Clinical Trials /

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

NCT03816332

Description:

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 or has spread to other places in the body. 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.

Related Conditions:
  • Basal Cell Carcinoma
  • Malignant Solid Tumor
  • Melanoma
  • Merkel Cell Carcinoma
  • Skin Squamous Cell Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Tacrolimus, Nivolumab, and Ipilimumab in Treating Kidney Transplant Recipients With Selected Unresectable or Metastatic Cancers
  • Official Title: Immune Checkpoint Blockade for Kidney Transplant Recipients With Selected Unresectable or Metastatic Cancers

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-00239
  • SECONDARY ID: NCI-2019-00239
  • SECONDARY ID: ETCTN10214
  • SECONDARY ID: 10214
  • SECONDARY ID: 10214
  • SECONDARY ID: UM1CA186691
  • NCT ID: NCT03816332

Conditions

  • Clinical Stage III Cutaneous Melanoma AJCC v8
  • Clinical Stage III Merkel Cell Carcinoma AJCC v8
  • Clinical Stage IV Cutaneous Melanoma AJCC v8
  • Clinical Stage IV Merkel Cell Carcinoma AJCC v8
  • High-Frequency Microsatellite Instability
  • Metastatic Basal Cell Carcinoma
  • Metastatic Melanoma
  • Metastatic Skin Squamous Cell Carcinoma
  • Pathologic Stage III Cutaneous Melanoma AJCC v8
  • Pathologic Stage III Merkel Cell Carcinoma AJCC v8
  • Pathologic Stage IIIA Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIIA Merkel Cell Carcinoma AJCC v8
  • Pathologic Stage IIIB Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIIB Merkel Cell Carcinoma AJCC v8
  • Pathologic Stage IIIC Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIID Cutaneous Melanoma AJCC v8
  • Pathologic Stage IV Cutaneous Melanoma AJCC v8
  • Pathologic Stage IV Merkel Cell Carcinoma AJCC v8
  • Unresectable Melanoma

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTreatment (tacrolimus, prednisone, nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (tacrolimus, prednisone, nivolumab, ipilimumab)
Prednisone.delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisonum, Prednitone, Promifen, Servisone, SK-PrednisoneTreatment (tacrolimus, prednisone, nivolumab, ipilimumab)
TacrolimusFK 506, Fujimycin, Hecoria, Prograf, ProtopicTreatment (tacrolimus, prednisone, nivolumab, ipilimumab)

Purpose

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 or has spread to other places in the body. 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.

Detailed Description

      PRIMARY OBJECTIVES:

      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 histopathological characteristics of allograft rejection/loss.

      II. To characterize correlates of the host immune response, possibly including, but not
      limited to 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.

      III. To characterize correlates of the host immune response, possibly including, but not
      limited to changes in donor-derived cell-free DNA (dd-cfDNA) as a marker for allograft
      rejection.

      IV. To characterize correlates of the host immune response, possibly including, but not
      limited to 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) daily 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) at 16 weeks receive nivolumab IV over 30
      minutes and ipilimumab IV over 30 minutes on day 1. Patients also receive tacrolimus PO daily
      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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (tacrolimus, prednisone, nivolumab, ipilimumab)ExperimentalPatients receive tacrolimus PO daily 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 at 16 weeks receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Patients also receive tacrolimus PO daily 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.
  • Ipilimumab
  • Nivolumab
  • Prednisone
  • Tacrolimus

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must be kidney transplant recipients with a functioning allograft who do not
             currently require dialysis

          -  Patients must have histologically or cytologically confirmed melanoma, basal cell
             carcinoma, Merkel cell carcinoma, cutaneous squamous cell carcinoma, or microsatellite
             instability (MSI)-high cancers for which standard non-immunological medical, surgical,
             or radiation therapy would be insufficient (i.e., patients who are not surgical
             candidates). This trial is not intended to provide therapy as a neoadjuvant approach

          -  Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)
             1.1 criteria, i.e., at least one lesion that can be accurately measured in at least
             one dimension (longest diameter to be recorded for non-nodal lesions and short axis
             for nodal lesions) as >= 20 mm by chest x-ray or as >= 10 mm with computed tomography
             (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam is
             preferred, but not required. Patients with evaluable disease but no target lesions
             (e.g., evaluable bone metastases) may be included after discussion with the Principal
             Investigator (PI)

          -  Patients must have documentation, in consultation with the PI, that they received,
             refused, or were ineligible for the following non-immunologic therapies:

               -  For patients with:

                    -  BRAF-mutant melanoma: prior therapies include BRAF/MEK inhibitors

                    -  Merkel cell carcinoma: prior therapies include platinum + VP-16

                    -  Basal cell carcinoma: prior therapies include Hedgehog pathway inhibitors

                    -  Cutaneous squamous cell carcinoma: prior therapies include cetuximab

                    -  MSI colorectal carcinoma: prior therapies include: leucovorin calcium,
                       5-fluorouracil and oxaliplatin (FOLFOX)

          -  Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 2
             (Karnofsky >= 60%)

          -  Leukocytes >= 2,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN

          -  Serum creatinine =< 3 x ULN

               -  Note: patients with creatinine levels above 3 x ULN may be eligible after
                  consultation with the study PI

