Nivolumab in Treating Patients With Metastatic Adrenocortical Cancer

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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


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


      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.


      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


      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

Study Phase

Phase 2

Study Type


Primary Outcome

Overall Response Rate

Secondary Outcome

 Progression-free Survival (PFS)


Metastatic Carcinoma in the Adrenal Cortex


Laboratory Biomarker Analysis

Study Arms / Comparison Groups

 Treatment (Nivolumab)
Description:  Patients receive nivolumab IV over 30 minutes every 2 weeks in the absence of disease progression or unacceptable toxicity.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

March 30, 2016

Completion Date

November 2, 2018

Primary Completion Date

April 17, 2017

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

          -  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

          -  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

          -  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




18 Years - N/A

Accepts Healthy Volunteers



Benedito Carneiro, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID

NU 15E01

Secondary IDs


Responsible Party


Study Sponsor

Northwestern University


 National Cancer Institute (NCI)

Study Sponsor

Benedito Carneiro, MD, Principal Investigator, Northwestern University

Verification Date

February 2019