In Situ Immunomodulation with CDX-301, Radiation Therapy, CDX-1140 and Poly-ICLC in Patients W/ Unresectable and Metastatic Solid Tumors

Inclusion Criteria:

• Have clinically or pathologically confirmed diagnosis of unresectable and metastaticmelanoma, cutaneous SCC, basal cell carcinoma, Merkel cell carcinoma, high-gradebone and soft tissue sarcoma or HER2/neu (-) breast cancer with no curativetreatment options.

• The unresectable disease to be irradiated and injected with medications must belocated in breast, dermal, subcutaneous, or soft tissue, or lymph nodes with thelongest axis of the tumor 2-7 centimeters, and should be considered safe forinjection by the investigator.

• The metastatic disease must be measured per irRECIST criteria.

• Patient must have lesion that can be biopsied and is willing to undergo theprocedure as part of the protocol.

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 1.

• Participants of child-bearing potential and men must agree to use adequatecontraceptive methods (e.g., hormonal or barrier method of birth control;abstinence) prior to study entry. Should a woman become pregnant or suspect she ispregnant while she or her partner is participating in this study, she should informher treating physician immediately.

• For patients with history of radiotherapy to the same location that will be treatedon study, he/she will be eligible only if the prior radiation dose was under orequal to 68 Gy total and delivered more than 6 months prior to planned re-treatment. (The cumulative dose received to the irradiated area will be no more than 87 Gytotal, including a maximum of 68 Gy allowed from prior treatment course.)

• Patient requires the use of radiation therapy to the target lesion of palliation ofsymptoms and/or achieving local control as part of standard of care as deemedappropriate by treating radiation oncologist.

• Patients must agree to radiation to the tumor.

• Any line of therapy allowed, radiologically or clinically confirmed progression onprior therapy

• Must have adequate organ and marrow function present as defined below:

• Platelets >= 100,000/uL

• Hemoglobin >= 8.0 g/dL

• Absolute neutrophil count (ANC) >= 1500/uL

• Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvatetransaminase [SGPT]) =< 2.5 X institutional ULN.

• Creatinine =< 1.5 X ULN OR creatinine clearance >= 50 mL/min perCockcroft-Gault equation for patients with creatinine levels greater than ULN.

• Participant or legal representative must understand the investigational nature ofthis study and sign an Independent Ethics Committee/Institutional Review Boardapproved written informed consent form prior to receiving any study relatedprocedure.

• Patients must agree to injections of CDX-301, CDX-1140, and poly-ICLC.

• Patients must agree to appropriate clinical monitoring to receive the studyregimens.

• Patients must agree to photos of tumors and use of the photos for publication.

• Patients should have an administration site for all injections that is free ofpotentially complicating dermatologic conditions such as rashes.

Exclusion Criteria:

• Patients currently treated with systemic immunosuppressive agents, includingsteroids, are ineligible until 3 weeks after removal from immunosuppressivetreatment. (inhaled steroids are allowed)

• Patients with HER2+ breast cancer

• Concurrent use of targeted therapy including CDK4/6, mTOR, PIK3CA, PARP, BRAF, MEK,hedgehog inhibitors or chemotherapy (endocrine therapy is allowed).

• Targeted therapy including CDK4/6, mTOR, PIK3CA, PARP, BRAF, MEK, hedgehoginhibitors, chemotherapy, or immunotherapy within 2 weeks prior to first dosing ofstudy agent. (endocrine therapy is allowed).

• Patients with active or history of autoimmune disease or history of transplantationexcept for the patients with Graves' disease with ablative therapy of totalthyroidectomy.

• Patients with history of (non-infectious) pneumonitis/interstitial lung disease,including grade 1 pneumonitis (asymptomatic; clinical or diagnostic observationsonly; intervention not indicated).

• Patients with prior history of acute myeloid leukemia (AML) or known FLT3aberrations

• Pregnant or nursing female participants.

• Unwilling or unable to follow protocol requirements.

• Patients with known serious mood disorders. (Major depression diagnosis is anexclusion: Other stable mood disorders on stable therapy for > 6 months or notrequiring therapy may be allowed after consultation with principal investigator [PI]).

• Cardiac risk factors including:

• Patients experiencing cardiac event(s) (acute coronary syndrome, myocardialinfarction, or ischemia) within 3 months of signing consent.

• Patients with a New York Heart Association classification of III or IV.

• Patients with uveal melanoma.

• Patients with uncontrolled diseases other than cancer may be excluded if afterconsultation with PI and research team it is decided it might affect the treatmentefficacy or toxicity.

• Evidence of current drug or alcohol abuse or psychiatric impairment, which in theinvestigator's opinion will prevent completion of the protocol therapy or follow-up.Specific testing is not required, however may be done as clinically indicated.

• Any condition which in the investigator's opinion deems the participant anunsuitable candidate to receive study drug.

• Participants with symptomatic known brain metastases < 4 weeks from radiationtreatment should be excluded from this clinical trial because of their poorprognosis and because they often develop progressive neurologic dysfunction thatwould confound the evaluation of neurologic and other adverse events.

• Other invasive cancers diagnosed < 3 years back that required systemic treatment. Ifdiagnosed with other invasive cancer >= 3 years, should have complete recovery fromall systemic toxicity except neuropathy, vitiligo, alopecia, and endocrinopathies onstable hormone replacement therapy.

• Live vaccines within 30 days prior to the first dose of trial treatment and whileparticipating in the trial. Examples of live vaccines include, but are not limitedto, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies,Bacillus Calmette-Guerin (BCG), and typhoid vaccine.

• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).

• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) orhepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] isdetected).

• Current use of anticoagulants (warfarin, heparin) at therapeutic levels.

• Patients who have had stroke/TIA and DVT/PE within the last 12 months.

• Patients at risk for impending visceral crisis of the liver and lungs as follows, orany condition which in the patient's primary treating oncologist's opinion deems theparticipant an unsuitable candidate to receive study drug:

• A visceral crisis of the liver exists when bilirubin levels increase veryrapidly (>1.5 times the upper limit of normal) without the presence of Gilbertsyndrome (i.e., Meulengracht syndrome) or a biliary tract obstruction.

• A visceral crisis of the lungs can be assumed when dyspnea at rest increasesmore rapidly and cannot be relieved by pleural drainage.

• Radiation induced angiosarcoma.