Nivolumab Alone or in Combination With Ipilimumab in Treating Patients With Advanced Uterine Leiomyosarcoma

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Active, not recruiting
CT.gov ID
NCT02428192
Collaborator
(none)
20
Enrollment
2
Locations
2
Arms
10
Patients Per Site

Study Details

Study Description

Brief Summary

This phase II trial studies how well nivolumab alone or in combination with ipilimumab works in treating patients with uterine cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment. Monoclonal antibodies, such as nivolumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread.

Condition or DiseaseIntervention/TreatmentPhase
  • Biological: Ipilimumab
  • Other: Laboratory Biomarker Analysis
  • Biological: Nivolumab
Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. To evaluate the objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of patients with advanced leiomyosarcoma of the uterus (ULMS) treated with nivolumab.

  2. To evaluate the objective response rate per RECIST 1.1 of patients with advanced ULMS treated with nivolumab in combination with ipilimumab.

SECONDARY OBJECTIVES:
  1. To evaluate the toxicity of nivolumab in patients with advanced ULMS. II. To evaluate the toxicity of nivolumab in combination with ipilimumab in patients with advanced ULMS.

  2. To evaluate the progression-free survival of ULMS treated with nivolumab. IV. To evaluate the progression-free survival of ULMS treated with nivolumab in combination with ipilimumab.

  3. To explore the relationship between PDL1, PD1 in infiltrating lymphocytes and PD2 status in archival tumor, and pre/post treatment biopsies in a minimum of 10 patients.

TERTIARY OBJECTIVES:
  1. To explore the relationship between general immune response and specific markers of immunomodulation and response to nivolumab.

  2. To explore the relationship between tumor inflammatory gene signature and response to nivolumab in archival material.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

Cohort A (closed to accrual on 21-Oct-2015): Patients receive nivolumab intravenously (IV) over approximately 60 minutes once every 2 weeks for up to 46 doses in the absence of disease progression or unacceptable toxicity.

Cohort B: Patients receive nivolumab IV over approximately 60 minutes followed by a saline flush and ipilimumab IV over 90 minutes. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 100 days.

Study Design

Study Type:
Interventional
Actual Enrollment :
20 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 2 Study of Nivolumab and Ipilimumab in Advanced Leiomyosarcoma of the Uterus
Actual Study Start Date :
Apr 22, 2015
Actual Primary Completion Date :
Sep 20, 2018

Arms and Interventions

ArmIntervention/Treatment
Experimental: Cohort A (nivolumab - closed to accrual on 21-Oct-2015)

Patients receive nivolumab IV over approximately 60 minutes once every 2 weeks for up to 46 doses in the absence of disease progression or unacceptable toxicity.

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • CMAB819
  • MDX-1106
  • NIVO
  • Nivolumab Biosimilar CMAB819
  • ONO-4538
  • Opdivo
  • Experimental: Cohort B (nivolumab and Ipilimumab)

    Patients receive nivolumab IV over approximately 60 minutes followed by a saline flush and ipilimumab IV over 90 minutes. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

    Biological: Ipilimumab
    Given IV
    Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • Ipilimumab Biosimilar CS1002
  • MDX-010
  • MDX-CTLA4
  • Yervoy
  • Other: Laboratory Biomarker Analysis
    Correlative studies

    Outcome Measures

    Primary Outcome Measures

    1. Objective Response Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Among Patients With Advanced Leiomyosarcoma of the Uterus (ULMS) Treated With Nivolumab (Cohort A) [Up to 100 days]

      For the primary endpoint of overall response with a null hypothesis of 5% and an alternative hypothesis of 20%, 37 patients are needed in a two-stage design with 12 patients in the first stage and 25 patients in the second stage. At the first stage analysis, overall response, at least 1 response out of 12 patients will need to be observed to continue through the second stage. At the second stage, at least 4 responses out of 37 patients will need to be observed to accept the treatment. The overall power for overall response rate is 90%. The overall type I error, the chance of incorrectly rejecting the null hypothesis is 9%. The probability of stopping at the first stage under the null hypothesis is 54%. The operating characteristics of this design are calculated using the exact binomial distribution.

