ZELENECTIDE PEVEDOTIN for Urothelial carcinoma | Transitional cell carcinoma

Inclusion criteria

• {"criterion_text":"- 1. Able to understand the study procedures and agree to participate in the study by providing written informed consent.\n- 10. WOCBP and male participants willing to follow highly effective contraception at least as conservative as Clinical Trial Facilitation Group (CTFG, 2020) 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 zelenectide pevedotin (BT8009), and 6 months following the last dose of platinum treatment or gemcitabine, whichever comes last.\n- 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 zelenectide pevedotin (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 zelenectide pevedotin (BT8009), and 6 months following the last dose of platinum treatment or gemcitabine, whichever comes last.\n- 12. Additional cohort specific inclusion criteria may apply (see synopses)\n- 2. ≥ 18 years of age on day of signing informed consent.\n- 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%).\n- 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.\n- 5. Archival or fresh tumor tissue comprising primary or metastatic UC should be available for submission to central laboratory.Tissue samples from a bladder biopsy showing only non-muscle invasive UC is not permitted. Cytology specimens are not permitted.\n- 6. Life expectancy ≥ 12 weeks.\n- 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)\n- 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.\n- 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)."}

Exclusion criteria

• {"criterion_text":"- 1. Active keratitis or corneal ulcerations.\n- 10. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).\n- 11. Uncontrolled hypertension (HTN) (systolic blood pressure (BP) ≥ 150 mm mercury (Hg) or diastolic BP ≥ 95 mm Hg) prior to first dose.\n- 12. Prior allogeneic stem cell or solid organ transplantation.\n- 13. Active interstitial lung disease or pneumonitis, or a history of interstitial lung disease or pneumonitis requiring treatment with steroids or other immunosuppressive medications.\n- 14. Prior treatment with an agent directed to another stimulatory or co-inhibitory T-cell receptor, including, but not limited to TIGIT therapy, CD137 agonists, OX-40 agonist or CTLA-4 inhibitors.\n- 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. d. Treatment with any systemic anticancer immunotherapy > 28 days prior to initiation of study treatment.\n- 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.\n- 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).\n- 18. Any prior Grade ≥ 3 immune-related adverse event while receiving immune checkpoint inhibitor.\n- 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. **Not applicable in China. Participants with known HIV or AIDS in China are excluded.\n- 2. 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.\n- 20. Known active hepatitis B, defined as positive surface antigen (HBsAg) and/or anti-hepatitis B core antibody (anti-HBc) and a positive hepatitis B polymerase chain reaction (a detectable hepatitis B viral load).\n- 21. Known active hepatitis C infection with positive viral load (detectable hepatitis C virus [HCV RNA]) if HCV 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 HCV RNA is undetectable for ≥ 12 weeks.\n- 22. History or another active malignancy that would interfere with the safety or efficacy evaluation of the clinical study.\n- 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.\n- 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.\n- 26. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.\n- 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.\n- 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.\n- 28. Additional cohort-specific exclusion criteria may apply.\n- 3. Any condition requiring current treatment with high dose corticosteroids (> 10 mg daily prednisone or equivalent).\n- 4. Known hypersensitivity or allergy to any of the ingredients of any of the study interventions, or to MMAE.\n- 5. Has not adequately recovered from recent major surgery (excluding placement of vascular access, in the opinion of the Investigator.\n- 6. Receipt of live or attenuated vaccine within 30 days of first dose.\n- 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 based on at least 2 scans done at least 4 weeks apart, either without the use of steroids or on stable or decreasing dose of ≤ 10 mg daily prednisone or equivalent and are without any symptoms.\n- 8. Uncontrolled diabetes, defined as hemoglobin A1C (HbA1c) ≥ 8%.\n- 9. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade ≥ 2 peripheral neuropathy."}

Primary endpoints

• {"endpoint_text":"- 1. (Cohort 1) PFS, measured by the length of time from date of randomization to date of first documentation of disease progression per RECIST v1.1 assessed by BICR or death (due to any cause), whichever occurs first.","definition_or_measurement_approach":"Progression-free survival (PFS) defined as time from randomization to first documentation of disease progression per RECIST v1.1 assessed by Blinded Independent Central Review (BICR) or death from any cause, whichever occurs first."}
• {"endpoint_text":"- 1. (Cohort 2) ORR, measured by the percentage of participants who have achieved either confirmed CR or PR per RECIST v1.1 assessed by BICR.","definition_or_measurement_approach":"Objective response rate (ORR) defined as percentage of participants with confirmed complete response (CR) or partial response (PR) per RECIST v1.1 assessed by BICR."}

