Metastatic Urothelial Cancer
Conditions
Keywords
Metastatic Urothelial Cancer, BT8009, Bladder cancer, Pembrolizumab, Chemotherapy, Avelumab, Zelenectide pevedotin
Brief summary
This is a global, multicenter, randomized, open-label study. The main objective of the study is to measure the clinical activity and safety of zelenectide pevedotin formally BT8009, in combination with pembrolizumab versus chemotherapy, and as monotherapy in participants with locally advanced or metastatic urothelial cancer (UC). The study includes a dose selection for zelenectide pevedotin and is comprised of 2 cohorts. Cohort 1 will include participants who have not received any prior systemic therapy for locally advanced or metastatic UC and are eligible to receive platinum-based chemotherapy, whereas Cohort 2 will include participants who have received ≥ 1 prior systemic therapy for locally advanced or metastatic UC.
Interventions
Participants will receive zelenectide pevedotin on Days 1, 8, and 15 of every 21-day cycle.
DRUGPembrolizumab
Participants will receive Pembrolizumab on Day 1 of every 21-day cycle. Pembrolizumab infusion will be started 30 minutes following the completion of the zelenectide pevedotin infusion.
DRUGGemcitabine + cisplatin Or carboplatin
Participants will receive Gemcitabine on Days 1 and 8 of every 21-day cycle plus cisplatin Or carboplatin on Day 1 of every 21-day cycle.
DRUGAvelumab
After 4-6 cycles of Gemcitabine + Cisplatin or Carboplatin participants will receive maintenance Avelumab, if clinically indicated, on Days 1 and 15 each 28-day cycle.
Sponsors
BicycleTx Limited
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Life expectancy ≥ 12 weeks. * Measurable disease as defined by RECIST v1.1. * Histologically or cytologically confirmed locally advanced (unresectable) or metastatic UC of the renal pelvis, ureter, bladder, or urethra. * Archival or fresh tumor tissue comprising primary or metastatic UC should be available for submission to central laboratory. * Negative pregnancy test for women of childbearing potential (WOCBP) (negative serum test at Screening and negative urine or serum test within 72 hours prior to the first dose). * Cohort 1: Previously Untreated: Eligible to receive platinum-based chemotherapy (either cisplatin- or carboplatin-based chemotherapy based on Investigator decision. * Cohort 1: Participants must not have received prior systemic therapy for locally advanced or metastatic UC with the following exceptions: 1. Prior local intravesical chemotherapy, local surgery when full resection is not achieved, local immunotherapy, and radiotherapy are permitted if completed at least 4 weeks prior to the initiation of study treatment and all acute toxicities have resolved. 2. Prior neoadjuvant/adjuvant chemotherapy or monomethyl auristatin E (MMAE)-based therapy with recurrence \>12 months from completion of therapy. 3. Prior neoadjuvant/adjuvant immune checkpoint inhibitor therapy with recurrence \>12 months from completion of therapy. * Cohort 2: Previously Treated: Participants must have received ≥ 1 prior systemic treatment for locally advanced or metastatic UC. This includes neoadjuvant/adjuvant platinum-based chemotherapy if recurrence occurred within 12 months of completing therapy. * Cohort 2: Progression or recurrence of UC during or following receipt of most recent therapy. Key
Exclusion criteria
* Active keratitis or corneal ulcerations. * Requirement, while receiving study medications, for treatment with strong inhibitors or strong inducers of human cytochrome P450 3A (CYP3A) or inhibitors of P-glycoprotein (P-gp) including herbal- or food-based inhibitors. * Any condition requiring current treatment with high dose corticosteroids (\> 10 mg daily prednisone or equivalent). * Known hypersensitivity or allergy to any of the ingredients of any of the study interventions, or to MMAE. * Has not adequately recovered from recent major surgery (excluding placement of vascular access). * Receipt of live or attenuated vaccine within 30 days of first dose. * Cohort 1: Previously Untreated: Prior treatment with a checkpoint inhibitor (CPI) for any other malignancy within the last 12 months. * Cohort 2: Previously Treated: Received more than 1 prior platinum-based chemotherapy regimen for locally advanced or metastatic UC. This includes neoadjuvant/adjuvant platinum-based chemotherapy if recurrence occurred within 12 months of completing therapy. * Cohort 2: Prior treatment with enfortumab vedotin or any other MMAE-based therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1: Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1(RECIST v1.1) by blinded central independent review (BICR) of optimal dose zelenectide pevedotin with pembrolizumab versus chemotherapy | Up to approximately 4 years | The time from randomization to date of first documentation of disease progression or death. |
| Cohort 2: PFS per RECIST v1.1 assessed by BICR of zelenectide pevedotin monotherapy in each treatment regimen | Up to approximately 4 years | The time from randomization to date of first documentation of disease progression or death. |
| Cohort 2: Objective response rate (ORR) per RECIST v1.1 assessed by BICR of zelenectide pevedotin monotherapy in each treatment regimen | Up to approximately 4 years | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1: PFS per RECIST v1.1 assessed by BICR of zelenectide pevedotin combined treatment arms versus chemotherapy | Up to approximately 4 years | The time from randomization to date of first documentation of disease progression or death. |
| Cohort 1: ORR per RECIST v1.1 assessed by BICR of optimal dose zelenectide pevedotin in combination with pembrolizumab versus chemotherapy. | Up to approximately 4 years | — |
| Cohort 1: ORR per RECIST v1.1 assessed by BICR of zelenectide pevedotin combined treatment arms versus chemotherapy | Up to approximately 4 years | — |
| Cohort 1: Overall survival (OS) rate of optimal dose zelenectide pevedotin in combination with pembrolizumab versus chemotherapy | Up to approximately 4 years | The time from randomization to date of death from any cause. |
