ORB-021 In Patients With Advanced Solid Tumors

Inclusion Criteria:

All patients must meet the following criteria for inclusion:

1. Age 18 years or older

2. Patients with evidence of recurrent or refractory solid tumors deemed medically safeto undergo serial biopsies.

3. Must have received or be ineligible for all standard of care therapies as deemedappropriate by the treating physician.

4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

5. Adequate organ and marrow function as defined below:

• Hemoglobin ≥ 9.0 g/dL

• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (> 1500 per mm3)

• Platelet count ≥ 75 × 109/L (> 75,000 per mm^3)

• Serum bilirubin less than or equal to 1.5 × institutional upper limit of normal (ULN).

• AST (SGOT)/ALT (SGPT) less than or equal to 2.5 × institutional ULN forpatients without known liver metastases and up to 5 x institutional ULN forpatients with known liver metastases.

• Creatinine clearance (CL) > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976)

• Women of childbearing potential (WCBP) must have a negative serum or urinepregnancy test within 3 days prior to treatment. NOTE: Females are consideredof childbearing potential unless they are surgically sterile (have undergone ahysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or arepostmenopausal (at least 12 consecutive months with no menses without analternative medical cause)

6. Patients and their partners must practice approved forms of contraception. Sexuallyactive WCBP must agree to use a highly effective method of contraception prior tostudy entry and continuing for 30 days after ORB-021 administration. Highlyeffective methods of contraception are highly effective birth control methods with afailure rate of < 1% per year when used consistently and correctly. Additionally,male patients should refrain from donating sperm for 3 months following the lastdose of study drug.

7. Ability to understand and willingness to sign an Institutional Review Board (IRB)-approved written informed consent document.

Exclusion Criteria:

• Patients are to be excluded from the study if they meet any of the followingcriteria:

1. Patients who are receiving any other investigational agents

2. History of allergic reactions attributed to compounds of similar chemical orbiologic composition to ORB-021 or its excipients.

3. Uncontrolled intercurrent illness including, but not limited to, ongoing oractive infection, symptomatic congestive heart failure, unstable anginapectoris, cardiac arrhythmia, or psychiatric illness/social situations thatwould limit compliance with study requirements. Urinary tract infections (UTIs)are excluded from being an exclusion criterion for treatment unless they areGrade 3 or higher.

4. Pregnant women are excluded from this study because the effects of ORB-021 on apregnant woman or fetus are unknown. Breastfeeding should be discontinued asthe potential risk for AEs in nursing infants treated with ORB-021 is unknown.

5. Patients with unresolved symptomatic hydronephrosis.

6. Any other anticancer therapy (eg, chemotherapy, biologic therapy,immunotherapy, targeted therapy, endocrine therapy, radiation therapy,intravesical therapy, investigational agent) within 28 days or 5 half-lives (whichever is shorter) of the study treatment

7. The patient has a diagnosis of another malignancy within 2 years before thefirst dose of study treatment, except for superficial skin cancer, localizedprostate cancer on active surveillance, or localized solid tumors deemed curedby surgery and not treated with systemic anticancer therapy and not expected torequire anticancer therapy in the next 2 years

8. Patients with primary malignant brain tumors, untreated and/or unresolved orsymptomatic brain metastasis

9. Current or prior use of immunosuppressive medication within 28 days beforeORB-021 treatment with the exceptions of ophthalmic, intranasal and inhaledcorticosteroids or systemic corticosteroids at physiological doses, which arenot to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.

10. Active or prior documented autoimmune or inflammatory disorders requiringsystemic immunosuppressive medications (including inflammatory bowel disease [eg. colitis or Crohn s disease], systemic lupus erythematosus, Sarcoidosissyndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves'disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following areexceptions to this criterion:

• Patients with vitiligo or alopecia
• Patients with hypothyroidism stable on hormonal replacement
• Patients without active disease in the last 5 years may be included
• Patients with celiac disease controlled by diet alone

11. History of primary immunodeficiency

12. History of allogeneic organ transplant

13. History of hypersensitivity to interferon alpha 2b or any excipient

14. Active infection with:

• Tuberculosis (clinical evaluation that includes clinical history, physicalexamination, and radiographic findings, and PPD testing if indicated),
• Hepatitis B (HBV) or hepatitis C Virus (HBC): Patients with active HBVinfection or active HCV infection are ineligible. However, patients with ahistory of HBV infection who have undetectable or low levels of HBV DNAand normal ALT are eligible. Patients with chronic HBV infection who meetthe criteria for anti-HBV therapy are eligible if they have initiatedanti-HBV therapy prior to treatment with ORB-021. Patients with a historyof HCV infection are eligible if they have completed curative antiviraltreatment and have a viral load that is below the limit of detection.
• HIV: Patients living with HIV infection are ineligible only if they have aCD4 count less than 350 cells/µL and a history of an AIDS-defininginfection within the last 12 months. Patients with a CD4 count greaterthan 350 cells/µL or who have not had an AIDS-defining infection withinthe last 12 months are eligible. Eligible patients living with HIV shouldmaintain effective anti-retroviral therapy.
• SARS-COV2 (PCR positive)

15. Receipt of live attenuated vaccination within 28 days prior to the studytreatment

16. Any condition that, in the opinion of the investigator, would interfere withevaluation of study treatment or interpretation of patient safety or studyresults.

17. Patients with uncontrolled seizures

18. Any unresolved toxicity National Cancer Institute-Common Terminology Criteriafor Adverse Events (NCI-CTCAE) Grade ≥ 2 from previous anticancer therapy withthe exception of alopecia, vitiligo, endocrinopathies, and the laboratoryvalues defined in the inclusion criteria.

19. Patients with irreversible toxicity not reasonably expected to be exacerbatedby treatment with ORB-021 may be included only after consultation with thePrincipal Investigator

20. Patients with QTcF > 480 ms

21. Patients with prior grade 3 irAE or any irAE that resulted in discontinuationof PD-1 or PD-L1 ICI treatment.