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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part A-1 -BT8009 Monotherapy Dose Escalation | Experimental | Participants will receive escalating doses of BT8009. |
|
| Part A-2 -BT8009 in Combination with Pembrolizumab Dose De-Escalation | Experimental | Participants will receive BT8009 and a standard dose of pembrolizumab. |
|
| Cohort B-1 - BT8009 Monotherapy Dose Expansion | Experimental | Participants will receive a selected dose of BT8009. |
|
| Cohort B-2- BT8009 Monotherapy Dose Expansion | Experimental | Participants will receive a selected dose of BT8009. |
|
| Cohort B-3- BT8009 Monotherapy Dose Expansion | Experimental | Participants will receive a selected dose of BT8009. . |
|
| Cohort B-4- BT8009 Monotherapy Dose Expansion | Experimental |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| BT8009 | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Parts A-1, A-2 and C: Number of participants with treatment emergent adverse events, receiving BT8009 as a monotherapy or in combination with pembrolizumab to assess safety and tolerability. | Safety reported as incidence of treatment-emergent adverse events using CTCAE v5.0 criteria. | From cycle 1 day 1 until 30 days after the end of treatment or approximately 1 year |
| Parts A-1 and A-2 (escalations): Number of participants with dose limiting toxicities on BT8009 as a monotherapy or in combination with pembrolizumab | Number of patients who experience dose limiting toxicities BT8009 when given as a monotherapy or in combination with pembrolizumab. | 28 days (for cycles that are either 21 or 28 days in length depending on dosing schedule assigned) |
| Part B1-B7: Objective response rate (ORR) to assess the clinical activity of BT8009 as a monotherapy or in combination with pembrolizumab using RECIST 1.1. | Proportion of participants with confirmed complete response or partial response to BT8009 as a monotherapy or in combination with pembrolizumab according to RECIST 1.1 criteria. | Every 8 weeks for 12 months then every 12 weeks thereafter until disease progression or, death, or up to three years |
| Part D: Maximum plasma concentration (Cmax) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy | Plasma concentrations of BT8009 and MMAE from all participants taking BT8009 alone. | From Cycle 1 Day 1 through end of treatment or for up to 1 year |
| Part D: Minimum plasma concentration (Cmin) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy | Plasma concentrations of BT8009 and MMAE from all participants taking BT8009 alone | From Cycle 1 Day 1 through end of treatment or for up to 1 year |
| Measure | Description | Time Frame |
|---|---|---|
| Parts B-1-B-7: Number of participants with treatment emergent adverse events receiving BT8009 as a monotherapy or in combination with pembrolizumab to assess safety and tolerability. | Number of participants with advanced solid tumor malignancies associated with Nectin-4 expression receiving BT8009 as a monotherapy or in combination with pembrolizumab who experience treatment-emergent adverse events using CTCAE v5.0 criteria. |
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Key Inclusion Criteria
Key Exclusion Criteria (all patients):
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| Name | Affiliation | Role |
|---|---|---|
| Meredith McKean, MD, MPH | Tennessee Oncology | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Sarah Cannon Research Institute at HealthONE | Denver | Colorado | 80218 | United States | ||
| Ocala Oncology Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41197088 | Derived | 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 Dec 10;43(35):3728-3738. doi: 10.1200/JCO-25-00559. Epub 2025 Nov 6. | |
| 37286457 |
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Participants will receive a selected dose of BT8009. |
|
| Cohort B-5- BT8009 Monotherapy Dose Expansion | Experimental | Participants will receive a selected dose of BT8009. |
|
| Cohort B-6- BT8009 Monotherapy Dose Expansion | Experimental | Participants will receive a selected dose of BT8009. |
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| Cohort B-7- BT8009 in Combination with Pembrolizumab Dose Expansion | Experimental | Participants will receive a selected dose of BT8009 and standard dose of pembrolizumab. |
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| Part C - Renal Insufficiency BT8009 Monotherapy Dose Expansion | Experimental | Participants will receive a selected dose of BT8009. |
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| Part D - BT8009 Monotherapy Supplementary PK | Experimental | Participants will receive a selected dose of BT8009. |
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| Part B-8 - BT8009 Monotherapy Dose Expansion | Experimental | Participants will receive a selected dose of BT8009. |
|
| Part B-9 - BT8009 Monotherapy Dose Expansion | Experimental | Participants will receive a selected dose of BT8009. |
|
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| Pembrolizumab | 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 D: Area under the plasma concentration-time curve (AUC) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy | Plasma concentrations of BT8009 and MMAE from all participants taking BT8009 alone. | From Cycle 1 Day 1 through end of treatment or for up to 1 year |
| Part D: Elimination half-life (t1/2) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy | Plasma concentrations of BT8009 and MMAE from all participants taking BT8009 alone. | From Cycle 1 Day 1 through end of treatment or for up to 1 year |
