Dose Ranging, Toxicity Seeking, Phase 1 Trial of Oncolytic Adenoviral Therapy for Melanoma Intracranial and Extracranial Metastases

(For both Groups):

1. Patients must be 18 years old or older. 2. Patients must have a diagnosis of stage IV melanoma. 3.Patients must have an ECOG Performance status of 0 or 1 (may be obtained from medical records within 24 days of screening if not performed at screening).

4.Patients must be able to complete an MRI of the head with contrast. 5.For women of childbearing potential only, a negative urine or serum pregnancy test is required at screening. Women must agree to notify investigator immediately if they become pregnant at any time during the trial period.

6.Men and women of childbearing potential must be willing to employ adequate contraception throughout the study and for men for up to 6 months from administration of virus. Birth control that is acceptable to use in this study:

• Using twice the normal protection of birth control (i.e., double barrier) by using a condom AND spermicidal jelly or foam, or a diaphragm AND spermicidal jelly or foam. A spermicidal jelly or foam must be used in addition to a barrier method (e.g., condom or diaphragm)

• Birth control pills ("The Pill")

• Depot or injectable birth control
• IUD (Intrauterine Device)
• Birth Control Patch (e.g., Othro Evra®)
• NuvaRing®

• Surgical sterilization (i.e., tubal ligation or hysterectomy for women or vasectomy for men)

  8.Patients must be able and willing to provide informed consent. A legally authorized representative (LAR) may provide consent if the potential subject lacks the capacity to provide consent themselves. Patient assent will be sought where feasible in this situation.

  8.- For patients enrolled in Groups A and B, patients must be relapsed or refractory to standard of care therapy. Additionally, patients must continue with immunotherapy while undergoing oncolytic viral treatment at the discretion of the medical oncologist. 9. Patients enrolled in Group A or Group B must be on one of the following FDA approved immunotherapy agents: Ipilimumab, Nivolumab, Pembrolizumab, Relatlimab.

  10. Normal hematologic, renal and liver function as defined by:

  - ANC ≥1000/ mm3

  - AGC ≥1500/ mm3

  • WBC ≥3000/mm3
  • Platelets ≥100,000/ mm3
  • PT, INR or PTT \<1.5 x institutional upper limit
  • Hemoglobin >8.0 g/dL
  • Total serum bilirubin ≤ 1.5 upper normal institutional limits
  • AST(SGOT)/ALT(SGPT) ≤2 × institutional upper limit of normal; ≤5 ULN if there is liver involvement secondary to the tumor

  • Serum creatinine ≤ 1.5 x ULN OR

    ≥40 mL/min for participant with creatinine levels > 1.5 x institutional ULN

(For Group A):

1. Patients must have radiographic evidence of stable extracranial disease or no evidence of extracranial disease on current immunotherapy regimen based on RECIST v1.1 criteria.
2. Patients must have between one and five brain metastases secondary to intracranial disease progression, identified on the screening MRI, from histologically confirmed metastatic melanoma. At least one of those lesions must be untreated, be suitable for accurate repeated measurements and have a tumor diameter of either 1.0-3.5cm (Group A- Arm 1) or 1.0-2.0cm (Group A- Arm 2) on the screening magnetic resonance imaging [MRI]) in at least one dimension. One of those lesions will be designated as the index lesion and planned for stereotactic intraoperative biopsy to ensure viable tumor tissue and oncolytic viral administration. The other four may be newly diagnosed, stable or recurrent.
3. All intracranial metastases (the index lesion, and the non-index lesions, as defined below) must be located >5 mm from the optic chiasm and outside the brainstem.

4. The brain metastases must be an independently verified measurable brain metastasis in accordance with the mRECIST (Appendix 1) by Neuro Radiology.

   • Previous radiation and/or excision of brain metastases are permitted, provided that neurologic sequelae have completely resolved and at least one untreated lesion(s) remain.

   o Patients treated with SRS or surgical resection but who have one or more measurable lesion(s) that remained untreated will be eligible and the untreated lesions will be considered measurable target lesions.

