MONOMETHYL AURISTATIN E LINKED TO A SARCOSINE DECAMER WITH A BETA-ALANINE N-TERMINUS AND BCY9594 VIA A CLEAVABLE LINKER for Advanced solid tumours associated with EphA2 expression

Inclusion criteria

• {"criterion_text":"- 1. Written informed consent, according to local guidelines, signed and dated by the patient or by a legal guardian prior to the performance of any study-specific procedures, sampling, or analyses If a patient declines to participate in any voluntary component of the study (e.g., tumor biopsy), there will be no penalty or loss of benefit to the patient, and he/she will not be excluded from other aspects of the study.\n- 10. Must be willing and able to comply with the protocol and study procedures.\n- 11. Additional cohort specific inclusion criteria may apply.\n- 2. At least 18 years-of-age at the time of signature of the informed consent form\n- 3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 (see Appendix A)\n- 4. Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1\n- 5. Acceptable organ function, as evidenced by the following laboratory data: - Renal function, as follows: estimated glomerular filtration rate (eGFR) ≥50 mL/min by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation adjusted by patient’s body surface area as measured by 24-hour urine collection or by local institutional standard. - Total bilirubin ≤1.5 × ULN (upper limit of normal) or ≤ 3 × ULN for Gilbert disease - Serum albumin ≥2.5 g/dL - Aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 ×ULN in the presence of liver metastases - Alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 ×ULN in the presence of liver metastases - International normal ratio (INR) <1.3 or ≤ institutional ULN\n- 6. Acceptable hematologic function (no red blood cell or platelet transfusions or growth factors are allowed within 4 weeks of the first dose of BT5528): - Hemoglobin ≥9 g/dL - Absolute neutrophil count (ANC) ≥1500 cells/mm3 - Platelet count ≥75,000 cells/mm3\n- 7. Negative pregnancy test for women of childbearing potential (WOCBP) (negative serum test at screening and negative urine or serum test within 3 days prior to the first dose of BT5528). Definition of non-WOCBP is in Appendix C. Male patients with female partners of childbearing potential and female patients of childbearing potential are required to follow highly effective contraception (oral and hormonal contraceptives allowed) at least as conservative as CTFG recommendations for less than 1% failure rate (acceptable contraception methods are listed in Appendix C) during their participation in the study and for 6 months following last dose of BT5528 (BT5528 IB) or 5 months following last dose of nivolumab (Nivolumab USPI or SmPC) for patients continuing treatment with nivolumab only after stopping treatment with BT5528. Male patients must also refrain from donating sperm during their participation in the study and for 5 or 6 months following last dose of either nivolumab or BT5528, respectively, and women must not breastfeed during that time or donate eggs.\n- 8. All patients must have tumor tissue (fresh or archived) available for analysis of EphA2 tumor expression and other biomarkers. In the absence of available tumor tissue, patients must be willing to undergo a biopsy to provide fresh tumor samples. Specifications on tissue requirements are provided in the laboratory manual.\n- 9. Life expectancy ≥12 weeks after the start of BT5528 treatment according to the Investigator’s judgment."}

