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Gino K. In

Sunandana Chandra

George Ansstas

Evan J. Lipson

Maya Dimitrova

Diwakar Davar

Evan J Lipson

This phase I/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.

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 evaluate molecular determinants of response using next generation sequencing and other sequencing techniques.

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.. 6 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 undergo computed tomography (CT) scan at screening, at cycle 3 day 1, on day 1 of odd numbered cycles, and at follow up. Patients may undergo magnetic resonance imaging (MRI) at screening. Patients undergo tumor biopsy at cycle 1 day 8, cycle 2 day 1. Patients may undergo kidney biopsy if rejection is suspected. Patients undergo blood sample collection on cycle 1 day 8, cycle 2 day 1, at disease progression and if an immune mediated adverse reaction occurs.

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.

Immunotherapy in Combination With Prednisone and Sirolimus for Kidney Transplant Recipients With Unresectable or Metastatic Skin Cancer

A Phase 1/2 Study of Nivolumab and Ipilimumab in Combination With Sirolimus and Prednisone in Kidney Transplant Recipients With Selected Unresectable or Metastatic Cutaneous Cancers

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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).

Defined as the proportion of subjects whose best overall response from baseline is either a CR or PR, based on RECIST 1.1 criteria. ORR will be estimated along with 95% exact CI.

Renal allograft rejection rate will be estimated as the proportion of subjects who experience markers of allograft rejection. Allograft loss is defined as allograft rejection leading to complete, permanent, and irreversible loss-of-function of the renal allograft.

DOR will be summarized using the Kaplan-Meier method.

Kaplan-Meier curves will be used to summarize PFS.

Kaplan-Meier curves will be used to summarize OS.

National Cancer Institute (NCI)

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 evaluate molecular determinants of response using next generation sequencing and other sequencing techniques.

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 28 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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Immunotherapy in Combination With Prednisone and Sirolimus for Kidney Transplant Recipients With Unresectable or Metastatic Skin Cancer	NCT05896839	Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Metastatic Basa... Metastatic Carc... Metastatic Mela... Metastatic Merk... Metastatic Skin... Unresectable Ba... Unresectable Me... Unresectable Me... Unresectable Sk...	Biopsy Biospecimen Col... Computed Tomogr... Ipilimumab Kidney Biopsy Magnetic Resona... Nivolumab Prednisone Sirolimus	18 Years -	National Cancer Institute (NCI)
Immunotherapy in Combination With Prednisone and Sirolimus for Kidney Transplant Recipients With Unresectable or Metastatic Skin Cancer	NCT05896839	Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Metastatic Basa... Metastatic Carc... Metastatic Mela... Metastatic Merk... Metastatic Skin... Unresectable Ba... Unresectable Me... Unresectable Me... Unresectable Sk...	Biopsy Biospecimen Col... Computed Tomogr... Ipilimumab Kidney Biopsy Magnetic Resona... Nivolumab Prednisone Sirolimus	18 Years -	National Cancer Institute (NCI)
Immunotherapy in Combination With Prednisone and Sirolimus for Kidney Transplant Recipients With Unresectable or Metastatic Skin Cancer	NCT05896839	Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Metastatic Basa... Metastatic Carc... Metastatic Mela... Metastatic Merk... Metastatic Skin... Unresectable Ba... Unresectable Me... Unresectable Me... Unresectable Sk...	Biopsy Biospecimen Col... Computed Tomogr... Ipilimumab Kidney Biopsy Magnetic Resona... Nivolumab Prednisone Sirolimus	18 Years -	National Cancer Institute (NCI)

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