A Phase 2 Study of Nivolumab and Ipilimumab in Combination With Sirolimus and Prednisone in Kidney Transplant Recipients With Selected Unresectable or Metastatic Cutaneous Cancers
Summary
This phase II trial tests the combination of nivolumab and ipilimumab with sirolimus and prednisone for the treatment of skin (cutaneous) cancer that cannot be removed by surgery (unresectable) or that has spread from where it first started to other places in the body (metastatic) in kidney transplant recipients. Immunotherapy with nivolumab and ipilimumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Sirolimus and prednisone are immunosuppressants that are given to keep the body from rejecting the transplanted kidney. Giving nivolumab and ipilimumab in combination with sirolimus and prednisone may kill more cancer cells, while also keeping the transplanted kidney healthy, in patients with unresectable or metastatic cutaneous cancer who have received a kidney transplant.
Detailed description
PRIMARY OBJECTIVE: I. To evaluate the proportion of kidney transplant recipients with selected advanced cutaneous cancers who at 14 weeks after administration of prednisone, sirolimus, nivolumab, and ipilimumab experience complete response (CR), partial response (PR), or stable disease (SD) without allograft loss. SECONDARY OBJECTIVE: I. To estimate the objective response rate (ORR), rate of allograft loss, and durations of progression-free survival (PFS) and overall survival (OS) in the study population. EXPLORATORY OBJECTIVES: I. To characterize correlates of the host immune response including, but not limited to: Ia. Histopathological characteristics of allograft rejection/loss; Ib. Immunological changes in the tumor microenvironment (e.g., changes in T-cell subset populations or expression of immune checkpoint molecules) in paired biopsies obtained pre-treatment and on-treatment; Ic. Characteristics of anti-programmed death-1 (PD-1)-associated immune-mediated adverse reactions (IMARs) in this patient population treated with immunosuppression; Id. To identify upregulated immune-related genes using multiplex quantitative reverse transcription polymerase chain reaction (qRT-PCR). II. To observe whether changes in donor-derived cell-free deoxyribonucleic acid (DNA) (dd-cfDNA) as a marker for allograft rejection. III. To compare baseline patient allograft/donor characteristics, to include human leukocyte antigen (HLA) status, date of transplant, presence of donor specific antibodies, history of prior rejection, and Calculated Panel Reactive Antibodies score, in patients who experience and do not experience rejection while on this study. IV. To observe the objective response rate (ORR) of patients who achieve PR/CR or stable disease for \>= 6 months with eventual progressive disease requiring re-induction with nivolumab + ipilimumab (receive \> 4 doses of nivolumab + ipilimumab). OUTLINE: Patients receive sirolimus orally (PO) and prednisone PO daily, starting 7 days prior to cycle 1 day 1 of immunotherapy. Patients also receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 30 minutes on day 8 of cycle 1 and day 1 of cycle 2. Six weeks after the first dose of nivolumab and ipilimumab, patients undergo tumor response assessment. Patients who achieve stable disease (SD), partial response (PR), or complete response (CR) receive nivolumab IV on day 1 of each cycle. Cycles repeat every 4 weeks for a total of 24 cycles in the absence of disease progression or unacceptable toxicity. Patients who had disease progression at this time or any time on trial may receive nivolumab IV and ipilimumab IV on day 1 of each cycle. Cycles repeat every 3 weeks for 2 cycles, in the absence of unacceptable toxicity. Patients are then assessed for tumor response again after 6 weeks and receive nivolumab monotherapy if they achieve SD, PR, or CR. If patients have progressive disease, they may receive nivolumab monotherapy or discontinue study treatment. Patients may undergo magnetic resonance imaging (MRI) during screening, undergo tumor biopsy on study and undergo computed tomography (CT) scan and blood sample collection throughout the study. Patients may undergo kidney biopsy if rejection is suspected. Patients follow up every 12 weeks for 1 year after stopping therapy, then every 16 weeks for the second year after stopping and then every 20 weeks for up to 5 years.
Arms & interventions
- ProcedureBiopsy Procedure
Undergo tumor biopsy
- ProcedureBiospecimen Collection
Undergo blood sample collection
- ProcedureComputed Tomography
Undergo CT scan
- BiologicalIpilimumab
Given IV
- ProcedureKidney Biopsy
Undergo kidney biopsy
- ProcedureMagnetic Resonance Imaging
Undergo MRI
- BiologicalNivolumab
Given IV
- DrugPrednisone
Given PO
- DrugSirolimus
Given PO
Outcome measures
Primary
Disease control without allograft loss
Defined as complete or partial response (CR; PR) or stable disease (SD), at 14 weeks per response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. The percent of kidney transplant recipients who experience CR/PR/SD at 14 weeks and do not experience allograft loss after administration of nivolumab, ipilimumab, sirolimus, and prednisone will be calculated, along with the corresponding exact 95% confidence interval (CI).
Time frame: At 14 weeks
Secondary
Objective response rate (ORR)
Time frame: Up to 5 years
Rate of allograft loss and rejection
Time frame: Up to 5 years
Duration of response (DOR) among patients who experience CR or PR
Time frame: From the time criteria are met for CR/PR (whichever is first recorded) until the first date that recurrent disease or PD is documented, up to 5 years
Progression-free survival (PFS)
Time frame: From the first dose of nivolumab + ipilimumab to the date of the first documented tumor progression or death due to any cause, whichever occurs first, up to 5 years
Overall survival
Time frame: From the first dose of nivolumab + ipilimumab to the date of death from any cause, up to 5 years
Eligibility criteria
Study locations (26)
UC San Diego Moores Cancer Center
La Jolla, California, 92093
Keck Medicine of USC Koreatown
Los Angeles, California, 90020
Los Angeles General Medical Center
Los Angeles, California, 90033
USC / Norris Comprehensive Cancer Center
Los Angeles, California, 90033
Sibley Memorial Hospital
Washington D.C., District of Columbia, 20016
UM Sylvester Comprehensive Cancer Center at Aventura
Aventura, Florida, 33180
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, 33146
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, 33442
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136
UM Sylvester Comprehensive Cancer Center at Kendall
Miami, Florida, 33176
University of Miami Sylvester Comprehensive Cancer Center at Sole Mia
North Miami, Florida, 33181
UM Sylvester Comprehensive Cancer Center at Plantation
Plantation, Florida, 33324
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
Northwestern University
Chicago, Illinois, 60611
Memorial Hospital East
Shiloh, Illinois, 62269
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, 40536
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, 21287
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141
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
NYU Langone Hospital - Long Island
Mineola, New York, 11501
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, 15232
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112