    2. Objective Response Per RECIST 1.1 Among Patients With Advanced ULMS Treated With Nivolumab and Ipilimumab (Cohort B) [Up to 100 days]

      For the primary endpoint of overall response with a null hypothesis of 5% and an alternative hypothesis of 30%, 25 patients are needed in a two-stage design with 8 patients in the first stage and 17 patients in the second stage. At the first stage analysis, overall response, at least 1 response out of 8 patients will need to be observed to continue through the second stage. At the second stage, at least 3 responses out of 25 patients will need to be observed to accept the treatment. The overall power for overall response rate is 94%. The overall type I error, the chance of incorrectly rejecting the null hypothesis is 9%. The probability of stopping at the first stage under the null hypothesis is 66%. The operating characteristics of this design are calculated using the exact binomial distribution.

    Secondary Outcome Measures

    1. Incidence of Toxicity, Graded Using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Version 5.0 Beginning April 1, 2018) (Cohort A) [Up to 4 cycles]

      Among the first phase of 12 patients, there is at least 58% probability of observing one or more rare (7% true probability) events, and 83% probability of observing toxicities that have a true occurrence of at least 15%. Among the total cohort of 37 patients, there is at least 85% probability of observing one or more rare (5% true probability) events, and 95% probability of observing toxicities that have a true occurrence of at least 8%. With 37 treated patients, the maximum width of a 90% two-sided exact binomial confidence interval for any estimated adverse event proportion will be no wider than +/- 14%.

    2. Incidence of Toxicity, Graded Using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Version 5.0 Beginning April 1, 2018) (Cohort B) [Up to 4 cycles]

      Among the first phase of 8 patients, there is at least 57% probability of observing one or more rare (10% true probability) events, and 73% probability of observing one or more toxicities that have a true occurrence rate as low as 15%. Among the total cohort of 25 patients, there is at least 84% probability of observing one or more rare (7% true probability) events, and 93% probability of observing toxicities that have a true occurrence of at least 10%. With 25 treated patients, the maximum width of a 90% two-sided exact binomial confidence interval for any estimated adverse event proportion will be no wider than +/- 18%.

    3. Rate of Progression-free Survival (Cohort A) [Time from start of treatment to time of progression or death, whichever occurs first, assessed at 12 weeks]

      A null hypothesis of 20% and an alternative hypothesis of 40% at 12 weeks will be investigated. Patients lost to follow-up or deaths within 12 weeks will be counted as failures. The overall power for overall progression-free rate at 12 weeks is 87%, using the exact binomial distribution. The operating characteristics of this design are calculated using a one-sided exact test with 10% type I error.

    4. Rate of Progression-free Survival (Cohort B) [Time from start of treatment to time of progression or death, whichever occurs first, assessed at 6 months]

      A null hypothesis of 18% and an alternative hypothesis of 40% at 6 months will be investigated. Patients lost to follow-up or deaths within 6 months will be counted as failures. The overall power for overall progression-free rate at 6 months is 85%, using the exact binomial distribution. The operating characteristics of this design are calculated using a one-sided exact test with 10% type I error.

    5. PDL1 Status [Up to 100 days]

      The relationship between PDL1 status and response to nivolumab will be explored. A Fisher's exact test will be used to assess the relationship between each biomarker and response to treatment. The power to detect the relationship of interest increases as the prevalence of the biomarker increases.

    Other Outcome Measures

    1. PD2 Status in Archival Tumor [Baseline]

      The relationship between PD2 status in archival tumor and response to nivolumab will be explored. A Fisher's exact test will be used to assess the relationship between each biomarker and response to treatment. The power to detect the relationship of interest increases as the prevalence of the biomarker increases. Analysis is pending.

    2. PD1 in Infiltrating Lymphocytes [Up to 100 days]

      The relationship between PD1 in infiltrating lymphocytes and response to nivolumab will be explored. A Fisher's exact test will be used to assess the relationship between each biomarker and response to treatment. The power to detect the relationship of interest increases as the prevalence of the biomarker increases. Analysis is pending.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients must have histologically or cytologically confirmed advanced leiomyosarcoma of the uterus (ULMS); advanced ULMS is defined as metastatic ULMS or unresectable primary ULMS

    • Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam

    • Patients must have received at least one prior line of chemotherapy, for ULMS (either in the adjuvant or metastatic setting)

    • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

    • Life expectancy of greater than 9 months

    • Absolute neutrophil count >= 1,500/mcL

    • 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/ =< 5 x ULN for subjects with liver metastases

    • Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula)

    • Patients with a requirement for steroid treatment or other immunosuppressive treatment: 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

