A Phase I/II Study of Combination Immunotherapy for Advanced Cancers Including HPV-Associated Malignancies, Small Bowel, and Colon Cancers

• INCLUSION CRITERIA:

• Phase I: Subjects with cytologically or histologically confirmed locally advanced ormetastatic HPV associated malignancies or MSS small bowel or colorectal cancer (Cohort 1).

• Phase II: Subjects with cytologically or histologically confirmed locally advancedor metastatic HPV associated malignancies (Cohort 2), or MSS small bowel orcolorectal cancer (Cohort 3).

• Cohort 2 includes:

• Cervical cancers;

• P16+ Oropharyngeal cancers;

• Anal cancers;

• Vulvar, vaginal, penile, and squamous cell rectal cancers;

• Other locally advanced or metastatic solid tumors (e.g., lung, esophagus) thatare known HPV+.

• Subjects with MSS colorectal or small bowel cancer must have received two priorlines of systemic chemotherapy. Subjects with HPV associated malignancies must havereceived one prior line of systemic chemotherapy as well as checkpoint therapy ifcheckpoint therapy is FDA approved for that specific tumor type (e.g., HNSCC andPDL1+ cervical cancer). Prior checkpoint therapy is not needed where checkpointtherapy has not been FDA approved for that specific tumor type (e.g., anal, vaginal,vulvar, penile, PDL1 negative cervical). Exceptions to the above include participantwho are not eligible to receive the above therapies or who decline these standardtreatment options after appropriate counseling has been provided.

• Subjects must have measurable disease, per RECIST 1.1.

• Age >=18 years.

• ECOG performance status <=2

• Adequate hematologic function at screening, as follows:

• Absolute neutrophil count (ANC) >=1.5 x 10^9/L;

• Hemoglobin >= 9 g/dL;

• Platelets >= 100,000/microliter.

• Adequate renal and hepatic function at screening, as follows:

• Measured or calculated creatinine clearance (using the Cockcroft-Gaultequation) > 50 mL/min

• Bilirubin <= 1.5 x ULN OR in subjects with Gilbert s syndrome, a totalbilirubin <= 3.0 x ULN

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 2.5 xULN, unless liver metastases are present, then values must be <= 3 x ULN).

• The effects of the immunotherapies on the developing human fetus are unknown. Forthis reason and because immunotherapeutic agents as well as other therapeutic agentsused in this trial are known to be teratogenic, individuals of child-bearingpotential and those who can father children must agree to use highly effectivecontraception (hormonal or barrier method of birth control; abstinence) at the studyentry and for 4 months after the last bintrafusp alfa dose, 3 months after the lastentinostat dose and 2 months after the last PDS01ADC dose, whichever occurs later.

• Participants serologically positive for HIV, Hep B, Hep C are eligible as long asthe viral loads are undetectable by quantitative PCR. HIV positive participants musthave CD4 count >= 200 cells per cubic millimeter at enrollment, be on stableantiretroviral therapy for at least 4 weeks and have no reported opportunisticinfections or Castleman's disease within 12 months prior to enrollment.

• Subjects must be able to understand and be willing to sign a written informedconsent document.

EXCLUSION CRITERIA:

• Participants with prior investigational drug, chemotherapy, immunotherapy or anyprior radiotherapy (except for palliative bone directed therapy) within the past 28days prior to enrollment except if the investigator has assessed that all residualtreatment-related toxicities have resolved or are at grade 1 severity and feel theparticipant is otherwise suitable for enrollment.

• Administration of live vaccine within 30 days prior to enrollment

• Major surgery within 28 days prior to enrollment (minimally invasive procedures suchas diagnostic biopsies are permitted).

• Known active brain or central nervous system metastasis (less than a month out fromdefinitive radiotherapy or surgery), seizures requiring anticonvulsant treatment (<3months) or clinically significant cerebrovascular accident (<3 months). In order tobe eligible participants must have repeat CNS imaging at least a month afterdefinitive treatment showing CNS disease that has not progressed. Participants withCNS disease that has not progressed at least a month after definitive treatment andcontinued on <=10 mg of prednisone (or equivalent) for treatment of brain or centralnervous system metastasis are eligible to enroll in this study. Participants withevidence of intratumoral or peritumoral hemorrhage on baseline imaging are alsoexcluded unless the hemorrhage is grade <= 1 and has been shown to be stable on twoconsecutive imaging scans.

• Active autoimmune disease that might deteriorate when receiving an immunostimulatoryagent with exception of:

• Diabetes type I, eczema, vitiligo, alopecia, psoriasis, hypo- or hyperthyroiddisease or other mild autoimmune disorders not requiring immunosuppressivetreatment;

• Administration of steroids for other conditions through a route known to resultin a minimal systemic exposure (topical, intranasal, intro-ocular, orinhalation) is acceptable;

• Subjects on systemic intravenous or oral corticosteroid therapy with the exceptionof hormone replacement or physiologic doses of corticosteroids (<= the equivalent ofprednisone 10 mg/day) or other immunosuppressive drugs such as azathioprine orcyclosporin A are excluded on the basis of potential immune suppression. For thesesubjects these excluded treatments must be discontinued at least 1 weeks prior toenrollment for recent short course use (<= 14 days) or discontinued at least 4 weeksprior to enrollment for long term use (> 14 days). In addition, the use ofcorticosteroids as premedication for contrast-enhanced studies is allowed prior toenrollment and on study.

• Subjects with a history of serious intercurrent chronic or acute illness, such ascardiac or pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3 months before enrollment) clinically significant bleeding events, or other illnessor medical condition considered by the Investigator as high risk for investigationaldrug treatment. Note: For participants otherwise eligible to be assigned to receivejust PDS01ADC and entinostat (without bintrafusp alfa, Arm 3), bleeding diathesis orrecent bleeding will not be an exclusion.

• Subjects unwilling to accept blood products as medically indicated.

• Subjects with conditions associated with significant necrosis of nontumor-bearingtissues: esophageal or gastroduodenal ulcers < 3 months prior to enrollment, organinfarction < 3 months prior to enrollment, or active ischemic bowel disease.

• Presence of medically significant third space fluid (symptomatic pericardialeffusion, ascites or pleural effusion requiring repetitive paracentesis).

• History of second malignancy within 3 years of enrollment except for the following:adequately treated localized skin cancer, cervical carcinoma in situ, superficialbladder cancer, or other localized malignancy which has been adequately treated ormalignancy

which does not require active systemic treatment (e.g. low risk chronic lymphocytic leukemia (CLL)).

• Subjects with a known severe hypersensitivity reaction to compounds of similarchemical or biologic composition to any of study drugs (grade >/= 3 NCI-CTCAE v5)will be evaluated by the allergy/immunology team prior to enrollment.

• Pregnant individuals are excluded from this study because these drugs have not beentested in pregnant individuals and there is potential for teratogenic orabortifacient effects. Because there is an unknown but potential risk for adverseevents in nursing infants secondary to treatment of the mother with theseimmunotherapies, nursing should be discontinued if the mother is treated on thisprotocol.