Study BT8009-100 in Subjects With Nectin-4 Expressing Advanced Malignancies

NCT ID: NCT04561362

Last Updated: 2025-11-14

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 329 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-17
• Study Completion Date: 2026-12-31

Brief Summary

This study is a Phase I/II, multicenter, first-in-human, open-label dose-escalation study of BT8009 given as a single agent and in combination with pembrolizumab in participants with advanced solid tumors associated with Nectin-4 expression or in participants with advanced solid tumor malignancies having renal insufficiency. The primary endpoints are: Dose limiting toxicities (Parts A-1 and A-2), Overall response rate per RECIST v1.1 (Parts B1-B7), Safety and tolerability (Parts B-8, B-9 and C), and characterization of the pharmacokinetics (Part D).

Detailed Description

This study will assess the safety and tolerability of BT8009 alone and in combination with pembrolizumab in patients with select advanced solid tumors. BT8009 will be given as a single agent in 3 different dosing schedules- weekly (28 day cycle), biweekly (28 day cycle) or dosing on day 1 and day 8 of a 3-weekly (21 day cycle) and in combination with pembrolizumab. There are four parts to this study. Part A is a dose escalation in patients with select advanced solid tumors primarily designed to evaluate safety and tolerability of BT8009 as monotherapy or in combination with pembrolizumab and to determine a recommended Phase II dose (RP2D). Following a selection of an RP2D, Part B, a dose expansion portion, will be initiated with the primary objective of clinical activity of BT8009 as a monotherapy or in combination with pembrolizumab in patients with select advanced solid tumors. Additionally Parts B-8 and B-9 will evaluate the safety and tolerability of an alternate dose and schedule of BT8009 monotherapy. Part C will evaluate safety and tolerability of RP2D in patients with renal insufficiency. Part D will further characterize the pharmacokinetics of BT8009 and MMAE.

Conditions

Urinary Bladder Neoplasm; Triple Negative Breast Neoplasms; Hormone Receptor Positive, HER2-negative Neoplasms; Hormone Receptor Positive, HER2-low Neoplasms; Breast Neoplasms; Non-Small-Cell Lung Neoplasms; Ovarian Neoplasm; Advanced Solid Tumor

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Part A-1 -BT8009 Monotherapy Dose Escalation

Participants will receive escalating doses of BT8009.

Group Type: EXPERIMENTAL

BT8009

Intervention Type: DRUG

Bicyclic Toxin Conjugate (BTC) administered either weekly (i.e., on Days 1, 8, 15, and 22) or biweekly (Days 1 and 15) on a 28-day cycle or on Days 1 and 8 of a 21-day cycle for participants in A-1. Participants in Cohorts A-2 and B-7 will receive BT8009 weekly on 21-day cycle. Participants in Parts B-1-B-6 will receive BT8009 weekly either on a 21-day or 28-day cycle. Participants in Parts B-8 and B-9 will receive BT8009 on Days 1 and 8 of a 21-day cycle. Participants in Cohort C will receive BT8009 once weekly (i.e., on Days 1, 8, 15, and 22) on a 28-day cycle. Participants in Part D will receive BT8009 once weekly on a 28-day cycle.

Part A-2 -BT8009 in Combination with Pembrolizumab Dose De-Escalation

Participants will receive BT8009 and a standard dose of pembrolizumab.

Group Type: EXPERIMENTAL

BT8009

Intervention Type: DRUG

Bicyclic Toxin Conjugate (BTC) administered either weekly (i.e., on Days 1, 8, 15, and 22) or biweekly (Days 1 and 15) on a 28-day cycle or on Days 1 and 8 of a 21-day cycle for participants in A-1. Participants in Cohorts A-2 and B-7 will receive BT8009 weekly on 21-day cycle. Participants in Parts B-1-B-6 will receive BT8009 weekly either on a 21-day or 28-day cycle. Participants in Parts B-8 and B-9 will receive BT8009 on Days 1 and 8 of a 21-day cycle. Participants in Cohort C will receive BT8009 once weekly (i.e., on Days 1, 8, 15, and 22) on a 28-day cycle. Participants in Part D will receive BT8009 once weekly on a 28-day cycle.

