Urothelial Bladder Cancer
Conditions
Brief summary
This is a Phase 2 clinical intervention trial to assess efficacy of induction EVP to spare the bladder in stage T2-4aN0-1 urothelial bladder cancer (UBC), using a response-adapted approach
Detailed description
Fifty-six adult patients with cT2-4aN0-1 urothelial bladder cancer, who are amenable for a bladder-sparing approach, will be included All patients receive induction (4x) Enfortumab vedotin (d1,8; 1.25mg/kg) and Pembrolizumab (d1; 200mg). Patients having a clinical complete response (cCR) are randomized 1:1 to receive: 1. No bladder consolidation therapy, pembrolizumab 400 mg q6 weeks maintenance (total 1 year from start of therapy), or 2. Consolidative radiotherapy followed by pembrolizumab 400 mg q6 weeks maintenance (total 1 year from start of therapy). Patients having residual disease: 1. may still receive bladder-sparing treatment using chemoradio-therapy (by local protocol; Mitomycin C/fluoropyrimidines in the Netherlands) if the following criteria are met: * No disease outside the bladder (e.g. involvement of ureter, prostatic urethra or (suspected) lymph node metastases) * No bilateral hydronephrosis * No multifocal CIS * Adequate bladder function: post-micturition residual volume of \< 200 cc, IPSS score \< 15 points; revised urinary incontinence scale \< 8 points; no daily or continuous catheter use. Bladder sparing treatment is followed by pembrolizumab 400 mg q6 weeks maintenance (total 1 year from start of therapy). 2. In addition, patients having residual disease without the option of bladder sparing treatment, will undergo radical cystectomy followed by pembrolizumab 400 mg q6 weeks maintenance (total 1 year from start of therapy). The induction phase will be approximately 14 weeks up until the point of consolidation/observation, which is followed by pembrolizumab maintenance for a maximum of six cycles. Protocol-specified follow-up (excluding survival follow-up) will continue until 36 months after consolidation. Survival follow-up will continue as long as the study remains open.
Interventions
DRUGEnfortumab Vedotin
Induction: 4 cycles (d1,8; 1.25 mg/kg)
DRUGPembrolizumab
Induction: 4 cycles 200mg and after cCR 400 mg q6 weeks. Total 1 year from start of therapy
RADIATIONRadiation
The preference will be a four-week schedule, in which 55 Gy radiotherapy will be administered using intensity modulated radiation therapy (IMRT)
OTHERChemoradiation
by local protocol; by local protocol; Mitomycin C/fluoropyrimidines in the Netherlands) * No disease outside the bladder (e.g. involvement of ureter, prostatic urethra or (suspected) lymph node metastases) * No bilateral hydronephrosis * No multifocal CIS * Adequate bladder function: Post-micturition residual volume of \< 200 cc, International Prostate Symptom Score (IPSS) \< 15 points; revised urinary incontinence scale \< 8 points; no daily or continuous catheter use.
PROCEDURECystectomy
Surgical removal of the bladder
Sponsors
The Netherlands Cancer Institute
Merck Sharp & Dohme LLC
Astellas Pharma Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All patients receive four 3-weekly cycles of induction therapy with Enfortumab Vedotin (Days 1 and 8) and Pembrolizumab (Day 1). After tumor assessment, patients are classified as clinical complete response (cCR) or non-cCR. Patients with cCR are randomized 1:1 to either no consolidation with maintenance pembrolizumab or consolidative radiotherapy followed by maintenance pembrolizumab. Patients with non-cCR are assigned to treatment arms based on their eligibility for bladder-sparing therapy. Patients with non-cCR who are eligible for bladder-sparing therapy will receive maintenance pembrolizumab following completion of bladder-sparing treatment. If these criteria are not met, patients will be advised to undergo radical cystectomy, followed by maintenance pembrolizumab. Further details on treatment arms and eligibility criteria are provided in the treatment arm specifications.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participants who are at least 18 years of age on the day of signing informed consent. 2. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial. 3. Patients with histologically confirmed cT2-4aN0-1M0 urothelial bladder cancer, seeking an alternative to radical cystectomy and/or patients who are medically unfit for surgery. Variant histology allowed, exceptions: * no pure (\>90%) squamous * no \>50% adenocarcinoma * no \>50% sarcomatoid component * no \>10% plasmacytoid component * no small cell component 4. Archival tumor tissue sample or newly obtained TURB of the bladder tumor is available. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. 5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention. 6. Have adequate organ function as defined in Table 3 below. Specimens must be collected within 14 days prior to the start of study intervention. 7. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: * Not of childbearing potential (see section 9.2.1) OR * Of childbearing potential 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) during the intervention period and for at least 120 days (pembrolizumab) or 180 days (EV) after the last dose of study intervention and agrees not to donate ova to others or freeze/store for her own use for the purpose of reproduction before start of study treatment. More details on contraceptive guidance can be found in section 9.2.1. The investigator should evaluate the potential for contraceptive method failure (i.e., noncompliance, recently initiated) in relationship to the first dose of study intervention. * Has a negative urine or serum pregnancy test within 72 hours before the first dose of study intervention. Female subjects with false positive results and documented verification of negative pregnancy status may be eligible in consultation with the sponsor. * Abstains from breastfeeding during the study intervention period and for at least 120 days after study intervention (for pembrolizumab) or 180 days (EV) after the last dose of study intervention. A male participant 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 * Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause)
Exclusion criteria
1. Previous pelvic irradiation 2. Upper tract urothelial cancer 3. Extensive carcinoma in situ (CIS) of the bladder 4. Bilateral hydronephrosis 5. Previous intravenous systemic therapy for bladder cancer, including chemotherapy, checkpoint inhibition or antibody-drug conjugate. 6. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration. 7. Contra-indication to one of the study treatment components 8. Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. 9. 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 to the first dose of study drug. 10. Known additional malignancy that is progressing or has required active treatment within the past 3 years. Exceptions: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ that have undergone potentially curative therapy are not excluded. Patients with low-risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤ 6, and PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active surveillance are eligible. 11. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, EV and/or any of its excipients in drug formulations (including histidine, trehalose dihydrate, and polysorbate 20). 12. Has active autoimmune disease that has required systemic treatment in the past 2 years. Exceptions that can still be included: * Endocrine disease with replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid) * Patients with vitiligo, psoriasis or other mild skin disease * Gout is not considered an auto-immune disease. Patients should not have had an episode of active arthritis within 30 days of start of therapy. 13. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 14. Ongoing sensory or motor neuropathy Grade 2 or higher. 15. 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. 16. 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. 17. Severe infections within 2 weeks prior to enrolment in the study including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia. Active infection requiring systemic therapy is excluded as well. 18. Known active Human Immunodeficiency Virus infection, or tuberculosis, or other active infection: HIV-positive patients are eligible if the following applies: * Receives antiretroviral therapy (ART), without changes in drugs or dose modification, for at least 4 weeks prior to treatment and continued while enrolled on study. * CD4+ T-cell count ≥350 cells/mm3 at the time of screening * Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening * No AIDS defining opportunistic infection within the past 12 months, or a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease. * In patients with a known history of hepatitis B infection, Hepatitis B surface antigen should be negative at time of screening. Patients having chronic hepatitis B are not eligible. * Participants with a history of HCV infection are eligible if HCV viral load is undetectable at screening. Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization. 19. Has not adequately recovered from major surgery or has ongoing surgical complications. 20. Major pelvic surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for the disease under study. 21. Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's ability to cooperate with the requirements of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator. 22. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 23. Has had an allogenic tissue/solid organ transplant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Estimated 2-year bladder-intact event-free survival (BI-EFS) for the intention-to-treat population, measured from day 1 of treatment until the moment of analysis | From the first dose of study treatment up to 2 years of follow-up | Bladder-intact event-free survival (BI-EFS). The primary analysis will be performed after the last participant has completed at least 15 months of follow-up from the first dose of study treatment or when 21 BI-EFS events have been observed, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of observation vs consolidative RT (followed by maintenance pembrolizumab) in cCR patients after induction EVP: rate of cystectomy and/or muscle-invasive and non-muscle invasive recurrence per arm. | From cCR assesment until cystectomy and/or muscle-invasive or non-muscle-invasive recurrence, assessed up to 66 months. | Rate of cystectomy and/or muscle-invasive and non-muscle invasive recurrence per cCR treatment arm |
| Overall survival (OS) | From the date of enrollment until death from any cause, assessed up to 66 months. | OS is defined as the time between the date of enrollment and the date of death. OS will be estimated using the Kaplan-Meier method. The median OS and 95% confidence interval will be reported. |
| Progression-free survival (PFS) | From the first dose of study treatment until the first documented disease progression or death from any cause, assessed up to 66 months. | PFS is defined as time from start of therapy until an event or death by any cause |
| Metastasis-free survival (MFS) | From the first dose of study treatment until the first documented disease progression or death from any cause, assessed up to 66 months. | • Time from start of therapy until occurrence of nodal or distant metastases, or progression of nodal metastases present at baseline by RECIST1.1 measurement |
| Bladder function of no consolidation vs consolidative RT in cCR patients after induction EVP using bladder-specific QOL assessments. | At baseline C1D1, C3D1, Response Evaluation and 6, 12, 18 and 24 months after response evaluation, regardless of consolidative therapy | Bladder-specific quality of life assessed using the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30; scores range 0-100; for functional scales, higher scores indicate better functioning; for symptom scales, higher scores indicate worse symptoms) and the EORTC Quality of Life Questionnaire Bladder Muscle Invasive (BLM-30 module, scores range 0-100; higher scores indicate \[better/worse\] outcome). |
| Muscle-invasive recurrence in patients not undergoing cystectomy | From cCR/non-CR assessment until muscle-invasive recurrence, assessed up to 66 months | Measured in patients not undergoing a cystectomy, per relevant arm |
| Non-muscle-invasive bladder recurrence in patients not undergoing cystectomy | From cCR/non-CR assessment until non-muscle-invasive recurrence, assessed up to 66 months. | Measured in patients not undergoing a cystectomy, per relevant arm |
| Safety of EVP induction | After induction therapy: at a minimum of 22 months until up to 66 months of follow-up | Safety in terms of immunotherapy-related adverse events by National Cancer Institute Common Terminology Criteria for Adverse Events 5.0 criteria (NCI CTC-AE 5.0 criteria) |
| Prediction of BI-EFS by circulating tumor DNA (ctDNA) assessment | From the date of enrollment until up to 66 months of follow-up | ctDNA assessment in urine and plasma. Interim analysis is allowed |
Countries
Netherlands
Contacts
CONTACTMichiel S van der Heijden, MD,PhD
CONTACTOkan Ghedri, MD
PRINCIPAL_INVESTIGATORMichiel S van der Heijden, MD,PhD
The Netherlands Cancer Institute
Outcome results
None listed