A Multi-Institutional Phase 2 Study of Nivolumab or Nivolumab in Combination With Ipilimumab in Refractory Metastatic Squamous Cell Carcinoma of the Anal Canal
Overview
- Phase
- Phase 2
- Intervention
- Computed Tomography
- Conditions
- Anal Canal Squamous Cell Carcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 143
- Locations
- 112
- Primary Endpoint
- Progression-free survival (PFS) (Part B)
- Status
- Active, not recruiting
- Last Updated
- 10 days ago
Overview
Brief Summary
This phase II trial studies how well nivolumab with or without ipilimumab works in treating patients with anal canal cancer that has not responded to previous treatment (refractory) and that has spread from where it first started (primary site) to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate overall response rate (ORR) with nivolumab in patients with previously treated metastatic squamous cell carcinoma (SCCA) of the anal canal. (Part A) II. To determine an improvement in progression-free survival (PFS) when nivolumab is combined with ipilimumab versus (vs.) nivolumab alone in patients with previously treated metastatic SCCA (Part B). SECONDARY OBJECTIVES: I. To evaluate progression-free survival (PFS) of nivolumab in patients with previously treated metastatic SCCA of the anal canal. (Part A) II. To evaluate overall survival (OS) in patients with previously treated metastatic SCCA of the anal canal treated with nivolumab. (Part A) 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. (Part A) IV. To evaluate the overall response rate (ORR) of nivolumab plus or minus ipilimumab in patients with previously treated metastatic SCCA of the anal canal. (Part B) V. To evaluate overall survival (OS) in patients with previously treated metastatic SCCA of the anal canal treated with nivolumab plus or minus ipilimumab. (Part B) VI. To evaluate the grade 3 and 4 toxicity rate in patients with previously treated metastatic SCCA of the anal canal when treated with nivolumab plus or minus ipilimumab. (Part B) EXPLORATORY OBJECTIVES: 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. (Part A) 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. (Part A) III. To evaluate ORR, PFS, and OS based on expression of PD-L1, PD-1, peritumoral CD8+ 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 plus or minus ipilimumab. (Part B) IV. To evaluate radiographic responses according to relative changes in proportions of anti-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 plus or minus ipilimumab. (Part B) OUTLINE: PART A: Patients receive nivolumab intravenously (IV) over 60 minutes once every two weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI) and blood sample collection throughout the study. PART B: Patients are randomized to 1 of 2 arms. ARM I: Patients receive nivolumab IV over 30 minutes once every 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study. ARM II: Patients receive nivolumab as in Arm I. Patients also receive ipilimumab IV over 30 minutes once every 8 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study. After completion of study treatment, patients are followed up for 100 days and then every 3 months for 2 years.
Investigators
Eligibility Criteria
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.
- •CT scans or 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 palliative radiotherapy to a site of tumor must wait a minimum \>= 28 days from the date of completion of radiotherapy prior to initiating treatment with nivolumab (Part A and B) or nivolumab +/- Ipilimumab (Part B) on this study
- •Patients must be of age \>= 18 years at the time of study registration; because no dosing or adverse event data are currently available on the use of nivolumab in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
- •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
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 (Parts A+ B) and/or ipilimumab (Part B)
- •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 because of the risk of recurrence or exacerbation of disease
- •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
Arms & Interventions
Part A (nivolumab)
Patients receive nivolumab IV over 60 minutes once every two weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.
Intervention: Computed Tomography
Part A (nivolumab)
Patients receive nivolumab IV over 60 minutes once every two weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.
Intervention: Biospecimen Collection
Part A (nivolumab)
Patients receive nivolumab IV over 60 minutes once every two weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging
Part B Arm I (nivolumab)
Patients receive nivolumab IV over 30 minutes once every 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.
Intervention: Biospecimen Collection
Part B Arm I (nivolumab)
Patients receive nivolumab IV over 30 minutes once every 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.