Pembrolizumab

Intervention Type: DRUG

Participants in Cohorts A-2 and B-7 will receive 200 mg IV over 30-minute infusion of pembrolizumab on Day 1 of each Q3W.

Cohort B-1 - BT8009 Monotherapy Dose Expansion

Participants will receive a selected dose of BT8009.

Group Type: EXPERIMENTAL

BT8009

Intervention Type: DRUG

Bicyclic Toxin Conjugate (BTC) administered either weekly (i.e., on Days 1, 8, 15, and 22) or biweekly (Days 1 and 15) on a 28-day cycle or on Days 1 and 8 of a 21-day cycle for participants in A-1. Participants in Cohorts A-2 and B-7 will receive BT8009 weekly on 21-day cycle. Participants in Parts B-1-B-6 will receive BT8009 weekly either on a 21-day or 28-day cycle. Participants in Parts B-8 and B-9 will receive BT8009 on Days 1 and 8 of a 21-day cycle. Participants in Cohort C will receive BT8009 once weekly (i.e., on Days 1, 8, 15, and 22) on a 28-day cycle. Participants in Part D will receive BT8009 once weekly on a 28-day cycle.

Cohort B-2- BT8009 Monotherapy Dose Expansion

Participants will receive a selected dose of BT8009.

Group Type: EXPERIMENTAL

BT8009

Intervention Type: DRUG

Bicyclic Toxin Conjugate (BTC) administered either weekly (i.e., on Days 1, 8, 15, and 22) or biweekly (Days 1 and 15) on a 28-day cycle or on Days 1 and 8 of a 21-day cycle for participants in A-1. Participants in Cohorts A-2 and B-7 will receive BT8009 weekly on 21-day cycle. Participants in Parts B-1-B-6 will receive BT8009 weekly either on a 21-day or 28-day cycle. Participants in Parts B-8 and B-9 will receive BT8009 on Days 1 and 8 of a 21-day cycle. Participants in Cohort C will receive BT8009 once weekly (i.e., on Days 1, 8, 15, and 22) on a 28-day cycle. Participants in Part D will receive BT8009 once weekly on a 28-day cycle.

Cohort B-3- BT8009 Monotherapy Dose Expansion

Participants will receive a selected dose of BT8009. .

Group Type: EXPERIMENTAL

BT8009

Intervention Type: DRUG

Bicyclic Toxin Conjugate (BTC) administered either weekly (i.e., on Days 1, 8, 15, and 22) or biweekly (Days 1 and 15) on a 28-day cycle or on Days 1 and 8 of a 21-day cycle for participants in A-1. Participants in Cohorts A-2 and B-7 will receive BT8009 weekly on 21-day cycle. Participants in Parts B-1-B-6 will receive BT8009 weekly either on a 21-day or 28-day cycle. Participants in Parts B-8 and B-9 will receive BT8009 on Days 1 and 8 of a 21-day cycle. Participants in Cohort C will receive BT8009 once weekly (i.e., on Days 1, 8, 15, and 22) on a 28-day cycle. Participants in Part D will receive BT8009 once weekly on a 28-day cycle.

Cohort B-4- BT8009 Monotherapy Dose Expansion

Participants will receive a selected dose of BT8009.

Group Type: EXPERIMENTAL

BT8009

Intervention Type: DRUG

Bicyclic Toxin Conjugate (BTC) administered either weekly (i.e., on Days 1, 8, 15, and 22) or biweekly (Days 1 and 15) on a 28-day cycle or on Days 1 and 8 of a 21-day cycle for participants in A-1. Participants in Cohorts A-2 and B-7 will receive BT8009 weekly on 21-day cycle. Participants in Parts B-1-B-6 will receive BT8009 weekly either on a 21-day or 28-day cycle. Participants in Parts B-8 and B-9 will receive BT8009 on Days 1 and 8 of a 21-day cycle. Participants in Cohort C will receive BT8009 once weekly (i.e., on Days 1, 8, 15, and 22) on a 28-day cycle. Participants in Part D will receive BT8009 once weekly on a 28-day cycle.