    • Women of child-bearing potential (WOCBP) 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; WOCBP should use an adequate method to avoid pregnancy for 31 weeks after the last dose of investigational drug; 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) 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; in addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL

    • WOCBP receiving nivolumab will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product; these durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days

    • Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform the treating physician immediately

    • Ability to understand and the willingness to sign a written informed consent document

    • For enrollment in the first stage of Cohort B, patients must have accessible pre-treatment and post-treatment (4-6 weeks) tumor for biopsy

    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 3 weeks earlier; patients who have had prior pelvic radiation may be at increased risk for bowel perforation, and therefore may not have residual inflammatory disease of the bowel or residual bowel toxicity based on baseline imaging and clinical assessment; palliative (limited-field) radiation therapy is permitted, if all of the following criteria are met:

    • Repeat imaging demonstrates no new sites of bone metastases

    • The lesion being considered for palliative radiation is not a target lesion

    • Bowel toxicity is not expected from the target field due to increased risk of perforation

    • Patients who are receiving any other investigational agents

    • Patients are excluded if they have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-ligand 2 (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

    • Active brain metastasis or leptomeningeal disease; patients with known brain metastases are allowed if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 12 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

    • 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

    • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with nivolumab

    • Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) or if they have a positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection

    • 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 systemic corticosteroids, are 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, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible

    • Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event)

    • 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

    • Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, fistula and abdominal carcinomatosis should be evaluated for the potential need for additional treatment before coming on study

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Brigham and Women's HospitalBostonMassachusettsUnited States02115
    2Dana-Farber Cancer InstituteBostonMassachusettsUnited States02215

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Suzanne George, Dana-Farber - Harvard Cancer Center LAO

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT02428192
    Other Study ID Numbers:
    • NCI-2014-02403
    • NCI-2014-02403
    • DFCI- 15-707
    • 9672
    • 9672
    • UM1CA186709
    First Posted:
    Apr 28, 2015
    Last Update Posted:
    Oct 4, 2021
    Last Verified:
    Sep 1, 2021
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleCohort A (Nivolumab - Closed to Accrual on 21-Oct-2015)Cohort B (Nivolumab and Ipilimumab)
    Arm/Group DescriptionPatients receive nivolumab IV over approximately 60 minutes once every 2 weeks for up to 46 doses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IVPatients receive nivolumab IV over approximately 60 minutes followed by a saline flush and ipilimumab IV over 90 minutes. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Ipilimumab: Given IV Laboratory Biomarker Analysis: Correlative studies
    Period Title: Overall Study
    STARTED128
    COMPLETED07
    NOT COMPLETED121

    Baseline Characteristics

    Arm/Group TitleCohort A (Nivolumab - Closed to Accrual on 21-Oct-2015)Cohort B (Nivolumab and Ipilimumab)Total
    Arm/Group DescriptionPatients receive nivolumab IV over approximately 60 minutes once every 2 weeks for up to 46 doses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IVPatients receive nivolumab IV over approximately 60 minutes followed by a saline flush and ipilimumab IV over 90 minutes. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Ipilimumab: Given IV Laboratory Biomarker Analysis: Correlative studiesTotal of all reporting groups
    Overall Participants12820
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    54
    61
    54
    Sex: Female, Male (Count of Participants)
    Female
    12
    100%
    8
    100%
    20
    100%
    Male
    0
    0%
    0
    0%
    0
    0%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    1
    8.3%
    0
    0%
    1
    5%
    Not Hispanic or Latino
    11
    91.7%
    8
    100%
    19
    95%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    1
    8.3%
    0
    0%
    1
    5%
    White
    11
    91.7%
    7
    87.5%
    18
    90%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    1
    12.5%
    1
    5%

    Outcome Measures

    1. Primary Outcome
    TitleObjective Response Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Among Patients With Advanced Leiomyosarcoma of the Uterus (ULMS) Treated With Nivolumab (Cohort A)
    DescriptionFor the primary endpoint of overall response with a null hypothesis of 5% and an alternative hypothesis of 20%, 37 patients are needed in a two-stage design with 12 patients in the first stage and 25 patients in the second stage. At the first stage analysis, overall response, at least 1 response out of 12 patients will need to be observed to continue through the second stage. At the second stage, at least 4 responses out of 37 patients will need to be observed to accept the treatment. The overall power for overall response rate is 90%. The overall type I error, the chance of incorrectly rejecting the null hypothesis is 9%. The probability of stopping at the first stage under the null hypothesis is 54%. The operating characteristics of this design are calculated using the exact binomial distribution.
    Time FrameUp to 100 days

