Nivolumab in Treating Patients With Metastatic Adrenocortical Cancer

• ClinicalTrials.gov Identifier: NCT02720484
• Recruitment Status: Terminated
• First Posted: March 28, 2016
• Results First Posted: May 1, 2019
• Last Update Posted: May 1, 2019
• Sponsor: Northwestern University
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Northwestern University

Tracking Information

• First Submitted Date: March 16, 2016
• First Posted Date: March 28, 2016
• Results First Submitted Date: April 11, 2019
• Results First Posted Date: May 1, 2019
• Last Update Posted Date: May 1, 2019
• Actual Study Start Date: March 30, 2016
• Actual Primary Completion Date: April 17, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 11, 2019)

Overall Response Rate [ Time Frame: From the start of treatment and every 8 weeks/2 cycles with a range of cycles attempted 1-15. ]

Overall Response Rate of nivolumab treatment for patients with metastatic adrenocortical carcinoma will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI scans every 8 weeks: Complete Response (CR) = disappearance of all target lesions. Partial Response (PR) >=30% decrease in the sum of the longest diameter of target lesions (should be confirmed 8 weeks after initial response otherwise considered unconfirmed PR). Stable Disease, neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. Progressive Disease, defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions..

Original Primary Outcome Measures (submitted: March 21, 2016)

Overall Response Rate [ Time Frame: Every 8 weeks up to 2 years ]

Overall response rate will be measured according to RECIST criteria 1.1 at every 8 weeks interval using CT scans.

Current Secondary Outcome Measures (submitted: April 11, 2019)

• Progression-free Survival (PFS) [ Time Frame: From start of treatment and every 8 weeks/2 cycles until progressive disease or death. Median follow up of 4.5 months ]
  Progression Free Survival (PFS) of nivolumab treatment in patients with metastatic adrenocortical carcinoma is defined as the duration of time from start of treatment to time of documented progression or death, whichever comes first. It will measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI scans every 8 weeks.
• Overall Survival (OS) at 3 Months and 6 Months [ Time Frame: At 3 months and 6 months from the initiation of treatment ]
  Overall Survival (OS) of nivolumab treatment in patients with metastatic adrenocortical carcinoma and will be defined as the duration of time from treatment initiation until death. OS will be assessed as the percentage of patients alive at 3 months and at 6 months from initiation of treatment on study.
• Toxicity of Nivolumab [ Time Frame: From treatment initiation, twice every Cycle (every 14 days) while on treatment, up to 12 weeks after final dose. Range of cycles completed 1-15 (1 Cycle=28 days) ]
  Safety and tolerability profile of Nivolumab will be assessed by describing by number, frequency, and severity of Adverse Events (AEs) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.3. All AEs that were considered related to Nivolumab were collected and are shown below. Patients with multiple events in the same category are counted only once in that category. Patients with events in more than one category are counted in each of those categories. Categories with no events are not shown. In general AEs will be graded according to the following: Grade 1 = Mild AE Grade 2= Moderate AE Grade 3 = Severe AE Grade 4 = Life-threatening or disabling AE Grade 5 = Death related to AE

Original Secondary Outcome Measures (submitted: March 21, 2016)

• Progression-free survival (PFS) [ Time Frame: Every 8 weeks from time of first treatment up to 2 years ]
  PFS will be assessed from date of first nivolumab infusion until date of death or evidence of progression of disease by CT imaging every 8 weeks according to RECIST criteria 1.1.
• Overall survival (OS) [ Time Frame: Every 2 weeks while on treatment then every 3 months, up to 2 years ]
  Patients will be assessed for survival (either by routine clinic visit our by phone) every 2 weeks while on treatment and every 3 months for up to 2 years after completion of trial to document survival and disease progression.
• Incidence of adverse events [ Time Frame: Every 2 weeks while on treatment, up to 12 weeks after final dose ]
  To access the safety and tolerability profile of nivolumab described by number, frequency, and severity of adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.3.

Current Other Pre-specified Outcome Measures (submitted: April 11, 2019)

• Levels of Cytokines [ Time Frame: At baseline and at 4 weeks of treatment ]
  Humoral and cellular responses to tumor antigens on serum samples will be evaluated by measuring the levels of cytokines (ie, IL-2, IL-6, IL-8, IL-10, IL-18, IFN gamma and TNF-alpha). Potential correlations between differential measures of response and the toxicity and efficacy of nivolumab will be explored.
• Levels of Peripheral Blood Lymphocyte Phenotype [ Time Frame: At baseline and at 4 weeks of treatment ]
  Humoral and cellular responses to tumor antigens on serum samples will be evaluated by measuring the levels of peripheral blood lymphocyte phenotype. Potential correlations between differential measures of response and the toxicity and efficacy of nivolumab will be explored.
• PD-L1 Expression [ Time Frame: At baseline and at 4 weeks of treatment ]
  PD-L1 expression will assist in assessing Overall response rate, PFS, and OS for this treatment.
• PD-L2 Expression [ Time Frame: At baseline and at 4 weeks of treatment ]
  PD-L2 expression will assist in assessing Overall response rate, PFS, and OS for this treatment.
• Peripheral T Cell Profile Levels [ Time Frame: At baseline and at 4 weeks of treatment ]
  Peripheral T cell profile levels will assist in assessing Overall response rate, PFS, and OS for this treatment.
• Serum Interleukin Levels [ Time Frame: At baseline and at 4 weeks of treatment ]
  Serum interleukin levels will assist in assessing Overall response rate, PFS, and OS for this treatment.

Original Other Pre-specified Outcome Measures (submitted: March 21, 2016)

• Levels of cytokines [ Time Frame: At baseline and at 4 weeks of treatment ]
  Humoral and cellular responses to tumor antigens on serum samples will be evaluated by measuring the levels of cytokines (ie, IL-2, IL-6, IL-8, IL-10, IL-18, IFN gamma and TNF-alpha). Potential correlations between differential measures of response and the toxicity and efficacy of nivolumab will be explored.
• Levels of peripheral blood lymphocyte phenotype [ Time Frame: At baseline and at 4 weeks of treatment ]
  Humoral and cellular responses to tumor antigens on serum samples will be evaluated by measuring the levels of peripheral blood lymphocyte phenotype. Potential correlations between differential measures of response and the toxicity and efficacy of nivolumab will be explored.
• PD-L1 expression [ Time Frame: At baseline and at 4 weeks of treatment ]
  PD-L1 expression will assist in assessing Overall response rate, PFS, and OS for this treatment.
• PD-L2 expression [ Time Frame: At baseline and at 4 weeks of treatment ]
  PD-L2 expression will assist in assessing Overall response rate, PFS, and OS for this treatment.
• Peripheral T cell profile levels [ Time Frame: At baseline and at 4 weeks of treatment ]
  Peripheral T cell profile levels will assist in assessing Overall response rate, PFS, and OS for this treatment.
• Serum interleukin levels [ Time Frame: At baseline and at 4 weeks of treatment ]
  Serum interleukin levels will assist in assessing Overall response rate, PFS, and OS for this treatment.

Descriptive Information

• Brief Title: Nivolumab in Treating Patients With Metastatic Adrenocortical Cancer
• Official Title: Phase II Study of Nivolumab (Anti-PD-1 Antibody) for Treatment of Metastatic Adrenocortical Carcinoma
• Brief Summary: The primary objective will be to assess overall response rate of nivolumab in patients with metastatic or locally advanced adrenocortical carcinoma. Nivolumab was recently approved by U.S. Food and Drug Administration (FDA) for the treatment of advanced melanoma, non-small cell lung cancer and renal cell carcinoma. It is considered investigational for the treatment of advanced or refractory adrenocortical carcinoma. "Investigational" means that the drug is not approved by the USFDA or not approved for the indication under investigation. Nivolumab could shrink adrenocortical carcinoma but it could also cause side effects. Researchers hope to learn if the study drug will shrink the cancer and hopefully to relieve symptoms that are related to the cancer.

Detailed Description

PRIMARY OBJECTIVES:

I. To assess overall response rate of nivolumab in patients with metastatic or locally advanced adrenocortical carcinoma (ACC).

SECONDARY OBJECTIVES:

I. To assess the progression free survival defined as time from date of first nivolumab infusion until date of death or evidence of progression of disease as assessed by computed tomography (CT) imaging every 8 weeks according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1.

II. To assess the overall survival defined as time from date of first nivolumab infusion until death of patients with metastatic or locally advanced ACC.

III. To assess the safety and tolerability profile of nivolumab described by number, frequency, and severity of adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.3 assessed every 2 weeks while patients are on therapy.

TERTIARY OBJECTIVES:

I. To assess the overall response rate, progression free survival and overall survival according to tumor programmed cell death 1 ligand 1 (PD-L1) and programmed cell death 1 ligand 2 (PD-L2) expression.

II. To assess the overall response rate, progression free survival and overall survival according to serum interleukin levels and peripheral T cell profile levels.

III. To measure humoral and cellular responses to tumor antigens on serum samples by measuring the levels of cytokines (ie, interleukin [IL] -2, IL-6, IL-8, IL-10, IL-18, interferon [IFN] gamma and tumor necrosis factor [TNF]-alpha) and peripheral blood lymphocyte phenotype.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes every 2 weeks in the absence of disease progression or unacceptable toxicity, or withdrawal of consent.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Metastatic Carcinoma in the Adrenal Cortex
• Recurrent Adrenal Cortex Carcinoma
• Stage III Adrenal Cortex Carcinoma
• Stage IV Adrenal Cortex Carcinoma

Intervention

• Other: Laboratory Biomarker Analysis
  Correlative studies
• Drug: Nivolumab
  Given IV
  Other Names:

  • BMS-936558
  • MDX-1106
  • ONO-4538
  • Opdivo

Study Arms

Experimental: Treatment (Nivolumab)

Patients receive nivolumab IV over 30 minutes every 2 weeks in the absence of disease progression or unacceptable toxicity.

Interventions:

• Other: Laboratory Biomarker Analysis
• Drug: Nivolumab

• Publications *: Carneiro BA, Konda B, Costa RB, Costa RLB, Sagar V, Gursel DB, Kirschner LS, Chae YK, Abdulkadir SA, Rademaker A, Mahalingam D, Shah MH, Giles FJ. Nivolumab in Metastatic Adrenocortical Carcinoma: Results of a Phase 2 Trial. J Clin Endocrinol Metab. 2019 Dec 1;104(12):6193-6200. doi: 10.1210/jc.2019-00600.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: May 24, 2017): 10
• Original Estimated Enrollment (submitted: March 21, 2016): 33
• Actual Study Completion Date: November 2, 2018
• Actual Primary Completion Date: April 17, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients must have a histologically confirmed stage IV or unresectable locally advanced adrenocortical carcinoma
• Patients must have disease progressing after treatment with at least one line of therapy including mitotane and/or chemotherapy; Note: patients declining first line treatment with mitotane and/or chemotherapy based on limited efficacy are also eligible for this study
• Patients must have measurable disease according to the standard RECIST version 1.1; CT scans or magnetic resonance imaging (MRIs) used to assess the measurable disease must have been completed within 28 days prior to registration
• Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3
• Leukocytes >= 2,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Hemoglobin >= 9 g/dL
• Platelets >= 100,000/mcL
• Total bilirubin =< 1.5 × institutional upper limit of normal (ULN) (except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
• Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine transferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
• Serum creatinine of < 3.0 x ULN (upper limit of normal) or creatinine clearance (CrCl) > 30 mL/minute (using Cockcroft/Gault formula below)
• Patients with history of central nervous system (CNS) metastases are eligible if CNS disease has been radiographically and neurologically stable for at least 6 weeks prior to study registrations and do not require corticosteroids (of any dose) for symptomatic management
• Females of childbearing potential (FOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 72 hours prior to the start of study drug; NOTE: a FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy; has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)
• FOCBP must agree to follow instructions for method(s) of contraception (e.g. hormonal or barrier method of birth control; abstinence) for the duration of treatment with nivolumab plus 5 half-lives of nivolumab (19 weeks) plus 30 days (duration of ovulatory cycle) for a total of 23 weeks post-treatment completion
• Males who are sexually active with women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception (e.g. hormonal or barrier method of birth control; abstinence) for the duration of treatment with nivolumab plus 5 halflives of the study drug (19 weeks) plus 90 days (duration of sperm turnover) for a total of 31 weeks days post-treatment completion
• Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study are not eligible
• Patients who have not recovered to =< grade 1 from adverse events due to agents administered more than 4 weeks earlier are not eligible
• Patients may not be receiving any other investigational agents
• Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab are not eligible
• Patients should be excluded if they have had prior treatment with an anti-PD1 or anti-PD-L1. Please contact principal investigator, Benedito Carneiro, for specific questions on potential interactions

• 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
  • Patients with a history of toxic epidermal necrolysis (TEN)
  • Stevens-Johnson syndrome
  • Anti-phospholipid syndrome; Note: subjects with 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 are permitted to enroll
• Any condition requiring systemic treatment with corticosteroids (> 10mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug; Note: inhaled steroids and adrenal replacement steroid doses > 10mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; a brief (less than 3 weeks) course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted
• Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible
• Hypertension that is not controlled on medication (Note: hypertension is defined as blood pressure >= 140/90)
• Ongoing or active infection requiring systemic treatment
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Cardiac arrhythmia
• Psychiatric illness/social situations that would limit compliance with study requirements
• Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints
• Female patients who are pregnant or nursing are not eligible
• 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
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) is not permitted
• Any known positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection is not permitted

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02720484
• Other Study ID Numbers: NU 15E01; STU00202153 ( CTRP (Clinical Trial Reporting Program) ); NU 15E01 ( Other Identifier: Northwestern University ); P30CA060553 ( U.S. NIH Grant/Contract ); NCI-2016-00194 ( Other Identifier: CTRP (Clinical Trial Reporting Program) )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Northwestern University
• Original Responsible Party: Same as current
• Current Study Sponsor: Northwestern University
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Benedito Carneiro, MD; Northwestern University

• PRS Account: Northwestern University
• Verification Date: February 2019