Using an oncolytic virus with chemotherapy and TILs to treat metastatic melanoma

A Phase 1, Open-label, Single-arm Study to Investigate the Safety, Tolerability, and Preliminary Efficacy of TNFa and IL-2 Coding Oncolytic Adenovirus TILT-123 in Combination With Lymphocyte-depleting Chemotherapy and Tumor-infiltrating Lymphocytes in Melanoma Patients.

This study is testing a new virus treatment combined with chemotherapy and immune cells to see if it can help people with advanced melanoma fight their cancer better.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 9 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: TILT Biotherapeutics Ltd. (Industry-sponsored)
• Drugs / interventions: chemotherapy, immunotherapy, radiation, Prednisone, cyclophosphamide, fludarabine
• Locations: 1 site (Copenhagen)
• Trial ID: NCT06961786 on ClinicalTrials.gov

What this trial studies

This open-label, phase 1 trial evaluates the safety of TILT-123, an oncolytic adenovirus, in combination with lymphocyte-depleting chemotherapy and tumor-infiltrating lymphocytes (TILs) for patients with metastatic melanoma. The study aims to enhance the efficacy of TILT-123 by reducing regulatory T cells that inhibit T-cell activity against tumors. Participants will receive TILT-123 alongside cyclophosphamide and fludarabine phosphate, which are intended to deplete irrelevant T cells. This is the second investigation of TILT-123 in this patient population, building on previous findings regarding its safety and preliminary efficacy.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 to 75 with previously treated refractory or recurrent stage 3-4 melanoma.

Not a fit: Patients with melanoma that can be treated with curative intent or those who do not meet the eligibility criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could provide a novel treatment option for patients with advanced melanoma who have limited therapeutic alternatives.

How similar studies have performed: Other studies using oncolytic viruses and immunotherapy have shown promise, suggesting potential for success in this novel combination approach.

Eligibility criteria

Inclusion Criteria:

1. Patients must be 18 to 75 years of age inclusive, at the time of signing the informed consent.
2. Patients with pathologically confirmed previously treated refractory or recurrent stage 3-4 melanoma, which cannot be treated with curative intent with available therapies.
3. Patients who have had at least 1 prior line of medical treatment (eg, checkpoint inhibitors, kinase inhibitors, IL-2). Multiple prior therapies (eg, surgery, checkpoint inhibitors, kinase inhibitors, IL-2, interferon, chemotherapy, radiation) are allowed.
4. Patients must have a demonstrated WHO/ECOG performance score of 0-1 at screening.
5. A tumor of \>9 mm 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.
6. At least 1 additional tumor (\>14 mm in diameter) must be available for injections and biopsies for correlative analyses. The disease burden must be evaluable according to RECIST 1.1.
7. Patients must have adequate hepatic, cardiac, and renal function as follows:

   1. Platelets ≥ 100,000/µl and \< 700,000/µl
   2. Hemoglobin ≥100 g/L
   3. AST and ALT ≤2.5×ULN
   4. GFR \>60 mL/min (CKD-EPI)
   5. Leukocytes (WBC) \>3.0G/L
   6. Absolute neutrophil count greater than 1500/mm3 without the support of filgrastim
   7. Bilirubin \<1.5×ULN
   8. Patients of 60 years or older, or have a history of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, heart block, will undergo cardiac evaluation: LVEF assessment with documented LVEF ≥ 50% by either TTE (trans thoracal echocardiography) or MUGA (multigated acquisition scan). Further cardiac evaluations in patients with cardiac risk factors (e.g. diabetes, hypertension, obesity) will be evaluated by the investigator as deemed necessary.
8. Must be willing to use adequate forms of contraception from screening, during the study, and for a minimum of 90 days after the end of treatment, in accordance with the following:

   1. Woman of childbearing potential: Barrier contraceptive method (ie, condom) must be used in addition to 1 of the following methods: Intrauterine devices or hormonal contraception (oral contraceptive pills, implants, transdermal patches, vaginal rings or long-acting injections).
   2. Women not of childbearing potential: Barrier contraceptive method (ie, condom) must be used.
   3. Men: Barrier contraceptive method (ie, condom) must be used.
9. Patients must be capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
10. Patients must be capable of understanding and complying with the parameters outlined in the protocol.
11. Patients must have a life expectancy longer than 3 months.
12. Patients must be eligible for adoptive T-cell therapy with Lymphocyte-depleting chemotherapy and TILs.

Exclusion Criteria:

1. History of another active invasive cancer as judged by the investigator within the past 3 years except basal cell carcinoma.
2. Uncontrolled cardiac or vascular diseases.
3. History of heart attack or cerebral stroke within the previous 12 months before screening or is not recovered from a previous heart attack or cerebral stroke.
4. History of hepatic dysfunction, hepatitis, or human immunodeficiency virus.

   1. Patients should be seronegative for HIV antibody.
   2. Patients should be seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
5. History of coagulation disorder.
6. Untreated brain metastases. Treated brain metastases that have not progressed in the 3 months prior to screening are allowed.
7. Concurrent opportunistic and/or active systemic infections.
8. Use of immunosuppressive medications (corticosteroids or drugs used in treatment of autoimmune disease), except for the following, which can be allowed at screening and during the study:

   1. Replacement corticosteroids (eg, if the patient has adrenal insufficiency after prior immunotherapy)
   2. Pulmonary and topical treatments
   3. Prednisone/prednisolone at doses up to 20 mg/day
9. Treated with any anticancer therapy (eg, immunotherapy, signal-transduction inhibitors \[eg. BRAF and MEK inhibitors\], cytotoxic chemotherapy, radiotherapy, or investigational agents \[ie, any drug or therapy that is currently not approved for use in humans\]) within 30 days prior to enrollment.
10. Previously treated with any oncolytic adenovirus that was administered IT.
11. Previously treated with adoptive cell therapy.
12. Administered an IMP or device in another clinical study within 30 days prior to baseline.
13. Lactate dehydrogenase value \>5×ULN.
14. Allergy to any ingredients present in the IMPs (as listed in the respective IBs).
15. Women of childbearing potential who are pregnant, breastfeeding, or intending to become pregnant.
16. Any other medical condition or laboratory abnormality that, in the judgment of the principal investigator, could increase the risk associated with study participation, interfere with interpretation of study results, or otherwise render study participation inappropriate.

Where this trial is running

Copenhagen

• National Center for Cancer Immune Therapy Herlev Hospital, Copenhagen University — Copenhagen, Denmark (Recruiting)

Study contacts

• Principal investigator: Inge Marie Svane — CCIT, Herlev Hospital, Copenhagen University
• Study coordinator: Herlev Hospital

Conditions Metastatic Melanoma; oncolytic virus; TILT; immunotherapy