A Phase 1 Study of OTS-412 (Recombinant Oncolytic Vaccinia Virus) in Treatment-refractory Solid Tumor Patients

A Phase 1 Study of OTS-412 (Recombinant Oncolytic Vaccinia Virus) in Combination With Hydroxyurea or Hydroxyurea/Atezolizumab in Treatment-refractory Solid Tumor Patients

This clinical trial aims to determine whether the administration of the investigational drug OTS-412, OTS-412 in combination with hydroxyurea or hydroxyurea/atezolizumab is safe and effective for patients with various types of cancer.

The primary objective of this study is:

• to evaluate the safety of OTS-412 monotherapy, combination therapy of OTS-412 and hydroxyurea, or combination therapy of OTS-412, hydroxyurea, and atezolizumab
• to find an optimal dosage of hydroxyurea when used in combination with OTS 412. Hydroxyurea is currently used at dosages of 15-35 mg/kg/day for certain conditions, and the optimal dosage when combined with the oncolytic virus will be determined within this range.
• to find an optimal dosage of OTS-412 when used in combined with hydroxyurea and atezolizumab.

The secondary objectives include evaluating anti-tumor effects, immune responses, and pharmacokinetics (PK) of OTS-412 in blood over time after administration.

This study focuses on various solid tumors that are resistant to standard therapies, particularly immune checkpoint inhibitors alone or in combination with other therapies.

Inclusion Criteria:

1. 19 years of age or older

2. Diagnosed with a malignant solid tumor via histology or cytology, although a radiological diagnosis is permissible for hepatocellular carcinoma

3. Solid tumors that demonstrate limited response or resistant to SOC therapy, particularly when atezolizumab or other PD-L1 inhibitors, or PD-1 inhibitors are administered as monotherapy or in combination therapy. This may include, but not limited to, hepatocellular carcinoma, melanoma, renal cell carcinoma, urothelial carcinoma, biliary cancer, head and neck cancer, gastric cancer, breast cancer, colorectal cancer, and any solid tumor with microsatellite instability (MSI)-high status. At minimum, SOC treatment presented in the Protocol should have been received for each cancer type.

4. Patients with tumors that have known actionable molecular alterations (i.e. EGFR, ALK, BRAF, etc) must have progressed on targeted therapy.

5. Lesions that are deemed feasible for injection either directly (palpable subcutaneous tumors) or under ultrasound guidance (deep-seated tumors). Additionally, tumor(s) should not be adjacent or encasing vital structures such as major nerves or blood vessels, pericardium, gastrointestinal tract or other hollow organs, mucosal regions or spinal cord that could cause occlusion or compression in case of tumor swelling or erosion and major bleeding in the case of necrosis.

6. At least one measurable (longest diameter, LD ≥1 cm) and injectable tumor that has not been previously received local treatment on computed tomography (CT) or magnetic resonance imaging (MRI)

7. The total volume of injectable tumor(s) should be 2 cm3 or more in 1x10E8 pfu dosing cohorts and 6 cm3 or more in 3x10E8 pfu dosing cohorts.

8. Life expectancy of 12 weeks or more

9. Eastern cooperative oncology group (ECOG) performance status is 0, 1, or 2

10. Adequate pulmonary function, such as baseline pulse oximetry of at least 92% on room air

11. Laboratory test results meet the following:

    • ANC ≥ 1,500 /μL
    • White blood cell (WBC) ≥ 2,500 /μL
    • Hemoglobin (Hb) ≥ 9.0 g/dL without packed red blood cell transfusion within the prior 2 weeks
    • Platelet ≥ 75,000 /μL without platelet transfusion
    • AST and ALT ≤ 5 × ULN
    • Total bilirubin ≤ 1.5 × ULN
    • Creatinine clearance ≥ 60 mL/minute (measured using Cockcroft-Gault formula).
    • LDH ≤ 3 × ULN
    • INR or aPTT ≤ 1.5 × ULN.

12. Voluntarily decided to participate in this clinical study and provided written consent

Exclusion Criteria:

1. Patients who have previously received talimogene laherparepvec (Imlygic) or any other oncolytic virus, have received any systemic or local anti-cancer therapy for tumors within 4 weeks prior to the first administration of the study drugs(C1D1), or have not recovered from the adverse events due to these therapies to at least Grade 1 severity or returned to baseline levels prior to C1D1, with the exceptions of any grade of alopecia and Grade 2 neuropathy.

2. Patients who have untreated symptomatic brain metastases, have treated brain metastases without evidence of stability or improvement on two scans at least two weeks apart, have leptomeningeal disease regardless of treatment, or have received anti-convulsants within the last 28 days.

3. Tumors adjacent to vital neurovascular structures or at risk of airway compromise in the event of post injection tumor swelling, bleeding, or inflammation. Patients with tumors near vital structures can be enrolled as long as they have other lesions that are appropriate for injection (these tumors near vital structures will not be injected).

4. History of other malignancies that developed within 5 years (However, cervical carcinoma in situ, basal cell carcinoma, or squamous cell skin cancer, and all cancers after 5 years since it was cured are acceptable.)

5. History of organ transplant surgery

6. Known significant immunodeficiency due to underlying illness (e.g., HIV/AIDS) and/or immune-suppressive medication including high-dose systemic corticosteroids (prednisone 20 mg/day or equivalent which is ongoing and/or was taken more than 4 weeks within the preceding 2 months of study treatment)

7. History of or active autoimmune disease

8. Ongoing severe inflammatory skin disease (as determined by the Investigator) requiring medical treatment or history of severe eczema (as determined by the Investigator) requiring prior medical treatment

9. Anticoagulation or anti-platelet medication that cannot be withheld for the required period prior to and after the OTS-412 injection, specifically:

   • Coumadin for 7 days
   • Direct Factor Xa inhibitor (rivaroxaban, apixaban, edoxaban) for 4 days
   • Oral direct thrombin inhibitor (dabigatran) for 4 days
   • Aspirin, clopidogrel, ticagrelor for 7 days
   • Prasugrel for 9 days
   • Low molecular weight heparin for 24 hours
   • Unfractionated heparin for 12 hours Please contact the Sponsor for questions regarding the management of other antithrombotic agents prior to treatment.

10. Taking antiviral drugs (immunoglobulin, interferon, etc.) or being unable to discontinue these medications at least 7 days prior to receiving the study drugs (note that oral antiviral drugs for hepatitis B and C are allowed).

11. Severe medical conditions, as determined by the Investigator, that may increase the patient's susceptibility to adverse medical risks during or after OTS-412 treatment, such as volume loading, tachycardia, or hypotension.

12. Current or history of significant cardiovascular disease, including significant coronary artery disease (e.g., requiring angioplasty or stent), congestive heart failure within the preceding 12 months, myocardial infarction, ischemic cardiomyopathy, or myocarditis, unless cardiology consultation and clearance have been obtained for study participation

13. History of the side effects of past smallpox vaccinations

14. History of the hypersensitivity or severe/serious AEs to the components of the study drugs

15. Unable to receiving a contrast medium for a radiological scan due to a history of allergy to iodide contrast agents

16. Vaccination with live vaccines within 4 weeks before the first administration of the study drugs

17. Receiving an investigational product within 4 weeks prior to the first administration of the study drugs

18. Pregnant or breastfeeding women

19. Patient who does not consent to the use of appropriate contraceptive methods for at least 6 months, when the woman is of childbearing age, or at least 1 year, when the male patient's spouse is a woman of childbearing age, after the last administration of the study drugs

20. Other medical condition that in the judgement of the 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 study participation

21. Patient unable or unwilling to comply with the protocol