| PartsB-8, B-9: Number of participants with treatment emergent adverse events receiving an alternative dosing regimen of BT8009 monotherapy to assess safety and tolerability. | Number of participants with advanced solid tumor malignancies associated with Nectin-4 expression receiving an alternative dose regimen of BT8009 as a monotherapy who experience treatment-emergent adverse events using CTCAE v5.0 criteria. | From cycle 1 day 1 until at least 30 days after the end of treatment (each cycle is 21 days) |
| From cycle 1 day 1 until at least 30 days after the end of treatment (each cycle is 21 or 28 days depending on the assigned dosing schedule) |
| Part B: Duration of Response time to assess preliminary anti-tumor activity of BT8009 as a monotherapy or in combination with pembrolizumab | Duration of objective response (complete or partial response) by RECIST 1.1 in participants receiving BT8009 as a monotherapy or in combination with pembrolizumab | Every 8 weeks for 12 months then every 12 weeks thereafter until disease progression or, death, or up to three years |
| Part B: Clinical benefit rate to assess the clinical activity of BT8009 as a monotherapy or in combination with pembrolizumab | Proportion of participants who have complete response (CR), partial response (PR), or stable disease (SD) for at least 16 weeks according to RECIST Version 1.1 criteria. | Every 8 weeks Parts A-1, A-2, and C) and every 9 weeks (cohorts B-8 and B-9) for 12 months then every 12 weeks thereafter until disease progression or death or up to 3 years |
| Part B: Progression-free survival time to assess the clinical activity of BT8009 as a monotherapy or in combination with pembrolizumab. | The time from the first day of study drug administration (Day 1) to disease progression according to RECIST 1.1 criteria in participants receiving BT8009 as a monotherapy or in combination with pembrolizumab. | Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death for up to three years |
| Part B: Overall survival time to assess the clinical activity of BT8009 as a monotherapy or in combination with pembrolizumab using RECIST 1.1 | The time from start of study drug administration (Day 1) until death due to any cause in participants receiving BT8009 as a monotherapy or in combination with pembrolizumab. | Every 8 weeks for the first 12 months then every 12 weeks until death, then every 3 months for up to 1 year after last patient accrued |
| Cohorts B-4, B-5, and B-6: Objective response rate by Nectin-4 status of BT8009 as a monotherapy in patients with selected solid tumor using RECIST 1.1. | Proportion of participants with confirmed complete response or partial response to BT8009 as a monotherapy according to RECIST 1.1 criteria categorized by Nectin-4 expression status. | Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death for up to three years |
| Parts A-1, A-2, B-8, B-9, and C: Objective response rate to assess preliminary anti-tumor activity of BT8009 as a monotherapy or in combination with pembrolizumab. | Proportion of participants with advanced solid tumor malignancies associated with Nectin-4 expression or advanced solid tumor malignancies having renal insufficiency with confirmed complete response or partial response according to RECIST 1.1 criteria | Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death or up to three years |
| Parts A-1, A-2, C and D: Duration of Response time to assess preliminary anti-tumor activity of BT8009 as a monotherapy or in combination with pembrolizumab. | Duration of objective response (complete or partial response) by RECIST 1.1 in participants with advanced solid tumor malignancies associated with Nectin-4 expression or advanced solid tumor malignancies having renal insufficiency receiving BT8009 as a monotherapy or in combination with pembrolizumab. | Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death or up to three years |
| Parts A-1, A-2, C and D: Clinical benefit rate to assess preliminary anti-tumor activity of BT8009 as a monotherapy or in combination with pembrolizumab | Proportion of participants with advanced solid tumor malignancies associated with Nectin-4 expression or advanced solid tumor malignancies having renal insufficiency who have complete response (CR), partial response (PR) or stable disease (SD) for at least 16 weeks according to the RECIST Version 1.1 criteria. | Every 8 weeks for the first 12 months then every 12 weeks until disease progression for up to 3 years |
| Parts A-1, A-2, C and D: Progression-free survival time (months) to assess preliminary anti-tumor activity of BT8009 as a monotherapy or in combination with pembrolizumab | The time from start of study drug administration until disease progression according to RECIST 1.1 in participants with advanced solid tumor malignancies associated with Nectin-4 expression or advanced solid tumor malignancies having renal insufficiency receiving BT8009 as a monotherapy or in combination with pembrolizumab. | Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death for up to three years |
| Parts A-1, A-2, C and D: Overall survival time (months) to assess preliminary anti-tumor activity of BT8009 as a monotherapy or in combination with pembrolizumab. | The time from start of study drug administration until death due to any cause in participants with advanced solid tumor malignancies associated with Nectin-4 expression or advanced solid tumor malignancies having renal insufficiency receiving BT8009 as a monotherapy or in combination with pembrolizumab. | Every 8 weeks for the first 12 months then every 12 weeks until disease progression, then every 3 months for up to 1 year after last patient is accrued |
| Part A, B and C: Maximum plasma concentration (Cmax) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy and in combination with pembrolizumab. | Plasma concentrations of BT8009 and MMAE from all participants taking BT8009 alone and in combination with pembrolizumab. | From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule) |
