Clinical trial NCT04561362: Study BT8009-100 in Subjects With Nectin-4 Expressing Advanced Malignancies
Official title: Phase I/II Study of the Safety, Pharmacokinetics, and Preliminary Clinical Activity of BT8009 in Patients With Nectin-4 Expressing Advanced Malignancies
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
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
Keywords: Nectin-4
Solid tumor
Transitional urothelial carcinoma
Renal insufficiency
Lead sponsor: BicycleTx Limited
Sponsor class: INDUSTRY
First posted: 2020-09-23
Enrollment: 329
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: Key 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.

Key Exclusion Criteria (all patients):

* 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-2 and B-3: Prior treatment with enfortumab vedotin Other protocol-defined Inclusion/Exclusion criteria may apply
* Parts B-8 and B-9: Prior treatment with an ADC containing an MMAE (vedotin) payload.

Primary outcomes:
measure: 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.
timeFrame: From cycle 1 day 1 until 30 days after the end of treatment or approximately 1 year
measure: Parts A-1 and A-2 (escalations): Number of participants with dose limiting toxicities on BT8009 as a monotherapy or in combination with pembrolizumab
timeFrame: 28 days (for cycles that are either 21 or 28 days in length depending on dosing schedule assigned)
measure: 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.
timeFrame: Every 8 weeks for 12 months then every 12 weeks thereafter until disease progression or, death, or up to three years
measure: Part D: Maximum plasma concentration (Cmax) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy
timeFrame: From Cycle 1 Day 1 through end of treatment or for up to 1 year
measure: Part D: Minimum plasma concentration (Cmin) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy
timeFrame: From Cycle 1 Day 1 through end of treatment or for up to 1 year
measure: Part D: Area under the plasma concentration-time curve (AUC) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy
timeFrame: From Cycle 1 Day 1 through end of treatment or for up to 1 year
measure: Part D: Elimination half-life (t1/2) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy
timeFrame: From Cycle 1 Day 1 through end of treatment or for up to 1 year
measure: 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.
timeFrame: From cycle 1 day 1 until at least 30 days after the end of treatment (each cycle is 21 days)
Secondary outcomes:
measure: 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.
timeFrame: 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)
measure: Part B: Duration of Response time to assess preliminary anti-tumor activity of BT8009 as a monotherapy or in combination with pembrolizumab
timeFrame: Every 8 weeks for 12 months then every 12 weeks thereafter until disease progression or, death, or up to three years
measure: Part B: Clinical benefit rate to assess the clinical activity of BT8009 as a monotherapy or in combination with pembrolizumab
timeFrame: Every 8 weeks for 12 months then every 12 weeks thereafter until disease progression or death or up to 3 years
measure: Part B: Progression-free survival time to assess the clinical activity of BT8009 as a monotherapy or in combination with pembrolizumab.
timeFrame: Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death for up to three years
measure: Part B: Overall survival time to assess the clinical activity of BT8009 as a monotherapy or in combination with pembrolizumab using RECIST 1.1
timeFrame: 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
measure: 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.
timeFrame: Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death for up to three years
measure: 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.
timeFrame: Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death or up to three years
measure: 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.
timeFrame: Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death or up to three years
measure: 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
timeFrame: Every 8 weeks for the first 12 months then every 12 weeks until disease progression for up to 3 years
measure: 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
timeFrame: Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death for up to three years
measure: 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.
timeFrame: 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
measure: 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.
timeFrame: 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)
measure: 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.
timeFrame: 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)
measure: 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.
timeFrame: 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)
measure: 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.
timeFrame: 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)
measure: Part C: Maximum plasma concentration (Cmax) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy.
timeFrame: 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)
measure: Part C: Minimum plasma concentration (Cmin) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherap.
timeFrame: 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)
measure: Part C: Area under the plasma concentration-time curve (AUC) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy.
timeFrame: 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)
measure: Part C: Elimination half-life (t1/2) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy.
timeFrame: 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)
measure: All cohorts: Number of participants positive for anti-drug antibodies (ADA) to determine incidence of ADA
timeFrame: 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)
measure: 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.
timeFrame: From cycle 1 day 1 until at least 30 days after the end of treatment
Other outcomes:
Locations:
city: Denver
country: United States
facility: Sarah Cannon Research Institute at HealthONE
state: Colorado
city: Ocala
country: United States
facility: Ocala Oncology Center
state: Florida
city: Orlando
country: United States
facility: Advent Health
state: Florida
city: Lafayette
country: United States
facility: Horizon Oncology Research
state: Indiana
city: Louisville
country: United States
facility: Norton Cancer Institute, Downtown
state: Kentucky
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson University, Sidney Kimmel Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Center
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Toronto
country: Canada
facility: University Health Network, Princess Margaret Cancer Centre
state: Ontario
city: Bordeaux
country: France
facility: Institut Bergonie
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Institut Paoli-Calmettes
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
state: MI
city: Milan
country: Italy
facility: Ospedale San Raffaele
city: Barcelona
country: Spain
facility: Vall d'Hebron Institute of Oncology
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: START Madrid Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Pozuelo de Alarcon
country: Spain
facility: Next Oncology - Hospital Quironsalud Madrid
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute UK
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
affiliation: Tennessee Oncology
name: Meredith McKean, MD, MPH
role: STUDY_CHAIR
References: