Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Capecitabine and Bevacizumab With or Without Atezolizumab in Treating Patients With Refractory Metastatic Colorectal Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02873195
Recruitment Status : Active, not recruiting
First Posted : August 19, 2016
Last Update Posted : May 24, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Academic and Community Cancer Research United

Brief Summary:
This randomized phase II trial studies how well capecitabine and bevacizumab with or without atezolizumab work in treating patients with colorectal cancer that is not responding to treatment and has spread to other places. Immunotherapy with atezolizumab and bevacizumab, may induce changes in body?s immune system and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving atezolizumab with capecitabine and bevacizumab may be a better way in treating colorectal cancer.

Condition or disease Intervention/treatment Phase
Metastatic Colorectal Carcinoma Recurrent Colorectal Carcinoma Refractory Colorectal Carcinoma Stage IV Colorectal Cancer AJCC v7 Stage IVA Colorectal Cancer AJCC v7 Stage IVB Colorectal Cancer AJCC v7 Drug: Atezolizumab Biological: Bevacizumab Drug: Capecitabine Other: Laboratory Biomarker Analysis Other: Placebo Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the efficacy of capecitabine/bevacizumab + atezolizumab, as compared with capecitabine/bevacizumab + placebo in refractory metastatic colorectal cancer (mCRC) as measured by progression-free survival (defined as the time of randomization to the first occurrence of progression based on Response Evaluation Criteria in Solid Tumors version 1.1, clinical progression, or death from any cause on study as determined by the investigator).

SECONDARY OBJECTIVES:

I. To estimate the efficacy of capecitabine/bevacizumab + atezolizumab, as compared with capecitabine/bevacizumab + placebo in refractory mCRC as measured by objective response rate (defined as partial response plus complete response) as determined by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1 and immune-related response criteria (irRC).

II. To estimate the efficacy of capecitabine/bevacizumab + atezolizumab as compared with capecitabine/bevacizumab + placebo in refractory mCRC as measured by overall survival (defined as death from any cause from the time of randomization until study completion).

III. To evaluate the safety and tolerability of atezolizumab in combination with bevacizumab and capecitabine in refractory mCRC as measured by the serious adverse events and adverse events >= grade 3 according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

CORRELATIVE OBJECTIVES:

I. To explore any correlation between tissue and blood based biomarkers and clinical outcomes.

OUTLINE: Patients are randomized 2:1 to Arm I:Arm II.

ARM I (ATEZOLIZUMAB, BEVACIZUMAB, CAPECITABINE): Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine orally (PO) twice daily (BID) on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II (PLACEBO, BEVACIZUMAB, CAPECITABINE): Patients receive placebo IV over 30-60 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 3 months until progressive disease, then every 6 months thereafter.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 135 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: BACCI: A Phase II Randomized, Double-Blind, Placebo-Controlled Study of Capecitabine Bevacizumab Plus Atezolizumab Versus Capecitabine Bevacizumab Plus Placebo in Patients With Refractory Metastatic Colorectal Cancer
Actual Study Start Date : July 7, 2017
Estimated Primary Completion Date : November 30, 2020
Estimated Study Completion Date : November 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm I (atezolizumab, bevacizumab, capecitabine)
Patients receive atezolizumab IV over 30-60 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Atezolizumab
Given IV
Other Names:
  • MPDL 3280A
  • MPDL 328OA
  • MPDL-3280A
  • MPDL3280A
  • MPDL328OA
  • RG7446
  • RO5541267
  • Tecentriq

Biological: Bevacizumab
Given IV
Other Names:
  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab Biosimilar BEVZ92
  • Bevacizumab Biosimilar BI 695502
  • Bevacizumab Biosimilar CBT 124
  • Bevacizumab Biosimilar FKB238
  • Bevacizumab Biosimilar MIL60
  • Bevacizumab Biosimilar QL 1101
  • BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED
  • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
  • Recombinant Humanized Anti-VEGF Monoclonal Antibody
  • rhuMab-VEGF

