PRIMARY OBJECTIVE:
I. To determine the maximum tolerated dose (MTD) of ipilimumab that can be administered
through the DoseConnect device followed 30 minutes later by nivolumab intravenously (IV) on
day 1 of a 21-day cycle in patients with metastatic melanoma. (Dose-De-escalation Cohort)
SECONDARY OBJECTIVE:
I. To assess the pharmacokinetics of ipilimumab administered using the DoseConnect followed
30 minutes later by nivolumab IV in patients with metastatic melanoma demonstrating
in-transit metastases. (Dose De-escalation Cohort)
CORRELATIVE OBJECTIVE:
I. To assess the changes in immunologic profile after one cycle of ipilimumab administered
using the DoseConnect followed 30 minutes later by nivolumab IV. (Dose-De-escalation Cohort)
OUTLINE: This is a dose-escalation study of ipilimumab.
Patients receive ipilimumab via DoseConnect on day 1 of cycle 1 and via IV over 30 minutes on
day 1 of cycles 2-4. Patients also receive nivolumab IV over 30 minutes on day 1. Treatment
repeats every 21 days for up to 4 cycles in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up every 4 months until disease
progression, and then every 6 months for up to 2 years after registration.
Inclusion Criteria:
- Age >=18 years
- ALL patients with measurable disease
- Dose De-escalation Cohort: Confirmed diagnosis of unresectable stage III or IV
metastatic melanoma, meeting one of the following criteria:
- Progressed after at least one line of Food and Drug Administration (FDA) approved
therapy (either immune checkpoint inhibitor [ICI] or targeted therapy)
- Recurrent disease following initial surgical resection (may or may not have
received adjuvant therapy)
- Newly diagnosed or recurrent in-transit metastatic melanoma (may or may not be
treatment naive)
- Hemoglobin >= 8.0 g/dL (obtained =< 15 days prior to registration)
- Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 15 days prior to
registration)
- Platelet count >= 75,000/mm^3 (obtained =< 15 days prior to registration)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 15 days prior to
registration)
- Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3.0 x ULN (obtained
=< 15 days prior to registration)
- Serum creatinine =< 2.0 x ULN (obtained =< 15 days prior to registration)
- Calculated creatinine clearance >= 40 ml/min using the Cockcroft-Gault formula
(obtained =< 15 days prior to registration)
- Prothrombin time (PT)/institutional normalized ratio (INR)/activated partial
thromboplastin time (aPTT) =< 1.5 x ULN OR if patient is receiving anticoagulant
therapy INR or aPTT is within target range of therapy (obtained =< 15 days prior to
registration)
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
- Negative pregnancy test done =< 7 days prior to registration, for persons of
childbearing potential only
- Persons able to become pregnant OR able to father a child must be willing to use an
adequate method of contraception while on treatment and for 180 days (6 months) after
last treatment dose on this study
- Provide written informed consent
- Patients enrolling in Rochester, Minnesota (MN), ONLY: Willingness to provide
mandatory blood specimens for correlative research
- Willing to return to enrolling institution for follow-up (during the Active Monitoring
Phase of the study)
Exclusion Criteria:
- Metastatic sites that drain lymphatic fluid into nodal beds which are not amenable to
lymphatic infusion
- Sites of metastases limited only to the head and neck
- Sites of metastatic disease limited to the lungs and/or hilar lymph nodes
- Metastatic uveal melanoma
- Any of the following because this study involves an investigational agent whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown:
- Pregnant persons
- Nursing persons
- Persons of childbearing potential who are unwilling to employ adequate
contraception
- Persons expecting to conceive or father children during the study or within 180
days (6 months) after the last treatment on this study
- Active central nervous system (CNS) metastases not previously treated
- NOTE: patients with history of previously treated CNS metastases, not
demonstrating evidence of progression for at least 12 weeks will be allowed
- NOTE: patients with leptomeningeal metastases are not eligible
- Any of the following prior therapies:
- Allogeneic hematopoietic stem cell transplantation (HSCT)
- Solid organ transplantation
- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens
- Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
positive and currently receiving antiretroviral therapy.
- NOTE: Patients known to be HIV positive, but without clinical evidence of an
immunocompromised state, are eligible for this trial
- Active autoimmune disease requiring systemic treatment < 2 years prior to
registration, documented history of severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents with use of disease modifying
agents, corticosteroids or immunosuppressive drugs. NOTE: Exceptions are allowed for
the following conditions:
- Vitiligo
- Resolved childhood asthma/atopy
- Intermittent use of bronchodilators or inhaled steroids
- Daily steroids at dose of =< 10 mg of prednisone (or equivalent)
- Local steroid injections
- Stable hypothyroidism on replacement therapy
- Stable diabetes mellitus on therapy (with or without insulin)
- Sjogren's syndrome
- Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) which is not
considered a form of systemic treatment and is allowed
- Uncontrolled intercurrent illness including, but not limited to:
- Ongoing or active infection requiring systemic therapy
- Interstitial lung disease
- Serious, chronic gastrointestinal conditions associated with diarrhea (e.g.,
Crohn's disease or others)
- Known history of hepatitis B (i.e., known positive hepatitis B virus [HBV]
surface antigen [HBsAg] reactive)
- Known active hepatitis C (i.e., positive for hepatitis C virus [HCV] ribonucleic
acid [RNA] detected by polymerase chain reaction [PCR])
- Known active tuberculosis (TB)
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Unstable cardiac arrhythmia or
- Psychiatric illness/social situations that would limit compliance with study
requirements (e.g., known substance abuse)
- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm
- History of severe hypersensitivity reactions to other monoclonal antibodies or known
hypersensitivity to the study intervention or its excipients, indocyanine green (ICG)
dye or iodine
- Prior history of grade 4 immune related adverse event (irAE) with prior
intracavernosal injection (ICI) therapy or failure to recover (< grade 1) from
immune-related adverse event(s) from prior ICI therapy
- Any of the following therapies prior to registration:
- Chemotherapy =< 28 days
- Immunotherapy =< 28 days
- Targeted therapies (e.g., dabrafenib) =< 21 days
- Other investigational agents =< 28 days
- Radiation therapy =< 14 days
- Minor surgical or interventional procedure =< 7 days
- Major surgical procedure =< 21 days
