Nivolumab in Treating Patients With Autoimmune Disorders and Advanced, Metastatic, or Unresectable Cancer

Phase 1

Recruiting

• Conditions: Hematopoietic and Lymphoid Cell Neoplasm; Psoriatic Arthritis; Rheumatoid Arthritis; Psoriasis; Ulcerative Colitis; Autoimmune Disease; Inflammatory Bowel Disease; Malignant Solid Neoplasm; Multiple Sclerosis; Systemic Scleroderma
• Interventions: Procedure: Biospecimen Collection; Biological: Nivolumab

• Registration Number: NCT03816345
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase Ib trial studies the side effects of nivolumab and to see how well it works in treating patients with autoimmune disorders and cancer that has spread to other places in the body or cannot removed by surgery. Immunotherapy with monoclonal antibodies, such as nivolumab, 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 OBJECTIVE:

I. To assess the overall safety, and toxicities associated with the use of the anti-programmed death 1 (PD-1) antibody nivolumab in patients with varying severity of dermatomyositis (DM)/systemic sclerosis (SSc), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) (ulcerative colitis \[UC\] and Crohn's disease \[CD\]), multiple sclerosis (MS), Sjogren's syndrome \[SjS\], Psoriasis (PsO)/Psoriatic Arthritis (PsA), and other autoimmune diseases.

SECONDARY OBJECTIVES:

I. To evaluate the efficacy of nivolumab in terms of objective response rates (ORRs), progression-free survival (PFS), and overall survival (OS) in patients with cancer and DM/SSc, RA, SLE, IBD (UC and CD), MS, SjS, PsO/PsA, and other autoimmune diseases.

II. To observe and record anti-tumor activity. III. To propose dosing recommendations for anti-PD-1 antibodies based on the severity of the autoimmune disorder.

IV. To evaluate the impact of nivolumab on the disease severity indices for: DM/SSc, RA, SLE, IBD: UC and CD, not specified (NS), MS, SjS, PsO/PsA.

V. To identify biomarkers of response and toxicity.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood, cerebrospinal fluid (CSF), tissue, stool, and urine samples throughout the trial.

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

Study Timeline

• Study First Submitted: 2019-01-24
• Study First Submitted QC: 2019-01-24
• Study First Posted: 2019-01-25
• Study Start: 2019-07-16
• Status Verified: 2024-08
• Last Update Submitted: 2025-01-07
• Last Update Posted: 2025-01-08
• Primary Completion: 2026-08-31
• Study Completion: 2026-08-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

• Patients can have either histologically confirmed malignancy that is radiologically evaluable and metastatic or unresectable, or have a malignancy for which a PD-1/PD-L1 inhibitor has been approved in the adjuvant setting. Eligible tumor types include solid tumors and malignancies in which there is known evidence of clinical activity for single agent PD-1 or PD-L1 antibodies. Nivolumab is Food and Drug Administration (FDA)-approved for the treatment of melanoma, non-small cell lung cancer (NSCLC), Merkel cell cancer, bladder cancer, renal cell carcinoma (RCC), gastric cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer, Hodgkin lymphoma (HL), metastatic small cell lung cancer (SCLC), and any solid tumor with microsatellite instability (MSI)-high status confirmed. Patients with HL are eligible but must follow standard response criteria. Additional tumor types may be eligible on a case by case basis upon discussion with principal investigator (PI). Patients enrolling on the trial for adjuvant use will be restricted to those with histology for which a PD-1/PD-L1 inhibitor has been approved in the adjuvant setting including but not limited to NSCLC, melanoma, RCC, cervical cancer, and bladder cancer
• Patients who have previously received other forms of immunotherapy (high-dose [HD] IL-2, IFN, CTLA-4) are allowed. Patients must not have received cytokine immunotherapy for at least 4 weeks before nivolumab administration. Patients who have received prior anti-CTLA4 will be allowed and the washout period is 6 weeks
• Age >= 18 years; children are excluded from this study but may be eligible for future pediatric phase 1 combination trials
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Karnofsky >= 60)
• Life expectancy of greater than 12 weeks
• Leukocytes >= 1,000/mcL
• Absolute neutrophil count >= 500/mcL
• Platelets >= 50,000/mcL
• Total bilirubin =< 2 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional ULN or =< 8 x institutional ULN for patients with liver metastases or an autoimmune disease that is contributing to the elevation of these values
• Creatinine ULN OR glomerular filtration rate (GFR) >= 30 mL/min (if using the Cockcroft-Gault formula)
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated
• If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load
• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required for at least 4 weeks (or scheduled assessment after the first cycle of treatment), and a risk-benefit analysis (discussion) by the patient and the investigator favors participation in the clinical trial
• The effects of nivolumab on the developing human fetus are unknown. For this reason, women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. WOCBP receiving nivolumab will be instructed to adhere to contraception for a period of 5 months after the last dose of investigational product. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of nivolumab. Women must not be breastfeeding. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception. 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. 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, and men who are sexually active with WOCBP use contraception for 5 half-lives plus 90 days. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she (or the participating partner) should inform the treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document
• Patients with more than one autoimmune disease are eligible. The treating physician would determine which autoimmune disease is dominant and the patient would be treated under that specific cohort

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Exclusion Criteria

• Patients who have had chemotherapy or radiotherapy within 2 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 have not resolved or stabilized. Palliative (limited-field) radiation therapy (RT) is permitted (2 week washout from start of treatment), 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

• Patients with prior therapy with an anti-PD-1 or anti-PD-L1

• Patients with prior allogeneic hematologic transplant

• Patients who are receiving any other anticancer investigational agents

• 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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (nivolumab)	Nivolumab	Patients receive nivolumab IV over 30 minutes every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood, CSF, tissue, stool, and urine samples throughout the trial.
Treatment (nivolumab)	Biospecimen Collection	Patients receive nivolumab IV over 30 minutes every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood, CSF, tissue, stool, and urine samples throughout the trial.