    Outcome Measure Data

    Analysis Population Description
    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
    Arm/Group TitleCohort A (Nivolumab - Closed to Accrual on 21-Oct-2015)
    Arm/Group DescriptionPatients receive nivolumab IV over approximately 60 minutes once every 2 weeks for up to 46 doses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV
    Measure Participants12
    Count of Participants [Participants]
    0
    0%
    2. Primary Outcome
    TitleObjective Response Per RECIST 1.1 Among Patients With Advanced ULMS Treated With Nivolumab and Ipilimumab (Cohort B)
    DescriptionFor the primary endpoint of overall response with a null hypothesis of 5% and an alternative hypothesis of 30%, 25 patients are needed in a two-stage design with 8 patients in the first stage and 17 patients in the second stage. At the first stage analysis, overall response, at least 1 response out of 8 patients will need to be observed to continue through the second stage. At the second stage, at least 3 responses out of 25 patients will need to be observed to accept the treatment. The overall power for overall response rate is 94%. The overall type I error, the chance of incorrectly rejecting the null hypothesis is 9%. The probability of stopping at the first stage under the null hypothesis is 66%. The operating characteristics of this design are calculated using the exact binomial distribution.
    Time FrameUp to 100 days

    Outcome Measure Data

    Analysis Population Description
    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
    Arm/Group TitleCohort B (Nivolumab and Ipilimumab)
    Arm/Group DescriptionPatients receive nivolumab IV over approximately 60 minutes followed by a saline flush and ipilimumab IV over 90 minutes. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Ipilimumab: Given IV Laboratory Biomarker Analysis: Correlative studies
    Measure Participants8
    Count of Participants [Participants]
    0
    0%
    3. Secondary Outcome
    TitleIncidence of Toxicity, Graded Using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Version 5.0 Beginning April 1, 2018) (Cohort A)
    DescriptionAmong the first phase of 12 patients, there is at least 58% probability of observing one or more rare (7% true probability) events, and 83% probability of observing toxicities that have a true occurrence of at least 15%. Among the total cohort of 37 patients, there is at least 85% probability of observing one or more rare (5% true probability) events, and 95% probability of observing toxicities that have a true occurrence of at least 8%. With 37 treated patients, the maximum width of a 90% two-sided exact binomial confidence interval for any estimated adverse event proportion will be no wider than +/- 14%.
    Time FrameUp to 4 cycles

    Outcome Measure Data

    Analysis Population Description
    Please see the adverse events module for detailed list of adverse events. Percentage of participants who experienced an adverse event.
    Arm/Group TitleCohort A (Nivolumab - Closed to Accrual on 21-Oct-2015)
    Arm/Group DescriptionPatients receive nivolumab IV over approximately 60 minutes once every 2 weeks for up to 46 doses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV
    Measure Participants12
    Count of Participants [Participants]
    12
    100%
    4. Secondary Outcome
    TitleIncidence of Toxicity, Graded Using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Version 5.0 Beginning April 1, 2018) (Cohort B)
    DescriptionAmong the first phase of 8 patients, there is at least 57% probability of observing one or more rare (10% true probability) events, and 73% probability of observing one or more toxicities that have a true occurrence rate as low as 15%. Among the total cohort of 25 patients, there is at least 84% probability of observing one or more rare (7% true probability) events, and 93% probability of observing toxicities that have a true occurrence of at least 10%. With 25 treated patients, the maximum width of a 90% two-sided exact binomial confidence interval for any estimated adverse event proportion will be no wider than +/- 18%.
    Time FrameUp to 4 cycles

    Outcome Measure Data

    Analysis Population Description
    Please refer to adverse event module for detailed list of adverse events. Percentage of participants who experienced adverse events.
    Arm/Group TitleCohort B (Nivolumab and Ipilimumab)
    Arm/Group DescriptionPatients receive nivolumab IV over approximately 60 minutes followed by a saline flush and ipilimumab IV over 90 minutes. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Ipilimumab: Given IV Laboratory Biomarker Analysis: Correlative studies
    Measure Participants8
    Count of Participants [Participants]
    8
    66.7%
    5. Secondary Outcome
    TitleRate of Progression-free Survival (Cohort A)
    DescriptionA null hypothesis of 20% and an alternative hypothesis of 40% at 12 weeks will be investigated. Patients lost to follow-up or deaths within 12 weeks will be counted as failures. The overall power for overall progression-free rate at 12 weeks is 87%, using the exact binomial distribution. The operating characteristics of this design are calculated using a one-sided exact test with 10% type I error.
    Time FrameTime from start of treatment to time of progression or death, whichever occurs first, assessed at 12 weeks

