Study BT8009-100 in Patients with Nectin-4 Expressing Advanced Malignancies.

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

12 Apr 2021 → ongoing

Decision date (initial)

2024-05-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

BicycleTx Ltd

External identifiers

EU CT number

2023-509781-37-00

EudraCT number

2020-002719-23

WHO UTN

U1111-1302-3293

ClinicalTrials.gov

NCT04561362

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety

Primary obj. for escalation (A-1 & A-2) and renal insufficiency (C) and supplementary PK (D) cohorts: - Assess safety and tolerability of zelenectide pevedotin in pts with advanced solid tumor malignancies associated with Nectin-4 expression: a) as monotherapy (A- 1); b) in combination with pembrolizumab (A-2); c) moderate to severe renal insufficiency (C). - Define MTD and determine RP2D[s] (A-1&A-2). - To further characterize the PK of zelenectide pevedotin (BT8009) and MMAE (D). Primary obj. for expansion (B): - Assess the ORR of zelenectide pevedotin (BT8009) as a monotherapy in pts with EV-exposed (B-1) or EV-naïve (B-2&B-3) urothelial carcinoma using RECIST V1.1 (metastatic urothelial cancer pts). - Assess ORR of zelenectide pevedotin (BT8009) as a monotherapy in pts with solid tumor with Nectin-4 expression B-4 [ovarian], B5 [TNBC], and B-6 [NSCLC]) using RECIST V1.1. - Assess ORR of zelenectide pevedotin (BT8009) in cisplatin-ineligible pts with locally advanced or metastatic urothelial carcinoma in combination with pembrolizumab using RECIST 1.1 (B-7). - Further characterize the PK of zelenectide pevedotin (BT8009) and MMAE(D). - Assess the safety and tolerability of the alternative dosing regimen of zelenectide pevedotin (BT8009) monotherapy of 6mg/m^2 day 1 and 8 of a 21 day cycle (B-8 and B-9).

Secondary objectives 9

1. 1. (A-1&A-2&C&D) Assess preliminary signals of anti-tumor activity in pts with adv solid tumor malignancies with Nectin-4 expression using RECIST 1.1: a)(A-1); b)(A-2); c)(C); d) in pts with advanced solid tumor malignancies having normal renal function or mild renal insufficiency(D).
2. 2. (C) Evaluate the impact of renal impairment on PK of zelenectide pevedotin (BT8009) and MMAE.
3. 3. (D) Assess safety and tolerability of zelenectide pevedotin with normal renal function or mild renal insufficiency.
4. 4. (A-1&A-2&C) Determine PK parameters of zelenectide pevedotin (BT8009) and MMAE.
5. 5. (A-1&A-2&C&D) Determine incidence of ADA development.
6. 6. (Expansion Parts B-1-B-9) Assess safety and tolerability of zelenectide pevedotin (BT8009) in pts with solid tumors as a monotherapy (Parts B-1-B-6, B-8, B-9) and in combination with pembrolizumab (Part B-7).
7. 7. (Expansion Parts B-1-B-9) Assess other parameters of clinical activity.
8. 8. (Expansion Parts B-1-B-9) Determine PK parameters of zelenectide pevedotin (BT8009) and MMAE.
9. 9. (Expansion Parts B-1-B-9) Determine incidence of ADA development.

Conditions and MedDRA coding

Nectin-4 Expressing Advanced Malignancies.

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.
2. 10. Must be willing and able to comply with the protocol, the scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
3. 2. At least 18 years-of-age at the time of signature of the informed consent form.
4. 3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. Patients who are in Cohort B-7 (cisplatin-ineligible urothelial cancer) can have an ECOG of 2 but must meet additional criteria (see Incl #29).
5. 4. Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (see Appendix B). Target lesions that were previously irradiated may be measurable if demonstrated progression has occurred.
6. 5. Acceptable organ function, as evidenced by the following lab data: a) Renal function, as follows: creatinine clearance (CrCl) of ≥50 mL/min by the Cockcroft-Gault equation or equivalent. (See Cohort specific criteria for Part B-7 and Part C.) b) Total bilirubin ≤1.5 × upper limit of normal (ULN) or ≤3 × ULN and conjugated bilirubin ≤1.5 × ULN for patients with Gilbert syndrome. c) Serum albumin ≥2.5 g/dL d) Aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 × ULN in the presence of liver metastases. e) Alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 × ULN in the presence of liver metastases. f) International normal ratio (INR) ≤1.5 or ≤ institutional ULN unless patient is receiving a stable dose of anticoagulant therapy and PT or aPPT is within therapeutic range of intended use of anticoagulants.
7. 6. Acceptable hematologic function (no red blood cell or platelet transfusions or growth factors are allowed within 4 weeks of the first dose of zelenectide pevedotin (BT8009); except for patients in the renal impairment cohorts; [Part C]): a) Hemoglobin ≥9 g/dL. b) Absolute neutrophil count (ANC) ≥1500 cells/mm3. c) Platelet count ≥75,000 cells/mm3.
8. 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 zelenectide pevedotin (BT8009)).
9. 8. Availability of archived tumor samples or willingness to provide fresh tumor biopsy during screening.
10. 9. Life expectancy ≥12 weeks after the start of zelenectide pevedotin (BT8009) treatment according to the Investigator's judgment.
11. 11. Additional cohort-specific inclusion criteria may apply.

