Study BT8009-230 in Subjects with Locally Advanced or Metastatic Urothelial Cancer (Duravelo-2)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Bicycletx Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2024-04-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2023-504231-41-00

WHO UTN

U1111-1300-3791

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

-[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.

Secondary objectives 6

1. 1. (Cohort 1) To assess clinical activity by the objective response rate (ORR) per RECIST v1.1 assessed by BICR and by the Investigator.
2. 2. (Cohort 1) To evaluate overall survival (OS).
3. 3. (Cohort 1) To assess clinical activity by duration of response (DoR) per RECIST v1.1 assessed by BICR and by the Investigator
4. 1. (Cohort 2) To evaluate DoR per RECIST v1.1 assessed by BICR.
5. 2. (Cohort 2) To evaluate ORR per RECIST v1.1 assessed by Investigator.
6. 3. (Cohort 2) To evaluate DoR per RECIST v1.1 assessed by Investigator.

Conditions and MedDRA coding

Locally advanced or metastatic urothelial cancer

Regulatory references

Scientific advice from competent authorities

Federal Institute For Drugs And Medical Devices, Food And Drug Administration, Danish Medicines Agency

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Able to understand the study procedures and agree to participate in the study by providing written informed consent.
2. 2. ≥ 18 years of age on day of signing informed consent.
3. 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. 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. 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. 6. Life expectancy ≥ 12 weeks.
7. 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. 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. 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. 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. 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.
12. Additional cohort specific inclusion criteria may apply (see synopses)

Exclusion criteria 28

1. 1. Active keratitis or corneal ulcerations.
2. 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. 3. Any condition requiring current treatment with high dose corticosteroids (> 10 mg daily prednisone or equivalent).
4. 4. Known hypersensitivity or allergy to any of the ingredients of any of the study interventions, or to MMAE.
5. 5. Has not adequately recovered from recent major surgery (excluding placement of vascular access).
6. 6. Receipt of live or attenuated vaccine within 30 days of first dose.
7. 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. 8. Uncontrolled diabetes, defined as hemoglobin A1C (HbA1c) ≥ 8%.
9. 9. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade ≥ 2 peripheral neuropathy.
10. 10. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).
11. 11. Uncontrolled hypertension (HTN) (systolic blood pressure (BP) ≥ 150 mm mercury (Hg) or diastolic BP ≥ 95 mm Hg) prior to first dose.
12. 12. Prior allogeneic stem cell or solid organ transplantation.
13. 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. 14. Prior treatment with an agent directed to another stimulatory or co-inhibitory T-cell receptor.
15. 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. 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. 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. 18. Any prior Grade ≥ 3 immune-related adverse event while receiving immune checkpoint inhibitor.
19. 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. 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. 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. 22. History or another active malignancy that would interfere with the safety or efficacy evaluation of the clinical study.
23. 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.
24. 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.
25. 26. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
26. 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.
27. 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.
28. Additional cohort specific exclusion criteria may apply (see synopses)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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.
2. 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.

Secondary endpoints 6

1. 1. (Cohort 1) 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 BICR. - ORR, measured by the percentage of participants who have achieved either a confirmed CR or PR per RECIST v1.1 assessed by Investigator
2. 2. (Cohort 1) OS, defined as length of time from date of randomization to date of death from any cause.
3. 3. (Cohort 1) DoR, measured by the time from first documentation of objective response (that is subsequently confirmed) per RECIST v1.1 assessed by - BICR to the first documentation of objective tumor progression (per RECIST v1.1), or to death (due to any cause), whichever occurs first - Investigator to the first documentation of objective tumor progression (per RECIST v1.1), or to death (due to any cause), whichever occurs first
4. 1. (Cohort 2) DoR, measured by the time from first documentation of objective response (that is subsequently confirmed) per RECIST v1.1 assessed by BICR to the first documentation of objective tumor progression (per RECIST v1.1), or to death (due to any cause), whichever occurs first.
5. 2. (Cohort 2) ORR, measured by the percentage of participants who have achieved either confirmed CR or PR per RECIST v1.1 assessed by the Investigator.
6. 3. (Cohort 2) DoR, measured by the time from first documentation of objective response (that is subsequently confirmed) per RECIST v1.1 assessed by Investigator to the first documentation of objective tumor progression (per RECIST v1.1), or to death (due to any cause), whichever occurs first.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Bicycletx Limited

Sponsor organisation

Bicycletx Limited

Address

Portway Building, Granta Park, Great Abington Granta Park Great Abington

City

Cambridge

Postcode

CB21 6GS

Country

United Kingdom

Scientific contact point

Organisation

Bicycletx Limited

Contact name

BicycleTx Limited Medical Affairs

Public contact point

Organisation

Bicycletx Limited

Contact name

BicycleTx Limited Medical Affairs

Third parties 13

Locations

1 EU/EEA country · 13 investigational sites

By country

Investigational sites

Application history

1 submissions — initial application plus substantial / non-substantial modifications