Exclusion criteria

• {"criterion_text":"- 1. Chemotherapy treatments within 14 days prior to first dose of study treatment. For other anticancer treatments, treatment within 28 days or 5 half-lives, whichever is shorter. For immunotherapy, including immune checkpoint inhibitors, treatment within 28 days prior to the first dose of study treatment.\n- 10. Uncontrolled hypertension (systolic BP ≥160 mmHg or diastolic BP ≥100 mm Hg that is not responsive to intervention) at screening or prior to initiation of study drug.\n- 11. History or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation, or is not in the best interest of the patient to participate in the opinion of the Investigator including but not limited to: a. Patients 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 Class III-IV documented within 6 months prior to first dose of BT5528 or: i. Mean resting corrected QT interval (QTcF) >470 msec ii. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval iii. Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting electrocardiograms (ECGs), e.g., complete left bundle branch block, third degree heart block\n- 12. Known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS) Note: Well controlled HIV will be allowed if the patient meets all the following criteria at inclusion: a) CD4+ T-cell (CD4+) counts ≥350 cells/uL; b) HIV viral load <400 copies/mL c) Without a history of opportunistic infection within the last 12 months. d) On established antiretroviral therapy (ART) for at least 4 weeks. Use of anti-retroviral therapy is permitted but should be discussed with the Medical Monitor on a caseby-case basis\n- 13. Patients with a positive hepatitis B surface antigen and/or antihepatitis B core antibody. Patients with a negative polymerase chain reaction (PCR) assay are permitted with appropriate antiviral therapy\n- 14. Active hepatitis C infection with positive viral load if hepatitis C virus (HCV) antibody positive (if antibody is negative then viral load not applicable). Patients who have been treated for hepatitis C infection can be included if they have documented sustained virologic response of ≥12 weeks.\n- 15. Thromboembolic events and/or bleeding disorders within 3 months (e.g., deep vein thrombosis [DVT] or pulmonary embolism [PE]) prior to the first dose of BT5528 study treatment.\n- 16. Prior history of pneumonitis with presence of residual symptoms.\n- 17. History of another malignancy within 3 years before the first dose of BT5528, or any evidence of residual disease from a previously diagnosed malignancy (excluding adequately treated with curative intent basal cell carcinoma, squamous cell of the skin, cervical intraepithelial neoplasia/cervical carcinoma in situ or melanoma in situ or ductal carcinoma in situ of the breast).\n- 18. Systemic anti-infective treatment or fever within the last 14 days prior to first dose of BT5528 study treatment.\n- 19. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.\n- 2. Experimental treatments within 4 weeks of first dose of BT5528 study treatment.\n- 20. Additional cohort specific exclusion criteria may apply.\n- 3. Prior toxicities must have resolved to Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 (except alopecia which can be Grade 2), or well-controlled Grade 2 hypothyroidism or Grade 2 adrenal insufficiency on appropriate therapy).\n- 4. Current treatment with strong inhibitors or inducers of CYP3A4 or strong inhibitors of P-gp including herbal- or food-based as defined in the Flockhart Table of drug-drug interactions.\n- 5. Known sensitivity to any of the ingredients of the investigational product or monomethyl auristatin E (MMAE).\n- 6. Significant medical condition, life-threatening illness, active uncontrolled infection or organ system dysfunction (such as ascites, coagulopathy, encephalopathy), or other reasons which, in the Investigator’s opinion, could compromise the patient’s safety, or interfere with or compromise the integrity of the study outcomes including consideration of gastrointestinal, skin and pulmonary comorbidities and including review of screening chest CT to ensure no clinically significant co-morbidities.\n- 7. Major surgery (excluding placement of vascular access) within 4 weeks of first dose of BT5528 study treatment and must have recovered adequately prior to starting study therapy\n- 8. Receipt of live vaccine within 30 days of study treatment\n- 9. Untreated CNS metastases. Subjects with treated CNS metastases are permitted on study if all the following are true: a. CNS metastases have been clinically stable for at least 6 weeks prior to screening b. If requiring steroid treatment for CNS metastases, the subject is on a stable or decreasing dose of ≤20 mg/day of prednisone or equivalent for at least 2 weeks Baseline scans show no evidence of new or enlarged brain metastasis d. Subject does not have leptomeningeal disease e. Subject must be without neurologic dysfunction that would confound the evaluation of neurologic and other AEs."}

Primary endpoints

• {"endpoint_text":"- 1. Treatment-emergent adverse events (TEAEs), laboratory, ECG and vital sign abnormalities using CTCAE v5.0 criteria.","definition_or_measurement_approach":"Assessment of TEAEs, laboratory, ECG and vital sign abnormalities graded per CTCAE v5.0."}
• {"endpoint_text":"- 2. Dose-limiting toxicities as defined in the protocol.","definition_or_measurement_approach":"Dose-limiting toxicities (DLTs) are to be identified according to the protocol-defined DLT definitions (referenced in protocol)."}
• {"endpoint_text":"- 3. Objective response rate (ORR [CR + PR]), duration of response (DOR), clinical benefit rate (CR + PR + SD ≥4 months), time to tumor progression (TTP), progression-free survival time (PFS), rate of PFS at 6 mos., all assessed per RECIST v1.1 criteria as assessed by the Investigator, and OS.","definition_or_measurement_approach":"Tumor response measures (ORR, DOR, clinical benefit rate, TTP, PFS, PFS rate at 6 months) assessed per RECIST v1.1 by Investigator; OS measured from treatment start to death."}

Secondary endpoints

• {"endpoint_text":"- 1. Objective response rate (ORR), duration of response (DOR), clinical benefit rate (CR + PR + SD ≥4 months), time to tumor progression (TTP), progression-free survival time (PFS), rate of PFS at 6 mos., all assessed per RECIST v1.1 criteria, and OS","definition_or_measurement_approach":"Tumor response and survival endpoints assessed per RECIST v1.1 and standard survival analysis for OS."}
• {"endpoint_text":"- 2. Treatment-emergent adverse events (TEAEs), laboratory, ECG and vital sign abnormalities using CTCAE v5.0 criteria","definition_or_measurement_approach":"Safety assessment per CTCAE v5.0 for TEAEs, labs, ECGs and vitals."}
• {"endpoint_text":"- 3. Objective response rate (ORR), duration of response (DOR), clinical benefit rate (CR + PR + SD ≥4 months), time to tumor progression (TTP), progression-free survival time (PFS), rate of PFS at 6 mos., all assessed per RECIST v1.1 criteria, per EphA2 expression, and OS.","definition_or_measurement_approach":"Efficacy endpoints as per RECIST v1.1 stratified by EphA2 tumor expression levels; OS measured conventionally."}
• {"endpoint_text":"- 4. Plasma concentrations of BT5528 and MMAE with appropriate pharmacokinetic derivations such as Cmax, Cmin, AUC, and elimination t½","definition_or_measurement_approach":"PK assessments measuring plasma concentrations of BT5528 and MMAE with derivations including Cmax, Cmin, AUC and half-life."}
• {"endpoint_text":"- 5. Measurement of ADA.","definition_or_measurement_approach":"Assessment of anti-drug antibody (ADA) incidence using immunogenicity assays as per protocol."}

Methods

• Site-based recruitment at participating oncology centres/hospitals listed in Belgium and Spain (trial sites named in CTIS Part II submissions).

Belgium

Earliest CTIS Part Ii Submission Date

10-04-2024

Latest Decision Or Authorization Date

19-11-2024

Processing Time Days

223

Number Of Sites

4

Number Of Participants

38

Spain

Earliest CTIS Part Ii Submission Date

10-04-2024

Latest Decision Or Authorization Date

15-01-2026

Processing Time Days

645

Number Of Sites

5

Number Of Participants

25

Primary sponsor

Full Name

Bicycletx Limited

Organisation Type

Pharmaceutical company

Country Of Registered Address

United Kingdom

Contract research organisations

Name

Medpace Finland Oy

Responsibilities

1,12,2,3,5

Name

Almac Clinical Services Limited

Responsibilities

14

Name

Sarah Cannon Research Institute LLC

Responsibilities

10,6,7,8

Third parties

• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Sarah Cannon Research Institute LLC","duties_or_roles":"10,6,7,8","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Finland","full_name":"Medpace Finland Oy","duties_or_roles":"1,12,2,3,5","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Labcorp Central Laboratory Services LP","duties_or_roles":"4","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"14","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Neogenomics Laboratories Inc.","duties_or_roles":"4","organisation_type":"Laboratory/Research/Testing facility"}