Using oncolytic adenovirus TILT-123 with Avelumab for treating advanced solid tumors

A Phase I Open-Label, Dose-escalation Clinical Trial of Tumor Necrosis Factor Alpha and IL-2 Coding Oncolytic Adenovirus TILT-123 and Avelumab in Solid Tumor Patients (Melanoma and SCCHN) Refractory to or Progressing After Anti-PD(L)1

This study is testing a new treatment combining a special virus and an immune booster to see if it can help people with advanced melanoma and head and neck cancer that hasn't responded to other therapies.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 15 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: TILT Biotherapeutics Ltd. (Industry-sponsored)
• Drugs / interventions: denosumab, avelumab, chemotherapy, immunotherapy, radiation, prednisone
• Locations: 2 sites (New York, New York and 1 other locations)
• Trial ID: NCT05222932 on ClinicalTrials.gov

What this trial studies

This phase 1, open-label, dose-escalation trial evaluates the safety of TILT-123, an oncolytic adenovirus, in combination with the immune checkpoint inhibitor Avelumab for patients with advanced solid tumors, specifically melanoma and head and neck squamous cell carcinoma, that are refractory to or have progressed after anti-PD(L)1 therapy. The trial aims to determine the appropriate dosing and assess the safety profile of this combination therapy. Participants must have a tumor lesion suitable for injection and biopsy, and the study is being conducted in Helsinki, Finland.

Who should consider this trial

Good fit: Ideal candidates are adults over 18 with advanced melanoma or head and neck squamous cell carcinoma that are refractory to or have progressed after anti-PD(L)1 therapy.

Not a fit: Patients with solid tumors that can still be treated with curative intent or those who have not received prior PD-1/PD-L1 blocking antibody therapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with advanced solid tumors that have not responded to existing immunotherapies.

How similar studies have performed: Other studies have shown promise with similar oncolytic virus approaches, but this specific combination is novel.

Eligibility criteria

Inclusion Criteria:

1. Subject must be over 18 years of age
2. Subject must have pathologically confirmed refractory or recurrent injectable solid tumor (melanoma or SCCHN), which cannot be treated with curative intent with available therapies and is refractory to or progressing after anti-PD(L)1 immunotherapy.
3. Standard therapy has failed, it does not exist, is not available or is unlikely to result in meaningful clinical benefit (as assessed by the investigator). Multiple prior therapies (eg. surgery, chemotherapy, radiation, checkpoint inhibitors, kinase inhibitors, biological therapies) are allowed.
4. At least one tumor lesion of 15 mm or bigger must be available for biopsy and injections that, in the opinion of the investigator, is accessible to repeated injections and biopsies without major safety concerns.
5. The disease burden must be evaluable, but does not need to fulfil RECIST 1.1
6. Patients must have received at least 6 weeks of prior PD-1/PDL-1 blocking antibody therapy (e.g. 3x 2w cycle or 3x 3w cycle) within the past up to 12 months
7. Patients must have experienced unequivocally documented radiographic progression of disease during or within 6 weeks after the last dose of such treatment.
8. Subject must have adequate hepatic and renal functions, including the following laboratory parameters:

   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
9. 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:

   1. Women of childbearing potential: Barrier contraceptive method (i.e. condom) must be used in addition to one of the following methods: Intrauterine device or hormonal contraception (oral contraceptive pills, implant, transdermal patches, vaginal ring or long-acting injections).
   2. Women not of childbearing potential: Barrier contraceptive method (i.e. condom) must be used.
   3. Men: Barrier contraceptive method (i.e. condom) must be used.
10. Subject must demonstrate a WHO/ECOG performance score of 0-1
11. Subject must have life expectancy longer than 3 months according to investigator assessment
12. Subject is capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent approved by the Independent Ethics committee prior to the initiation of any screening or study -specific procedure.

Exclusion Criteria:

1. Prior organ transplantation including allogenic stem-cell transplantation or subject is using systemic immunosuppressive medications (eg. corticosteroids or drugs used in treatment of autoimmune disease). Exempted are the following which can be allowed at screening and during the trial: a) replacement corticosteroids if e.g. the patient has adrenal insufficiency after prior immunotherapy b) inhaled and topical treatments c) up to 20 mg/d of prednisone/prednisolone (or equivalent).
2. Treated with any anti-cancer therapy within 30 days prior to the first virus injection. Anti-cancer therapy is defined as anti-cancer agents (e.g. cytotoxic chemotherapy, immunotherapy, signal-transduction inhibitors, biological therapies) and investigational agents. An investigational agent is any drug or therapy that is currently not approved for use in humans. Continuation of bone modifying agents (eg. bisphosphonate or denosumab) is allowed if started at least 3 months before. Palliative radiation is not allowed within 14 days of the first virus injection (before or after), but it is allowed after day 15 during the trial treatment period, if deemed necessary by the investigator.
3. Subject has a history of another active invasive cancer within the past 5 years, except curatively treated basalioma or squamous cell carcinoma of the skin
4. Clinically significant (i.e. active) cardiovascular disease: cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
5. Subject has a history of interstitial parenchymal lung disease.
6. Subject has a LDH value \> 3 x ULN (melanoma)
7. Subject has a history of severe hepatic dysfunction, hepatitis, HIV or other severe chronic but active infectious diseases requiring systemic therapy, e.g. tuberculosis
8. Subject is using proton pump inhibitors or antibiotics during screening period
9. Subject has a history of a coagulation disorder or abnormality in coagulation parameters, as defined by an international normalized ratio not within the normal range, or has received oral or parenteral anticoagulants or thrombolytic agents for therapeutic or prophylactic purposes (including coumadin and warfarin) within 10 days of the first dose of the study treatments. Low molecular weight heparin is permitted if the international normalized ratio is within the normal range
10. Any other medical condition or laboratory abnormality that in the judgment of the principal investigator, may increase the risk associated with study participation or may interfere with interpretation of study results and /or otherwise make the patient inappropriate for entry into this trial.
11. Subject is pregnant, breastfeeding or intend to become pregnant
12. Subject has untreated brain metastases. Treated and asymptomatic brain metastases which have not progressed in 3 months prior to study entry are allowed.
13. Any known or suspected allergy to TILT-123 or ingredients present in the drug product as listed in this protocol.
14. Any known or suspected allergy to avelumab or ingredients present in the drug product as listed in summary of product characteristics (SmPC), including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE Grade ≥ 3).
15. Known current alcohol or drug abuse
16. Vaccination with live vaccines in the past 30 days prior to start of investigational treatment
17. History of immune-related adverse events to previous immunotherapy which led to discontinuation from treatment

Where this trial is running

New York, New York and 1 other locations

• Memorial Sloan Kettering Cancer Center — New York, New York, United States (Recruiting)
• Docrates Cancer Center — Helsinki, Finland (Recruiting)

Study contacts

• Principal investigator: Tuomo Alanko — Docrates Cancer Center

Conditions Melanoma; Head and Neck Squamous Cell Carcinoma; oncolytic virus; immunotherapy; immune checkpoint inhibitor