ACT-TIL and ANV419 for Advanced Melanoma.

In brief, this trial consists of four study periods: screening, pre-treatment, treatment, and observational follow-up.

In the screening period, patients are screened for trial eligibility. In the pre-treatment period, patients have excisional biopsy/surgical resection of tumor lesion(s) (tumor collection) and TILs are expanded from this lesion/these lesions (TIL expansion). Patients are permitted to receive bridging therapy outside of the study protocol.

In the treatment period, patients have TIL-ACT. TIL-ACT includes a detailed procedure of preparative chemotherapy, followed by transfer of the TIL product, followed by in-vivo TIL expansion with ANV419 (2 doses). TIL transfer is defined as day 0 in the study protocol. Patients have an End of Treatment visit (14 days after the last study treatment), a safety follow-up (30 days after the last study treatment) and an efficacy follow up, which is the End of Study visit (day +90).

Thereafter, patients will transfer to observational follow-up, which is conducted every 3 months until 1 year after TIL transfer.

Patients who terminate the study prematurely during any of the treatment period due to e.g., disease progression, toxicity, patient wish, etc. will also transfer to observational follow-up.

The regimen (TIL-ACT with ANV419) has not been tested. Review by the IDSMB (independent data safety monitoring board) will be performed after 3 patients (safety check).

Inclusion criteria

Patients who meet all the following criteria will be eligible to participate in the study:

• Must provide written informed consent for the study.
• Must be able to comply with the study protocol as judged by the investigator.
• Are ≥ 18 years. 4. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
• Have pathologically confirmed stage III (unresectable) or stage IV (metastatic) cutaneous melanoma, as per the American Joint Committee on Cancer staging system, 8th edition, and have experienced disease progression and exhausted all approved treatment option with curative intent.
• Have received at least one prior systemic treatment line of PD-(L)1 inhibitor and BRAF/MEK inhibition in case of BRAFV600 mutated melanoma. Adjuvant systemic treatment terminated ≥12 months prior to diagnosis of metastatic disease is not counted as a treatment line.
• Accessible tumor lesion(s) for TIL collection and willingness of the patient to undergo biopsy/resection of tumor lesion(s).
• Measurable disease as per RECIST v1.1 (following biopsy/resection of tumor lesion(s) for TIL collection).
• Adequate organ function (pulmonary, cardiovascular, hematological, hepatic, and renal function) per investigator's judgment. Cardiac stress testing is mandatory for all patients with underlying cardiac conditions and patients with age ≥50 years. 10. Female patients of childbearing potential must have a negative serum pregnancy test at the screening visit and a negative serum pregnancy test within 72 hours prior to start of preparative chemotherapy (day -7 in the study protocol).
• Female patients who are not postmenopausal, and who have not undergone surgical sterilization, must agree to use highly effective methods of contraception during the entire study period and for 6 months after the last dose of study drug. They must also agree not to donate eggs (ova, oocytes) during the same timeframe.
• Male patients with partners of childbearing potential must agree to use highly effective methods of contraception and barrier contraception (condom) during the entire study period and for 6 months after the last dose of study drug. They must also agree not to donate sperm during the same timeframe.

Exclusion criteria

• LDH (lactate dehydrogenase) ≥ 2x upper limit of normal (ULN).
• Life-expectancy ≤ 3 months per investigator's judgment.
• Have not recovered (i.e., ≤ Grade 1 or at baseline with the exception of alopecia or fatigue [up to Grade 2 allowed]) from immune-related adverse events (irAEs) resulting from prior immunotherapies. Patients who have endocrine immune-related AEs controlled by replacement therapy (i.e., hypothyroidism) due to previous treatment are eligible provided replacement therapy has been initiated and toxicity has returned to Grade 1.
• Have not recovered (i.e., ≤ Grade 1 or at baseline) from toxicities due to a previously administered chemotherapy, targeted small molecule therapy, or radiation therapy.

Note: If the patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study drug. Major surgery is defined as any surgery requiring entrance into a body cavity (e.g., chest, abdomen, or brain), organ removal, normal anatomy alteration, or joint replacement. Minor surgery is defined as any surgery in which skin, mucosa, or connective tissue sections are altered (e.g., biopsy, cataract, endoscopic procedures, etc.).

• Have been diagnosed with uveal/ocular or mucosal melanoma.
• Have a known additional malignancy (including all in-situ carcinoma) that is progressing or required active treatment within 2 years prior to enrollment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that have undergone potentially curative therapy and have no evidence of disease or in situ cervical cancer in patients who completed cancer-directed therapy or have evidence of stable disease and do not require active treatment.
• Have active central nervous system metastases and/or carcinomatous meningitis regardless of clinical stability. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to study treatment (day -7 in the study protocol), and any neurologic symptom has returned to baseline. New or enlarging brain metastases, as well as the use of steroids (≥10 mg of prednisone daily or equivalent) within the last 7 days prior to study drug are excluded.
• Have a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study treatment (day -7 in the study protocol).
• Are receiving systemic steroid ≥10 mg of prednisone daily or equivalent for any reason. Local steroid therapies (e.g., otic, ophthalmic, intra-articular, or inhaled medications) are acceptable. -
• Have an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 11. Have a known history of, or any evidence of active, non-infectious pneumonitis.
• Have an active (measurable) and uncontrolled (unresponsive to current therapy) infectious disease (bacterial, fungal, viral, protozoic).
• Have a history of an acute coronary event (e.g., myocardial infarction) within 3 months prior to study treatment (day -7 in the study protocol), uncontrolled and symptomatic coronary artery disease, or congestive heart failure New York Heart Association Class III/IV.
• Have an average QTc interval > 470 msec at ECG-screening.
• Have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or it is not in the best interest of the patient to participate, in the opinion of the treating investigator.
• Have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
• Are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the Screening Visit through 6 months after the last dose of study drug.
• Are known to be human immunodeficiency virus (HIV) positive (or tests positive for HIV 1 or 2 at Screening), unless the following criteria are met:

• Cluster of differentiation (CD)4+ lymphocyte count > 350 μL.
• Had no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within the past 12 months.
• Have been on established anti-retroviral therapy for at least 4 weeks.
• Have an HIV viral load of > 400 copies/mL prior to study treatment (day -7 in the study protocol).

Note: Patients on strong cytochrome P450 (CYP)3A4 inhibitors or strong CYP3A4 inducers must be switched to an alternate effective anti-retroviral therapy regimen prior to study treatment or are excluded if regimen prior to study treatment cannot be altered.

• Have uncontrolled hepatitis B infection or hepatitis C infection. Note: Patients with hepatitis B (positive hepatitis B surface antigen) who have controlled infection (serum hepatitis B virus DNA by polymerase chain reaction that is below the limit of detection and receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of hepatitis B virus DNA. Note: Patients with hepatitis C (positive hepatitis C virus antibody) who have controlled infection (undetectable hepatitis C virus RNA by polymerase chain reaction either spontaneously or in response to a successful prior course of anti-hepatitis C virus therapy) are permitted.
• Have received a live vaccine within 30 days of study treatment (day -7 in the study protocol). Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
• Are positive for SARS-CoV2.
• Known hypersensitivity to any of the study therapies or drugs used for TIL production. - Any other conditions/diseases, dysfunctions, and/or findings, that would contraindicate the use of any of the study interventions or therapies.