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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

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

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)

Neoplasm Metastasis

Neoplastic Processes

Tacrolimus

Calcineurin Inhibitors

Enzyme Inhibitors

Patients receive tacrolimus PO BID and prednisone PO QD. Within 28 days, patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 4 weeks for up to 24 cycles (96 weeks) in the absence of disease progression or unacceptable toxicity.

Patients who experience PD or patients who have experienced allograft loss at 16 weeks receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Patients also receive tacrolimus PO BID and prednisone PO QD. Cycles repeat every 3 weeks for 4 cycles (12 weeks) in the absence of disease progression or unacceptable toxicity. Starting 6 weeks later, patients receive nivolumab IV over 30 minutes every 4 weeks for up to 21 cycles (84 weeks) in the absence of disease progression or unacceptable toxicity.

This phase I trial studies how well tacrolimus, nivolumab, and ipilimumab work in treating kidney transplant recipients with cancer that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Tacrolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. Giving tacrolimus, nivolumab, and ipilimumab may work better in treating kidney transplant recipients with cancer compared to chemotherapy, surgery, radiation therapy, or targeted therapies.

PRIMARY OBJECTIVE:

I. To estimate the percent of kidney transplant recipients with selected advanced cancers for whom standard therapies would be insufficient who, 16 weeks after administration of prednisone, tacrolimus, and nivolumab, experience complete response (CR), partial response (PR), or stable disease (SD) without allograft loss.

SECONDARY OBJECTIVES:

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.

II. To estimate the ORR and rate of allograft loss in patients who experience progressive disease (PD) after administration of nivolumab and 1) receive ipilimumab and nivolumab, or 2) decrease or discontinue immunosuppression.

EXPLORATORY OBJECTIVES:

I. To characterize correlates of the host immune response, possibly 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. Changes in donor-derived cell-free deoxyribonucleic acid (DNA) (dd-cfDNA) as a marker for allograft rejection.

Id. Characteristics of anti-programmed death-1 (PD-1)-associated immune-mediated adverse reactions (IMAR) in this patient population treated with immunosuppression.

OUTLINE:

Patients receive tacrolimus orally (PO) twice daily (BID) and prednisone PO once daily (QD). Within 28 days, patients then receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 4 weeks for up to 24 cycles (96 weeks) in the absence of disease progression or unacceptable toxicity.

Patients who experience progressive disease (PD) or patients who have experienced allograft loss at 16 weeks receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Patients also receive tacrolimus PO BID and prednisone PO QD. Cycles repeat every 3 weeks for 4 cycles (12 weeks) in the absence of disease progression or unacceptable toxicity. Starting 6 weeks later, patients receive nivolumab IV over 30 minutes every 4 weeks for up to 21 cycles (84 weeks) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 90 days, every 8 weeks for year 1, every 12 weeks for year 2, every 16 weeks for year 3, then every 24 weeks for year 4. Patients with PD are followed up every 12 weeks for up to 5 years.

Tacrolimus, Nivolumab, and Ipilimumab in Treating Kidney Transplant Recipients With Selected Unresectable or Metastatic Cancers

Immune Checkpoint Blockade for Kidney Transplant Recipients With Selected Unresectable or Metastatic Cancers

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Percentage of kidney transplant recipients who experienced complete response (CR), partial response (PR) or stable disease (SD) without allograft loss.

Number (and percentage) of patients with a complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria after receiving at least one dose of nivolumab.

Number of subjects who experienced allograft loss after receiving at least one dose of nivolumab.

From the first dose of nivolumab to the date of the first documented tumor progression or death due to any cause, whichever occurs first.

The time from the participant's first dose of nivolumab to the date of death from any cause.

The number of participants with a CR or PR response after receiving ipilimumab, nivolumab, tacrolimus, and prednisone.

Number of patients who experienced allograft loss after receiving nivolumab, ipilimumab, tacrolimus, and prednisone.

Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5mg by mouth once a day, and nivolumab 480mg by infusion every 4 weeks for up to 96 weeks in the absence of disease progression or unacceptable toxicity.

Nivolumab, Tacrolimus, and Prednisone

Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5mg by mouth once a day, nivolumab 3 mg/kg by infusion and ipilimumab 1 mg/kg by infusion every 3 weeks for 4 doses followed by maintenance nivolumab 480mg by infusion every 4 weeks for up to 96 weeks in the absence of disease progression or unacceptable toxicity.

Ipilimumab, Nivolumab, Tacrolimus, and Prednisone

Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5mg by mouth once a day, and nivolumab 480mg by infusion every 4 weeks for up to 96 weeks in the absence of disease progression or unacceptable toxicity.

Patients who experienced disease progression by the 16-week time point, could receive tacrolimus, prednisone, nivolumab 3 mg/kg IV + ipilimumab 1 mg/kg by infusion every 3 weeks for 4 doses followed by maintenance nivolumab 480mg by infusion every 4 weeks for up to 96 weeks in the absence of disease progression or unacceptable toxicity.

Treatment (Tacrolimus, Prednisone, Nivolumab, Ipilimumab)

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Height

Weight

The second treatment period where participants received ipilimumab, nivolumab, tacrolimus, and prednisone was optional.

Grants Administrative Manager

Complete response (CR), partial response (PR) or stable disease (SD) without allograft loss

Progressive Disease (PD) without allograft loss

Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5 mg by mouth once a day, and nivolumab 480 mg by infusion over 30 minutes on day 1. Cycles repeated every 4 weeks for up to 24 cycles (96 weeks) in the absence of disease progression or unacceptable toxicity.

Number (and Percentage) of Outcome Responses After Receiving Nivolumab, Tacrolimus, and Prednisone

Objective Response (CR or PR) Rate (ORR) After Receiving Nivolumab, Tacrolimus, and Prednisone

Rate of Allograft Loss After Receiving Nivolumab, Tacrolimus, and Prednisone

Duration of Progression-free Survival After Receiving Nivolumab, Tacrolimus, and Prednisone

Duration of Overall Survival After Receiving Nivolumab, Tacrolimus, and Prednisone

Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5 mg every day, nivolumab 3 mg/kg by infusion and ipilimumab 1 mg/kg by infusion every 3 weeks for 4 doses followed by maintenance nivolumab 480mg by infusion every 4 weeks for up to 96 weeks in the absence of disease progression or unacceptable toxicity.

Two participants who completed the initial treatment period did not start the second, optional treatment period due to disease progression or death.

Overall Response Rate (ORR) in Patients After Receiving Ipilimumab, Nivolumab, Tacrolimus, and Prednisone

Experienced allograft loss

Did not experience allograft loss

Rate of Allograft Loss After Receiving Ipilimumab, Nivolumab, Tacrolimus, and Prednisone

Treatment

Nivolumab, Ipilimumab, Tacrolimus, Pred

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)
Tacrolimus, Nivolumab, and Ipilimumab in Treating Kidney Transplant Recipients With Selected Unresectable or Metastatic Cancers	NCT03816332	Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Metastatic Basa... Metastatic Mela... Metastatic Merk... Metastatic Skin... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Unresectable Ba... Unresectable Me... Unresectable Me...	Ipilimumab Nivolumab Prednisone Tacrolimus	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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