    Outcome Measure Data

    Analysis Population Description
    Progression is defined as using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), 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.
    Arm/Group TitleCohort A (Nivolumab - Closed to Accrual on 21-Oct-2015)
    Arm/Group DescriptionPatients receive nivolumab IV over approximately 60 minutes once every 2 weeks for up to 46 doses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV
    Measure Participants12
    Median (95% Confidence Interval) [months]
    1.8
    6. Secondary Outcome
    TitleRate of Progression-free Survival (Cohort B)
    DescriptionA null hypothesis of 18% and an alternative hypothesis of 40% at 6 months will be investigated. Patients lost to follow-up or deaths within 6 months will be counted as failures. The overall power for overall progression-free rate at 6 months is 85%, using the exact binomial distribution. The operating characteristics of this design are calculated using a one-sided exact test with 10% type I error.
    Time FrameTime from start of treatment to time of progression or death, whichever occurs first, assessed at 6 months

    Outcome Measure Data

    Analysis Population Description
    Progression is defined as using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), 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.
    Arm/Group TitleCohort B (Nivolumab and Ipilimumab)
    Arm/Group DescriptionPatients receive nivolumab IV over approximately 60 minutes followed by a saline flush and ipilimumab IV over 90 minutes. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Ipilimumab: Given IV Laboratory Biomarker Analysis: Correlative studies
    Measure Participants8
    Median (95% Confidence Interval) [months]
    2.0
    7. Secondary Outcome
    TitlePDL1 Status
    DescriptionThe relationship between PDL1 status and response to nivolumab will be explored. A Fisher's exact test will be used to assess the relationship between each biomarker and response to treatment. The power to detect the relationship of interest increases as the prevalence of the biomarker increases.
    Time FrameUp to 100 days

    Outcome Measure Data

    Analysis Population Description
    to few responders to analyze biomarker data
    Arm/Group TitleCohort A (Nivolumab - Closed to Accrual on 21-Oct-2015)Cohort B (Nivolumab and Ipilimumab)
    Arm/Group DescriptionPatients receive nivolumab IV over approximately 60 minutes once every 2 weeks for up to 46 doses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IVPatients receive nivolumab IV over approximately 60 minutes followed by a saline flush and ipilimumab IV over 90 minutes. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Ipilimumab: Given IV Laboratory Biomarker Analysis: Correlative studies
    Measure Participants00
    8. Other Pre-specified Outcome
    TitlePD2 Status in Archival Tumor
    DescriptionThe relationship between PD2 status in archival tumor and response to nivolumab will be explored. A Fisher's exact test will be used to assess the relationship between each biomarker and response to treatment. The power to detect the relationship of interest increases as the prevalence of the biomarker increases. Analysis is pending.
    Time FrameBaseline

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    9. Other Pre-specified Outcome
    TitlePD1 in Infiltrating Lymphocytes
    DescriptionThe relationship between PD1 in infiltrating lymphocytes and response to nivolumab will be explored. A Fisher's exact test will be used to assess the relationship between each biomarker and response to treatment. The power to detect the relationship of interest increases as the prevalence of the biomarker increases. Analysis is pending.
    Time FrameUp to 100 days