Secondary endpoints

• {"endpoint_text":"- 1. (Cohort 1) To compare the clinical activity of zelenectide pevedotin (BT8009) in combination with pembrolizumab versus chemotherapy (cisplatin or carboplatin with gemcitabine and maintenance avelumab, if indicated), as measured by the objective response rate (ORR) per RECIST v1.1 assessed by BICR and by the Investigator.\n- ORR, measured by the percentage of participants who have achieved either a confirmed complete response (CR) or partial response (PR) per RECIST v1.1 assessed by Investigator","definition_or_measurement_approach":"ORR assessed by both BICR and Investigator per RECIST v1.1; measured as percentage achieving confirmed CR or PR."}
• {"endpoint_text":"- 2. (Cohort 1) To compare overall survival (OS) of participants treated with zelenectide pevedotin (BT8009) in combination with pembrolizumab versus chemotherapy (cisplatin or carboplatin with gemcitabine and maintenance avelumab, if indicated).","definition_or_measurement_approach":"Overall survival (OS) defined as time from randomization to death from any cause."}
• {"endpoint_text":"- 3. (Cohort 1) To evaluate clinical activity of each study treatment regimen, as measured by duration of response (DoR) per RECIST v1.1 assessed by BICR and by the Investigator.","definition_or_measurement_approach":"Duration of response (DoR) measured from first documentation of objective response (confirmed) per RECIST v1.1 to first documentation of disease progression per RECIST v1.1 or death, assessed by BICR and Investigator."}
• {"endpoint_text":"- 1. (Cohort 2) To evaluate DoR per RECIST v1.1 assessed by BICR.","definition_or_measurement_approach":"DoR per RECIST v1.1 assessed by BICR: time from first confirmed objective response to progression or death."}
• {"endpoint_text":"- 2. (Cohort 2) To evaluate ORR per RECIST v1.1 assessed by Investigator.","definition_or_measurement_approach":"ORR per RECIST v1.1 assessed by Investigator: percentage with confirmed CR or PR."}
• {"endpoint_text":"- 3. (Cohort 2) To evaluate DoR per RECIST v1.1 assessed by Investigator.","definition_or_measurement_approach":"DoR per RECIST v1.1 assessed by Investigator: time from first documented objective response to progression or death."}

Methods

• Brochure — patient-facing recruitment brochure (country-specific brochures documented).
• Website — study website content and privacy notice / cookie banner (digital recruitment channels documented).
• Participant Journey materials — participant journey handouts (patient-facing materials documented).
• Patient Handbook and Participant Handbook — study information and guidance for participants.
• GP letter — letter to general practitioners to facilitate referral.
• Study Reference Card / Patient Emergency Contact Card — short reference materials for participants.
• Patient travel / reimbursement materials — travel and reimbursement guidance (patient travel reimbursement documented).

Primary sponsor

Full Name

Bicycletx Limited

Organisation Type

Pharmaceutical company

Country Of Registered Address

United Kingdom

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

sponsorDuties code 8 (safety/pharmacovigilance responsibilities indicated in sponsorDuties)

Name

Medpace Inc.

Responsibilities

Multiple responsibilities (codes include 1,2,5,6,7,9,10,12,15) including operational support, pharmacovigilance, data management and patient travel reimbursement as listed in sponsor duties

Name

QPS Netherlands B.V.

Responsibilities

Laboratory/operational support (sponsorDuties code 4)

Name

Almac Clinical Services Limited

Responsibilities

Regulatory/clinical supply support (sponsorDuties code 14)

Third parties

• {"country":"United States","full_name":"Medpace Reference Laboratories LLC","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Lanterne Dx LLC","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"MEDPACE LABORATORIES","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Germany","full_name":"Discovery Life Sciences Biomarker Services GmbH","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Neogenomics Laboratories Inc.","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"4g Clinical LLC","duties_or_roles":"sponsorDuties codes: [3]","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Greece","full_name":"Medpace Ellas Monoprosopi I.K.E.","duties_or_roles":"sponsorDuties codes: [1,12]","organisation_type":"Pharmaceutical company"}
• {"country":"Canada","full_name":"Cellcarta Biosciences Inc.","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Pharmaceutical company"}
• {"country":"Lithuania","full_name":"Biomapas UAB","duties_or_roles":"sponsorDuties codes: [1,12,2]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Biotel Research LLC","duties_or_roles":"Central Imaging Review","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Novasco","duties_or_roles":"Patient travel reimbursement","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"QuanTx Consulting","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Industry"}
• {"country":"Germany","full_name":"Institute of Pathology University Hospital Erlangen","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Educational Institution"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"sponsorDuties codes: [14]","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"York Bioanalytical Solutions Limited","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Factor","duties_or_roles":"Legal Consultant","organisation_type":"Industry"}
• {"country":"Israel","full_name":"Imagene AI","duties_or_roles":"Data Analysis","organisation_type":"Industry"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"sponsorDuties codes: [8]","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"QPS Netherlands B.V.","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medpace Inc.","duties_or_roles":"Multiple sponsor duties including patient travel reimbursement and clinical operations (codes present: [1,10,12,15,2,5,6,7,9])","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Tempus Compass LLC","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Pharmaceutical company"}
• {"country":"Romania","full_name":"August Research S.R.L.","duties_or_roles":"sponsorDuties codes: [1,12,2]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Indica Labs Inc.","duties_or_roles":"Data Analysis","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Taxi Travel Ticket S.L.","duties_or_roles":"Patient travel reimbursement","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Discovery Life Sciences LLC","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Laboratory/Research/Testing facility"}