Drug: Capecitabine
Given PO
Other Names:
  • Ro 09-1978/000
  • Xeloda

Other: Laboratory Biomarker Analysis
Correlative studies

Active Comparator: Arm II (placebo, bevacizumab, capecitabine)
Patients receive placebo IV over 30-60 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Biological: Bevacizumab
Given IV
Other Names:
  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab Biosimilar BEVZ92
  • Bevacizumab Biosimilar BI 695502
  • Bevacizumab Biosimilar CBT 124
  • Bevacizumab Biosimilar FKB238
  • Bevacizumab Biosimilar MIL60
  • Bevacizumab Biosimilar QL 1101
  • BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED
  • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
  • Recombinant Humanized Anti-VEGF Monoclonal Antibody
  • rhuMab-VEGF

Drug: Capecitabine
Given PO
Other Names:
  • Ro 09-1978/000
  • Xeloda

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Placebo
Given IV
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy




Primary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: From randomization to first documentation of disease progression by RECIST v1.1, or death from any cause, assessed up to 4 years ]
    Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. The primary comparisons will be superiority of the active treatment for PFS of atezolizumab versus placebo. PFS will be compared between treatment arms using the un-stratified log-rank test at one-sided level of 0.10 and the p-value will be used for decision making. The hazard ratio (HR) for PFS will be estimated using a Cox proportional hazards model and the 95% confidence interval (CI) for the HR will be provided. Results from a stratified analysis will also be provided. Kaplan-Meier methodology will be used to estimate the median PFS for each treatment arm, and Kaplan-Meier curves will be produced. Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median PFS for each treatment arm.


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: From randomization to death due to any cause, assessed up to 4 years ]
    The distribution of survival time will be estimated using the method of Kaplan-Meier. OS will be compared between treatment arms using the log-rank test. OS medians, survival rates and HR will be estimated along with 95% confidence intervals.

  2. Objective response rate [ Time Frame: Up to 4 years ]
    Defined as partial response plus compete response as assessed using (partial response [PR] or complete response [CR] per RECIST v1.1) during treatment with study therapy divided by total number of evaluable patients. Rates of response will be compared across arms using a chi-square test for proportion. Point estimates will be generated for objective response rates within each arm along with 95% binomial confidence intervals.

  3. Incidence of adverse events [ Time Frame: Up to 4 years ]
    Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Toxicities will be evaluated via the ordinal CTCAE standard toxicity grading.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed colorectal cancer that is either clinically or histologically proven to be metastatic and has progressed on regimens containing a fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, bevacizumab and an anti-EGFR antibody (if tumor is RAS wild-type), or where the treatment was not tolerated or contraindicated
  • Measurable disease; Note: previously irradiated sites can be included if there is documented disease progression in that site
  • Capecitabine and bevacizumab considered appropriate treatment for the patient
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
  • Absolute neutrophil count >= 1,500/uL (obtained =< 7 days prior to randomization)
  • Platelets >= 100,000/uL (obtained =< 7 days prior to randomization)
  • Total bilirubin =< 1.5 X upper limit of normal (ULN) (obtained =< 7 days prior to randomization); patients with known Gilbert?s syndrome who have serum bilirubin =< 3 X ULN may enroll
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 1.5 X ULN; < 3 X ULN if known hepatic metastases (obtained =< 7 days prior to randomization)
  • Hemoglobin >= 9 g/dL continuation of erythropoietin products is permitted (obtained =< 7 days prior to randomization); hemoglobin must be stable >= 9 g/dL >= 14 days without blood transfusion to maintain hemoglobin level
  • Calculated creatinine clearance must be >= 50 ml/min using the Cockcroft-Gault formula or a 24 hour urine (obtained =< 7 days prior to randomization)
  • The following laboratory values obtained =< 14 days prior to randomization

    • Prothrombin time (PT)/partial thromboplastin time (PTT)/international normalized ratio (INR) =< 1.5 X ULN if not anticoagulated; within local institutional guidelines per local physician if anticoagulated
  • Negative pregnancy test done =< 7 days prior to randomization, for women of childbearing potential only
  • Provide informed written consent
  • Willingness to return to enrolling institution for follow-up (during the active monitoring phase of the study)
  • Willingness to provide tissue and blood samples for correlative research purposes
  • Life expectancy of >= 3 months

