A Randomized Open-Label Phase II/III Study of BT8009 as Monotherapy or in Combination in Participants With Locally Advanced or Metastatic Urothelial Cancer (Duravelo-2)
Study Identifier:
BT8009-230
CT.gov Identifier:
EudraCT Identifier:
N/A
EU Trial (CTIS) Number:
Study Contact Information:
Recruitment Complete
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Study Summary
To measure the efficacy and safety of BT8009 as monotherapy and in combination with pembrolizumab in participants with locally advanced or metastatic urothelial cancer (UC). To evaluate the safety and efficacy of BT8009 as monotherapy, or combined with pembrolizumab (pembro), vs chemotherapy in pts with locally advanced or metastatic UC (la/mUC) To evaluate zelenectide pevedotin plus pembrolizumab versus chemotherapy in first-line mUC (Cohort 1), and zelenectide pevedotin monotherapy and in combination with pembrolizumab in late-line mUC (Cohort 2). In each cohort, two doses of zelenectide pevedotin – 5 mg/m2 weekly and 6 mg/m2 two weeks on, one week off – are being initially assessed To evaluate the safety and efficacy of zele as monotherapy, or combined with pembrolizumab (pembro), vs chemotherapy in pts with la/mUC.
To report an interim analysis (IA) for zele + pembrolizumab (pembro) dosage selection from the Phase 2/3 Duravelo-2 study (NCT06225596/BT8009-230) in previously untreated (untx) pts with la/mUC
To report an interim analysis (IA) for zele monotherapy dosage selection from the Phase 2/3 Duravelo-2 study (NCT06225596/BT8009-230) in previously treated pts with la/mUC
-[Cohort 1] To compare the efficacy of BT8009 in combination with pembrolizumab versus chemotherapy (cisplatin or carboplatin with gemcitabine and maintenance avelumab, if indicated), as measured by progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) assessed by blinded independent central review (BICR).
-[Cohort 2] To evaluate the efficacy of BT8009 monotherapy as measured by ORR per RECIST v1.1 assessed by BICR -[Cohort 2] To evaluate the efficacy of BT8009 in combination with pembrolizumab as measured by ORR per RECIST v1.1 assessed by BICR.
Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Bladder
Renal
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase II/III
Sex
Female & Male
Age
18+ years
Study Drug
Drug: Experimental: Cohort 1: Zelenectide pevedotin Arm 1
Study Status
Indicates the current recruitment status or the expanded access status
Recruitment Complete
Requirements information
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 muscle-invasive UC or locally advanced 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. Pts must have la/mUC of the renal pelvis, ureter, bladder, or urethra, ECOG performance status ≤2 (Cohort 1) or ≤1 (Cohort 2), and adequate organ function. Cohort 1 will include n≤641 previously untreated pts eligible for platinum-based chemotherapy. Cohort 2 will include n≤315 pts with ≥1 prior systemic therapy, excluding enfortumab vedotin or other MMAE-based therapy.
- CTIS:
- 1. Able to understand the study procedures and agree to participate in the study by providing written informed consent.2. ≥ 18 years of age on day of signing informed consent.3. Histologically or cytologically confirmed locally advanced (unresectable) or metastatic UC of the renal pelvis, ureter, bladder, or urethra. a. Participants with mixed histologies are required to have a dominant transitional cell pattern (≥ 50%).4. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. a. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions post irradiation.5. Archival or fresh tumor tissue comprising muscle-invasive UC, or locally advanced or metastatic UC should be available for submission to central laboratory.6. Life expectancy ≥ 12 weeks.7. Adequate organ function: a. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for participants with Gilbert disease b. Serum albumin ≥ 2.5 g/dL c. Aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN in the presence of liver metastases d. Alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN in the presence of liver metastases e. Alkaline phosphatase ≤ 2.5 × ULN or ≤ 5 × ULN in the presence of liver or bone metastases f. Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min (using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine equation adjusted by the patient’s body surface area)8. International normalized ratio (INR)/prothrombin time (PT) ≤ 1.5 × ULN unless participant is receiving a stable dose of anticoagulant therapy and PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of the appropriate anticoagulants.9. 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).10. WOCBP and male participants with female partners of childbearing potential willing to follow highly effective contraception at least as conservative as Clinical Trial Facilitation Group (CTFG) recommendations of < 1% failure rate starting at Screening, throughout the study period, and for at least 1 month following the last dose of avelumab, 4 months following the last dose of pembrolizumab, 6.5 months following the last dose of BT8009, and 6 months following the last dose of platinum treatment or gemcitabine, whichever comes last.11. Fertile male participants must agree to refrain from sperm donation from first dose until at least 1 month following the last dose of avelumab, 4 months following the last dose of pembrolizumab, 6.5 months following the last dose of BT8009, and 6 months following the last dose of platinum treatment or gemcitabine, whichever comes last. Women must not breastfeed or donate eggs from first dose until 1 month following the last dose of avelumab, 4 months following the last dose of pembrolizumab, 6.5 months following the last dose of BT8009, and 6 months following the last dose of platinum treatment or gemcitabine, whichever comes last.Additional cohort specific inclusion criteria may apply (see synopses)
