Phase I, Open-Label, Study of Tumor Infiltrating Lymphocytes Engineered With Membrane Bound IL15 Plus Acetazolamide in Adult Patients With Metastatic Melanoma

Inclusion Criteria:

Male or female patients age ≥ 18 at the time of signing ICF
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
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.
ECOG Performance status 0-1

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)
Patients must have a 12-lead electrocardiogram (EKG) showing no active ischemia and Fridericia's corrected QT interval (QTcF) less than 480 ms
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%

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.
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
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)
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
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:

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
Patients on chronic steroid therapy for primary immunodeficiency; however, prednisone or its equivalent is allowed at ≤ 10 mg/day
Patients who are pregnant or breastfeeding
Chemotherapy within 2 weeks prior to TIL harvest
Treatment with small molecule targeted antineoplastics and chemotherapy within 2 weeks of initiation of lymphodepletion, or 5 half-lives, whichever is shorter
The use of immune checkpoint inhibitors as bridging therapy is not allowed.
Patients who have received live vaccines within 30 days prior to TIL harvest and initiation of lymphodepletion
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
Patient has active infection with human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus (HCV) requiring active antiviral therapy.
Cytomegalovirus (CMV) IgM antibody titer or PCR assay; and Epstein-Barr virus (EBV) IgM or PCR assay indicating active infection

Positive herpes simplex virus (HSV)-1 or PCR assay

• Patients who are HSV immunoglobulin M (IgM) or PCR assay positive will need to receive appropriate treatment and become IgM or PCR assay negative prior to starting the lymphodepletion

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.
History of organ or hematopoietic stem cell transplant
History of clinically significant autoimmune disease

The following are exceptions to the criterion:

Patients with vitiligo or alopecia.
Patients with hypothyroidism, type 1 diabetes or adrenal insufficiency stable on hormone replacement therapy.
Patients without active disease in the last 5 years may be included but only after consultation with the PI.
Any other history or questionable history of autoimmune disease is to be considered after consultation with the PI

15. History of active/untreated central nervous system metastases and/or leptomeningeal spread of melanoma. Treated stable brain metastases for at least 4 weeks are allowed.

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 inhibitor

In this phase 1 study, dose escalation cohorts will be implemented using a Bayesian optimal interval (BOIN) design (Liu 2015; Yuan 2016) with target toxicity rate of 30%.

A starting ACZ dose of 125 mg QD (Dose Level 1; DL1) will be given for cohort 1. Further dose escalation will proceed with increasing maximal cell doses of OBX-115 or ACZ. Each dose escalation cohort will contain 3 to 6 DLT evaluable patients. Alternative dosing schedules of ACZ may also be explored if deemed appropriate based on emerging PK and safety assessments.