A Phase 1/2, Umbrella Study of the Efficacy and Safety of Pembrolizumab plus Enfortumab vedotin +/- Investigational Agents in First-Line metastatic urothelial carcinoma

Phase 1

• Conditions: ocally advanced/unresectable or metastatic urothelial carcinoma previously untreated for their advanced disease; MedDRA version: 20.0Level: LLTClassification code 10064467Term: Urothelial carcinomaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2022-001371-14-ES
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2023-01-25
• Last Update Posted: 26 September 2023

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 390

Inclusion Criteria

1. 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).
2. 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.
3. Participants must not have received prior systemic therapy for la/mUC. The following therapies in earlier disease settings are permitted:
• Participants that received neoadjuvant or adjuvant chemotherapy are permitted.
• Participants who received neo-adjuvant or adjuvant anti-PD-1 or PD-L1 therapy for an earlier disease stage with recurrence >12 months from completion of therapy are permitted.
4. 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.
5. 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 6. Is male or female, and =18 years at the time the participant provides documented informed consent for the study.
7. 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 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.
- Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
8. 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
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, 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 ow

Exclusion Criteria

1. 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.
2. 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.
3. 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.
4. Received therapy with hematopoietic growth factor such as G-CSF or GM-CSF within 14 days prior to randomization.
5. 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).
6. Received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
7. Has received an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention administration.
8. Ongoing sensory or motor neuropathy Grade 2 or higher.
9. 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.
10. Severe hypersensitivity (=Grade 3) to mAb (including pembrolizumab) and/or any of their excipients.
11. Known severe hypersensitivity (=Grade 3) to any excipient contained in the drug formulation of EV (including histidine, trehalose dihydrate, and polysorbate 20).
12. 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.
13. Active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid).
14. 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.
15. A history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
16. An active infection (viral, bacterial, or fungal) requiring systemic therapy. Participant may be rescreened after resolution of the infection.
17. A known history of HIV infection. No HIV testing is required unless mandated by local health authority.
18. Hepatitis B (defined as HBsAg reactive) or hepatitis C virus (defined as HCV RNA qualitative is dete

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified