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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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A Phase 1, Open-Label, Dose-Escalation Clinical Trial of Tumor Necrosis Factor Alpha and Interleukin 2 Coding Oncolytic Adenovirus TILT-123 in Melanoma Patients Receiving Adoptive Cell Therapy With Tumor Infiltrating Lymphocytes

Conditions
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Metastatic Melanoma

Intervention / Treatment
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* Biological: TILT-123


Participation Criteria
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Eligibility Criteria
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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: Platelets > 75 000/mm3 Haemoglobin ≥ 100 g/L. AST and ALT < 3 x ULN. GFR >60 ml/min (Cockcroft-Gault formula). Leukocytes (WBC) > 3,0 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: open-label, single arm, dose escalation
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TILT-123<br>Patients will receive administrations of TILT-123. Patients will also receive Tumor Infiltrating Lymphocytes (TILs) during the treatment phase. Escalation to the next dose of TILT-123 level will occur when the safety data has been evaluated for all patients in the preceding dose level. | Biological: TILT-123<br>* TNFalpha and IL-2 coding oncolytic adenovirus TILT-123<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with any (serious and non-serious) Adverse Events prior to TIL administration. |  | 36 days | 
| Number of Participants with abnormal laboratory values prior to TIL administration. |  | 36 days | 
| Number of Participants with vital sign abnormalities prior to TIL administration. |  | 36 days | 
| Safety assessed by 12- lead electrocardiograms (ECGs) Adverse Events prior to TIL administration. | Any clinically significant adverse changes on the ECG will be reported as Adverse Events. | 36 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oncolytic virus, T-cell therapy, immunotherapy, TILT