Brief Title: Personalized Cancer Vaccine (PCV) Strategy in Patients with Solid Tumors and Molecular Residual Disease

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Safety as measured by treatment-emergent adverse events (TEAEs)

Primary Outcome 1 - Timeframe: From step 1 enrollment through 30 days following last dose of vaccine (estimated to be 13 months)

Primary Outcome 2 - Measure: Safety as measured by treatment-related adverse events (TRAEs)

Primary Outcome 2 - Timeframe: From step 1 enrollment through 30 days following last dose of vaccine (estimated to be 13 months)

Primary Outcome 3 - Measure: Safety as measured by serious adverse events (SAEs)

Primary Outcome 3 - Timeframe: From step 1 enrollment through 30 days following last dose of vaccine (estimated to be 13 months)

Primary Outcome 4 - Measure: Feasibility as measured by the success of enrolling patients with molecular residual disease

Primary Outcome 4 - Timeframe: Through 30 months

Primary Outcome 5 - Measure: Feasibility as measured by the expected time frame for vaccine design and manufacture

Primary Outcome 5 - Timeframe: Through 24 weeks

Primary Outcome 6 - Measure: Feasibility as measured by the rate of successful vaccine delivery

Primary Outcome 6 - Timeframe: Through 1st vaccine dose (estimated to be 24 weeks)

CONDITION

• Muscle-Invasive Bladder Carcinoma

ELIGIBILITY

Step 0 Inclusion Criteria:
* Age ≥ 18 years.

- * ECOG performance status ≤ 1 (Karnofsky ≥ 60%).

- * Histologically confirmed muscle-invasive bladder cancer (MIBC).

- * Patients with carcinomas showing mixed histologies are required to have a dominant transitional cell pattern.

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

- * Availability of a ctDNA report that is based on tumor tissue specimen and matched blood within 28 days of enrollment.

- * Radiologic confirmation (by conventional imaging) of absence of residual disease and absence of metastasis.

- * Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
Step 0 Exclusion Criteria:
* Receiving any other investigational agents, or planning to receive other investigational agents as part of neoadjuvant therapy.

- * Known allergy, or history of serious adverse reaction to vaccines such as anaphylaxis, hives, or respiratory difficulty.

- * A psychiatric illness or social situations that would limit compliance with study requirements as determined by the investigator from the medical history, physical exam, and/or medical record.

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

- * Pregnant and/or breastfeeding.

- * Known HIV-positive status.

- * History of positive test for Hepatitis B virus surface antigen (HBsAg) and/or positive 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 ≤ 1 (Karnofsky ≥ 60%).

- * Complete surgical resection of MIBC (R0).

- * 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 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 5 months after completion of study interventions. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform her treating physician immediately.

- * Women of childbearing potential and men must agree to use two forms of adequate contraception 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 suspect she is pregnant while participating in this study, she must inform her treating physician 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 days prior to vaccine administration with the exception of adjuvant SOC immunotherapy.

- * History of immuno-oncology treatment for MIBC in the neoadjuvant setting. (It is anticipated that patients will be treated with adjuvant nivolumab as per current SOC and this is allowed).

- * Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this 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 as anaphylaxis, hives, or respiratory difficulty.

- * Immunodeficiency, systemic steroid therapy, or any other immunosuppressive therapy within 30 days of enrollment.

- * Active autoimmune disease (excluding diabetes mellitus and/or vitiligo), solid organ or allogeneic bone marrow transplant, or other known contraindications to receiving immunotherapy.

- * Severe hypersensitivity (grade ≳ 3) to checkpoint inhibitors and/or any of its excipients.

- * A psychiatric illness or social situations that would limit compliance with study requirements, as determined by the investigator from the medical history, physical exam, 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 negative serum/urine pregnancy test within 14 days of study entry.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: William Gillanders, M.D.

Role: Principal Investigator

Affiliation: Washington University School of Medicine

Overall Contact

Name: William Gillanders, M.D., Russell Pachynski, M.D.

Phone: 314-747-0072, 314-286-2341

Email: [email protected], [email protected]

LOCATION