| Eligibility |
Inclusion Criteria:
1. Male or female patients age = 18 at the time of signing ICF
2. Patient has a pathologically confirmed diagnosis of metastatic melanoma that is
unresectable stage III or stage IV and has lesion(s) amenable to resection for the
generation of TILs and at least one separate lesion for RECIST v1.1 response
assessment
3. Patient must be relapsed and/or refractory to immune checkpoint inhibitor (ICI)
therapy including either anti PD-1 either with or without anti CTLA-4 blocking
antibody and/or anti LAG-3 antibody. Patients should have received standard-of-care
(SOC) therapy per standard clinical practice guidelines. Patients must not have had
exposure to more than 3 prior lines of anti-PD-1 antibody-containing therapeutic
regimens administered in the metastatic setting If the patient is BRAF V600
mutation-positive with rapidly progressing disease, the patient should have received
available FDA-approved targeted therapy.
4. ECOG Performance status 0-1
5. Within 7 days of tumor harvest and within 7 days of initiating lymphodepletion,
patients must meet the following laboratory criteria:
• Absolute neutrophil count (ANC) = 1000/mm3
• Hemoglobin = 8.0 g/dL (transfusion allowed)
• Platelet count = 75,000/mm3
• ALT/SGPT and AST/SGOT = 2.5 x the upper limit of normal (ULN)
• Patients with liver metastases may have liver function tests (LFT) = 5.0 x ULN
• Calculated creatinine clearance (Cockcroft-Gault) = 50.0 mL/min
• Total bilirubin = 1.5 X ULN
• Negative serum pregnancy test (female patients of childbearing potential)
6. Patients must have a 12-lead electrocardiogram (EKG) showing no active ischemia and
Fridericia's corrected QT interval (QTcF) less than 480 ms
7. Patients must have echocardiogram showing no evidence of congestive heart failure (as
defined by New York Heart Association Functional Classification III or IV) or LVEF
<50%
8. Women of child-bearing potential (WCBP), defined as a sexually mature woman who has
not undergone a hysterectomy or tubal ligation or who has not been naturally
postmenopausal for at least 24 consecutive months, must have a negative serum
pregnancy test prior to treatment. All sexually active WCBP and all sexually active
male patients must agree to use effective methods of birth control throughout the
study. Approved methods of birth control are as follows:
• Hormonal contraception (i.e. birth control pills, injection, implant, transdermal
patch, vaginal ring),
• Intrauterine device (IUD),
• Tubal Ligation or hysterectomy,
• Subject/partner status post vasectomy,
- Implantable or injectable contraceptives, and
- Condoms plus spermicide.
9. Patient (or legally authorized representative) has voluntarily agreed to participate
in the study by providing signed and dated informed consent (ICF) in accordance with
International Conference on Harmonization (ICH) Good Clinical Practice (GCP)
guidelines and applicable local regulations
10. Patient has agreed to abide by all protocol required procedures including study
related assessments, and management by treating institution for the duration of the
study and long-term follow-up (LTFU)
11. Patients who have received bridging therapy between time of TIL harvest and initiation
of lymphodepletion must meet all required clinical, laboratory and imaging criteria in
order to qualify for therapy initiation
12. Lesions amenable to radiotherapy or palliative radiotherapy (e.g.- bone metastases or
metastases causing nerve impingement) should be treated > 4 weeks prior to enrollment
and subjects must be fully recovered from the effects of radiation. However,
palliative radiation is permitted if subjects recover from all side effects to = Grade
1 toxicities (based on CTCAE, v.5) and is > 2 weeks prior to starting lymphodepletion.
Exclusion Criteria:
1. Patients with uncontrolled intercurrent medical illnesses, including active systemic
infection, coagulation disorders or major cardiovascular, respiratory or immune
diseases. PI or his/her designee shall make the final determination regarding
appropriateness of enrollment
2. Patients on chronic steroid therapy for primary immunodeficiency; however, prednisone
or its equivalent is allowed at = 10 mg/day
3. Patients who are pregnant or breastfeeding
4. Chemotherapy within 2 weeks prior to TIL harvest
5. Treatment with small molecule targeted antineoplastics and chemotherapy within 2 weeks
of initiation of lymphodepletion, or 5 half-lives, whichever is shorter
6. The use of immune checkpoint inhibitors as bridging therapy is not allowed.
7. Patients who have received live vaccines within 30 days prior to TIL harvest and
initiation of lymphodepletion
8. Patients with active infection requiring systemic therapy or causing fever
(temperature > 38.1oC) or patients with unexplained fever (temperature > 38.1oC)
within 7 days prior to day of investigational product administration
9. Patient has active infection with human immunodeficiency virus (HIV), hepatitis B
virus, hepatitis C virus (HCV) requiring active antiviral therapy.
10. Cytomegalovirus (CMV) IgM antibody titer or PCR assay; and Epstein-Barr virus (EBV)
IgM or PCR assay indicating active infection. Tumor harvest may take place even with
positive results as long as consult with infectious disease physician is planned and
the infection can be appropriately treated, if needed, prior to initiation of
lymphodepletion.
11. Positive herpes simplex virus (HSV)-1 serology or PCR assay • Patients who are HSV PCR
assay positive will need to receive appropriate treatment and become PCR assay
negative prior to starting the lymphodepletion Tumor harvest may take place even with
positive results as long as consult with infectious disease physician is planned and
the infection can be appropriately treated, if needed, prior to initiation of
lymphodepletion.
12. Persistent prior therapy-related toxicities greater than Grade 2 according to Common
Toxicity Criteria for Adverse Events (CTCAE) v5.0, except for peripheral neuropathy,
alopecia, or vitiligo prior to enrollment. Patients with prior immune mediated
hypophysitis or adrenal insufficiency or hypothyroidism are eligible for treatment as
long as they are on stable, physiologic doses of hormone repletion.
13. History of organ or hematopoietic stem cell transplant
14. History of clinically significant autoimmune disease
The following are exceptions to the criterion:
1. Patients with vitiligo or alopecia.
2. Patients with hypothyroidism, type 1 diabetes or adrenal insufficiency stable on
hormone replacement therapy.
3. Patients without active disease in the last 5 years may be included but only after
consultation with the PI.
4. Any other history or questionable history of autoimmune disease is to be considered
after consultation with the PI
15. History of central nervous system metastases and/or leptomeningeal spread of melanoma.
16. Patients with significant clinical cardiac abnormalities:
• Left ventricular ejection fraction (LVEF) <50%
• congestive heart failure, defined by New York Heart Association Functional Classification
III or IV
• unstable angina
- serious uncontrolled cardiac arrhythmia
- a myocardial infarction within 6 months prior to study entry or a history of
myocarditis
17. Patients with a history of interstitial lung disease
18. History of a concurrent second malignancy (diagnosed in the last 2 years).
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, localized thyroid cancer or in situ cervical cancer that has undergone
potentially curative therapy.
19. Patients unable to provide informed consent and follow the study procedures (e.g.,
due to language problems, psychological disorders, dementia).
20. Documented severe/life threatening sulfa allergy.
21. Chronic need for acetazolamide or other carbonic anhydrase inhibitors
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