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

Sponsor

BicycleTx Limited (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04561362

Collaborator

(none)

172

Enrollment

Locations

Arms

34.5

Anticipated Duration (Months)

8.6

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This clinical trial is evaluating a drug called BT8009 alone and in combination with nivolumab in participants with advanced solid tumors associated with Nectin-4 expression or in participants with advanced solid tumor malignancies having renal insufficiency.

The main goals of this study are to:

Find the recommended dose of BT8009 that can be given safely to participants alone and in combination with nivolumab
Learn more about the side effects and effectiveness of BT8009 alone and in combination with nivolumab
Learn more about BT8009 alone and in combination with nivolumab
Learn more about BT8009 alone in patients with kidney disease

Condition or Disease	Intervention/Treatment	Phase
Advanced Solid Tumor Urinary Bladder Neoplasm Pancreatic Neoplasms Triple Negative Breast Neoplasms Carcinoma, Non-Small-Cell Lung Stomach Neoplasm Esophageal Neoplasms Ovarian Neoplasm	Drug: BT8009 Drug: Nivolumab	Phase 1/Phase 2

Detailed Description

BT8009 consists of a Bicycle peptide (Bicycle®) which binds selectively to Nectin-4, and is covalently attached to a spacer and a cleavable linker attached to a cytotoxin (MMAE).

This study is a Phase I/II, multicenter, first-in-human, open-label dose-escalation study of BT8009 given as a single agent given once weekly and in combination with nivolumab. There are three 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 nivolumab and to determine a recommended Phase II dose (RP2D). Following a selection of a recommended Phase II dose (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 nivolumab in patients with select advanced solid tumors. Part C will evaluate safety and tolerability of chosen RP2D of BT8009 in patients with renal insufficiency.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

172 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I/II Study of the Safety, Pharmacokinetics, and Preliminary Clinical Activity of BT8009 in Patients With Nectin-4 Expressing Advanced Malignancies

Actual Study Start Date :

Jul 17, 2020

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Jun 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A-1 BT8009 Monotherapy Dose Escalation Participants will receive increasing doses of BT8009. It is expected that approximately 60 participants will participate in this dose escalation arm.	Drug: BT8009 Participants will receive a 60-minute IV infusion of BT8009 once weekly (i.e., on Days 1, 8, and 15, and 22) on a 28-day cycle.
Experimental: Cohort A-2 BT8009 and Nivolumab Dose Escalation Participants will receive increasing doses of BT8009 and a standard dose of nivolumab. It is expected that approximately 20 participants will participate in this dose escalation arm	Drug: BT8009 Participants will receive a 60-minute IV infusion of BT8009 once weekly (i.e., on Days 1, 8, and 15, and 22) on a 28-day cycle. Drug: Nivolumab Nivolumab will be a 240 mg dose every 2 weeks administered as per local labeling as a 30 minute intravenous infusion (window of -5 to +15 minutes). Other Names: Opdivo
Experimental: Cohort B-1 - Dose expansion (BT8009 alone) Participants will receive a selected dose of BT8009. It is expected that approximately 40 participants will participate in this dose expansion arm	Drug: BT8009 Participants will receive a 60-minute IV infusion of BT8009 once weekly (i.e., on Days 1, 8, and 15, and 22) on a 28-day cycle.
Experimental: Cohort B-2 - Dose expansion (BT8009 and nivolumab) Participants will receive a selected dose of BT8009 and a standard dose of nivolumab. It is expected that approximately 40 participants will participate in this dose expansion arm.	Drug: BT8009 Participants will receive a 60-minute IV infusion of BT8009 once weekly (i.e., on Days 1, 8, and 15, and 22) on a 28-day cycle. Drug: Nivolumab Nivolumab will be a 240 mg dose every 2 weeks administered as per local labeling as a 30 minute intravenous infusion (window of -5 to +15 minutes). Other Names: Opdivo
Experimental: Cohort C - Renal Insufficiency (BT8009 alone) Participants will receive a selected dose of BT8009. It is expected that approximately 12 participants will participate in this arm.	Drug: BT8009 Participants will receive a 60-minute IV infusion of BT8009 once weekly (i.e., on Days 1, 8, and 15, and 22) on a 28-day cycle.

