tnfalpha and interleukin 2 coding oncolytic adenovirus tilt-123 during til treatment of advanced melanoma

Conditions: Metastatic Melanoma

Summary: 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

Keywords: oncolytic virus t-cell therapy immunotherapy tilt