Cohort B-5- BT8009 Monotherapy Dose Expansion

Participants will receive a selected dose of BT8009.

Group Type: EXPERIMENTAL

BT8009

Intervention Type: DRUG

Bicyclic Toxin Conjugate (BTC) administered either weekly (i.e., on Days 1, 8, 15, and 22) or biweekly (Days 1 and 15) on a 28-day cycle or on Days 1 and 8 of a 21-day cycle for participants in A-1. Participants in Cohorts A-2 and B-7 will receive BT8009 weekly on 21-day cycle. Participants in Parts B-1-B-6 will receive BT8009 weekly either on a 21-day or 28-day cycle. Participants in Parts B-8 and B-9 will receive BT8009 on Days 1 and 8 of a 21-day cycle. Participants in Cohort C will receive BT8009 once weekly (i.e., on Days 1, 8, 15, and 22) on a 28-day cycle. Participants in Part D will receive BT8009 once weekly on a 28-day cycle.

Cohort B-6- BT8009 Monotherapy Dose Expansion

Participants will receive a selected dose of BT8009.

Group Type: EXPERIMENTAL

BT8009

Intervention Type: DRUG

Bicyclic Toxin Conjugate (BTC) administered either weekly (i.e., on Days 1, 8, 15, and 22) or biweekly (Days 1 and 15) on a 28-day cycle or on Days 1 and 8 of a 21-day cycle for participants in A-1. Participants in Cohorts A-2 and B-7 will receive BT8009 weekly on 21-day cycle. Participants in Parts B-1-B-6 will receive BT8009 weekly either on a 21-day or 28-day cycle. Participants in Parts B-8 and B-9 will receive BT8009 on Days 1 and 8 of a 21-day cycle. Participants in Cohort C will receive BT8009 once weekly (i.e., on Days 1, 8, 15, and 22) on a 28-day cycle. Participants in Part D will receive BT8009 once weekly on a 28-day cycle.

Cohort B-7- BT8009 in Combination with Pembrolizumab Dose Expansion

Participants will receive a selected dose of BT8009 and standard dose of pembrolizumab.

Group Type: EXPERIMENTAL

BT8009

Intervention Type: DRUG

Bicyclic Toxin Conjugate (BTC) administered either weekly (i.e., on Days 1, 8, 15, and 22) or biweekly (Days 1 and 15) on a 28-day cycle or on Days 1 and 8 of a 21-day cycle for participants in A-1. Participants in Cohorts A-2 and B-7 will receive BT8009 weekly on 21-day cycle. Participants in Parts B-1-B-6 will receive BT8009 weekly either on a 21-day or 28-day cycle. Participants in Parts B-8 and B-9 will receive BT8009 on Days 1 and 8 of a 21-day cycle. Participants in Cohort C will receive BT8009 once weekly (i.e., on Days 1, 8, 15, and 22) on a 28-day cycle. Participants in Part D will receive BT8009 once weekly on a 28-day cycle.

Pembrolizumab

Intervention Type: DRUG

Participants in Cohorts A-2 and B-7 will receive 200 mg IV over 30-minute infusion of pembrolizumab on Day 1 of each Q3W.

Part C - Renal Insufficiency BT8009 Monotherapy Dose Expansion

Participants will receive a selected dose of BT8009.

