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

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ClinicalTrials.gov Identifier: NCT03816332
Recruitment Status : Recruiting
First Posted : January 25, 2019
Last Update Posted : March 24, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE January 24, 2019
First Posted Date  ICMJE January 25, 2019
Last Update Posted Date March 24, 2020
Actual Study Start Date  ICMJE February 1, 2019
Estimated Primary Completion Date May 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 24, 2019)
  • Percentage of kidney transplant recipients who experience complete response (CR), partial response (PR) or stable disease (SD) [ Time Frame: At 16 weeks ]
    Will be calculated, along with the corresponding exact 95% confidence interval (CI).
  • Percentage of kidney transplant recipients who do not experience allograft loss [ Time Frame: Up to 4 years ]
    Will be calculated, along with the corresponding exact 95% CI.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 15, 2019)
  • Objective response (CR or PR) rate (ORR) [ Time Frame: At 8 and 16 weeks ]
    Based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, and immune-related objective response rate using immune-related response criteria (iRECIST). ORR will be estimated along with 95% exact CI.
  • Allograft rejection rate [ Time Frame: Up to 4 years ]
    Will be estimated as the proportion of subjects who experience markers of allograft rejection.
  • Duration of response 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 progressive disease (PD) is documented, assessed up to 4 years ]
    Will be summarized using the Kaplan-Meier method.
  • 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 ]
    Summarized using Kaplan-Meier curves.
  • Overall survival [ Time Frame: From the first dose of nivolumab to the date of death from any cause, assessed up to 4 years ]
    Summarized using Kaplan-Meier curves.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2019)
  • Objective response (CR or PR) rate (ORR) [ Time Frame: At 8 and 16 weeks ]
    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.
  • Allograft rejection rate [ Time Frame: Up to 4 years ]
    Will be estimated as the proportion of subjects who experience markers of allograft rejection.
  • Duration of response among patients who experience CR or PR [ Time Frame: Up to 4 years ]
    Will be summarized using the Kaplan-Meier method.
  • 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 ]
    Summarized using Kaplan-Meier curves.
  • Overall survival [ Time Frame: From the first dose of nivolumab to the date of death from any cause, assessed up to 4 years ]
    Summarized using Kaplan-Meier curves.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Tacrolimus, Nivolumab, and Ipilimumab in Treating Kidney Transplant Recipients With Selected Unresectable or Metastatic Cancers
Official Title  ICMJE Immune Checkpoint Blockade for Kidney Transplant Recipients With Selected Unresectable or Metastatic Cancers
Brief Summary 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.
Detailed Description

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) 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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 Merkel Cell Carcinoma
  • 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 Basal Cell Carcinoma
  • Unresectable Melanoma
  • Unresectable Merkel Cell Carcinoma
Intervention  ICMJE
  • Biological: Ipilimumab
    Given IV
    Other Names:
    • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
    • BMS-734016
    • MDX-010
    • MDX-CTLA4
    • Yervoy
  • Biological: Nivolumab
    Given IV
    Other Names:
    • BMS-936558
    • MDX-1106
    • NIVO
    • ONO-4538
    • Opdivo
  • Drug: Prednisone
    Given PO
    Other Names:
    • .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
    • Perrigo Prednisone
    • PRED
    • Predicor
    • Predicorten
    • Prednicen-M
    • Prednicort
    • Prednidib
    • Prednilonga
    • Predniment
    • Prednisone Intensol
    • Prednisonum
    • Prednitone
    • Promifen
    • Rayos
    • Servisone
    • SK-Prednisone
  • Drug: Tacrolimus
    Given PO
    Other Names:
    • FK 506
    • Fujimycin
    • Hecoria
    • Prograf
    • Protopic
Study Arms  ICMJE Experimental: Treatment (tacrolimus, prednisone, nivolumab, ipilimumab)

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 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.

Interventions:
  • Biological: Ipilimumab
  • Biological: Nivolumab
  • Drug: Prednisone
  • Drug: Tacrolimus
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 24, 2019)
16
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 30, 2021
Estimated Primary Completion Date May 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 with detectable DSA but negative dd-cfDNA may be eligible after consultation with the study PI
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03816332
Other Study ID Numbers  ICMJE NCI-2019-00239
NCI-2019-00239 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ETCTN10214
10214 ( Other Identifier: JHU Sidney Kimmel Comprehensive Cancer Center LAO )
10214 ( Other Identifier: CTEP )
UM1CA186691 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: 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
URL: https://grants.nih.gov/policy/sharing.htm
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Evan J Lipson JHU Sidney Kimmel Comprehensive Cancer Center LAO
PRS Account National Cancer Institute (NCI)
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP