A Phase 3 trial of perioperative pembrolizumab or enfortumab vedotin in combination with pembrolizumab for cisplatin-ineligible participants with MIBC
- 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-HU
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 836
-Have a histologically confirmed diagnosis of urothelial carcinoma (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 OR be eligible for treatment with cisplatin (by NOT meeting at least one of the following criteria) 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
*NYHA Class III heart failure
-Have a transurethral resection (TUR) of a bladder tumor (obtained within 60 days [+ 14 days] prior to study enrollment [ICF signed]) 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 labs should be performed within 14 days prior to randomization)
-Participant is male or female at least 18 years of age, at the time of signing the 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 least 120 days a
-Has a known additional non-urothelial 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 co-inhibitory T-cell 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 a history of 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
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