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.
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