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time FrameUp to 4 cyles
    Adverse Event Reporting Description Maximum grade toxicity by type was first calculated. Serious AEs were defined as events grade 3 or higher per CTCAEv4. Other AEs were defined as anticipated and unanticipated events (not included in the serious adverse event table) that exceed a frequency threshold of 5%. These are grouped by organ system, with number and frequency of such events in each arm/group of the clinical study.
    Arm/Group TitleCohort A (Nivolumab - Closed to Accrual on 21-Oct-2015)Cohort B (Nivolumab and Ipilimumab)
    Arm/Group DescriptionPatients receive nivolumab IV over approximately 60 minutes once every 2 weeks for up to 46 doses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IVPatients receive nivolumab IV over approximately 60 minutes followed by a saline flush and ipilimumab IV over 90 minutes. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Ipilimumab: Given IV Laboratory Biomarker Analysis: Correlative studies
    All Cause Mortality
    Cohort A (Nivolumab - Closed to Accrual on 21-Oct-2015)Cohort B (Nivolumab and Ipilimumab)
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/12 (0%) 0/8 (0%)
    Serious Adverse Events
    Cohort A (Nivolumab - Closed to Accrual on 21-Oct-2015)Cohort B (Nivolumab and Ipilimumab)
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total4/12 (33.3%) 3/8 (37.5%)
    Cardiac disorders
    Cardiopulmonary arrest1/12 (8.3%) 10/8 (0%) 0
    Gastrointestinal disorders
    Abdominal pain1/12 (8.3%) 11/8 (12.5%) 1
    Diarrhea0/12 (0%) 01/8 (12.5%) 1
    Small Intestinal Obstruction1/12 (8.3%) 10/8 (0%) 0
    Renal Colic1/12 (8.3%) 10/8 (0%) 0
    Small Bowel Obstruction0/12 (0%) 01/8 (12.5%) 1
    General disorders
    Fatigue1/12 (8.3%) 10/8 (0%) 0
    Surgical Procedures (debulking/palliative surgery)1/12 (8.3%) 10/8 (0%) 0
    Investigations
    Serum amylase increased1/12 (8.3%) 10/8 (0%) 0
    Lipase increased1/12 (8.3%) 10/8 (0%) 0
    White blood cell decreased0/12 (0%) 01/8 (12.5%) 1
    Psychiatric disorders
    Major Depression1/12 (8.3%) 10/8 (0%) 0
    Renal and urinary disorders
    Hematuria1/12 (8.3%) 10/8 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea2/12 (16.7%) 21/8 (12.5%) 1
    Other (Not Including Serious) Adverse Events
    Cohort A (Nivolumab - Closed to Accrual on 21-Oct-2015)Cohort B (Nivolumab and Ipilimumab)
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total12/12 (100%) 8/8 (100%)
    Blood and lymphatic system disorders
    Anemia1/12 (8.3%) 0/8 (0%)
    Cardiac disorders
    Cardiac Arrest1/12 (8.3%) 0/8 (0%)
    Sinus tachycardia1/12 (8.3%) 0/8 (0%)
    Ear and labyrinth disorders
    Ear pain1/12 (8.3%) 0/8 (0%)
    Endocrine disorders
    Heat Intolerance1/12 (8.3%) 0/8 (0%)
    Hypothyroidism1/12 (8.3%) 1/8 (12.5%)
    Eye disorders
    Eye disorders - Other, specify - Eye Redness1/12 (8.3%) 0/8 (0%)
    Eye Pain0/12 (0%) 1/8 (12.5%)
    Gastrointestinal disorders
    Constipation9/12 (75%) 1/8 (12.5%)
    Diarrhea5/12 (41.7%) 3/8 (37.5%)
    Nausea5/12 (41.7%) 2/8 (25%)
    Stomach pain0/12 (0%) 1/8 (12.5%)
    Abdominal Distention3/12 (25%) 1/8 (12.5%)
    Abdominal Pain3/12 (25%) 3/8 (37.5%)
    Dry Mouth1/12 (8.3%) 0/8 (0%)
    Small Intestine Obstruction0/12 (0%) 1/8 (12.5%)
    Vomiting0/12 (0%) 1/8 (12.5%)
    General disorders
    Chills2/12 (16.7%) 3/8 (37.5%)
    Edema Limbs1/12 (8.3%) 0/8 (0%)
    Fatigue8/12 (66.7%) 2/8 (25%)
    Fever1/12 (8.3%) 1/8 (12.5%)
    Flu like Symptoms1/12 (8.3%) 0/8 (0%)
    Pain1/12 (8.3%) 0/8 (0%)
    Infections and infestations
    Upper respiratory infection0/12 (0%) 1/8 (12.5%)
    Urinary Tract Infection0/12 (0%) 1/8 (12.5%)
    Vaginal Infection0/12 (0%) 1/8 (12.5%)
    Injury, poisoning and procedural complications
    Bruising1/12 (8.3%) 0/8 (0%)
    Investigations
    Weight Loss3/12 (25%) 1/8 (12.5%)
    White Blood Cell Decreased1/12 (8.3%) 1/8 (12.5%)
    Alanine aminotransferase increased0/12 (0%) 2/8 (25%)
    Alkaline phosphatase increased0/12 (0%) 1/8 (12.5%)
    Aspartate aminotransferase increased0/12 (0%) 1/8 (12.5%)
    Lipase increased1/12 (8.3%) 1/8 (12.5%)
    Serum amylase increased1/12 (8.3%) 1/8 (12.5%)
    Neutrophil count decreased0/12 (0%) 1/8 (12.5%)
    Metabolism and nutrition disorders
    Anorexia4/12 (33.3%) 2/8 (25%)
    Hyponatremia1/12 (8.3%) 0/8 (0%)
    Dehydration0/12 (0%) 1/8 (12.5%)
    Hyperglycemia0/12 (0%) 1/8 (12.5%)
    Musculoskeletal and connective tissue disorders
    Muscle Cramps1/12 (8.3%) 0/8 (0%)
    Myalgia0/12 (0%) 1/8 (12.5%)
    Arthralgia1/12 (8.3%) 0/8 (0%)
    Back Pain2/12 (16.7%) 0/8 (0%)
    Buttock pain1/12 (8.3%) 0/8 (0%)
    Neck Pain1/12 (8.3%) 0/8 (0%)
    Nervous system disorders
    Akathisia1/12 (8.3%) 0/8 (0%)
    Dysgeusia2/12 (16.7%) 0/8 (0%)
    Headache4/12 (33.3%) 2/8 (25%)
    Psychiatric disorders
    Anxiety1/12 (8.3%) 0/8 (0%)
    Depression1/12 (8.3%) 0/8 (0%)
    Insomnia0/12 (0%) 1/8 (12.5%)
    Renal and urinary disorders
    Hematuria1/12 (8.3%) 0/8 (0%)
    Renal colic1/12 (8.3%) 0/8 (0%)
    Urinary urgency1/12 (8.3%) 0/8 (0%)
    Urinary frequency0/12 (0%) 1/8 (12.5%)
    Reproductive system and breast disorders
    Pelvic Pain1/12 (8.3%) 1/8 (12.5%)
    Vaginal hemorrhage1/12 (8.3%) 0/8 (0%)
    Vaginal Dryness0/12 (0%) 1/8 (12.5%)
    Respiratory, thoracic and mediastinal disorders
    cough2/12 (16.7%) 3/8 (37.5%)
    Nasal congestion1/12 (8.3%) 1/8 (12.5%)
    Dyspnea3/12 (25%) 1/8 (12.5%)
    Laryngeal hemorrhage1/12 (8.3%) 0/8 (0%)
    Postnasal drip3/12 (25%) 0/8 (0%)
    Productive cough1/12 (8.3%) 0/8 (0%)
    Renal & urinary disorders - Other - Dysuria1/12 (8.3%) 0/8 (0%)
    Resp, thoracic & mediast - Other - Rhinorrhea2/12 (16.7%) 0/8 (0%)
    Sneezing1/12 (8.3%) 0/8 (0%)
    Sore Throat2/12 (16.7%) 0/8 (0%)
    Skin and subcutaneous tissue disorders
    Erythema Nodosum1/12 (8.3%) 0/8 (0%)
    Pruritus2/12 (16.7%) 2/8 (25%)
    Urticaria1/12 (8.3%) 0/8 (0%)
    Periorbital edema0/12 (0%) 1/8 (12.5%)
    Rash maculo-papular0/12 (0%) 1/8 (12.5%)
    Nail ridging1/12 (8.3%) 0/8 (0%)
    Resp, thoracic & mediast - Other - Sinus Pressure1/12 (8.3%) 0/8 (0%)
    Skin & subcutaneous tissue -Other - Skin Sensitivity1/12 (8.3%) 0/8 (0%)
    Surgical and medical procedures
    Surgical and medical - Other - Debulking/Palliative Surgery1/12 (8.3%) 0/8 (0%)
    Vascular disorders
    Flushing1/12 (8.3%) 0/8 (0%)
    Hypertension1/12 (8.3%) 0/8 (0%)
    Thromboembolic event0/12 (0%) 1/8 (12.5%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/TitleDr. Suzanne George
    OrganizationDFCI
    Phone617-632-5204
    EmailSuzanne_George@dfci.harvard.edu
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT02428192
    Other Study ID Numbers:
    • NCI-2014-02403
    • NCI-2014-02403
    • DFCI- 15-707
    • 9672
    • 9672
    • UM1CA186709
    First Posted:
    Apr 28, 2015
    Last Update Posted:
    Oct 4, 2021
    Last Verified:
    Sep 1, 2021