| Part A, B and C: Minimum plasma concentration (Cmin) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy and in combination with pembrolizumab. | Plasma concentrations of BT8009 and MMAE from all participants taking BT8009 alone and in combination with pembrolizumab. | From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule) |
| Part A, B and C: Area under the plasma concentration-time curve (AUC) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy and in combination with pembrolizumab. | Plasma concentrations of BT8009 and MMAE from all participants taking BT8009 alone and in combination with pembrolizumab. | From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule) |
| Part A, B and C: Elimination half-life (t1/2) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy and in combination with pembrolizumab. | Plasma concentrations of BT8009 and MMAE from all participants taking BT8009 alone and in combination with pembrolizumab. | From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule) |
| Part C: Maximum plasma concentration (Cmax) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy. | Plasma concentrations (for impact of renal impairment) of BT8009 and MMAE from Part C participants taking BT8009 as a monotherapy. | From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule) |
| Part C: Minimum plasma concentration (Cmin) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherap. | Plasma concentrations (for impact of renal impairment) of BT8009 and MMAE from Part C participants taking BT8009 as a monotherapy. | From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule) |
| Part C: Area under the plasma concentration-time curve (AUC) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy. | Plasma concentrations (for impact of renal impairment) of BT8009 and MMAE from Part C participants taking BT8009 as a monotherapy. | From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule) |
| Part C: Elimination half-life (t1/2) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy. | Plasma concentrations (for impact of renal impairment) of BT8009 and MMAE from Part C participants taking BT8009 as a monotherapy. | From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule) |
| All cohorts: Number of participants positive for anti-drug antibodies (ADA) to determine incidence of ADA | Number of participants positive for anti-drug antibodies (ADA) from all participants receiving BT8009 as a monotherapy or in combination with pembrolizumab | From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule) |
| Part D: Number of participants with treatment emergent adverse events receiving BT8009 as a monotherapy to assess safety and tolerability in participants with normal renal function or mild renal insufficiency. | Number of participants with advanced solid tumor malignancies associated with Nectin-4 expression receiving BT8009 with normal renal function or mild renal insufficiency who experience treatment-emergent adverse events using CTCAE v5.0 criteria. | From cycle 1 day 1 until at least 30 days after the end of treatment |
| Ocala |
| Florida |
| 34474 |
| United States |
| Advent Health | Orlando | Florida | 34747 | United States |
| Icahn School of Medicine at Mount Sinai | New York | New York | 10029 | United States |
| University Hospitals Cleveland Medical Center | Cleveland | Ohio | 44106 | United States |
| Thomas Jefferson University, Sidney Kimmel Cancer Center | Philadelphia | Pennsylvania | 19107 | United States |
| Tennessee Oncology, PLLC | Nashville | Tennessee | 37203 | United States |
| Mary Crowley Cancer Research Center | Dallas | Texas | 75230 | United States |
| The University of Texas MD Anderson Cancer Center | Houston | Texas | 77030 | United States |
| University Health Network, Princess Margaret Cancer Centre | Toronto | Ontario | M5G IZ5 | Canada |
| Institut Bergonie | Bordeaux | 33076 | France |
| Centre Leon Berard | Lyon | 69373 | France |
| Institut Paoli-Calmettes | Marseille | 13009 | France |
| Centre Eugene Marquis | Rennes | 35042 | France |
| Institut Gustave Roussy | Villejuif | 94805 | France |
| Fondazione IRCCS Istituto Nazionale dei Tumori | Milan | MI | 20133 | Italy |
| Ospedale San Raffaele | Milan | 20132 | Italy |
| Vall d'Hebron Institute of Oncology | Barcelona | 08035 | Spain |
| Hospital Clinic de Barcelona | Barcelona | 08036 | Spain |
| START Madrid Fundacion Jimenez Diaz | Madrid | 28040 | Spain |
| Next Oncology - Hospital Quironsalud Madrid | Pozuelo de Alarcón | 28223 | Spain |
| Hospital Universitario Marques de Valdecilla | Santander | 39008 | Spain |
| Sarah Cannon Research Institute UK | London | W1G 6AD | United Kingdom |
| The Christie NHS Foundation Trust | Manchester | M20 4BX | United Kingdom |
| Derived |
| 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. |
| ID | Term |
|---|---|
| D001749 | Urinary Bladder Neoplasms |
| D064726 | Triple Negative Breast Neoplasms |
| D001943 | Breast Neoplasms |
| D010051 | Ovarian Neoplasms |
| D051437 | Renal Insufficiency |
| ID | Term |
|---|---|
| D014571 | Urologic Neoplasms |
| D014565 | Urogenital Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D001745 | Urinary Bladder Diseases |
| D014570 | Urologic Diseases |
| D052801 | Male Urogenital Diseases |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D004701 | Endocrine Gland Neoplasms |
| D010049 | Ovarian Diseases |
| D000291 | Adnexal Diseases |
| D005831 | Genital Diseases, Female |
| D005833 | Genital Neoplasms, Female |
| D000091662 | Genital Diseases |
| D004700 | Endocrine System Diseases |
| D006058 | Gonadal Disorders |
| D007674 | Kidney Diseases |
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| ID | Term |
|---|---|
| C582435 | pembrolizumab |
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