5. Patients in Group A will need to consent to have a biopsy of the intracranial index lesion taken at the time of the stereotactic oncolytic viral injection, before each injection of oncolytic virus. This is to obtain histologic confirmation of the tumor.
6. For patients enrolled in Group A-Arm1, the index lesion must be surgically accessible for both stereotactic viral inoculation and surgical resection at the discretion of the treating neurosurgeon at the time of patient enrollment.
7. For patients enrolled in Group A- Arm1, eligibility is restricted to patients who are undergoing surgical resection of the index lesion as part of standard of care of treatment.
8. For patients enrolled into Group A- Arm 2, the index lesion must be surgically accessible for stereotactic viral inoculation at the discretion of the treating neurosurgeon. Amongst patients in DL2 or DL3 of Arm A.2, if the pre-treatment biopsy at the second or third viral inoculation does not demonstrate viable tumor, the patient will not receive further injections and for safety analysis will be considered to have not experienced a DLT at the number of serial doses administered.
9. Index lesions in GroupA-Arm1 and GroupA-Arm2 that are located in or near eloquent cortex, as defined as the sensorimotor strip, speech and memory cortices, or proximity to corticospinal tracts, must be reviewed and approved by the enrolling neurosurgeon.
10. Non-index lesions, which are not planned for oncolytic virus administration, must measure up to 4.0 cm in maximal extent on the screening MRI brain scan. The non-index lesion(s) can be treated with SRT or surgical resection at the discretion of the radiation oncologist and neurosurgeon.

(For Group B):

1. Patients must have radiographic evidence of progressive extracranial disease on current immunotherapy regimen based on RECIST v1.1 criteria.
2. Patients enrolled in Group B must have at least 1 injectable extracranial lesion amenable for direct injection or through the use of image guidance, such as ultrasound. The lesion must be an injectable cutaneous, subcutaneous, or nodal melanoma lesion greater than or equal to 5mm in at least one dimension.
3. Patients enrolled in Group B must have an injectable lesion that is not be adjacent or encasing vital structures such as an airway, major nerves or blood vessels, mucosal regions or spinal cord that, in the opinion of the Investigator, could cause occlusion or compression in the case of tumor swelling or erosion into a major vessel in the case of necrosis.
4. Patients enrolled in Group B can have up to 5 intracranial metastases up to 4.0 cm in size; however, the presence of intracranial metastases is not a requirement for patients enrolled in this Arm. For patients with intracranial metastases, these lesions can be treated with SRT, surgical resection, or WBRT at the discretion of the radiation oncologist and neurosurgeon.

Exclusion Criteria

(For Both Groups):

1. Patients with >5 diagnosed intracranial metastases on screening MRI
2. Patients who received prior WBRT or SRT for brain metastases within 2 days of study treatment initiation
3. Patients with symptomatic intracranial metastases
4. Patients who received high dose corticosteroids defined as dexamethasone greater than 2mg per day within 7 days of initiating therapy. However, if they have been on a stable dose of 2 mg or less per day for 7 days they can be enrolled.
5. Patients with suspected or confirmed leptomeningeal disease defined as radiographic evidence by MRI of leptomeningeal involvement in addition to positive cerebrospinal fluid (CSF) cytology
6. Serum lactate dehydrogenase ≥1.5x upper limit of normal
7. Primary uveal or mucosal melanoma

8 Patients who are checkpoint inhibitor naïve.

9 Active uncontrolled infection or unstable or severe intercurrent medical conditions which would impact the ability to participate in the study. All patients must be afebrile at baseline and not taking antiviral or oral antibiotics.

10. Evidence of bleeding diathesis or use of anticoagulant medication or any medication that may increase the risk of bleeding that cannot be stopped prior to surgery. If the medication can be discontinued, based on the clinical judgment of the surgeon, prior to oncolytic viral administration, the patient may be eligible.

11. Past radiation or surgical therapy to the index lesion is exclusionary. However, up to a total of 2 prior courses of radiation treatment or surgical resection to non-index lesions are allowed as long as any treated lesions were >15mm from the index lesion.

12. Known infections with hepatitis B (positive HBsAg), hepatitis C (positive hepatitis C RNA), or HIV

13. Patients with known or suspected immunosuppressive disorders, such as acquired or congenital/immune deficiency syndromes and autoimmune diseases

14. Tumor position that, in the Investigator's opinion, would require ventricular, brainstem or posterior fossa injection in order to deliver the virus

15. Any contraindication for undergoing MRI such as: individuals with pacemakers, epicardial pacer wires, infusion pumps, surgical and/or aneurysm clips, shrapnel, metal prosthesis, implants with potential magnetic properties, metallic bodies in the eyes, etc.

16. Inoculation with a live vaccine within 30 days prior to oncolytic virus administration

17. History of encephalitis, multiple sclerosis, other CNS infection or primary CNS disease that would interfere with subject evaluation

18. Females who are pregnant or lactating females who are breastfeeding