A Phase 1/2 Randomized, Umbrella Study to Evaluate the Safety and Efficacy of Pembrolizumab Plus Enfortumab Vedotin (EV) in Combination With Investigational Agents Versus Pembrolizumab Plus EV, as First-Line Treatment for Participants With Advanced Urothelial Carcinoma (KEYMAKER-U04): Substudy 04B
- Conditions
- bladder cancerinoperable or metastatic UC1002765610004994
- Registration Number
- NL-OMON53800
- Lead Sponsor
- Merck Sharp & Dohme (MSD)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 3
1. The participants must have histologically documented, la/mUC (ie, cancer of
the bladder, renal pelvis, ureter, or urethra). Histology will be confirmed
locally.
2. Participants must have measurable disease by investigator assessment
according to RECIST 1.1.
3. 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.
• 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.
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 2 neuropathy are eligible.
6. Is male or female, and >=18 years at the time the participant (or their
legally acceptable
representative) 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
(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 per protocol.
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 (Refer to Appendix 5 for definition of WOCBP)
OR
• A WOCBP and
-Uses a contraceptive method that is highly effective as er protocol.
-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.
-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.
9. Provides documented informed consent/assent for the study.
10. An ECOG performance status of 0 to 1 assessed within 7 days prior to
randomization.
11. Adequate organ function as defined in Table 3 of the protocol.
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 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 infectio
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>- Objective Response (OR): complete response (CR) or partial response (PR).<br /><br>- AEs.<br /><br>- Discontinuations of study interventions due to an AE.<br /><br>- Dose-limiting toxicity (DLT).<br /><br>- Progression Free Survival (PFS): The time from randomization to the first<br /><br>documented disease progression or death due to any cause, whichever occurs<br /><br>first.</p><br>
- Secondary Outcome Measures
Name Time Method