Group Type: EXPERIMENTAL

BT8009

Intervention Type: DRUG

Bicyclic Toxin Conjugate (BTC) administered either weekly (i.e., on Days 1, 8, 15, and 22) or biweekly (Days 1 and 15) on a 28-day cycle or on Days 1 and 8 of a 21-day cycle for participants in A-1. Participants in Cohorts A-2 and B-7 will receive BT8009 weekly on 21-day cycle. Participants in Parts B-1-B-6 will receive BT8009 weekly either on a 21-day or 28-day cycle. Participants in Parts B-8 and B-9 will receive BT8009 on Days 1 and 8 of a 21-day cycle. Participants in Cohort C will receive BT8009 once weekly (i.e., on Days 1, 8, 15, and 22) on a 28-day cycle. Participants in Part D will receive BT8009 once weekly on a 28-day cycle.

Part D - BT8009 Monotherapy Supplementary PK

Participants will receive a selected dose of BT8009.

Group Type: EXPERIMENTAL

BT8009

Intervention Type: DRUG

Bicyclic Toxin Conjugate (BTC) administered either weekly (i.e., on Days 1, 8, 15, and 22) or biweekly (Days 1 and 15) on a 28-day cycle or on Days 1 and 8 of a 21-day cycle for participants in A-1. Participants in Cohorts A-2 and B-7 will receive BT8009 weekly on 21-day cycle. Participants in Parts B-1-B-6 will receive BT8009 weekly either on a 21-day or 28-day cycle. Participants in Parts B-8 and B-9 will receive BT8009 on Days 1 and 8 of a 21-day cycle. Participants in Cohort C will receive BT8009 once weekly (i.e., on Days 1, 8, 15, and 22) on a 28-day cycle. Participants in Part D will receive BT8009 once weekly on a 28-day cycle.

Part B-8 - BT8009 Monotherapy Dose Expansion

Participants will receive a selected dose of BT8009.

Group Type: EXPERIMENTAL

BT8009

Intervention Type: DRUG

Bicyclic Toxin Conjugate (BTC) administered either weekly (i.e., on Days 1, 8, 15, and 22) or biweekly (Days 1 and 15) on a 28-day cycle or on Days 1 and 8 of a 21-day cycle for participants in A-1. Participants in Cohorts A-2 and B-7 will receive BT8009 weekly on 21-day cycle. Participants in Parts B-1-B-6 will receive BT8009 weekly either on a 21-day or 28-day cycle. Participants in Parts B-8 and B-9 will receive BT8009 on Days 1 and 8 of a 21-day cycle. Participants in Cohort C will receive BT8009 once weekly (i.e., on Days 1, 8, 15, and 22) on a 28-day cycle. Participants in Part D will receive BT8009 once weekly on a 28-day cycle.

Part B-9 - BT8009 Monotherapy Dose Expansion

Participants will receive a selected dose of BT8009.

Group Type: EXPERIMENTAL

BT8009

Intervention Type: DRUG

Bicyclic Toxin Conjugate (BTC) administered either weekly (i.e., on Days 1, 8, 15, and 22) or biweekly (Days 1 and 15) on a 28-day cycle or on Days 1 and 8 of a 21-day cycle for participants in A-1. Participants in Cohorts A-2 and B-7 will receive BT8009 weekly on 21-day cycle. Participants in Parts B-1-B-6 will receive BT8009 weekly either on a 21-day or 28-day cycle. Participants in Parts B-8 and B-9 will receive BT8009 on Days 1 and 8 of a 21-day cycle. Participants in Cohort C will receive BT8009 once weekly (i.e., on Days 1, 8, 15, and 22) on a 28-day cycle. Participants in Part D will receive BT8009 once weekly on a 28-day cycle.

Interventions

BT8009

Bicyclic Toxin Conjugate (BTC) administered either weekly (i.e., on Days 1, 8, 15, and 22) or biweekly (Days 1 and 15) on a 28-day cycle or on Days 1 and 8 of a 21-day cycle for participants in A-1. Participants in Cohorts A-2 and B-7 will receive BT8009 weekly on 21-day cycle. Participants in Parts B-1-B-6 will receive BT8009 weekly either on a 21-day or 28-day cycle. Participants in Parts B-8 and B-9 will receive BT8009 on Days 1 and 8 of a 21-day cycle. Participants in Cohort C will receive BT8009 once weekly (i.e., on Days 1, 8, 15, and 22) on a 28-day cycle. Participants in Part D will receive BT8009 once weekly on a 28-day cycle.

Intervention Type: DRUG

Pembrolizumab

Participants in Cohorts A-2 and B-7 will receive 200 mg IV over 30-minute infusion of pembrolizumab on Day 1 of each Q3W.

Intervention Type: DRUG

Other Intervention Names

Keytruda

Eligibility Criteria

Inclusion Criteria

• Life expectancy ≥12 weeks.
• Patients must have measurable disease per RECIST 1.1.
• Part A-1 cohorts:
• Must have exhausted all standard treatment options, including appropriate targeted therapies; or patients for which no standard therapy is considered appropriate
• Patients with advanced, histologically confirmed urothelial (transitional cell) carcinoma that recurred after or has been refractory to prior therapy (fresh tumor biopsy or an archived sample must be submitted); or
• Patients with advanced, histologically confirmed pancreatic, breast, non-small-cell lung cancer (NSCLC), gastric, esophageal, head and neck, or ovarian tumors that recurred after or has been refractory to prior therapy (fresh tumor biopsy or an archived sample testing for Nectin-4 expression).
• Part A-2:
• Must have exhausted all standard treatment options, including appropriate targeted therapies; or patients for which no standard therapy is considered appropriate
• Patients with advanced, histologically confirmed urothelial (transitional cell) carcinoma that have progressed following prior therapy
• Cohort B-1: Histologically documented urothelial carcinoma, previously treated with enfortumab vedotin (EV). Patients with resectable, locally advanced urothelial carcinoma are ineligible. Must have had progression or recurrence of urothelial cancer during or following receipt of most recent therapy.
• Cohort B-2 and B-3: Histologically documented urothelial carcinoma, not previously treated with enfortumab vedotin (EV). Patients with resectable, locally advanced urothelial carcinoma are ineligible. Must have had progression or recurrence of urothelial cancer during or following receipt of most recent therapy.
• Cohort B-4: Patients with histologically confirmed non-mucinous epithelial ovarian, fallopian tube, or primary peritoneal cancer that is Stage III or IV according to the International Federation of Gynecology and Obstetrics (FIGO) or tumor, node and metastasis staging criteria that have progressed following prior therapy.
• Cohort B-5: Patients with triple-negative breast cancer confirmed negative for estrogen receptor (ER) and progesterone receptor (PR) and negative for human epidermal growth factor receptor 2 (HER2) (i.e., triple-negative) that have progressed following prior therapy.
• Cohort B-6: Patients with histologically confirmed non-small cell lung cancer (NSCLC) with no actionable mutations, such as Epidermal Growth Factor Receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) fusion oncogene, or ROS1 that have progressed following prior therapy.
• Cohort B-7: Locally advanced or metastatic, histologically confirmed urothelial (transitional cell) carcinoma, ineligible for cisplatin, no prior systemic anticancer treatment for advanced urothelial carcinoma.
• Cohort B-8: Locally advanced (unresectable) or metastatic, histologically confirmed breast cancer, either TNBC or hormone receptor (HR) positive and HER-2 negative according to ASCO/CAP guidelines and up to 3 prior lines of therapy for advanced (unresectable) or metastatic disease.
• Cohort B-9: Histologically confirmed advanced/metastatic squamous or non-squamous NSCLC, negative for oncogenic driver mutations (EGFR, KRAS, ALK, BRAF, MET, ERRB2).
• Cohort C renal insufficiency cohort: Patients with histologically documented urothelial carcinoma, ovarian, triple negative breast, or non-small cell lung cancer that have been previously treated with a locally approved therapy.
• Part D supplementary PK: Patients must have histologically confirmed urothelial (transitional cell) carcinoma (patients with squamous differentiation or mixed cell types are eligible); ovarian; triple-negative breast; or non-small cell lung cancer that have been previously treated with a locally approved therapy.

