Study BT5528-100 in Patients with Advanced Solid Tumors Associated with EphA2 Expression

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]

Trial duration

1 Feb 2022 → ongoing

Decision date (initial)

2024-04-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

BicycleTx Ltd

External identifiers

EU CT number

2024-510655-36-00

EudraCT number

2019-003653-29

WHO UTN

U1111-1305-3451

ClinicalTrials.gov

NCT04180371

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacokinetic

Parts A-1 and A-2:
• To assess safety and tolerability of BT5528 in patients with advanced solid tumor malignancies associated with EphA2-expression and/or tumors identified as positive for EphA2 tumor expression as a monotherapy (Part A-1) and in combination with nivolumab (Part A-2)
• To define the maximum tolerated dose (MTD) of BT5528, if observed, and determine one or more recommended Phase II dose/s (RP2D) as a monotherapy (Part A-1) and in combination with nivolumab (Part A-2).
Part B:
• To assess the clinical activity of BT5528 as monotherapy in patients with solid tumors historically known for high expression of EphA2 (Cohort B-1: urothelial cancer, Cohort B-2: ovarian cancer, Cohort B-3: non-small cell lung cancer [NSCLC], Cohort B-4: head and neck cancer, Cohort B-5: triple negative breast cancer (TNBC), and Cohort B-6: gastric/upper gastrointestinal cancer [GI], Cohort B-7: monomethyl auristatin E (MMAE)-exposed urothelial cancer (UC), and Cohort B-8: head and neck squamous cell carcinoma) at one or more RP2D dosing regimens.

Secondary objectives 7

1. 1. Parts A-1 and A-2: To assess preliminary signals of anti-tumor activity achieved with BT5528 administration in patients with advanced solid tumor malignancies associated with EphA2-expression and/or specified tumors identified as positive for EphA2 tumor expression as a monotherapy (Parts A-1) and in combination with nivolumab (Parts A-2)
2. 2. Parts A-1 and A-2: To determine pharmacokinetic (PK) parameters of BT5528 and MMAE (as appropriate)
3. 3. Parts A-1 and A-2: To determine incidence of anti-drug antibody (ADA) development
4. 4. "Part B: To assess safety and tolerability of BT5528 as monotherapy in patients with tumors historically known for high expression of EphA2"
5. 5. Part B: To investigate whether tumor EphA2 expression levels are predictive of clinical activity with BT5528 monotherapy in patients with tumors historically known for high expression of EphA2
6. 6. Part B: To determine pharmacokinetic (PK) parameters of BT5528 and MMAE (as appropriate)
7. 7. Part B: To determine incidence of anti-drug antibody (ADA) development

Conditions and MedDRA coding

Advanced Malignancies Associated with EphA2 Expression

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 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.
2. 2. At least 18 years-of-age at the time of signature of the informed consent form
3. 3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 (see Appendix A)
4. 4. Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
5. 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
6. 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
7. 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.
8. 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.
9. 9. Life expectancy ≥12 weeks after the start of BT5528 treatment according to the Investigator’s judgment.
10. 10. Must be willing and able to comply with the protocol and study procedures.
11. 11. Additional cohort specific inclusion criteria may apply.

Exclusion criteria 20

1. 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.
2. 2. Experimental treatments within 4 weeks of first dose of BT5528 study treatment.
3. 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).
4. 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.
5. 5. Known sensitivity to any of the ingredients of the investigational product or monomethyl auristatin E (MMAE).
6. 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.
7. 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
8. 8. Receipt of live vaccine within 30 days of study treatment
9. 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.
10. 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.
11. 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
12. 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
13. 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
14. 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.
15. 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.
16. 16. Prior history of pneumonitis with presence of residual symptoms.
17. 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).
18. 18. Systemic anti-infective treatment or fever within the last 14 days prior to first dose of BT5528 study treatment.
19. 19. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.
20. 20. Additional cohort specific exclusion criteria may apply.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. 1. Treatment-emergent adverse events (TEAEs), laboratory, ECG and vital sign abnormalities using CTCAE v5.0 criteria.
2. 2. Dose-limiting toxicities as defined in the protocol.
3. 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.

Secondary endpoints 5

1. 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
2. 2. Treatment-emergent adverse events (TEAEs), laboratory, ECG and vital sign abnormalities using CTCAE v5.0 criteria
3. 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.
4. 4. Plasma concentrations of BT5528 and MMAE with appropriate pharmacokinetic derivations such as Cmax, Cmin, AUC, and elimination t½
5. 5. Measurement of ADA.

Investigational products

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

Test 2

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 6

Locations

2 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 21 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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