Nivolumab in Treating Patients With Refractory Metastatic Anal Canal 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. Identifier: NCT02314169
Recruitment Status : Active, not recruiting
First Posted : December 11, 2014
Last Update Posted : May 24, 2017
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies how well nivolumab works in treating patients with anal canal cancer that has not responded to previous treatment (refractory) and has spread to other places in the body (metastatic). Monoclonal antibodies, such as nivolumab, may block tumor growth in different ways by targeting certain cells.

Condition or disease Intervention/treatment Phase
Anal Canal Squamous Cell Carcinoma Metastatic Anal Canal Carcinoma Recurrent Anal Canal Carcinoma Stage IV Anal Canal Cancer Other: Laboratory Biomarker Analysis Biological: Nivolumab Phase 2

Detailed Description:


I. To evaluate overall response rate (ORR) with nivolumab in patients with previously treated metastatic squamous cell carcinoma (SCCA) of the anal canal.


I. To evaluate progression-free survival (PFS) of nivolumab in patients with previously treated metastatic SCCA of the anal canal.

II. To evaluate overall survival (OS) in patients with previously treated metastatic SCCA of the anal canal treated with nivolumab.

III. To evaluate the grade 3 and 4 toxicity rate in patients with previously treated metastatic SCCA of the anal canal when treated with nivolumab.


I. To evaluate ORR, PFS, and OS based on expression of programmed cell death 1 ligand 1 (PD-L1), programmed cell death 1 (PD-1), peritumoral cluster of differentiation (CD)8+ tumor infiltrating lymphocytes (TILs), peritumoral CD4+ TILs, and regulatory T cells as analyzed from tumor biopsies in previously treated patients with metastatic SCCA of the anal canal when treated with nivolumab.

II. To evaluate radiographic responses according to relative changes in proportions of anti-human papillomavirus (HPV) specific CD8+ and CD4+ TILs and regulatory T cells in patients with previously treated metastatic SCCA of the anal canal following treatment with nivolumab, analyzed from serial peripheral blood samples.


Patients receive nivolumab intravenously (IV) over approximately 60 minutes once every two weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 100 days and then every 3 months for 2 years.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 39 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multi-Institutional Phase 2 Study of Nivolumab in Refractory Metastatic Squamous Cell Carcinoma of the Anal Canal
Actual Study Start Date : May 1, 2015
Actual Primary Completion Date : September 1, 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Treatment (nivolumab)
Patients receive nivolumab IV over approximately 60 minutes once every two weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Primary Outcome Measures :
  1. Overall response rate [ Time Frame: Up to 2 years ]
    Responses will be assessed using CT scans or magnetic resonance imaging according to standard RECIST 1.1 criteria in order to assess disease progression.

Secondary Outcome Measures :
  1. Incidence of toxicities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 100 days post-treatment ]
    The frequency of each serious adverse event will be measured relative to the total number of patients treated. Toxicities will be tabulated by type and grade.

  2. Overall survival [ Time Frame: From initiation of treatment with nivolumab until death, assessed up to 2 years ]
    Kaplan-Meier analysis will be performed to estimate the median overall survival with a 90% confidence interval.

  3. Progression-free survival [ Time Frame: From initiation of treatment with nivolumab until the time of disease progression, assessed up to 2 years ]
    Kaplan-Meier analysis will be performed to estimate the median progression-free survival with a 90% confidence interval.

Other Outcome Measures:
  1. Expression of biomarkers using immunohistochemistry and blood samples [ Time Frame: Up to time of treatment discontinuation ]
    Descriptive statistics including plots, mean, median and standard deviations will be used to summarize data. For continuous outcomes, t-test and analysis of variance will be used to compare outcome measures across patient characteristics. Pair-wise comparisons will be performed using pre- and post-therapy samples from each patient. The chi-square test or Fisher's exact test will be used to test the association between two categorical variables. Both univariate and multivariate logistic regressions will be performed to model prognostic factors.

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

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed previously treated metastatic squamous cell carcinoma of the anal canal
  • Patients must have measurable disease according to the standard Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, computed tomography (CT) scans or magnetic resonance imagings (MRIs) used to assess the measurable disease must have been completed within 28 days prior to study drug initiation
  • Patients must have been treated with at least one prior systemic treatment for incurable advanced or metastatic SCCA of the anal canal; prior treatment for metastatic disease is not required for patients who develop new metastatic lesions during or within 6 months of completion of chemoradiation for limited-stage disease; patients who receive chemotherapy for incurable advanced or metastatic SCCA of the anal canal must wait a minimum >= 28 days (6 weeks for nitrosoureas or mitomycin C) after the date of completion of chemotherapy prior to initiating treatment with nivolumab on this study; patients who undergo radiotherapy to a site of tumor must wait a minimum >= 3 months from the date of completion of radiotherapy prior to initiating treatment with nivolumab on this study
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >= 80%)
  • Leukocytes >= 2,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Hemoglobin >= 9.0 gm/dL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (except patients with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
  • Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula)
  • Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of nivolumab; women must not be breastfeeding; women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception
  • Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes
  • WOCBP receiving nivolumab will be instructed to adhere to contraception for a period of 23 weeks after the last dose of investigational product; men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product
  • Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she (or the participating partner) should inform the treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document
  • Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and have been stable for at least three months prior to registration; eligible subjects should be neurologically asymptomatic; there is no magnetic resonance imaging (MRI) evidence of progression for a minimum of 4 weeks after treatment is complete and within 28 days prior to the first dose of nivolumab administration; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration
  • All patients must be willing to undergo testing for human immunodeficiency virus (HIV) testing if not tested within the past 6 months
  • If HIV+ positive, all patients infected with human immunodeficiency virus (HIV) may be eligible for study provided that their CD4+ count >= 300/uL; their viral load is undetectable; they are currently receiving highly active antiretroviral therapy (HAART)
  • All HIV+ patients will be under the care of an infectious diseases specialist; if a relationship with an infectious diseases specialist is not established, infectious disease specialist will be consulted; records of all viral counts and peripheral T-cell counts must be sent to the study coordinator in order to follow these values over the course of treatment
  • All patients must be willing to be tested for hepatitis screening; patients co-infected with hepatitis B virus and/or hepatitis C virus may be included in this study provided that their liver function tests remain within the limits listed above; patients must be followed by a hepatologist during the course of this study

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events (AEs) due to agents administered more than 4 weeks earlier (i.e., grade >= 2 AE present); palliative (limited-field) radiation therapy is permitted, as long as the lesion being considered for palliative radiation is not a target lesion
  • Patients who are receiving any other investigational agents
  • Patients should be excluded if they have had prior treatment with an anti-PD-1, anti-PD-L1, anti-programmed cell death ligand 2 (PD-L2), anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab
  • History of severe hypersensitivity reaction to any monoclonal antibody
  • 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
  • Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including chronic prolonged systemic corticosteroids (defined as corticosteroid use of duration one month or greater), should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or anti-phospholipid syndrome should be excluded
  • Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
  • No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for at least three years

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 identifier (NCT number): NCT02314169

United States, California
Los Angeles County-USC Medical Center
Los Angeles, California, United States, 90033
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States, 90033
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States, 95817
United States, District of Columbia
MedStar Georgetown University Hospital
Washington, D.C., District of Columbia, United States, 20007
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States, 60637
Decatur Memorial Hospital
Decatur, Illinois, United States, 62526
UC Comprehensive Cancer Center at Silver Cross
New Lenox, Illinois, United States, 60451
Southern Illinois University School of Medicine
Springfield, Illinois, United States, 62702
United States, Missouri
Barnes-Jewish West County Hospital
Creve Coeur, Missouri, United States, 63141
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
United States, Pennsylvania
Penn State Milton S Hershey Medical Center
Hershey, Pennsylvania, United States, 17033-0850
United States, Tennessee
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, United States, 37232
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Canada, Ontario
University Health Network-Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
National Cancer Institute (NCI)
Principal Investigator: Cathy Eng University of Texas MD Anderson Cancer Center LAO

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI) Identifier: NCT02314169     History of Changes
Other Study ID Numbers: NCI-2014-02420
NCI-2014-02420 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9673 ( Other Identifier: University of Texas MD Anderson Cancer Center LAO )
9673 ( Other Identifier: CTEP )
N01CM00032 ( U.S. NIH Grant/Contract )
N01CM00038 ( U.S. NIH Grant/Contract )
N01CM00039 ( U.S. NIH Grant/Contract )
N01CM00071 ( U.S. NIH Grant/Contract )
N01CM00099 ( U.S. NIH Grant/Contract )
N01CM00100 ( U.S. NIH Grant/Contract )
P30CA016672 ( U.S. NIH Grant/Contract )
UM1CA186704 ( U.S. NIH Grant/Contract )
UM1CA186712 ( U.S. NIH Grant/Contract )
First Posted: December 11, 2014    Key Record Dates
Last Update Posted: May 24, 2017
Last Verified: March 2017

Additional relevant MeSH terms:
Carcinoma, Squamous Cell
Anus Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Squamous Cell
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Anus Diseases
Rectal Diseases
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs