TNFalpha and Interleukin 2 Coding Oncolytic Adenovirus TILT-123 During TIL Treatment of Advanced Melanoma

This is an open-label, phase 1, first-in-human (FIH), dose-escalation, multicenter, multinational trial evaluating the safety of oncolytic adenovirus TILT-123 as monotherapy and in association with T-cell therapy with TILs in metastatic melanoma patients.

The primary objective of the trial is to evaluate the safety of TILT-123. The approach has the potential to a) increase the efficacy of adoptive T-cell therapy, b) remove the need for toxic pre- and post-conditioning regimens, c) yield the combined anti-tumor benefits of armed oncolytic viruses and T-cell therapy.

Dose escalation of TILT-123 injection will take place between cohorts not intra-patient and will be determined based on Dose Limiting Toxicities (DLTs).

Eligibility Criteria:
Inclusion Criteria:

* Signed and dated informed consent before any trial-related activities.
* Male or female, between 18-75 years of age (both included).
* Pathologically confirmed previously treated refractory or recurrent stage 3-4 melanoma, which cannot be treated with curative intent with available therapies.
* At least one prior line of medical treatment is required (for example checkpoint inhibitors, kinase inhibitors, interleukin-2). Multiple prior therapies (e.g. surgery, checkpoint inhibitors, kinase inhibitors, interleukin-2, interferon, chemotherapy, radiation) are allowed.
* A \> 9 mm tumor (in diameter, typically a minimum of 1 cm3 in volume) without signs of necrosis must be available for biopsy/operation to enable growing of TILs.
* At least one additional tumor (\>14 mm in diameter) must be available for injections and biopsies for correlative analyses. The disease burden must be measurable, but does not need to fulfil RECIST 1.1.
* Eligible for adoptive T-cell therapy with tumor infiltrating lymphocytes

Adequate hepatic, cardiac and renal functions as following:

1. Platelets \> 75 000/mm3
2. Haemoglobin ≥ 100 g/L.
3. AST and ALT \< 3 x ULN.
4. GFR \>60 ml/min (Cockcroft-Gault formula).
5. Leukocytes (WBC) \> 3,0
6. Bilirubin \<1.5 x ULN

   * Men and women must be willing to use adequate forms of contraception from screening, during the trial, and for a minimum of 90 days after end of treatment, in accordance with the following:
   * Women of childbearing potential: Barrier contraceptive method (i.e. condom) must be used in addition to one of the following methods: Intrauterine devices or hormonal contraception (oral contraceptive pills, implants, transdermal patches, vaginal rings or long-acting injections).
   * Women not of childbearing potential: Barrier contraceptive method (i.e. condom) must be used.
   * Men: Barrier contraceptive method (i.e. condom) must be used.
   * Demonstrated WHO performance score of 0-1 at screening.
   * Life expectancy time longer than 3 months.
   * Capable of understanding and complying with parameters as outlined in the protocol.
   * BRAF negative or positive.

Exclusion Criteria:

* Use of immunosuppressive medications (corticosteroids or drugs used in treatment of autoimmune disease). Exempted are the following which can be allowed at screening and during the trial: replacement corticosteroids if e.g. the patient has adrenal insufficiency after prior immunotherapy; pulmonal and topical treatments; up to 20 mg of prednisone/prednisolone.
* History of another active invasive cancer as judged by the investigator within the past 3 years except basalioma.
* Treated with any anti-cancer therapy for melanoma 30 days prior to enrolment. Anti-cancer therapy for melanoma is defined as anti-cancer agents (immunotherapy, signal-transduction inhibitors \[e.g. BRAF and MEK inhibitors\], cytotoxic chemotherapy), radiotherapy and investigational agents. An investigational agent is any drug or therapy that is currently not approved for use in humans.
* Uncontrolled cardiac or vascular diseases.
* History of heart attack or cerebral stroke within the previous 12 months before screening or is not recovered from an older heart attack or cerebral stroke.
* LDH value \> 3 x ULN.
* History of hepatic dysfunction, hepatitis or HIV.
* History of coagulation disorder.
* Any other disease which prevent participation in the opinion of the investigator.
* Female patients who are pregnant, breastfeeding or intends to become pregnant.
* Untreated brain metastases. Treated brain metastases which have not progressed in 3 months prior to screening are allowed.
* Previously treated with any oncolytic adenovirus that was administered intratumorally.
* Previously treated with adoptive cell therapy.
* Allergy to TILT-123, TIL, or ingredients present in the investigational medicinal products.
* Administered an investigational medicinal product or device in another clinical trial within 30 days prior to screening