| Cohort 1: Duration of response (DoR) per RECIST v1.1 assessed by BICR of optimal dose of zelenectide pevedotin in combination with pembrolizumab | Up to approximately 4 years | The time from time of first documentation of objective response that is subsequently confirmed to date of first documentation of disease progression or death. |
| Cohort 1: Disease control rate (DCR) per RECIST v1.1 assessed by BICR of optimal dose of zelenectide pevedotin in combination with pembrolizumab | Up to approximately 4 years | The time from randomization to date of first documentation of disease progression or death. |
| Cohort 1: PFS per RECIST v1.1 assessed by BICR of unselected zelenectide pevedotin dose in combination with pembrolizumab | Up to approximately 4 years | The time from randomization to date of first documentation of disease progression or death. |
| Cohort 1: OS rate of zelenectide pevedotin combined treatment arms in combination with pembrolizumab versus chemotherapy | Up to approximately 4 years | The time from randomization to date of death from any cause |
| Cohort 2: DoR per RECIST v1.1 assessed by BICR in each treatment regimen | Up to approximately 4 years | The time from time of first documentation of objective response that is subsequently confirmed to date of first documentation of disease progression or death. |
| Cohort 2: DCR per RECIST v1.1 assessed by BICR in each treatment regimen | Up to approximately 4 years | The time from cycle 1 Day 1 to date of first documentation of disease progression or death |
| Cohort 2: OS rate in each treatment regimen | Up to approximately 4 years | The time from randomization to date of death from any cause |
| Cohorts 1 and 2: Safety and tolerability of each treatment regimen | Until 30 days post last dose, up to approximately 4 years | Safety will be reported as incidence, severity, seriousness, relationship to study and types of adverse events |
| Cohorts 1 and 2: Exposure-efficacy relationships for zelenectide pevedotin area under the plasma concentration-time curve (AUC) | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured zelenectide pevedotin pharmacokinetic (PK) parameter (AUC) and ORR. |
| Cohorts 1 and 2: Exposure-efficacy relationships for zelenectide pevedotin AUC | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured zelenectide pevedotin PK parameter (AUC) and PFS. |
| Cohorts 1 and 2: Exposure-efficacy relationships for monomethyl auristatin (MMAE) AUC | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured MMAE PK parameter (AUC) and ORR. |
| Cohorts 1 and 2: Exposure-efficacy relationships for MMAE AUC | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured MMAE PK parameter (AUC) and PFS. |
| Cohorts 1 and 2: Exposure-efficacy relationships for zelenectide pevedotin maximum plasma concentration (Cmax) | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured zelenectide pevedotin PK parameter (Cmax) and ORR. |
| Cohorts 1 and 2: Exposure-efficacy relationships for zelenectide pevedotin Cmax | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured zelenectide pevedotin PK parameter (Cmax) and PFS. |
| Cohorts 1 and 2: Exposure-efficacy relationships for MMAE Cmax | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured MMAE PK parameter (Cmax) and ORR. |
| Cohorts 1 and 2: Exposure-efficacy relationships for zelenectide pevedotin average plasma concentration (Cavg) | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured zelenectide pevedotin PK parameter (Cavg) and ORR. |
| Cohorts 1 and 2: Exposure-efficacy relationships for zelenectide pevedotin Cavg | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured zelenectide pevedotin PK parameter (Cavg) and PFS. |
| Cohorts 1 and 2: Exposure-efficacy relationships for MMAE Cavg | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured MMAE PK parameter (Cavg) and ORR. |
| Cohorts 1 and 2: Exposure-safety relationships for zelenectide pevedotin AUC | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured zelenectide pevedotin PK parameter (AUC) and clinical safety, measured by incidence of most frequent or relevant treatment emergent adverse events and treatment related adverse events |
| Cohorts 1 and 2: Exposure-safety relationships for MMAE AUC | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured MMAE PK parameter (AUC) and clinical safety, measured by incidence of most frequent or relevant treatment emergent adverse events and treatment related adverse events. |
| Cohorts 1 and 2: Exposure-safety relationships for zelenectide pevedotin Cmax | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured zelenectide pevedotin PK parameter (Cmax) and clinical safety, measured by incidence of most frequent or relevant treatment emergent adverse events and treatment related adverse events. |
| Cohorts 1 and 2: Exposure-safety relationships for MMAE Cmax | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured MMAE PK parameter (Cmax) and clinical safety, measured by incidence of most frequent or relevant treatment emergent adverse events and treatment related adverse events. |
| Cohorts 1 and 2: Exposure-safety relationships for zelenectide pevedotin Cavg | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured zelenectide pevedotin PK parameter (Cavg) and clinical safety, measured by incidence of most frequent or relevant treatment emergent adverse events and treatment related adverse events. |
| Exposure-safety relationships for MMAE Cavg | Until the end of treatment, up to approximately 4 years | Quantitative modeling of the association between measured MMAE PK parameter (Cavg) and clinical safety, measured by incidence of most frequent or relevant treatment emergent adverse events and treatment related adverse events. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Chile, France, Georgia, Germany, Hungary, Israel, Italy, Poland, Serbia, Singapore, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Outcome results
None listed