Inclusion Criteria:
- - Participants must have histologically confirmed, unresectable (Stage III/IV) or
metastatic melanoma as follows: Cutaneous, non-acral, melanoma (including melanoma
of unknown primary); Cutaneous acral melanoma; Mucosal melanoma; Ocular melanoma
(including uveal, iris, conjunctival melanoma).
- - Participants must have failed, be refractory to, or unable to tolerate at least one
line of standard of care in the opinion of the Investigator.
For participants with
cutaneous non-acral melanoma, standard of care therapy includes a PD-1/L1 or
combination therapy with anti-PD1 and anti-CTLA4 or combination therapy of anti-PD1
and anti-LAG3 or if BRAF V600 activating mutation positive, a BRAF ± MEK inhibitor.
Participants are allowed to be enrolled in this trial if they failed one line of any
of those standards of care therapy regimens.
- - Any systemic therapy, including anti-cancer monoclonal antibodies, must have been
completed at least 4 weeks from the start of lymphodepleting therapy, and any prior
therapy-related AEs must have resolved to Grade ≤ 1 except for alopecia and
vitiligo.
- - Participants must be ages ≥18.
Additionally, participants who are ≥ 65 years of age
may need to undergo a cardiology evaluation including a cardiac stress test or
coronary computed tomography after which they must be deemed to be low/acceptable
risk. This cardiac evaluation may be omitted for patients who underwent testing
within 6 months and have no interval change in cardiopulmonary clinical status. Note
1: Cardiac stress test may be omitted for patients ≥65 years old (y/o) who are fully
functional with no relevant medical comorbidities and are able to carry ≥4 METS
activities at baseline. For patients who demonstrate abnormal cardiac stress test
cardiac evaluation by cardiologist will be done and if deemed low acceptable risk,
will be allowed to participate in this trial per PI discretion. Cardiac stress test
may be indicated for any patient <65 y/o who have relevant medical comorbidities or
demonstrate clinically worrisome symptoms. Note 2: While age preference will be
between 18-75 years, this study allows age >75 years if the patient meets
eligibility criteria and demonstrates no significant medical comorbidities per PI.
- - ECOG performance status of 0 or 1.
- - Participants must have adequate organ and marrow function as defined within the
protocol.
- - Seronegative for Human immunodeficiency virus (HIV) antibody, hepatitis B surface
antigen, and hepatitis C (HCV) antibody (if HCV antibody positive, must be tested
for HCV RNA, which must be negative to be eligible).
- - Participants with brain metastases are eligible provided that the brain metastases
have been successfully treated with stereotactic radiosurgery or resection and
clinically stable for at least 4 weeks (±14 days).
Note: Participants who develop
brain metastases after tumor harvest and/or lymphodepleting therapy will be allowed
to remain on study and may proceed with cell therapy after undergoing definitive
radiation therapy and/or surgery. For those participants who develop brain
metastases during lymphodepleting therapy and undergo definitive radiation therapy
and/or surgery careful decision will be made to proceed with TIL infusion after
discussion with treating physician, neurosurgeon, radiation oncologist and PI.
- - Women of child-bearing potential must have a negative pregnancy test.
- - The effects of CD40L-augmented TIL on the developing human fetus are unknown.
For
this reason and because TIL agents, as well as other therapeutic agents used in this
trial including IL-2 are known to be teratogenic, both males and females of
childbearing potential must be willing to practice birth control starting with
screening through 1 year after the last study drug is administered for females or 6
months for males.
- - Should a woman become pregnant or suspect she is pregnant while she or her partner
are participating in this study, she should inform her treating physician
immediately.
- - Ability to understand and the willingness to sign a written informed consent
document.
- - Participants should have at least one surgically accessible lesion for tumor harvest
for preparation of TIL, and at least one RECIST v1.1 measurable lesion after tumor
harvest to follow for response assessment.
Note: Tumor harvest lesion will be
considered as target lesion if after harvest remaining portion of tumor meets RECIST
v1.1 measurable lesion criteria.
Exclusion Criteria:
- - Participants, regardless of age, who have a current or past medical history of
ischemic heart disease, or clinically significant atrial or ventricular rhythm
abnormality are excluded unless they undergo a cardiac stress test and cardiology
clearance examination and are determined to be low or acceptable risk.
- - Participants with either a primary immunodeficiency disorder (i.e., severe combined
immunodeficiency syndrome) or acquired immunodeficiency disorders (such as
HIV/AIDS).
- - Pregnant women are excluded from this study because the agents used in this study
have teratogenic or abortifacient effects.
Because there is an unknown but potential
risk for adverse events in nursing infants secondary to treatment of the mother with
CD40L-augmented TIL or the other agents in the study, breastfeeding should be
discontinued if the mother is enrolled in the study.
- - Participants taking systemic steroid therapy (other than replacement therapy or
prednisone equivalent of ≤10mg daily) or therapy with any immunosuppressive
medications such as mycophenolate mofetil (MMF).
Participants who require more than
10mg of prednisone or equivalent other steroid therapy should taper their steroid
therapy to 10 mg prednisone 1 week prior to planned first interventional drug
therapy (lymphodepleting therapy). Participants who are on baseline replacement
therapy or prednisone equivalent of ≤10mg daily and require stress doses of steroid
therapy will be allowed to receive stress dose steroids during the trial
interventions. Participants who require dapsone for pneumocystis pneumonia (PCP)
prophylaxis during TIL therapy are eligible.
- - Participants who have a history of severe immediate hypersensitivity reaction to the
study agents including cyclophosphamide, fludarabine, or IL-2 or any of their
constituents.
- - Participants with a left ventricular ejection fraction (LVEF) ≤ 45% or New York
Heart Association (NYHA) functional classification > 1.
- - Forced expiratory volume (FEV1) ≤ 60% of predicted value and DLCO (corrected) < 60%
of predicted value.
Participants who underwent pulmonary function testing within 6
months of screening may omit PFTs if they demonstrate stable cardiopulmonary status.
- - Participants who, in the opinion of the Investigator, have a medical condition that
would subject the patient to prohibitive risk by participation in this study, or who
may be unable to safely complete tumor harvest, lymphodepletion regimen, TIL
infusion, or aldesleukin administration.
- - Participants with active infections requiring antibiotics.
- - Participants with active autoimmune diseases currently requiring systemic treatment
with immunosuppressive doses of corticosteroids (>10 mg of prednisone-equivalent
daily dosing), immunosuppressive biologic agents, or disease modifying antirheumatic
drug agents (DMARDs).
- - Patients who received prior live cell therapy are excluded, unless express written
permission is provided by the clinical PI.