Primary Outcome Measures

Name	Time	Method
Changes in serum chemokines and circulating immune cells over time	Baseline up to 100 days	Will be summarized and assessed using generalized linear mixed modeling.
Gene expression in normal tissues	Up to 100 days	Will be compared with gene expression in malignant tissues based on two-sample t-test and Wilcoxon rank sum test. False discovery rate, if appropriate, will be used to control for multiple testing.
Change in disease assessments	Baseline up to 100 days	Will be summarized at each time point for each disease severity cohort.
Incidence of adverse events	Up to 100 days	Will be reported overall and by severity, and dose limiting toxicities will be summarized for all patients and by disease severity cohort.
Overall response rate	Up to 100 days	Will be computed along with its associated exact 95% confidence interval for all patients and by disease severity cohort.
Clinical measures of interest	Up to 100 days	The association between demographic and clinical measures of interest with overall response rate and toxicity will be evaluated using logistic regression modeling to identify potential predictors of outcomes.

Trial Locations

Locations (51)

University of Alabama at Birmingham Cancer Center; 🇺🇸 Birmingham, Alabama, United States

Stanford Cancer Institute Palo Alto; 🇺🇸 Palo Alto, California, United States

University of California Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

Smilow Cancer Center/Yale-New Haven Hospital; 🇺🇸 New Haven, Connecticut, United States

Yale University; 🇺🇸 New Haven, Connecticut, United States

MedStar Georgetown University Hospital; 🇺🇸 Washington, District of Columbia, United States

Emory University Hospital/Winship Cancer Institute; 🇺🇸 Atlanta, Georgia, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

University of Chicago Comprehensive Cancer Center; 🇺🇸 Chicago, Illinois, United States

University of Kansas Clinical Research Center; 🇺🇸 Fairway, Kansas, United States

HaysMed; 🇺🇸 Hays, Kansas, United States

University of Kansas Cancer Center; 🇺🇸 Kansas City, Kansas, United States

Lawrence Memorial Hospital; 🇺🇸 Lawrence, Kansas, United States

The University of Kansas Cancer Center - Olathe; 🇺🇸 Olathe, Kansas, United States

University of Kansas Cancer Center-Overland Park; 🇺🇸 Overland Park, Kansas, United States

University of Kansas Hospital-Indian Creek Campus; 🇺🇸 Overland Park, Kansas, United States

Ascension Via Christi - Pittsburg; 🇺🇸 Pittsburg, Kansas, United States

Salina Regional Health Center; 🇺🇸 Salina, Kansas, United States

University of Kansas Health System Saint Francis Campus; 🇺🇸 Topeka, Kansas, United States

University of Kansas Hospital-Westwood Cancer Center; 🇺🇸 Westwood, Kansas, United States

Johns Hopkins University/Sidney Kimmel Cancer Center; 🇺🇸 Baltimore, Maryland, United States

National Cancer Institute Developmental Therapeutics Clinic; 🇺🇸 Bethesda, Maryland, United States

National Institutes of Health Clinical Center; 🇺🇸 Bethesda, Maryland, United States

Massachusetts General Hospital Cancer Center; 🇺🇸 Boston, Massachusetts, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Wayne State University/Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Siteman Cancer Center at West County Hospital; 🇺🇸 Creve Coeur, Missouri, United States

University Health Truman Medical Center; 🇺🇸 Kansas City, Missouri, United States

University of Kansas Cancer Center - North; 🇺🇸 Kansas City, Missouri, United States

University of Kansas Cancer Center - Lee's Summit; 🇺🇸 Lee's Summit, Missouri, United States

University of Kansas Cancer Center at North Kansas City Hospital; 🇺🇸 North Kansas City, Missouri, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Siteman Cancer Center-South County; 🇺🇸 Saint Louis, Missouri, United States

Siteman Cancer Center at Christian Hospital; 🇺🇸 Saint Louis, Missouri, United States

Siteman Cancer Center at Saint Peters Hospital; 🇺🇸 Saint Peters, Missouri, United States

Rutgers Cancer Institute of New Jersey; 🇺🇸 New Brunswick, New Jersey, United States

NYU Langone Hospital - Long Island; 🇺🇸 Mineola, New York, United States

Laura and Isaac Perlmutter Cancer Center at NYU Langone; 🇺🇸 New York, New York, United States

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center; 🇺🇸 New York, New York, United States

NYP/Weill Cornell Medical Center; 🇺🇸 New York, New York, United States

Ohio State University Comprehensive Cancer Center; 🇺🇸 Columbus, Ohio, United States

Thomas Jefferson University Hospital; 🇺🇸 Philadelphia, Pennsylvania, United States

University of Pittsburgh Cancer Institute (UPCI); 🇺🇸 Pittsburgh, Pennsylvania, United States

UT Southwestern Simmons Cancer Center - RedBird; 🇺🇸 Dallas, Texas, United States

UT Southwestern/Simmons Cancer Center-Dallas; 🇺🇸 Dallas, Texas, United States

UT Southwestern/Simmons Cancer Center-Fort Worth; 🇺🇸 Fort Worth, Texas, United States

M D Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

UT Southwestern Clinical Center at Richardson/Plano; 🇺🇸 Richardson, Texas, United States

Huntsman Cancer Institute/University of Utah; 🇺🇸 Salt Lake City, Utah, United States

Virginia Commonwealth University/Massey Cancer Center; 🇺🇸 Richmond, Virginia, United States

University Health Network-Princess Margaret Hospital; 🇨🇦 Toronto, Ontario, Canada