PRIMARY OBJECTIVE:
I. To compare progression free survival (PFS) of patients with advanced melanoma refractory
to an anti-PD-1 or anti-PD-L1 agent, treated with combination therapy ipilimumab plus
nivolumab versus ipilimumab alone.
SECONDARY OBJECTIVES:
I. To estimate difference in T-cell infiltrate between on-study biopsy samples of patients
who respond to combination therapy (including confirmed and unconfirmed, complete and partial
response per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1, in each treatment
arm).
II. To evaluate the objective response rate (ORR), defined as confirmed complete or partial
response per RECIST 1.1, in each treatment arm.
III. To evaluate the overall survival (OS) of patients in each treatment arm. IV. To evaluate
the toxicity profile of patients in each treatment arm.
TRANSLATIONAL OBJECTIVES:
I. To assess the marginal prognostic value of baseline T-cell density, T-cell receptor (TCR)
clonality, mutational load, messenger ribonucleic acid (mRNA) and other phenotypical
expression levels, and circulating tumor deoxyribonucleic acid (DNA) in terms of response.
II. To assess the joint prognostic value of T-cell density, TCR clonality, and mutational
load, mRNA and other phenotypical expression levels, and circulating tumor DNA in terms of
response.
III. To identify T-cell poor subtype(s) that are associated with response.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive ipilimumab intravenously (IV) over 90 minutes on day 1. Treatment
repeats every 21 days for up to 4 cycles in the absence of disease progression or
unacceptable toxicity.
ARM II: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes on
day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease
progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on
day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up every 6 months for 2 years and
then annually for 1 year.
Inclusion Criteria:
- Patients must have pathologically confirmed melanoma that is either stage IV or
unresectable stage III; patients may have primaries of cutaneous, mucosal or unknown
origin; patients with uveal (ocular) primary are not eligible
- Patients must have measurable disease per RECIST 1.1; all measurable lesions must be
assessed by physical examination, computed tomography (CT) scans or magnetic resonance
imaging (MRI)s within 28 days prior to registration; if the only measurable disease is
cutaneous or subcutaneous, lesions must be at least 10 mm in greatest dimension and
able to be serially recorded using calipers and photographs; tests used to assess
non-measurable disease must have been performed within 42 days prior to registration;
all disease must be assessed and documented on the Baseline Tumor Assessment Form
- Patients with central nervous system (CNS) metastases must have all lesions adequately
treated with stereotactic radiation therapy, craniotomy, gamma knife therapy, or whole
brain radiotherapy, with no subsequent evidence of CNS progression; patients must not
have required steroids for at least 14 days prior to registration; patients with a
history of central nervous system metastases must have MRI of the brain within 42 days
prior to registration
- Patients must have had prior treatment with anti-PD1 or anti-PD-L1 agents and had
documented disease progression per the treating physician either while on these agents
or after stopping therapy with these agents without intervening therapy; patients who
received adjuvant therapy for previously resected disease with PD-1 or PD-L1 agents
may also be eligible if disease recurrence occurred while still receiving the PD-1 or
PD-L1 therapy and no intervening therapy was received; patients must have discontinued
anti-PD-1 or anti-PD-L1 therapy at least 21 days prior to registration
- Patients must have Zubrod performance status of =< 2
- Patients must have complete history and physical examination within 28 days prior to
registration
- Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 days prior to registration)
- Hemoglobin >= 8 g/dL (within 28 days prior to registration)
- Platelets >= 100,000/mcL (within 28 days prior to registration)
- Total bilirubin =< 2.5 x institutional upper limit of normal (IULN) (except patients
with Gilbert's syndrome) (within 28 days prior to registration)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x IULN
(within 28 days prior to registration)
- Serum creatinine =< 2.0 x IULN within 28 days prior to registration
- Patients with a known history of human immunodeficiency virus (HIV) must have CD4
count >= institutional lower limit of normal within 28 days prior to registration
- Patients with a known history of congestive heart failure (CHF), cardiomyopathy,
myocarditis, myocardial infarction (MI), exposure to cardiotoxic medications, or with
a clinical history suggestive of the above must have an electrocardiography (EKG) and
echocardiogram (ECHO) performed within 42 days prior to registration and as clinically
indicated while on treatment
- Patients with new symptoms of congestive heart failure (CHF), cardiomyopathy,
myocarditis, myocardial infarction (MI), or exposure to cardiotoxic medications must
have a cardiology consultation, creatinine phosphokinase (CPK), and troponin testing
at prestudy and as clinically indicated
- Males who are sexually active with women of reproductive potential must have agreed to
use birth control throughout the study and for 7 months after completion of protocol
treatment; in addition to routine contraceptive methods, "effective contraception"
also includes heterosexual celibacy and surgery intended to prevent pregnancy
(vasectomy); if at any point a previously celibate patient chooses to become
heterosexually active during or within 7 months after completion of protocol
treatment, he is responsible for beginning effective contraceptive measures
- Patients must submit archival tissue (if available) for translational medicine;
patients must also be willing to undergo biopsies and submit tissue and blood for
translational medicine
- Patients must be offered the opportunity to participate in specimen banking of
leftover tissue for future research
- Patients must be informed of the investigational nature of this study and must sign
and give written informed consent in accordance with institutional and federal
guidelines
- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system
Exclusion Criteria:
- Patients must not have achieved a partial or complete response to the anti-PD-1 or
anti-PD-L1 agents prior to progression per the treating physician
- Patients must not have had any systemic therapy, including anti-PD-1 or anti-PD-L1
agents, within 21 days prior to registration
- Patients must not have had prior radiation therapy within 14 days prior to
registration
- Patients must not have had:
- Prior treatment with ipilimumab or other CTLA-4 antagonists
- Systemic therapy between progression on the anti-PD-1 or anti-PD-L1 agents and
registration
- Note: Systemic therapy (including BRAF-targeting agents) prior to anti-PD-1 or
anti-PD-L1 therapy is allowed
- Patients must not be planning to require any additional form of systemic anti-tumor
therapy while on protocol treatment
- Patients must not have known active hepatitis B virus (HBV) or hepatitis C virus (HCV)
infection prior to registration
- Patients must not have an active infection requiring systemic therapy at time of
registration
- Patients must not have organ allografts
- Patients must not have received systemic treatment with corticosteroids (> 10 mg daily
prednisone or equivalent) or other immunosuppressive medications within 14 days prior
to registration; inhaled or topical steroids, and adrenal replacement doses =< 10 mg
daily prednisone or equivalent are permitted in the absence of active autoimmune
disease
- Patients must not have a history of immune-mediated pneumonitis or colitis that
required interruption of therapy or treatment of steroids
- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage 0, I or II cancer from which the patient is currently in complete remission, or
any other cancer from which the patient has been disease free for two years
- Patients must not be pregnant or nursing due to risk of fetal or nursing infant harm;
females of reproductive potential must have negative serum pregnancy test within 2
days prior to registration and agree to use an effective contraceptive method
throughout the study and for 5 months after completion of protocol treatment; a woman
is considered to be of "reproductive potential" if she has had menses at any time in
the preceding 12 consecutive months; in addition to routine contraceptive methods,
"effective contraception" also includes heterosexual celibacy and surgery intended to
prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a
hysterectomy, bilateral oophorectomy or bilateral tubal ligation; if at any point a
previously celibate patient chooses to become heterosexually active during or within 5
months after protocol treatment, she is responsible for beginning effective
contraceptive measures