Exclusion Criteria

• Clinically relevant troponin elevation
• Uncontrolled diabetes
• Known active or untreated CNS and/or carcinomatous meningitis
• Grade ≥2 peripheral neuropathy
• Active keratitis or corneal ulcerations
• Patients with uncontrolled hypertension
• History of another malignancy within 3 years before first dose of BT8009 or residual disease from a previously diagnosed malignancy (with some exceptions).
• Active systemic infection requiring therapy, or fever within the last 14 days prior to first dose of BT8009.
• Prior Stevens-Johnson syndrome/toxic epidermal necrolysis on any MMAE-conjugated drug
• Parts A-2 and B-7 Pembrolizumab Combination Cohorts:
• Prior organ transplant (including allogeneic)
• Diagnosis of clinically relevant immunodeficiency
• History of interstitial lung disease
• Parts B-8 and B-9: Prior treatment with an ADC containing an MMAE (vedotin) payload.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

BicycleTx Limited

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Meredith McKean, MD, MPH

Role: STUDY_CHAIR

Tennessee Oncology

Locations

Sarah Cannon Research Institute at HealthONE

Denver, Colorado, United States

Ocala Oncology Center

Ocala, Florida, United States

Advent Health

Orlando, Florida, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States

Thomas Jefferson University, Sidney Kimmel Cancer Center

Philadelphia, Pennsylvania, United States

Tennessee Oncology, PLLC

Nashville, Tennessee, United States

Mary Crowley Cancer Research Center

Dallas, Texas, United States

The University of Texas MD Anderson Cancer Center

Houston, Texas, United States

University Health Network, Princess Margaret Cancer Centre

Toronto, Ontario, Canada

Institut Bergonie

Bordeaux, , France

Centre Leon Berard

Lyon, , France

Institut Paoli-Calmettes

Marseille, , France

Centre Eugene Marquis

Rennes, , France

Institut Gustave Roussy

Villejuif, , France

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, MI, Italy

Ospedale San Raffaele

Milan, , Italy

Vall d'Hebron Institute of Oncology

Barcelona, , Spain

Hospital Clinic de Barcelona

Barcelona, , Spain

START Madrid Fundacion Jimenez Diaz

Madrid, , Spain

Next Oncology - Hospital Quironsalud Madrid

Pozuelo de Alarcón, , Spain

Hospital Universitario Marques de Valdecilla

Santander, , Spain

Sarah Cannon Research Institute UK

London, , United Kingdom

The Christie NHS Foundation Trust

Manchester, , United Kingdom

Countries

United States; Canada; France; Italy; Spain; United Kingdom

References

Baldini C, Verlingue L, Goldschmidt V, Doger de Speville B, Lostes J, Italiano A, Cousin S, Falchook GS, Necchi A, Reig Torras O, Fontana E, Carter L, Rodon Ahnert J, Brown JR, DeMars LR, Josephs K, Dickson A, Xu C, Bader J, Campbell C, Sharma R, McKean M. First-in-Human, Phase I/II Dose Escalation and Expansion Study of Zelenectide Pevedotin in Patients With Advanced Solid Tumors: Results From Monotherapy Dose Escalation. J Clin Oncol. 2025 Nov 6:JCO2500559. doi: 10.1200/JCO-25-00559. Online ahead of print.

Reference Type: DERIVED

PMID: 41197088 (View on PubMed)

Klumper N, Eckstein M, Holzel M, Herrmann K, Hadaschik B, Grunwald V. Re: First-in-Human Study of the Radioligand 68Ga-N188 Targeting Nectin-4 for PET/CT Imaging of Advanced Urothelial Carcinoma: Navigating Metastatic Urothelial Cancer with Nectin-4 PET/CT. Eur Urol. 2023 Nov;84(5):514-515. doi: 10.1016/j.eururo.2023.05.029. Epub 2023 Jun 5. No abstract available.

Reference Type: DERIVED

PMID: 37286457 (View on PubMed)

Other Identifiers

BT8009-100

Identifier Type: -

Identifier Source: org_study_id