Bladder Cancer, High Grade Urothelial Carcinoma, Urothelial Carcinoma Bladder
Conditions
Keywords
Renal Retention in UTUC, High Grade UTUC, refusing nephroureterectomy, Enfortumab vedotin, Padcev, Pembrolizumab, Keytruda
Brief summary
This trial will evaluate the use of combination pembrolizumab and enfortumab vedotin for patients with high grade non-metastatic (cN0/NxMx, no measurable regional lymph nodes, no metastases) upper tract urothelial cancer (UTUC), preferring to forego standard of care radical nephroureterectomy (RNU) surgery. Currently these patients would not be suitable candidates for neoadjuvant trials, as the patients intention is to forego surgery. The patients are also not candidates for metastatic trials, as the patients have no measurable metastasis. The Investigators hypothesize the combination of pembrolizumab and enfortumab vedotin for patients with high grade cN0/NxMx UTUC deferring RNU will lead to event free survival outcomes similar to that achieved by RNU in a historic dataset.
Detailed description
This single arm phase II trial will evaluate the use of enfortumab vedotin and pembrolozumab for high grade upper tract urothelial cancer patients who are unable or unwilling to undergo standard of care nephroureterectomy. Enfortumab vedotin IV 1.25 mg/kg days 1,8 and pembrolizumab 200 mg IV will be delivered every 21 days in 20 patients with high grade UTUC cT2-T4N0 (non-metastatic) until disease progression outside of the renal/ureter unit and/or intolerance. Primary objective is event free survival (EFS), defined as the time to systemic relapse or death. The hypothesis is that the combination of pembrolizumab and enfortumab vedotin for patients with high grade non-metastatic UTUC deferring nephroureterectomy will lead to EFS outcomes similar to that achieved by RNU in historical dataset from the Brady Urologic Institute database (based on a subset of 85 patients with high grade UTUC cT2-T4N0 who underwent surgery without perioperative chemotherapy).
Interventions
DRUGEnfortumab vedotin
Enfortumab vedotin 1.25mg/kg on Days 1 and 8 every 3 weeks for up to 35 weeks (each cycle = 21 days)
DRUGPembrolizumab
Pembrolizumab 200mg on Day 1 every 3 weeks for up to 35 weeks (each cycle = 21 days)
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of histologically documented, high grade upper tract urothelial cancer, (UTUC can be diagnosed by direct visualization and biopsy, or by 3 dimensional imaging and positive urine cytology) will be enrolled in this study. 2. Patients must refuse definitive radical nephroureterectomy (RNU), or be medically ineligible for surgery. To be medically ineligible, patients must, in the opinion of the clinical team, be at high risk of complications intra or perioperative which would adversely impact morbidity and mortality, including risk of CKD and ESRD. 3. Subjects must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma (in other locations such as the bladder or contralateral ureter or renal pelvis) with the following exceptions: 1. Subjects who received neoadjuvant chemotherapy with recurrence \>12 months from completion of therapy are permitted 2. Subjects that received adjuvant chemotherapy following cystectomy with recurrence \>12 months from completion of therapy are permitted 4. Subjects may have radiographic evidence of N1 disease (Metastasis ≤2 cm in greatest dimension, in a single lymph node) 5. Subjects must be age 18 years or older. 6. Archival tumor tissue will be used for eligibility. 7. Subjects must have an ECOG Performance Status score of 0 or 2 8. Subjects must have adequate hematologic and organ function as defined by the baseline laboratory values in Table 3. Transfusion of red blood cells to meet eligibility criteria is allowed. Table 3 - Baseline Laboratory Values Hematological: ANC: ≥1500/μL Platelets: ≥100,000/μL Hemoglobin: ≥9.0 g/dL or ≥5.6 mmol/L Hepatic: Total Bilirubin: ≤1.5× ULN AST (SGOT) and ALT (SGPT): No adjustment in the starting dose is required when administering PADCEV to patients with mild hepatic impairment (total bilirubin 1 to 1.5 × ULN and AST any, or total bilirubin ≤ULN and AST \>ULN). 9. A female subject of childbearing potential is anyone born female who has experienced menarche and who has not undergone surgical sterilization (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or has not completed menopause. Menopause is defined clinically as 12 months of amenorrhea in a person over age 45 in the absence of other biological, physiological, or pharmacological causes. Female subjects of childbearing potential must meet the following conditions: * Agree not to try to become pregnant during the study and for at least 6 months after the final dose of study drug. * Must have a negative urine or serum pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta human chorionic gonadotropin \[β-hCG\]) within 1 day prior to administration of study drug. Female subjects with false positive results and documented verification of negative pregnancy status are eligible for participation. * If heterosexually active, must consistently use highly effective methods of birth control, with a failure rate of less than 1% (as described in Appendix L) starting at screening, throughout the study period, and for at least 6 months after the final dose of study drug. * Female subjects must agree not to breastfeed or donate ova starting at screening and throughout the study period, and for at least 6 months after the final dose of study drug. 10. A male subject who can father children is anyone born male who has testes and who has not undergone surgical sterilization (e.g., vasectomy followed by a clinical test proving that the procedure was effective). Male subjects who can father children, must meet the following conditions: * Must not donate sperm starting at screening and throughout the study period, and for at least 6 months after the final dose of study drug. Male subjects will be informed about the negative risk to reproductive function and fertility from the study treatment. Prior to treatment male subjects should be advised to seek information on fertility preservation and sperm cryoconservation. * Must consistently use highly effective methods of birth control, with a failure rate of less than 1% (as described in Appendix L) starting at screening and continue throughout study period and for at least 6 months after the final dose of study drug. * Male subjects with a pregnant or breastfeeding partner(s) must consistently use one of 2 contraception options for preventing secondary exposure to seminal fluid (as described in Appendix L) for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for at least 6 months after the final dose of study drug. 11. Subjects must provide written informed consent.
Exclusion criteria
1. Subjects who have previously received enfortumab vedotin or other MMAE-based ADCs. 2. Subjects who have received prior treatment with a PD-(L)-1 inhibitor for any malignancy, including earlier stage UC, defined as a PD-1 inhibitor or PD-L1inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). 3. Subjects who have previously received any prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor (including but not limited to CD137 agonists, CTLA-4 inhibitors, or OX-40 agonists). 4. Subjects who have received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed 4 weeks prior to first dose of study treatment (ongoing hormonal/anti hormonal treatment, e.g., for breast cancer, is allowed, provided that the subject is eligible per
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event free survival (EFS) | 12 months | Time to relapse or death based on 12 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glomerular Filtration Rate (GFR) | Baseline, 12 months | Change from baseline GFR to GFR 1 yr post enrollment |
Other
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 48 months | Number of participants alive end of trial. |
| To evaluate safety and tolerability of the combination of enfortumab vedotin and pembrolizumab | 25 months | Number of participants experiencing dose limiting toxicities and treatment-related adverse events, as defined by Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0). |
| To assess feasibility of obtaining immune biomarker data from UTUC biopsy specimens | 24 months | Number of participants with immune biomarker data available from UTUC biopsy specimens |
| To assess feasibility of obtaining tumor for DNA sequencing including, FGFR mutation / fusion status, from UTUC biopsy specimens | 24 months | Number participants with tumor available for DNA sequencing including, FGFR mutation / fusion status, from UTUC biopsy specimens |
| Progression free survival | 48 months | Number of participants without disease recurrence |
Countries
United States
Contacts
Primary ContactDebbie Schwartz, RN
Outcome results
None listed