A Phase Ib Study of Nivolumab in Patients With Autoimmune Disorders and Advanced Malignancies (AIM-NIVO)
Summary
This phase Ib trial studies the side effects of nivolumab and to see how well it works alone and in combination with other treatments, such as ipilimumab, cabozantinib, platinum containing therapy, and fluoropyrimidine, in treating patients with autoimmune disorders and cancer that has spread from where it first started (primary site) to nearby tissue, lymph nodes, or distant parts of the body (advanced), to other places in the body (metastatic) or cannot removed by surgery (unresectable). 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. Cabozantinib blocks certain proteins, which may help keep tumor cells from growing. It may also prevent the growth of new blood vessels that tumors need to grow. Cabozantinib is a type of tyrosine kinase inhibitor and a type of angiogenesis inhibitor. Chemotherapy drugs, such as platinum containing therapies and fluoropyrimidine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab alone and in combination with other treatments, including ipilimumab, cabozantinib, platinum containing therapy, or fluoropyrimidine, may be safe, tolerable, and/or effective in treating patients with autoimmune disorders and advanced, metastatic, or unresectable cancer.
Detailed description
PRIMARY OBJECTIVES: 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. II. To assess the overall safety, and toxicities associated with the use of the anti-programmed death 1 (PD-1) antibody nivolumab and other Food and Drug Administration (FDA)-approved combinations for given oncologic indications in patients with varying severity of DM/SSc, RA, SLE, IBD (ulcerative colitis \[UC\] and Crohn's disease \[CD\]), 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 are assigned to 1 of 11 arms. ARM I (MONOTHERAPY): Patients may receive single agent nivolumab intravenously (IV) over 30 minutes every 4 weeks for up to 2 years for patients with metastatic indications, for up to 1 year for adjuvant indications or for up to 3 months after surgery for neoadjuvant indications in the absence of disease progression or unacceptable toxicity. ARM II (UNRESECTABLE OR METASTATIC MELANOMA): Patients receive nivolumab IV over 30 minutes every 2 or 4 weeks in combination with ipilimumab IV every 3 weeks for up to 4 doses of combination therapy in the absence of disease progression or unacceptable toxicity. Treatment with nivolumab may continue every 4 weeks in the absence of disease progression or unacceptable toxicity. ARM III (NEOADJUVANT TREATMENT OF RESECTABLE NON-SMALL CELL LUNG CANCER \[NSCLC\]): Patients receive nivolumab IV over 30 minutes in combination with platinum doublet therapy every 3 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. ARM IV (METASTATIC PD-L1 POSITIVE NSCLC): Patients receive nivolumab IV over 30 minutes every 3 weeks and ipilimumab IV every 6 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. ARM V (METASTATIC OR RECURRENT NSCLC): Patients receive nivolumab IV over 30 minutes every 3 weeks, ipilimumab IV every 6 weeks and platinum doublet therapy every 3 weeks for up to 2 cycles of combination therapy. Treatment with nivolumab and ipilimumab repeats for up to 2 years in the absence of disease progression or unacceptable toxicity. ARM VI (MALIGNANT PLEURAL MESOTHELIOMA): Patients receive nivolumab IV over 30 minutes every 3 weeks and ipilimumab IV every 6 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. ARM VII (ADVANCED RENAL CELL CARCINOMA \[RCC\]): Patients receive nivolumab IV over 30 minutes in combination with ipilimumab IV every 3 weeks for up to 4 doses of combination therapy in the absence of disease progression or unacceptable toxicity. Patients may continue to receive single agent nivolumab every 2 or 4 weeks in the absence of disease progression or unacceptable toxicity. Patients may optionally receive nivolumab IV every 2 or 4 weeks in combination with cabozantinib orally (PO) once daily (QD) for up to 2 years of combination therapy in the absence of disease progression or unacceptable toxicity. Treatment with single agent cabozantinib may continue in the absence of disease progression or unacceptable toxicity. ARM VIII (MICROSATELLITE INSTABILITY-HIGH \[MSI-H\] OR MISMATCH REPAIR DEFICIENT \[dMMR\] METASTATIC COLORECTAL CANCER): Patient receive nivolumab IV over 30 minutes every 2 or 4 weeks in combination with ipilimumab IV every 3 weeks for up to 4 doses of combination therapy in the absence of disease progression or unacceptable toxicity. Patients may continue to receive single agent nivolumab every 2 or 4 weeks in the absence of disease progression or unacceptable toxicity. ARM IX (HEPATOCELLULAR CARCINOMA \[HCC\]): Patients receive nivolumab IV over 30 minutes in combination with ipilimumab IV every 3 weeks for up to 4 doses of combination therapy. Patients may continue to receive single agent nivolumab every 2 or 4 weeks in the absence of disease progression or unacceptable toxicity. ARM X (ESOPHAGEAL SQUAMOUS CELL CARCINOMA): Patients receive nivolumab IV over 30 minutes every 2 or 4 weeks in combination with fluoropyrimidine and platinum-containing chemotherapy for up to 2 years in the absence of disease progression or unacceptable toxicity OR receive nivolumab IV every 2 or 3 weeks in combination with ipilimumab IV every 6 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may then continue receiving fluoropyrimidine and platinum-containing chemotherapy in the absence of disease progression or unacceptable toxicity. ARM XI (GASTRIC CANCER, GASTROESOPHAGEAL JUNCTION CANCER, AND ESOPHAGEAL ADENOCARCINOMA): Patients receive nivolumab IV over 30 minutes in combination with fluoropyrimidine and platinum-containing chemotherapy every 2 or 3 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 without disease progression are followed for 100 days, and patients with disease progression are followed every 12 weeks for up to 5 years.
