IRB Study Number 22-1147
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
• To assess the safety and tolerability of investigational treatments
• To evaluate objective response rate (ORR) of each investigational treatment arm as assessed by BICR per RECIST 1.1
Secondary Objectives
• To evaluate the duration of response (DOR) of each investigational treatment arm as assessed by BICR per RECIST 1.1
Inclusion Criteria
Type of Participant and Disease Characteristics
- The participants must have histologically documented, la/mUC (ie, cancer of the bladder, renal pelvis, ureter, or urethra). Histology will be confirmed locally.
• Participants with mixed histology are eligible provided the urothelial component is ≥50% (and <10% plasmacytoid component).
• Participants whose tumors contain any neuroendocrine component are not eligible (variant histology to be confirmed locally).
- Participants must have measurable disease by investigator assessment according to RECIST 1.1.
• Participants treated with prior radiation therapy must have measurable disease per RECIST 1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy.
• Participants who have completed radiotherapy at least 2 weeks prior to randomization may be eligible. Participant must have recovered adequately from the toxicity from the intervention prior to starting study treatment.
- Participants must not have received prior systemic therapy for la/mUC. The following therapies in earlier disease settings (eg, MIUC) are permitted:
• Participants that received neoadjuvant or adjuvant chemotherapy are permitted. NOTE: There is no time limit on the duration between the last dose of chemotherapy and the start of study treatment. However, the chemotherapy should have been for an earlier disease stage (eg, MIUC).
• Participants who received anti-PD-1 or PD-L1 therapy for an earlier disease stage (eg, NMIBC, MIUC) with progression/recurrence >12 months from completion of therapy are permitted.
Participants must provide an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion demonstrating UC, not previously irradiated, and adequate for biomarker evaluation. A newly obtained biopsy is strongly preferred, but not required if archival tissue is evaluable. Note: Participants with disease progression while on treatment or after treatment for MIUC may provide a tissue sample from a biopsy of their muscle-invasive urothelial carcinoma or metastatic disease. Note: Participants must submit a tumor sample during screening to the central pathology laboratory for planned analyses (eg, biomarker status). Participants who do not submit a tumor tissue sample will not be randomized/allocated. Confirmation of adequacy of tumor tissue is NOT required before treatment randomization/allocation.
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. Demographics
Is male or female, and ≥18 years at the time the participant (or their legally acceptable representative) provides documented informed consent for the study.
Male Participants
- If male, agrees to the following during the intervention period and for at least 180 days after the last dose of EV:
• Refrains from donating sperm PLUS either:
• Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent OR
• Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview) as detailed below:
Uses a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penilevaginal penetration.
Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Female Participants
- A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Not a WOCBP (Refer to Appendix 5 for definition of WOCBP) OR
• A WOCBP and:
Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual 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 (MK-4280A, MK-7684A, or pembrolizumab) or 180 days (EV) after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. 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 women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Has a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours 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 5.1.
Abstains from breastfeeding during the study intervention period and for at least 120 days after study intervention (for MK-4280A, MK-7684A, or pembrolizumab) or 180 days (EV) days after the last dose of study intervention.
Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Informed Consent
- Provides documented informed consent/assent for the study (either the participant or a legally acceptable representative, if applicable).
Additional Categories
An ECOG performance status of 0 to 1 assessed within 7 days prior to randomization.
Adequate organ function as defined in Table 3. (All screening labs must be collected within 7 days prior to randomization).
Exclusion Criteria
Medical Conditions
Known additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for at least 3 years since initiation of that therapy. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer) who have undergone potentially curative therapy are not excluded. Participants with prior NMIBC receiving local therapy prior to randomization and participants with curatively treated localized prostate cancer with undetectable PSA 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.
Participants with treated CNS metastases are permitted on-study if all of the following are true: a) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b) the participant is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment); c) participant does not have leptomeningeal disease.
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, LAG3, TIGIT, OX-40, CD137). Exception includes participants who received neo-adjuvant or adjuvant anti-PD-1 or PD-L1 therapy for an earlier disease stage (eg, MIUC) with recurrence >12 months from completion of therapy.
Received therapy with hematopoietic growth factor such as G-CSF or GM-CSF within 14 days prior to randomization.
Received prior systemic anticancer therapy including investigational agents (including EV or other MMAE-based ADCs) within 3 years prior to randomization. Exception includes participants that received neoadjuvant or adjuvant chemotherapy or anti-PD-1/L1 therapy for an earlier disease stage (eg, MIUC).
Received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Administration of killed vaccines is allowed. Refer to Section 6.5 for information on COVID-19 vaccines.
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
Ongoing sensory or motor neuropathy Grade 2 or higher.
A 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 intervention. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency.
Severe hypersensitivity (≥Grade 3) to mAb (including pembrolizumab) and/or any of their excipients.
Known severe hypersensitivity (≥Grade 3) to any excipient contained in the drug formulation of EV (including histidine, trehalose dihydrate, and polysorbate 20).
Active keratitis or corneal ulcerations. Participants with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator.
Active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid).
A history of uncontrolled diabetes. Uncontrolled diabetes is defined as HbA1c ≥8% or HbA1c 7% to < 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
A history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
An active infection (viral, bacterial, or fungal) requiring systemic therapy. Participant may be rescreened after resolution of the infection.
A known history of HIV infection. No HIV testing is required unless mandated by local health authority.
Hepatitis B (defined as HBsAg reactive) or hepatitis C virus (defined as HCV RNA qualitative is detected) infection. Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
A history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
A 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 major surgery within 4 weeks prior to first dose of study intervention. Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility. Note: If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention.
Has had an allogenic tissue/solid organ transplant.
