5 x upper limit of normal (ULN)
• Aspartate transaminase (AST) =\< 2.5 x ULN (=\< 5 x ULN for patients with liver involvement)
• Alkaline phosphatase =\< 3 x ULN (=\< 5 x ULN for patients with liver involvement)
• Creatinine =\< 1.5 x ULN
• International normalized ratio (INR) \< 1.5 x ULN unless patients are receiving anti-coagulation therapy; patients receiving prophylactic anti-coagulation therapy with an agent such as warfarin or heparin are allowed to participate if INR =\< 3.0
• Urine protein creatinine (UPC) ratio \< 1 or urine dipstick \< 2+
• \* NOTE: Urine protein must be screened by urine analysis for urine protein creatinine (UPC) ratio or by dip stick; for UPC ratio \>= 1.0 or urine dipstick \>= 2+, 24-hour urine protein must be obtained and the level should be \< 1000 mg
• Life expectancy \>= 3 months
• Ability to complete questionnaire(s) by themselves or with assistance
• Provide informed written consent

You may not qualify if:

• Men of child bearing potential who are unwilling to employ adequate contraception
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of the safety and adverse events of the prescribed regimens
• Immunocompromised patients (other than that related to the use of corticoid steroids) including patients known to be human immunodeficiency virus (HIV) positive with cluster of differentiation (CD)4 \< 100 cells/uL
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
• Other active malignancy =\< 3 years prior to randomization; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: if there is a history of prior malignancy, patients must not be receiving other specific treatment (other than hormonal therapy) for this prior cancer
• Prior chemotherapy, radiation therapy, immunotherapy, or biological therapy for recurrent or metastatic colorectal cancer
• \* NOTE: prior chemotherapy or radiotherapy is permitted if they had been administered as adjuvant or neoadjuvant therapy and a complete surgical resection of the original colorectal cancer had been achieved
• Progressive disease =\< 12 months of completing oxaliplatin-containing adjuvant therapy
• Prior radiation to \> 30% of the bone marrow at any time
• Calculated creatinine clearance \< 60 mL/minute
• \* NOTE: If calculated creatinine clearance does not meet eligibility requirement, a 24-hour urine can be collected for a creatinine clearance, and the patient can been rolled if measured creatinine clearance \>= 60 mL/minute
• Known central nervous system or brain metastasis that are either symptomatic or untreated; Note: if a patient has a resection of the metastasis and is no longer symptomatic, the patient is eligible for the study; Note: patients with neurological symptoms must undergo a computed tomography (CT) scan/magnetic resonance imaging (MRI) of the brain to exclude brain metastasis
• New York Heart Association (NYHA) classification III or IV congestive heart failure
• Inadequately controlled hypertension (systolic blood pressure of \> 150 mm Hg or diastolic blood pressure \> 100 mm Hg on anti-hypertensive medications)

Sponsors & Collaborators

• Alliance for Clinical Trials in Oncology: lead
• National Cancer Institute (NCI): collaborator
• Cancer and Leukemia Group B: collaborator

Related Publications (1)

• McCleary NJ, Hubbard J, Mahoney MR, Meyerhardt JA, Sargent D, Venook A, Grothey A. Challenges of conducting a prospective clinical trial for older patients: Lessons learned from NCCTG N0949 (alliance). J Geriatr Oncol. 2018 Jan;9(1):24-31. doi: 10.1016/j.jgo.2017.08.005. Epub 2017 Sep 13.

  PMID: 28917648 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms; Neurotoxicity Syndromes; Colonic Neoplasms; Rectal Neoplasms

Interventions

Bevacizumab; Capecitabine; Fluorouracil; Leucovorin; Oxaliplatin

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Nervous System Diseases; Poisoning; Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Coordination Complexes; Organic Chemicals

Results Point of Contact

• Title: Joleen M. Hubbard, M.D.
• Organization: Mayo Clinic

hubbard.joleen@mayo.edu

507 284-3121

Study Officials

• Axel Grothey, MD

  Mayo Clinic

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 18, 2011
• First Posted: January 19, 2011
• Study Start: January 1, 2011
• Primary Completion: November 1, 2014
• Study Completion: November 1, 2014
• Last Updated: December 8, 2017
• Results First Posted: December 8, 2017

Record last verified: 2017-11