Arms & interventions
- ProcedureBiospecimen Collection
Undergo collection of blood, CSF, tissue, stool and urine samples
- DrugCabozantinib
Given PO
- DrugFluoropyrimidine
Given fluoropyrimidine
- BiologicalIpilimumab
Given IV
- BiologicalNivolumab
Given IV
- DrugPlatinum Compound
Given platinum containing chemotherapy
- DrugPlatinum Doublet
Given platinum doublet
Outcome measures
Primary
Incidence of adverse events
Will be reported overall and by severity, and dose limiting toxicities will be summarized for all patients and by disease severity cohort.
Time frame: Up to 100 days after completion of study treatment
Change in disease assessments
Will be summarized at each time point for each disease severity cohort.
Time frame: Baseline up to 100 days after completion of study treatment
Overall response rate
Will be computed along with its associated exact 95% confidence interval for all patients and by disease severity cohort.
Time frame: Up to 5 years after completion of study treatment
Changes in serum chemokines and circulating immune cells over time
Will be summarized and assessed using generalized linear mixed modeling.
Time frame: Baseline up to 100 days after completion of study treatment
Gene expression in normal tissues
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.
Time frame: Up to 100 days after completion of study treatment
Clinical measures of interest
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.
Time frame: Up to 100 days after completion of study treatment
Eligibility criteria
Study locations (51)
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, 35233
Stanford Cancer Institute Palo Alto
Palo Alto, California, 94304
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817
Smilow Cancer Center/Yale-New Haven Hospital
New Haven, Connecticut, 06510
Yale University
New Haven, Connecticut, 06520
MedStar Georgetown University Hospital
Washington D.C., District of Columbia, 20007
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
Northwestern University
Chicago, Illinois, 60611
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637
University of Kansas Clinical Research Center
Fairway, Kansas, 66205
HaysMed
Hays, Kansas, 67601
University of Kansas Cancer Center
Kansas City, Kansas, 66160
Lawrence Memorial Hospital
Lawrence, Kansas, 66044
The University of Kansas Cancer Center - Olathe
Olathe, Kansas, 66061
University of Kansas Cancer Center-Overland Park
Overland Park, Kansas, 66210
University of Kansas Hospital-Indian Creek Campus
Overland Park, Kansas, 66211
Mercy Hospital Pittsburg
Pittsburg, Kansas, 66762
Salina Regional Health Center
Salina, Kansas, 67401
University of Kansas Health System Saint Francis Campus
Topeka, Kansas, 66606
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, 66205
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, 40536
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, 21287
National Cancer Institute Developmental Therapeutics Clinic
Bethesda, Maryland, 20892
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, 02114
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, 48201
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141
University Health Truman Medical Center
Kansas City, Missouri, 64108
University of Kansas Cancer Center - North
Kansas City, Missouri, 64154
University of Kansas Cancer Center - Lee's Summit
Lee's Summit, Missouri, 64064
University of Kansas Cancer Center at North Kansas City Hospital
North Kansas City, Missouri, 64116
Washington University School of Medicine
St Louis, Missouri, 63110
Siteman Cancer Center-South County
St Louis, Missouri, 63129
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, 63136
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, 08903
NYU Langone Hospital - Long Island
Mineola, New York, 11501
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, 10032
NYP/Weill Cornell Medical Center
New York, New York, 10065
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, 19107
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, 15232
UT Southwestern Simmons Cancer Center - RedBird
Dallas, Texas, 75237
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, 75390
UT Southwestern/Simmons Cancer Center-Fort Worth
Fort Worth, Texas, 76104
UT MD Anderson Cancer Center
Houston, Texas, 77030
UT Southwestern Clinical Center at Richardson/Plano
Richardson, Texas, 75080
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112
VCU Massey Comprehensive Cancer Center
Richmond, Virginia, 23298
References
- Vaziri H, Turshudzhyan A, Vecchio E. Immunotherapy-induced Colitis: A Comprehensive Review of Epidemiology, Clinical Presentation, Diagnostic Workup, and Management Plan. J Clin Gastroenterol. 2022 Aug 1;56(7):555-564. doi: 10.1097/MCG.0000000000001705. Epub 2022 Apr 21.(PubMed)