The goal of this clinical research study is to determine if an investigational new drug, named ORB-021, developed by Orionis Biosciences is safe and can be tolerated in people diagnosed with an advanced solid tumor.

The study also aims to find the biologically optimal dose of the study medicine by assessing the safety and potential activity in the treatment of solid tumors.

There are three phases to this study: screening, treatment and end of treatment.

ORB-021 is a complex engineered biologic molecule that targets cytokine activation specifically to certain immune cells which may have benefit in solid tumors. The cytokine in ORB-021 is inactive to cells expressing the receptor but confers full activity to individual cells when also bound to the target, thereby markedly reducing the potential for toxicities caused by the cytokine. ORB-021 is administered by intravenous (IV) infusion/injection.

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 safe to undergo serial biopsies.

3. Must have received or be ineligible for all standard of care therapies as deemed appropriate 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 for patients without known liver metastases and up to 5 x institutional ULN for patients 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 urine pregnancy test within 3 days prior to treatment. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal (at least 12 consecutive months with no menses without an alternative medical cause)

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

  1. Patients who are receiving any other investigational agents

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

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

  4. Pregnant women are excluded from this study because the effects of ORB-021 on a pregnant woman or fetus are unknown. Breastfeeding should be discontinued as the 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 the first dose of study treatment, except for superficial skin cancer, localized prostate cancer on active surveillance, or localized solid tumors deemed cured by surgery and not treated with systemic anticancer therapy and not expected to require anticancer therapy in the next 2 years

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

  9. Current or prior use of immunosuppressive medication within 28 days before ORB-021 treatment with the exceptions of ophthalmic, intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.

  10. Active or prior documented autoimmune or inflammatory disorders requiring systemic immunosuppressive medications (including inflammatory bowel disease [eg. colitis or Crohn s disease], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions 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, physical examination, and radiographic findings, and PPD testing if indicated),
      • Hepatitis B (HBV) or hepatitis C Virus (HBC): Patients with active HBV infection or active HCV infection are ineligible. However, patients with a history of HBV infection who have undetectable or low levels of HBV DNA and normal ALT are eligible. Patients with chronic HBV infection who meet the criteria for anti-HBV therapy are eligible if they have initiated anti-HBV therapy prior to treatment with ORB-021. Patients with a history of HCV infection are eligible if they have completed curative antiviral treatment and have a viral load that is below the limit of detection.
      • HIV: Patients living with HIV infection are ineligible only if they have a CD4 count less than 350 cells/µL and a history of an AIDS-defining infection within the last 12 months. Patients with a CD4 count greater than 350 cells/µL or who have not had an AIDS-defining infection within the last 12 months are eligible. Eligible patients living with HIV should maintain effective anti-retroviral therapy.
      • SARS-COV2 (PCR positive)

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

  16. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.

  17. Patients with uncontrolled seizures

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

  19. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with ORB-021 may be included only after consultation with the Principal Investigator

  20. Patients with QTcF > 480 ms

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