A Phase 3 trial of perioperative pembrolizumab or enfortumab vedotin in combination with pembrolizumab for cisplatin-ineligible participants withMIBC
- Conditions
- Muscle-invasive Bladder Cancer (MIBC)MedDRA version: 21.1Level: LLTClassification code 10022877Term: Invasive bladder cancerSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2018-003809-26-DE
- Lead Sponsor
- Merck Sharp & Dohme LLC
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 608
-Have a histologically confirmed diagnosis of urothelial carcinoma/MIBC
(cT2-T4aN0M0 or T1-T4aN1M0) with predominant (=50%) urothelial
histology to be confirmed by BICR (central pathology and/or imaging):
* T1 disease (eligible only with N1 disease) and T2 disease will be
confirmed by central pathology review and T3, T4a, N0 and N1 disease
will be confirmed by central imaging review.
* Participants with mixed histology are eligible provided the urothelial
component is =50% as noted above (participants whose tumors contain
predominant [=50%] plasmacytoid variant are not eligible).
* Participants whose tumors contain any neuroendocrine histology are
not eligible.
* UCs not originating from the bladder (eg, upper tract [ureters, renal
pelvis], urethra) are not eligible. UCs invading into the prostatic stroma
with no histologic muscle invasion is allowed, provided that the extent of
disease is confirmed via imaging.
-Have clinically nonmetastatic bladder cancer (N=1M0) determined by
imaging (CT or MRI of the chest/abdomen/pelvis), confirmed by BICR
-Be deemed eligible for RC + PLND by his/her urologist and/or
oncologist and agree to undergo curative intent standard RC + PLND
(including prostatectomy if applicable) as per AUA/ASTRO/ASCO/SUO
guidelines
-Be ineligible for treatment with cisplatin, as defined by meeting at least
one of the following criteria listed below OR be eligible for treatment
with cisplatin, but decline treatment with cisplatin-based chemotherapy.
*Impaired renal function with measured or calculated CrCl 30 to 59
mL/min (calculated by Cockcroft-Gault method Modification of Diet of
Renal Disease (MDRD) equationsor measured by 24-hour urine
collection)
*ECOG Performance Status 2
*CTCAE v.4 Grade =2 audiometric hearing loss
*New York Heart Association (NYHA) Class III heart failure
-Have a transurethral resection (TUR) of a bladder tumor (obtained
within 60 days [+ 14 days] prior to study enrollment [documented
informed consent]) that is submitted for central pathology assessment
and adequate to determine urothelial histology and PD-L1 expression
assessment.
Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to
slides
-Must have an ECOG performance status of 0, 1, or 2
-Demonstrate adequate organ function (all screening laboratory tests
should be performed within 14 days prior to randomization)
-Participant is male or female at least 18 years of age, at the time of
providing informed consent
-Male participants are eligible to participate if they agree to the
following during the intervention period and for at least 180 days after
the last dose of enfortumab vedotin:
*Refrain from donating sperm
PLUS:
*Must agree to use contraception unless confirmed to be azoospermic.
If the male participants are receiving pembrolizumab only or undergoing
surgery only, there are no contraception requirements
*Contraceptive use by men should be consistent with local regulations
regarding the methods of contraception for those participating in clinical
studies.
-A female participant is eligible to participate if she is not pregnant or
breastfeeding, and at least 1 of the following conditions applies:
*Is not a WOCBP
OR
*Is a WOCBP and using 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), during the
intervention period and for at
-Has a known additional nonurothelial malignancy that is progressing or
has required active anticancer treatment =3 years of study
randomization.
-Participants with = N2 disease or metastatic disease (M1) as identified
by imaging.
-Has received any prior systemic treatment, chemoradiation, and / or
radiation therapy for MIBC or NMIBC.
-Has 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 Tcell
receptor (eg, CTLA-4, OX-40, CD137).
-Has received prior systemic anticancer therapy including investigational
agents (including enfortumab vedotin or other MMAE-based ADCs)
within 3 years prior to randomization.
-Has received any prior radiotherapy to the bladder.
-Has received a partial cystectomy of the bladder to remove any NMIBC
or MIBC.
-Received a live or live-attenuated vaccine within 30 days before the
first dose of study intervention. Administration of killed vaccines are
allowed.
-Is currently participating in or has participated in a study of an
investigational agent or has used an investigational device within 4
weeks prior to the first dose of study intervention
-Has ongoing sensory or motor neuropathy Grade 2 or higher
-Has 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 drug. 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
-Has hypersensitivity to monoclonal antibodies (including
pembrolizumab) and/or any of their excipients
-Has known severe hypersensitivity (= Grade 3) to enfortumab vedotin
or any excipient contained in the drug formulation of enfortumab vedotin
(including histidine, trehalose dihydrate, and polysorbate 20).
-Has 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
-Has an active autoimmune disease that has required systemic treatment
in past 2 years (ie, use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin,
or physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency) is not considered a form of systemic treatment and is
allowed
-Has uncontrolled diabetes. Uncontrolled diabetes is defined as
hemoglobin A1c (HbA1c) =8% or HbA1c 7% to <8% with associated
diabetes symptoms (polyuria or polydipsia) that are not otherwise
explained
-Has a history of (non-infectious) pneumonitis that required steroids or
has current pneumonitis
-Has an active infection (viral, bacterial, or fungal) requiring systemic
therapy. Participants may be rescreened once after resolution of the
infection
-Has a known history of human immunodeficiency virus (HIV) infection.
No HIV testing is required unless mandated by local health authority
-Has a known history of Hepatitis B (defined as Hepatitis B surface
antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as
detectable HCV RNA via qualitative nucleic acid testing) infection
-Has 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 part
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method