Exclusion criteria 24

1. 1. Chemotherapy treatments within 14 days prior to first dose of study treatment. For other anticancer treatments, treatment within 28 days or 5 terminal half-lives, whichever is shorter. If prior immunotherapy, the last dose must be at least 28 days prior to the first dose of zelenectide pevedotin (BT8009). If prior radiation therapy, the last dose must be at least 14 days prior to the first dose of zelenectide pevedotin (BT8009). Prior toxicities must have resolved to Grade ≤1 per Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 (except alopecia, which must be no greater than Grade 2).
2. 18. History or another active malignancy that would interfere with the safety or efficacy evaluation of the clinical study.
3. 19. Active systemic infection requiring therapy, or fever not attributable to underlying malignancy within the last 14 days prior to first dose of zelenectide pevedotin (BT8009).
4. 2. Experimental treatments within 4 weeks of first dose of zelenectide pevedotin (BT8009).
5. 20. Suspicion of relevant and recent systemic viral syndrome or need for quarantine/isolation that is not resolved in the opinion of the Investigator.
6. 21. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.
7. 22. Prior Stevens-Johnson syndrome (SJS)/ toxic epidermal necrolysis (TEN) on any MMAE-conjugated drug.
8. 23. Adults under a legal protection regime: protection of justice, curatorship, guardianship as well as people hospitalized without consent, people deprived of liberty and persons incapable of expressing their consent
9. 24. Additional cohort-specific exclusion criteria may apply.
10. 10. Major surgery (excluding placement of vascular access) within 4 weeks of first dose of zelenectide pevedotin (BT8009) and must have recovered adequately prior to starting study therapy.
11. 3. Current treatment with strong inhibitors or strong inducers of CYP3A or inhibitors of P-gp including herbal- or food-based.
12. 4. Known hypersensitivity to any of the ingredients of the investigational product(s), including MMAE.
13. 5. Significant medical condition including but not limited to skin (conditions related to or that may confound monitoring for rash including but not limited to autoimmune conditions such as eczema or psoriasis), life-threatening illness, active uncontrolled infection or organ system dysfunction (such as ascites, coagulopathy, encephalopathy), or other reasons which, in the Investigator 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 co-morbidities and including review of screening chest CT to ensure no clinically significant co-morbidities. Treatment induced ≤ Grade 2 endocrinopathy is allowed, if appropriately controlled with supplemental hormone replacement and stable for at least 2 months on therapy. Skin toxicity should resolve to Grade ≤1.
14. 6. Active keratitis or corneal ulcerations.
15. 7. Grade ≥2 peripheral neuropathy.
16. 8. Clinically relevant troponin elevation (considering local reference standards).
17. 11. Receipt of live or attenuated vaccine within 30 days of study treatment.
18. 9. Uncontrolled diabetes, defined as hemoglobin A1C (HbA1c) ≥8%.
19. 12. Known active or untreated CNS metastases and/or carcinomatous meningitis. (To be eligible, patients with treated brain metastasis 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 less than or equal to 10 mg daily prednisone or equivalent and are without any symptoms that would confound the evaluation of neurologic and other AEs).
20. 13. Patients with uncontrolled hypertension (systolic blood pressure [BP] Systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg) prior to first dose of zelenectide pevedotin (BT8009).
21. 14. 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 zelenectide pevedotin (BT8009) 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. 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.
22. 15. 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 case-by-case basis.
23. 16. Patients with a positive hepatitis B surface antigen and/or anti-hepatitis B core antibody and a positive polymerase chain reaction (PCR).
24. 17. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. 1. Incidence of TEAEs, including lab, ECG, vital sign abnormalities (CTCAE v5.0) (A-1,A-2, B-8, B-9, &C).
2. 2. Incidence of dose-limiting tox (A-1,A-2).
3. 3. ORR per RECIST v1.1 criteria (B).
4. 4. Plasma concentrations of zelenectide pevedotin (BT8009) and MMAE with derivations including Cmax, Cmin, AUC, and elimination t(1/2) (D).

Secondary endpoints 8

1. 1. ORR, DOR, clinical benefit rate (CR + PR + SD ≥ 16 weeks), PFS, all assessed per RECIST v1.1 criteria, and OS (A, C and D).
2. 2. Plasma concentrations of zelenectide pevedotin (BT8009) and MMAE with derivations including Cmax, Cmin, AUC, and elimination half-life t(1/2) (A, B, C and D).
3. 3. Measurement of ADA (A, C and D).
4. 4. TEAEs and laboratory, ECG and vital sign abnormalities using CTCAE v5.0 criteria (B, D).
5. 5. DOR, clinical benefit rate (CR + PR + SD ≥ 16 weeks), PFS, all assessed per RECIST v1.1 criteria, and OS (B).
6. 6. ORR by Nectin-4 status per RECIST v1.1 criteria (B).
7. 7. Plasma concentrations of zelenectide pevedotin (BT8009) and MMAE with derivations including Cmax, Cmin, AUC, and elimination half-life t(1/2) (B).
8. 8. Measurement of ADA (B).

Investigational products

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

Test 3

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 26

Locations

3 EU/EEA countries · 13 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 23 files

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

Application history

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