IRB Study Number 24-255
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective
To compare V940 plus pembrolizumab to placebo plus pembrolizumab with respect to DFS.
Secondary Objectives
To evaluate OS in participants treated with V940 plus pembrolizumab and placebo plus pembrolizumab.
To evaluate DMFS as assessed by the investigator in participants treated with V940 plus pembrolizumab and placebo plus pembrolizumab.
To evaluate the safety and tolerability of V940 plus pembrolizumab.
Inclusion Criteria
Type of Participant and Disease Characteristics
The participant must have MIUC originating in the lower tract (bladder, urethra) or upper tract (renal pelvis, ureter). NOTE: UTUC enrollment will be capped at 20%.
Dominant histology must be UC. Histology will be determined locally.
• Participants with mixed histology are eligible provided the urothelial component is ≥50%.
• Participants whose tumors contain any neuroendocrine component are not eligible.
- Participants must have undergone radical resection for MIUC ≤8 weeks before providing informed consent and ≤16 weeks before randomization. Radical resection refers to radical nephroureterectomy (for upper tract MIUC) or radical cystectomy with pelvic lymph node dissection per AUA/ASCO/ASTRO/SUO guidelines [Chang, S. S., et al 2017]. Partial cystectomy may be permitted upon Sponsor consultation.
• Participants with positive surgical margins for microscopic disease (R1) are eligible.
- Participants must have high-risk pathologic disease (determined locally) after radical resection, as per 1 of 2 definitions:
• For participants who received cisplatin-based neoadjuvant chemotherapy: ypT2-4a and/or ypN+
• For participants who have not received cisplatin-based neoadjuvant chemotherapy: pT3-4a and/or pN+
- Participants who have not received cisplatin-based neoadjuvant chemotherapy are eligible if cisplatin-ineligible per 1 or more of the following criteria:
CrCl (using the Cockcroft-Gault formula): <60 mL/min and >30 mL/min
CTCAE v5.0 Grade 2 or higher audiometric hearing loss
CTCAE v5.0, Grade 2 or higher peripheral neuropathy
ECOG performance status 2
- Participants must provide an FFPE tumor tissue sample that is suitable for the NGS required for this study. NOTE: Tissue from the radical resection is mandated for participants who received neoadjuvant chemotherapy followed by radical resection. For participants who did not receive neoadjuvant chemotherapy and underwent radical resection, tissue from radical resection is strongly preferred to ensure QC for NGS is successful, but tissue from TURBT is allowed as long as tissue requirements are met. The tumor tissue sample must meet the following criteria:
• Meet the minimum standards for tissue quantity and quality as defined in the laboratory manual.
• Pass the required QC checks for NGS by the Sponsor’s NGS vendor.
Participants must provide blood samples as specified in the protocol, to enable V940 production, and ctDNA testing.
Participants must be disease-free (N0M0) with no evidence of disease per investigator assessment based on imaging studies within 4 weeksbefore randomization.
• Imaging must include CT or MRI of the chest, abdomen, and pelvis.
• For participants with upper tract disease and an intact bladder, a cystoscopy (with or without biopsy) must be performed within 4 weeks before randomization.
• If there is clinical suspicion of CNS disease at screening, brain scan is required within 4 weeks before randomization. MRI of the brain is preferred, however, CT scan will be acceptable.
• Bone scan may be performed during screening if clinically indicated.
Participants must provide blood samples as specified in the protocol, to enable V940 production, and ctDNA testing.
Prior treatment for NMIBC with intravesical instillation therapy such as BCG or intravesical chemotherapy is permitted.
Prior systemic neoadjuvant cisplatin-based chemotherapy is permitted for MIUC. Demographics
Is an individual of any sex/gender, from 18 of age inclusive, at the time of providing the informed consent.
Male Participants
- No contraception measures are required for participants capable of producing sperm.
Female Participants
- A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a POCBP OR
• Is a POCBP and:
Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 5 during the intervention period and for at least 120 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by POCBPs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.
Has a negative highly sensitive pregnancy test (urine or serum) as required by local regulations within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Additional requirements for pregnancy testing during and after study intervention are in Section 8.3.5.
Abstains from breastfeeding during the study intervention period and for at least 120 days after study intervention with V940/placebo or pembrolizumab.
Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy.
Informed Consent
- The participant (or legally acceptable representative) has provided documented informed consent for the study.
Additional Categories
An ECOG performance status of 0 to 2 assessed within 7 days before randomization.
Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have <Grade 2 neuropathy are eligible.
Adequate organ function as defined in Table 3. Specimens must be collected within 7 days before the start of study intervention. (See protocol)
Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, and have undetectable HBV viral load before randomization. Note: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention. Hepatitis B screening tests are not required unless:
• Known history of HBV infection
• As mandated by local health authority (See Appendix 7or country-specific requirements)
- Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening. Note: Participants must have completed curative antiviral therapy at least 4 weeks before randomization.
Hepatitis C screening tests are not required unless:
• Known history of HCV infection
• As mandated by local health authority (See Appendix 7 for country-specific requirements)
- HIV-infected participants must have well controlled HIV on ART, defined as:
a. Having a CD4+ T-cell count ≥350 cells/mm3 at the time of screening.
b. Having achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening.
c. Have not had any AIDS-defining opportunistic infections within the past 12 months.
d. Have been on a stable ART regimen, without changes in drugs or dose modification, for at least 4 weeks before randomization and agree to continue ART throughout the study.
Exclusion Criteria
Medical Conditions
Not applicable in this study.
Prior/Concomitant Therapy
Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137). Exception includes participants who received anti-PD-1 or PD-L1 therapy for NMIBC with recurrence >12 months before study randomization.
Received prior systemic anticancer therapy including investigational agents in the adjuvant setting after radical surgery.
Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed. Refer to Section 6.5 for information on COVID-19 vaccines.
Received therapy with hematopoietic growth factor such as G-CSF or GM-CSF within 14 days before randomization.
Received prior treatment with a cancer vaccine.
Prior neoadjuvant therapy, with the exception of neoadjuvant cisplatin-based chemotherapy as stated in inclusion criterion #11.
Prior/Concurrent Clinical Study Experience
- Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
Diagnostic Assessments
Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication.
Known additional malignancy that is progressing or has required active treatment ≤3 years prior to study randomization. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Participants with low-risk earlystage prostate cancer (T1-T2a, Gleason score ≤6, and PSA <10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded.
Severe hypersensitivity (≥Grade 3) to either V940 or pembrolizumab and/or any of their excipients.
Active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed.
History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
Active infection requiring systemic therapy.
HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric Castleman’s Disease.
Concurrent active hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection. Note: Hepatitis B and C screening tests are not required unless:
Known history of HBV and HCV infection
As mandated by local health authority (See Appendix 7 for country-specific requirements)
History or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
Known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
Other Exclusions
Had radiation therapy for UC after radical resection.
History of allogeneic tissue/solid organ transplant.
Participants who have not adequately recovered from major surgery or have ongoing surgical complications.