Exclusion Criteria:

  • Any of the following:

    • Pregnant women
    • Nursing women
    • Women of child-bearing potential must agree to use two forms of adequate contraception from time of initial consent, for the duration of study participation, and for >= 6 months after the last dose of study drug; medically acceptable contraceptives include: (1) surgical sterilization (such as a tubal ligation or hysterectomy), (2) approved hormonal contraceptives (such as birth control pills, patches, implants or injections), (3) barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD); contraceptive measures such as Plan B, sold for emergency use after unprotected sex, are not acceptable methods for routine use; postmenopausal woman must have been amenorrheic for at least 2 years to be considered of non-childbearing potential; sexually active men must use at least one form of adequate contraception from time of initial consent, for the duration of study participation, and for >= 6 months after the last dose of study drug
  • Chemotherapy, biologic anti-cancer therapy, or central field radiation therapy =< 28 days prior to randomization; Note: local or stereotactic radiation =< 14 days prior to randomization
  • Any investigational agent =< 28 days or 5 half-lives prior to randomization (whichever is longer)
  • Prior treatment with atezolizumab or another PD-L1/PD-1 therapy
  • History of allergic reactions attributed to therapeutic antibodies; Note: patients with reactions to chimeric antibodies may be permitted on a case by case basis with approval by study chair by contacting the data manager
  • Known untreated central nervous system (CNS) metastases; Note: patients with radiated or resected lesions are permitted, provided the lesions are fully treated and inactive, patients are asymptomatic, and no steroids have been administered for this purpose =< 30 days prior to randomization
  • Inadequately controlled hypertension (defined as average systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg)
  • History of hypertensive crisis or hypertensive encephalopathy
  • New York Heart Association (NYHA) grade II or greater congestive heart failure
  • History of myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or surgery =< 12 months prior to randomization
  • Active coronary heart disease evidenced as angina or requiring medications to prevent angina
  • History of stroke or transient ischemic attack, or other arterial thrombosis =< 12 months prior to randomization
  • Symptomatic peripheral vascular disease
  • Any other significant vascular disease (e.g., aortic aneurysm, aortic dissection, or carotid stenosis that requires medical or surgical intervention, including angioplasty or stenting)
  • Any previous National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 4 venous thromboembolism
  • Clinically-significant evidence of bleeding diathesis or coagulopathy as so judged by the treating physician
  • History of active gastrointestinal (GI) bleeding or other major bleeding =< 12 months prior to randomization; Note: patients who do not have resolution of the predisposing risk factor (e.g., resection of a bleeding tumor, treatment and endoscopic documentation of a resolved ulcer) will also be excluded
  • Major surgical procedure, open biopsy, or significant traumatic injury =< 56 days prior to randomization
  • Anticipation of need for major surgical procedure =< 6 months after randomization
  • Minor surgical procedure =< 7 days prior to randomization; exception: insertion of an indwelling catheter or percutaneous needle biopsy =< 48 hours prior to randomization
  • History of intra-abdominal abscess =< 6 months prior to randomization; Note: if the affected area was surgically resected, and there is no further risk to the area, patients may enroll
  • History of abdominal or other significant fistula, gastrointestinal or other organ perforation; Note: if the affected area was surgically resected, and there is no further risk to the area, patients may enroll
  • Serious, non-healing wound, ulcer, or bone fracture as so judged by the treating physician
  • Known proteinuria defined by >= 2+ protein by urinalysis (UA) or >= 1 gram protein by 24 hour urine collection; Note: Subjects that are >= 2+ or greater on dipstick but < 1 g protein on 24 hour urine ARE eligible to participate
  • Intolerance to bevacizumab defined as any NCI CTCAE grade 3 or grade 4 toxicity attributed to this agent that required discontinuation of bevacizumab (e.g., arterial thromboembolism [ATE], perforation, wound healing difficulty, proteinuria, reversible posterior leukoencephalopathy syndrome [RPLS]); Note: patients with prior grade 3 bevacizumab-related hypertension may be permitted if hypertension was manageable with standard oral antihypertensives as so judged by the treating physician
  • Known dihydropyrimidine dehydrogenase (DPD) deficiency
  • Impairment of GI function or GI disease that may significantly alter capecitabine drug absorption
  • Active inflammatory bowel disease