          -  The effects of nivolumab and ipilimumab on the developing human fetus are unknown. For
             this reason, and because other therapeutic agents used in this trial are known to be
             teratogenic, women of child-bearing potential (WOCBP) and men must agree to use
             adequate contraception (e.g., hormonal or barrier methods of birth control, or
             abstinence) prior to study entry, for the duration of study participation, and for 31
             weeks after the last dose of nivolumab or ipilimumab. 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 must have a negative serum or
             urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human
             chorionic gonadotropin [B-HCG]) during the screening period. Follow-up evaluations
             will include interval sexual/menstrual histories as needed. Men who receive nivolumab
             or ipilimumab and are sexually active with WOCBP must use a contraceptive method with
             a failure rate of < 1% per year for the duration of the study and for a period of 7
             months after the last dose of nivolumab or ipilimumab. 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.
             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. Women under the
             age of 55 must have a documented serum follicle stimulating hormone (FSH) level less
             than 40 mIU/mL to be considered postmenopausal

          -  Human immunodeficiency virus (HIV)-infected patients will be eligible for this trial
             if they are on effective antiretroviral regimens utilizing non-CYP-interactive agents
             and have an undetectable viral load. If there is evidence of chronic hepatitis B virus
             (HBV) infection, HBV viral load must be undetectable on suppressive therapy, if
             indicated. If there is history of hepatitis C virus (HCV) infection, the patient must
             have been treated and have undetectable HCV viral load

          -  Patients must be able to understand and be willing to sign a written informed consent
             document

        Exclusion Criteria:

          -  Patients must not have received a liver, lung, heart, or pancreas transplant; or
             allogeneic stem cell transplant; or any kind of bone marrow transplant

          -  Patients must not be unwilling or unable to undergo dialysis

          -  Patients must not have prior evidence of human leukocyte antigen (HLA) or non-HLA
             donor-specific antibodies (DSA)

          -  Patients must not have a history of antibody- or cell-mediated allograft rejection
             within 3 months of study entry

          -  Patients must not have had chemotherapy or radiotherapy within 4 weeks of study entry
             or those who have not recovered from adverse events (AEs) due to agents administered
             more than 4 weeks earlier

          -  Patients must not have had prior treatment for their current cancer with an anti-PD-1,
             anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug
             specifically targeting T-cell co-stimulation or immune checkpoint pathways

          -  Patients must not be receiving any other investigational agents

          -  Patients must not have known central nervous system (CNS) metastases or leptomeningeal
             metastases because of poor prognosis and concerns regarding progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other AEs. Patients
             with brain metastases are permitted to enroll if metastases have been treated and
             there is no MRI evidence of progression for 4 weeks after treatment is complete and no
             evidence of progression within 28 days prior to study entry

          -  Patients must not have a history of severe hypersensitivity reaction to any monoclonal
             antibody

          -  Patients must not have a history of allergic reactions attributed to compounds of
             similar chemical or biologic composition to other agents used in study

          -  Patients must not have 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

          -  Pregnant women are excluded from this study because nivolumab and ipilimumab have the
             potential for teratogenic or abortifacient effects. Because there is an unknown but
             potential risk for AEs in nursing infants secondary to treatment of the mother,
             breastfeeding should be discontinued if the mother is treated with nivolumab or
             ipilimumab. These potential risks may also apply to other agents used in this study

          -  Patients must not have active autoimmune disease, or history of autoimmune disease
             that might recur, which may affect vital organ function, and will only be eligible
             after consultation with the study PI

               -  This includes but is not limited to:

                    -  Immune-related neurologic disease,

                    -  Multiple sclerosis,

                    -  Autoimmune (demyelinating) neuropathy,

                    -  Guillain-Barre (GB) syndrome,

                    -  Myasthenia gravis,

                    -  Systemic autoimmune diseases such as systemic lupus erythematosus (SLE),

                    -  Connective tissue diseases,

                    -  Scleroderma,

                    -  Inflammatory bowel disease (IBD; e.g., ulcerative colitis or Crohn's
                       disease),

                    -  Rheumatoid arthritis, and

                    -  Sjogren's syndrome

          -  Patients must not have had evidence of active or acute diverticulitis, intra-abdominal
             abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are
             known risk factors for bowel perforation should be evaluated for the potential need
             for additional treatment before coming on study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of kidney transplant recipients who experience complete response (CR), partial response (PR) or stable disease (SD)
Time Frame:At 16 weeks
Safety Issue:
Description:Will be calculated, along with the corresponding exact 95% confidence interval (CI).

Secondary Outcome Measures

Measure:Objective response (CR or PR) rate (ORR)
Time Frame:At 8 and 16 weeks
Safety Issue:
Description:Based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, and immune-related objective response rate (irORR) using immune-related response criteria (iRECIST). ORR will be estimated along with 95% exact CI.
Measure:Allograft rejection rate
Time Frame:Up to 4 years
Safety Issue:
Description:Will be estimated as the proportion of subjects who experience markers of allograft rejection.
Measure:Duration of response among patients who experience CR or PR
Time Frame:Up to 4 years
Safety Issue:
Description:Will be summarized using the Kaplan-Meier method.
Measure:Progression-free survival
Time Frame:From the first dose of nivolumab to the date of the first documented tumor progression or death due to any cause, whichever occurs first, assessed up to 4 years
Safety Issue:
Description:Summarized using Kaplan-Meier curves.
Measure:Overall survival
Time Frame:From the first dose of nivolumab to the date of death from any cause, assessed up to 4 years
Safety Issue:
Description:Summarized using Kaplan-Meier curves.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

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