| Eligibility |
Inclusion Criteria:
- Must have unresectable cutaneous or mucosal metastatic stage III/IV melanoma, and in
the opinion of the institutional principal investigator (PI) is an acceptable
candidate for adoptive cell therapy (ACT) with high dose IL-2.
- Must have anticipated residual measurable disease after resection of target lesion(s)
for TIL growth.
- Patients who have been previously treated for metastatic melanoma may be included
(e.g., prior treatment with Rapidly Accelerated Fibrosarcoma (BRAF) inhibitors and/or
ipilimumab will be allowed), provided that they have had a three week 'washout' prior
to signing consent and have not been treated with a Programmed Death-1 (PD-1) blocking
antibody.
- Age greater than or equal to 18 years.
- Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 - 1.
- Women of childbearing potential must have a negative serum pregnancy test within seven
days of screening and within 24 hours prior to the start of each nivolumab dose.
- Adequate renal, hepatic and hematologic function.
- Patients must have a positive screening Epstein Barr Virus (EBV) antibody titer on
screening test as this is required to protect against EBV infection during the time of
lymphodepletion.
- Patients with antibiotic allergies per se are not excluded; although the production of
TIL for adoptive transfer includes antibiotics, extensive washing after harvest will
minimize systemic exposure to antibiotics.
- At screening, patients with = 3 untreated central nervous system (CNS) metastases may
be included provided none of the untreated lesions are > 1 cm in greatest dimension,
and there is no peri-tumoral edema present on brain imaging (MRI or CT if MRI is
contraindicated), and if the patients with CNS metastases are not taking prednisone
>10 mg or equivalent daily.
- At screening, patients with = 3 CNS metastases and each = 1 cm size that were treated
with either surgical resection and/or radiation therapy may be included. Patients may
be included if the largest lesion is = 1 cm, and there is no evidence of progressive
CNS disease on brain imaging at least 30 days after definitive treatment, and if the
patients with CNS metastases are not taking prednisone >10 mg or equivalent daily.
- At screening, patients with> 1 cm or > 3 in number treated CNS metastases may be
included if there is no evidence of progressive CNS disease on brain imaging at least
90 days after treatment with surgery and/or radiation therapy, and if the patients
with CNS metastases are not taking prednisone >10 mg or equivalent daily.
Exclusion Criteria:
- Patients with active systemic infections requiring intravenous antibiotics,
coagulation disorders, or other major medical illness of the cardiovascular,
respiratory or immune system, which in the opinion of the PI or treating
co-investigator is not acceptable risk for ACT, are excluded.
- Patients who have received prior immunotherapy whose side effects have resulted in a
requirement of immunosuppressive medications (>10 mg of prednisone daily or equivalent
daily steroid daily, or infliximab, cyclosporine or equivalent immunosuppressive
medication) or who have other autoimmune conditions that require immunosuppressive
medications as above at the time of screening are excluded.
- Patients who test positive for Human Immunodeficiency Virus (HIV), Hepatitis B surface
antigen, Hepatitis B core antibody, Hepatitis C antibody, Human T-lymphotropic Virus
(HTLV) I or II antibody, or are both Rapid plasma reagin (RPR) and Fluorescent
treponemal antibody (FTA) positive are excluded.
- Patients who are pregnant or nursing are excluded.
- Patients with a significant psychiatric disease, who in the opinion of the principal
investigator or his designee, would prevent adequate informed consent or render
immunotherapy unsafe will be excluded.
- Patients with > 3 untreated CNS metastases or evidence of peri-tumoral edema will be
excluded, or patients with CNS metastases of any status who are taking prednisone >10
mg or equivalent steroid daily will be excluded.
- Patients with = 3 untreated CNS metastases but with at least one lesion >1 cm or
peri-tumoral edema will be excluded, or patients with CNS metastases of any status who
are taking prednisone >10 mg or equivalent steroid daily will be excluded.
- Patients with invasive malignancy other than melanoma at the time of enrollment and
within 2 years of screening are excluded, except for: adequately treated (i.e. with
curative intent) basal or squamous cell carcinoma, in situ carcinoma of the cervix, in
situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage
bladder cancer or other any other cancers from which the patient has been disease-free
for at least 2 years.
- Patients with treated CNS metastases > 1 cm or > 3 in number will be excluded if there
is evidence of progressive CNS disease on brain imaging at least 90 days after
treatment with surgery and/or radiation therapy, or patients with CNS metastases of
any status who are taking prednisone >10 mg or equivalent will be excluded.
- Male patients with female partners of childbearing potential who do not agree to use
two FDA-accepted forms of contraception during sexual intercourse with women of
child-bearing potential from the start of PD-1 antibody therapy and up to at least 31
weeks from the last dose of nivolumab are excluded.
- Females of childbearing potential who do not agree to use 2 FDA forms of contraception
according to study guidelines
- Prior systemic therapy with a PD-1 blocking antibody
- Patients who are greater than age 50, or who have a history of coronary artery
disease, will be required to undergo cardiac stress testing within 6 months of
screening and will be excluded if there is evidence of reversible ischemia.
- Patients who have a significant history of pulmonary disease that necessitates the use
of supplemental oxygen, is associated with dyspnea on walking one block or less, or
requires inhaler therapy more than once per week will be required to undergo pulmonary
function testing within 6 months of screening and will be excluded if forced
expiratory volume 1 (FEV1), forced vital capacity (FVC), or diffusion lung capacity
for carbon monoxide (DLCO) is less than 65% of predicted.
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