Intervention: Computed Tomography
Part B Arm I (nivolumab)
Patients receive nivolumab IV over 30 minutes once every 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging
Part B Arm II (nivolumab, ipilimumab)
Patients receive nivolumab as in Arm I. Patients also receive ipilimumab IV over 30 minutes once every 8 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.
Intervention: Biospecimen Collection
Part B Arm II (nivolumab, ipilimumab)
Patients receive nivolumab as in Arm I. Patients also receive ipilimumab IV over 30 minutes once every 8 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.
Intervention: Computed Tomography
Part B Arm II (nivolumab, ipilimumab)
Patients receive nivolumab as in Arm I. Patients also receive ipilimumab IV over 30 minutes once every 8 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging
Part A (nivolumab)
Patients receive nivolumab IV over 60 minutes once every two weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.
Intervention: Nivolumab
Part B Arm I (nivolumab)
Patients receive nivolumab IV over 30 minutes once every 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.
Intervention: Nivolumab
Part B Arm II (nivolumab, ipilimumab)
Patients receive nivolumab as in Arm I. Patients also receive ipilimumab IV over 30 minutes once every 8 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.
Intervention: Ipilimumab
Part B Arm II (nivolumab, ipilimumab)
Patients receive nivolumab as in Arm I. Patients also receive ipilimumab IV over 30 minutes once every 8 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.
Intervention: Nivolumab
Outcomes
Primary Outcomes
Progression-free survival (PFS) (Part B)
Time Frame: Time period from the date of randomization to the date of PD or death whichever occurred first, assessed up to 2 years
Overall response rate: number of participants with response (Part A)
Time Frame: Up to 2 years
Responses assessed using computed tomography (CT) scans or magnetic resonance imaging according to standard Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria in order to assess disease progression. Complete Response (CR): Disappearance all target lesions; any pathological lymph nodes reduction in short axis to \< 10 mm (\< 1 cm). Partial Response (PR): \> 30% decrease in sum diameters of target lesions. Progressive Disease (PD): \> 20% increase in sum diameters lesions. (Note: appearance of one or \> new lesions considered progressions). Stable Disease (SD): Neither shrinkage qualify for PR nor increase for PD.
Overall Response Rate: Number of Participants With Response (Part A)
Time Frame: Up to 2 years
Responses assessed using computed tomography (CT) scans or magnetic resonance imaging according to standard Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria in order to assess disease progression. Complete Response (CR): Disappearance all target lesions; any pathological lymph nodes reduction in short axis to \< 10 mm (\< 1 cm). Partial Response (PR): \> 30% decrease in sum diameters of target lesions. Progressive Disease (PD): \> 20% increase in sum diameters lesions. (Note: appearance of one or \> new lesions considered progressions). Stable Disease (SD): Neither shrinkage qualify for PR nor increase for PD.
Progression-free Survival (PFS) (Part B)
Time Frame: Time period from the date of randomization to the date of PD or death whichever occurred first, assessed up to 2 years
From initiation of treatment with nivolumab until the time of disease progression, time measured in months. Kaplan-Meier analysis performed to estimate the median progression-free survival with a 90% confidence interval.
Secondary Outcomes
- Overall survival (Part A and B)(From initiation of treatment with nivolumab until death, assessed up to 2 years)
- Overall response rates (Part B)(Up to 2 years)
- Incidence of grade 3/4/5 adverse events (Part B)(Up to 2 years)
- Number of participants with toxicities (Part A)(Up to 100 days post-treatment)
- Progression-free Survival (Part A)(From initiation of treatment with nivolumab until the time of disease progression, assessed up to 2 years)
- Treatment-related Toxicities That Occurred in at Least 1 Patient (Part A)(Adverse event data were collected during treatment (up to 100 months) and through 100 days post treatment)
- Overall Survival (Part A)(From initiation of treatment until death, assessed up to 2 years)
- Overall Survival (Part B)(From initiation of treatment until death, assessed up to 2 years)
- Overall Response Rate (Part B)(Up to 2 years)
- Incidence of Treatment-related Grade 3/4/5 Adverse Events (Part B)(Adverse event data were collected during treatment (up to 100 months) and through 100 days post treatment)