Exclusion criteria
- - Active keratitis or corneal ulcerations. - Requirement, while on study, 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
- CTIS:
- 1. Active keratitis or corneal ulcerations.2. Requirement, while on study, 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.3. Any condition requiring current treatment with high dose corticosteroids (> 10 mg daily prednisone or equivalent).4. Known hypersensitivity or allergy to any of the ingredients of any of the study interventions, or to MMAE.5. Has not adequately recovered from recent major surgery (excluding placement of vascular access).6. Receipt of live or attenuated vaccine within 30 days of first dose.7. Known active carcinomatous meningitis or untreated central nervous system (CNS) metastases. a. Participants with treated brain metastases may participate in the study if they are stable for at least 4 weeks prior to the first dose, either without the use of steroids or on stable or decreasing dose of ≤ 10 mg daily prednisone or equivalent and are without any symptoms.8. Uncontrolled diabetes, defined as hemoglobin A1C (HbA1c) ≥ 8%.9. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade ≥ 2 peripheral neuropathy.10. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).11. Uncontrolled hypertension (HTN) (systolic blood pressure (BP) ≥ 150 mm mercury (Hg) or diastolic BP ≥ 95 mm Hg) prior to first dose.12. Prior allogeneic stem cell or solid organ transplantation.13. Active interstitial lung disease or pneumonitis, or a history of interstitial lung disease or pneumonitis requiring treatment with steroids or other immunosuppressive medications.14. Prior treatment with an agent directed to another stimulatory or co-inhibitory T-cell receptor.15. Prior treatment with any systemic anticancer therapy within 2 weeks or 5 half-lives, whichever is longer, prior to initiation of study treatment; the following exceptions are permitted: a. Palliative radiotherapy for UC-related bone or soft tissue metastasis completed > 7 days prior to baseline imaging. b. Androgen deprivation therapy using gonadotropin-releasing hormone (GnRH) agonists. c. Females with hormone receptor-positive breast cancer who are receiving tamoxifen or aromatase inhibitors adjuvant therapy ≥ 3 years.16. Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 2 weeks or 5 half-lives, whichever is longer, prior to first dose of study treatment.17. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).18. Any prior Grade ≥ 3 immune-related adverse event while receiving immune checkpoint inhibitor.19. Known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS). a. Well controlled HIV will be allowed if the participant meets all the following criteria at inclusion: i. Cluster of differentiation (CD4+) counts ≥ 350 cells/uL; ii. HIV viral load < 400 copies/mL; iii. Without a history of opportunistic infection within the last 12 months; iv. On established antiretroviral therapy (ART) for at least 4 weeks.20. Known active hepatitis B, defined as positive surface antigen and/or anti-hepatitis B core antibody. Participants with a negative polymerase chain reaction assay are permitted with appropriate antiviral therapy.21. Known active hepatitis C infection with positive viral load if hepatitis C virus is antibody positive (if antibody is negative then viral load is not applicable). Participants who have been treated for hepatitis C infection can be included if they have documented sustained virologic response of ≥ 12 weeks.22. History or another active malignancy that would interfere with the safety or efficacy evaluation of the clinical study.24. Suspicion of relevant and recent systemic viral syndrome or need for quarantine/isolation that is not resolved prior to initiation of study treatment in the opinion of the Investigator.25. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s ability to take part in the full duration of the study, or is not in the best interest of the participant to take part, in the opinion of the Investigator. Participants with history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure or symptoms of New York Heart Association (NYHA) Class III or IV (Appendix 2) documented within 6 months prior to first dose of study treatment or: a. Mean resting corrected QT interval (QTc) > 470 msec by Fridericia QT correction. b. Any factors that increase the risk of QTc prolongation such as congenital long QT syndrome, or family history of long QT syndrome. c. Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting ECGs, eg, complete left bundle branch block, third degree heart block.26. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.27. Prior Stevens-Johnson syndrome (SJS)/ toxic epidermal necrolysis (TEN)/drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), erythema multiforme, symmetric drug-related intertriginous and flexural exanthema (SDRIFE), or Baboon syndrome.23. Active systemic infection or fever not attributable to underlying malignancy requiring therapeutic oral or IV antibiotics within 14 days prior to start of study treatment. Participants receiving prophylactic antibiotics are eligible.Additional cohort specific exclusion criteria may apply (see synopses)
Clinical Study Information for Healthcare Providers
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Study Locations
Location
Investigator
Status
Condition(s) Treated at Site
Location
START Carolinas
Myrtle Beach, SC, United States, 29572
Investigator
Neal Shore
Status
Recruitment Complete
Condition(s) Treated at Site
Bladder
Renal