  • History of diverticulitis, chronic ulcerative lower GI disease such as Crohn?s disease or ulcerative colitis, or other symptomatic lower GI conditions that might predispose to perforations
  • History of autoimmune disease including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener?s granulomatosis, Sjogren?s syndrome, Bell?s palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis; Note: patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study
  • Active current infection or history of recurrent bacterial, viral, fungal, mycobacterial or other infections, including but not limited to tuberculosis and atypical mycobacterial disease, hepatitis B and C, herpes zoster, and human immunodeficiency virus (HIV), but excluding fungal infections of nail beds
  • Vaccination with a live or attenuated vaccine =< 28 days prior to randomization; Note: other types of vaccines, including inactivated/killed, toxoid (inactivated toxoid), and subunit/conjugate are all permitted at any time
  • Any reversible treatment-related toxicity that has not resolved to NCI CTCAE grade =< 1 except neuropathy
  • Other concurrent severe and/or uncontrolled medical disease, psychiatric illness, or social situation, which could compromise safety of treatment as so judged by the treating physician; Note: this includes but is not limited to: severely impaired lung function, uncontrolled diabetes (history of consistent blood glucose readings above 300 mg/dL or less than 50 mg/dL), severe infection, severe malnutrition, ventricular arrhythmias, known active vasculitis of any cause, tumor invasion of any major blood vessel, chronic liver or renal disease, and active upper GI tract ulceration
  • Unwilling to or unable to comply with the protocol
  • Current or recent (=< 10 days prior to randomization) use of aspirin (> 325 mg/day), or clopidogrel (> 75 mg/day)
  • Current or recent (=< 10 days prior to randomization) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes, unless the patient has been on a stable dose of anticoagulants for at least 2 weeks at the time of randomization; Note: the use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or activated partial thromboplastin time (aPTT) is within therapeutic limits (according to the medical standard of the institution) and the patient has been on a stable dose of anticoagulants >= 14 days at the time of randomization; prophylactic use of anticoagulants is allowed
  • History or recent diagnosis of demyelinating disease
  • History of other carcinoma =< 3 years; exception: if risk of recurrence is known to be under 5% at time of randomization
  • Current or recent (=< 90 days prior to randomization) endoluminal stent in the stomach, bowel, colon or rectum
  • Colonoscopy, sigmoidoscopy, or proctoscopy =< 7 days prior to randomization
  • Current or recent (=< 28 days prior to randomization) use of sorivudine, brivudine, and St. John?s wort
  • Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation
  • Prior allogeneic bone marrow transplantation or prior solid organ transplantation
  • Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) =< 14 days prior to randomization; exception: patients who have received acute, low-dose, systemic immunosuppressant medications (e.g. a one-time dose of dexamethasone for nausea) are eligible; the use of inhaled corticosteroids and mineral-corticoids (e.g. fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02873195


Locations
Layout table for location information
United States, Arizona
Mayo Clinic Hospital
Phoenix, Arizona, United States, 85054
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259
United States, California
City of Hope Comprehensive Cancer Center
Duarte, California, United States, 91010
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States, 90033
United States, Georgia
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, United States, 30322
United States, Michigan
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Rhode Island
Rhode Island Hospital
Providence, Rhode Island, United States, 02903
Sponsors and Collaborators
Academic and Community Cancer Research United
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Niharika Mettu Academic and Community Cancer Research United

Layout table for additonal information
Responsible Party: Academic and Community Cancer Research United
ClinicalTrials.gov Identifier: NCT02873195     History of Changes
Other Study ID Numbers: RU021416I
NCI-2016-01263 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
RU021416I ( Other Identifier: Academic and Community Cancer Research United )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: August 19, 2016    Key Record Dates
Last Update Posted: May 24, 2019
Last Verified: April 2019

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma
Colorectal Neoplasms
Colonic Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Bevacizumab
Antineoplastic Agents, Immunological
Capecitabine
Atezolizumab
Endothelial Growth Factors
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunoglobulin G
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors