Personalized Cancer Vaccine (PCV) Strategy in Patients With Solid Tumors and Molecular Residual Disease

Step 0 Inclusion Criteria:

• Age ≥ 18 years.

• ECOG performance status ≤ 2 (Karnofsky ≥ 60%).

• Histologically confirmed muscle-invasive bladder cancer (MIBC) or upper tracturothelial carcinoma (renal pelvis and/or ureter).

• Patients with carcinomas showing mixed histologies are required to have a dominanttransitional cell pattern.

• Tumor, nodes, metastases (TNM) classification (based on the American Joint Committeeon Cancer (AJCC) Cancer Staging Manual 8th ed.) at pathological examination ofsurgical resection specimen as follows: pT2-4aN0M0 or pT0-4aN+M0. For patients beingtreated with neoadjuvant chemotherapy who are being considered for inclusion priorto surgery, clinical staging is acceptable.

• Availability of a ctDNA report that is based on tumor tissue specimen and matchedblood within 28 days of enrollment.

• Radiologic confirmation (by conventional imaging) of absence of residual disease andabsence of metastasis.

• Ability to understand and willingness to sign an IRB approved written informedconsent document. Legally authorized representatives may sign and give informedconsent on behalf of study participants.

Step 0 Exclusion Criteria:

• Receiving any other investigational agents, or planning to receive otherinvestigational agents as part of neoadjuvant therapy. Patients who have receivedperioperative neoadjuvant chemotherapy and durvalumab are allowed.

• Known allergy, or history of serious adverse reaction to vaccines such asanaphylaxis, hives, or respiratory difficulty.

• A psychiatric illness or social situations that would limit compliance with studyrequirements as determined by the investigator from the medical history, physicalexam, and/or medical record.

• Prior or currently active autoimmune disease requiring management withimmunosuppression. This includes inflammatory bowel disease, ulcerative colitis,Crohn's disease, systemic vasculitis, scleroderma, psoriasis, multiple sclerosis,hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis, systemiclupus erythematosus, Sjögren's syndrome, sarcoidosis, or other rheumatologic diseaseor any other medical condition or use of medication (e.g., corticosteroids) whichmight make it difficult for the patient to complete the full course of treatments orto generate an immune response to vaccines. In the case of asthma or chronicobstructive pulmonary disease taking inhaled corticosteroids that does not requiredaily systemic corticosteroids is acceptable. Additionally, local acting steroids (topical, inhaled, or intraarticular) will be allowed. Patients on intermittent orshort course steroids will be allow if the dose does not exceed 4 mg ofdexamethasone (or equivalent) per day for > 7 consecutive days. Premedication forchemotherapy does not apply to this criterion and may be administered as per SOCpractice. Any patients receiving steroids should be discussed with the PI todetermine if eligible.

• Pregnant and/or breastfeeding.

• Known HIV-positive status.

• History of positive test for Hepatitis B virus surface antigen (HBsAg) and/orpositive Hepatitis C antibody result with detectable hepatitis C virus (HCV)ribonucleic acid (RNA) indicating acute or chronic infection.

Step 1 Inclusion Criteria:

• ctDNA positive result as identified by Signatera.

• ECOG performance status ≤ 2 (Karnofsky ≥ 60%).

• Complete surgical resection of MIBC (R0) or upper tract urothelial carcinoma (renalpelvis and/or ureter).

• Full recovery from cystectomy and enrollment within 52 weeks following cystectomy.

• Adequate bone marrow and organ function as defined below:

• WBC ≥ 1.5 K/cumm

• Absolute neutrophil count ≥ 1.0 K/cumm

• Platelets ≥ 50 K/cumm

• Hemoglobin ≥ 8.0 g/dL

• Total bilirubin ≤ 1.5 x IULN

• AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN

• Creatinine clearance > 30 mL/min by Cockcroft-Gault

• The effects of synthetic long peptide personalized cancer vaccines and Hiltonol onthe developing human fetus are unknown. For this reason, women of childbearingpotential and men must agree to use adequate contraception prior to study entry, forthe duration of study participation, and for 5 months after completion of studyinterventions. Should a woman become pregnant or suspect she is pregnant whileparticipating in this study or should a man suspect he has fathered a child, s/hemust inform her treating physician immediately.

• Women of childbearing potential and men must agree to use two forms of adequatecontraception prior to study entry, for the duration of study participation, and for 3 months after completion of the study. Should a woman become pregnant or suspectshe is pregnant while participating in this study, she must inform her treatingphysician immediately.

• No concurrent investigational therapies outside of this protocol are allowed.

Step 1 Exclusion Criteria:

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia. For Step 1 Enrollment the patient must have completed all prior cancer treatments > 28 daysprior to vaccine administration with the exception of adjuvant SOC immunotherapy.

• History of immuno-oncology treatment for MIBC in the neoadjuvant setting. (It isanticipated that patients will be treated with adjuvant nivolumab as per current SOCand this is allowed). Additionally, patients who have received perioperativeneoadjuvant chemotherapy and durvalumab are allowed.).

• Prior or concurrent malignancy whose natural history has the potential to interferewith the safety or efficacy assessment of the investigational regimen. Patients withprior or concurrent malignancy that does NOT meet that definition are eligible forthis trial per discussion with the PI.

• Currently receiving any other investigational agents.

• Live vaccine administered within 30 days prior to enrollment.

• Known allergy, or history of serious adverse reaction to vaccines such asanaphylaxis, hives, or respiratory difficulty.

• Immunodeficiency, systemic steroid therapy, or any other immunosuppressive therapywithin 30 days of enrollment.

• Active autoimmune disease (excluding diabetes mellitus and/or vitiligo), solid organor allogeneic bone marrow transplant, or other known contraindications to receivingimmunotherapy.

• Severe hypersensitivity (grade ≳ 3) to checkpoint inhibitors and/or any of itsexcipients.

• A psychiatric illness or social situations that would limit compliance with studyrequirements, as determined by the investigator from the medical history, physicalexam, and/or medical record.

• Current pneumonitis, a history of (non-infectious) pneumonitis requiring steroids,or history of clinically significant interstitial lung disease.

• Active tuberculosis test within 3 months prior to treatment initiation.

• Pregnant and/or breastfeeding. Women of childbearing potential must have a negativeserum/urine pregnancy test within 14 days of study entry.