Anti-CD137 and Anti-CTLA-4 Monoclonal Antibody in Patients With Advanced Cancer

Inclusion Criteria:

1. Voluntarily agree to participate by giving signed, dated, and written informedconsent prior to any study specific procedures. Participation in pharmacogenomicstesting is optional.

2. ≥ 18 years of age.

3. Histologically or cytologically confirmed diagnosis of a solid tumor that iscurrently metastatic or locally advanced for which no standard therapy is availableor standard therapy has failed.

4. Measurable disease on imaging based on RECIST 1.1.

5. Life expectancy of ≥ 3 months and ECOG performance status of 0 or 1.

6. Adequate organ and bone marrow reserve function, as indicated by the followinglaboratory values:

• Adequate hematological function, defined as absolute neutrophil count ≥ 1.5 × 10^9/L, platelet count ≥ 100 × 10^9/L, and hemoglobin ≥ 8 g/dL without recenttransfusion (defined as a transfusion that has occurred within 2 weeks of thehemoglobin measurement)

• Adequate liver function, defined as total bilirubin level ≤ 1.5 × upper limitof normal (ULN), aspartate aminotransferase ≤ 2.5 × ULN, and alanineaminotransferase ≤ 2.5 × ULN, albumin ≥ 3 g/dL, and alkaline phosphatase ≤ 2.5 × ULN or ≤ 5 × ULN for patients with liver metastases

• Adequate renal function defined as creatinine ≤ 1.5 × ULN OR measured orcalculated creatinine clearance ≥ 40 mL/minute per institutional standard.Assessment methods should be recorded

• Adequate coagulation, defined as international normalized ratio or prothrombintime ≤ 1.5 × ULN and activated partial thromboplastin time ≤ 1.5 × ULN (unlesspatient is receiving anticoagulant therapy)

7. Patients with a history of prior malignancy are eligible if treatment was completed ≥ 2 years prior to the first dose of study treatment and the patient has no evidenceof disease.

8. Patients must provide a sufficient and adequate formalin-fixed paraffin-embeddedtumor tissue sample (biopsy) collected after the last dose of prior anti-cancertherapy and before the first dose of study treatment from a site not previouslyirradiated and agree to mandatory on-treatment biopsy if clinically feasible.

9. Female patients of childbearing potential must have a negative serum pregnancy testat screening (within 72 hours of first dose of study medication). Non-childbearingpotential is defined as 1 of the following:

• ≥ 45 years of age and has not had menses for > 1 year

• Amenorrheic for > 2 years without a hysterectomy and oophorectomy andfollicle-stimulating hormone value in the postmenopausal range upon prestudy (screening) evaluation

• Status is post-hysterectomy, -bilateral oophorectomy, or -tubal ligation

10. Female patients of childbearing potential must be willing to use highly effectivecontraceptive measures starting with the Screening Visit through 90 days after lastdose of study treatment. Note: Abstinence is acceptable if this is the establishedand preferred contraception method for the patient.

11. Male patients with a female partner(s) of childbearing potential must agree to usehighly effective contraceptive measures throughout the study starting with theScreening Visit through 90 days after the last dose of study treatment is received.Males with pregnant partners must agree to use a condom; no additional method ofcontraception is required for the pregnant partner. Note: Abstinence is acceptableif this is the established and preferred contraception method for the patient.

Specific Melanoma Criteria:

Note: these specific criteria below are in addition to the general criteria above and supersede the general criteria in some cases.

Inclusion:

1. Histological confirmation of cutaneous melanoma.

2. Progression on or within 24 weeks of stopping treatment with a PD-1/PD-L1 confirmedper Society for Immunotherapy of Cancer (SITC).

3. Patients with BRAF V600-positive tumor(s) should also have received prior treatmentwith a BRAF inhibitor (alone or in combination with a MEK inhibitor) or havedeclined targeted therapy.

Note: Patients with BRAF V600-positive tumors with no clinically significant tumor-related symptoms nor evidence of rapidly progressive disease are not required to be treated with a BRAF inhibitor (alone or in combination with a MEK inhibitor) based on Investigator's decision.

Exclusion Criteria:

1. Currently participating and receiving study therapy or has participated in a studyof an investigational agent and received study therapy or used an investigationdevice within 3 weeks of first dose of current study treatment.

2. Received prior systemic cytotoxic chemotherapy, biological therapy, radiotherapy, ormajor surgery outside of the acceptable washout period prior to first dose of studydrug. A 1-week washout is permitted for palliative radiation to non-central nervoussystem (CNS) disease, with Sponsor approval. The following washout windows are acceptable from prior treatments (i.e., patientswith time periods less than the following should be excluded):

• Cytotoxic agent ≥ 3 weeks is acceptable (i.e., < 3 weeks should be excluded)

• Monoclonal antibodies ≥ 4 weeks is acceptable (i.e., < 4 weeks should beexcluded)

• Proteasome inhibitors or corticosteroids ≥ 2 weeks is acceptable (i.e., < 2weeks should be excluded)

• Small molecule/tyrosine kinase inhibitor within 14 days or less than 5circulating half-lives of investigational drug

• Having a previous SARS-CoV-2 vaccine > 7 days before administration. Forvaccines requiring more than 1 dose, the full series should be completed priorto Cycle 1 Day 1, when feasible, and when the delay in initiation of studytreatment would not put the study patients at risk

3. Patients who have received prior anti-CD137 therapy may be enrolled upon agreementwith the Sponsor.

4. Persistent toxicity of NCI-CTCAE version 5.0 Grade > 1 severity that is related toprior therapy. Note: Sensory neuropathy or alopecia of Grade ≤ 2 are acceptable.

5. Expected to require any other form of systemic or localized antineoplastic therapywhile on study (including maintenance therapy with another agent, radiation therapy,and/or surgical resection).

6. History of:

• Severe (Grade ≥ 3) hypersensitivity reactions to fully human monoclonalantibodies

• Immune-related adverse event requiring treatment with systemic steroids for > 7days (refer to Exclusion Criterion #7 for exceptions) excluding Grade 1 or 2rash

• Interstitial lung disease or lung disease which may interfere with theassessment of pneumonitis

• Uncontrolled asthma (i.e., ≥ 3 features of partly controlled asthma)

• Pneumonitis that has required oral or IV corticosteroids

7. Receiving systemic corticosteroid therapy per Exclusion Criterion #2, or any otherform of systemic immunosuppressive medication. Note: Corticosteroid use as apremedication for IV contrast allergies/reactions is allowed. Patients who arereceiving daily corticosteroid replacement therapy are also an exception to thisrule. Daily prednisone at doses of ≤ 10 mg or equivalent hydrocortisone dose areexamples of permitted replacement therapy. Use of inhaled or topical corticosteroidsis permitted.

8. CNS tumor, metastasis(es), and/or carcinomatous meningitis identified either on thebaseline brain imaging obtained during the Screening Period or identified prior toconsent. Note: Patients with history of brain metastases that have been treated mayparticipate provided they show evidence of stable supra-tentorial lesions atscreening (defined as 2 brain images, both of which are obtained after treatment tothe brain metastases and obtained ≥ 4 weeks apart). In addition, any neurologicsymptoms that developed either as a result of the brain metastases or theirtreatment must have returned to baseline or resolved. Any steroids administered aspart of this therapy must be completed ≥ 3 days prior to first dose of studymedication.

9. Active or history of autoimmune disease that requires systemic treatment within 2years of the start of study treatment (i.e., with use of disease-modifying agents,corticosteroids, or immunosuppressive drugs). Note: Patients with autoimmuneconditions requiring hormone replacement therapy or topical treatment are eligible.

10. Has had an allogeneic tissue/solid organ transplant except for cornealtransplantation.

11. Active infection requiring systemic treatment.

12. Active infection with HIV and CD4+ T-cell count <350/μL. Patients not on establishedantiretroviral therapy for at least 4 weeks and having a detectable HIV viral load.Testing is not required for eligibility.

13. Active infection with hepatitis B (surface antigen); or infection with hepatitis C,defined by a detectable viral load. Testing is required for eligibility only ifpatient has a known or suspected history of infection.

14. Clinically significant (i.e., active) cardiovascular disease: cerebral vascularaccident/stroke or myocardial infarction within 6 months of enrollment, unstableangina, congestive heart failure (New York Heart Association class ≥ II), or seriousuncontrolled cardiac arrhythmia requiring medication.

15. History or current evidence of any condition, therapy, any active infections, orlaboratory abnormality that might confound the results of the study, interfere withthe patient's participation for the full duration of the study, or is not in thebest interest of the patient to participate, in the opinion of the treatingInvestigator.

16. Known psychiatric or substance abuse disorder that would interfere with cooperationwith the requirements of the study.

17. Legally incapacitated or has limited legal capacity.

18. Pregnant or breastfeeding.