Outcome Measures

Primary Outcome Measures

Cohorts A-1, A-2 and C: Number of participants with treatment emergent adverse events receiving BT8009 alone and in combination with nivolumab to assess safety and tolerability [From cycle 1 day 1 until 30 days after the end of treatment (each cycle is 28 days)]
Safety reported as incidence of treatment-emergent adverse events using CTCAE v5.0 criteria.
Cohort A-1 and A-2 (escalations): Number of participants with dose limiting toxicities on BT8009 alone and in combination with nivolumab [From cycle 1 day 1 to the end of cycle 1 (each cycle is 28 days)]
Number of patients who experience dose limiting toxicities BT8009 when given as a monotherapy and in combination with nivolumab.
Cohort B-1 and B-2 (expansions): Objective response rate (ORR) to assess the clinical activity of BT8009 as a monotherapy and in combination with nivolumab [Every 8 weeks for 12 months then every 12 weeks thereafter until disease progression or death or up to three years]
Proportion of participants with select solid tumors with confirmed complete response or partial response to BT8009 as a monotherapy and in combination with nivolumab according to RECIST 1.1 criteria
Cohort B-1 and B-2 (expansions): Duration of response to assess the clinical activity of BT8009 as a monotherapy and in combination with nivolumab [Every 8 weeks for 12 months then every 12 weeks thereafter until disease progression or death or up to three years]
Duration of response in participants with selected solid tumor indications receiving BT8009 treatment alone and in combination with nivolumab
Cohort B-1 and B-2 (expansions): Clinical benefit rate to assess the clinical activity of BT8009 as a monotherapy and in combination with nivolumab [Every 8 weeks for 12 months then every 12 weeks thereafter until disease progression or death or up to three years]
Proportion of participants with select solid tumors indications who have complete response (CR), partial response (PR) or stable disease (SD) for more than 6 weeks according to the RECIST Version 1.1 criteria.
Cohort B-1 and B-2 (expansions): Time to tumor progression to assess the clinical activity of BT8009 as a monotherapy and in combination [Every 8 weeks for 12 months then every 12 weeks thereafter until disease progression or death or up to 3 years]
Duration of time from start of study administration until disease progression according to RECIST 1.1 in participants with select solid tumor indications receiving BT8009 treatment alone and in combination with nivolumab
Cohort B-1 and B-2 (expansions): Progression free survival time to assess the clinical activity of BT8009 as a monotherapy and in combination with nivolumab [Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death for up to three years]
Duration of time from the first day of study drug administration (Day 1) to disease progression according to RECIST 1.1 criteria in participants receiving BT8009 treatment alone and in combination with nivolumab
Cohort B-1 and B-2 (expansions): Progression free survival rate at 6 months to assess the clinical activity of BT8009 as a monotherapy and in combination with nivolumab using RECIST 1.1 [Every 8 weeks after cycle 1 day 1 for 6 months (each cycle is 28 days)]
Proportion of participants receiving BT8009 as monotherapy and in combination with nivolumab and without disease progression at 6 months from the start of study drug administration according to RECIST 1.1 criteria
Cohort B-1 and B-2 (expansions): Overall survival rate at 12 months to assess the clinical activity of BT8009 as a monotherapy and in combination with nivolumab using RECIST 1.1 [Every 3 months for up to 1 year]
Proportion of participants receiving BT8009 as monotherapy and in combination with nivolumab who experience death within 1 year from start of study drug administration.

Secondary Outcome Measures

Part A-1 and A-2 and C: Objective response rate to assess preliminary anti-tumor activity of BT8009 as a monotherapy and in combination with nivolumab [Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death or up to three years]
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
Cohort A-1 and A-2 and C: Duration of Response time to assess preliminary anti-tumor activity of BT8009 as a monotherapy and in combination with nivolumab [Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death or up to three years]
Duration of 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 treatment alone and in combination with nivolumab
Cohort A-1 and A-2 and C: Clinical benefit rate to assess preliminary anti-tumor activity of BT8009 as a monotherapy and in combination with nivolumab [Every 8 weeks for the first 12 months then every 12 weeks until disease progression for up to 3 years]
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 more than 6 weeks according to the RECIST Version 1.1 criteria.
Cohort A-1 and A-2 and C: Time to progression to assess preliminary anti-tumor activity of BT8009 as a monotherapy and in combination with nivolumab [Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death for up to 3 years]
Duration of time from start of study 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 treatment alone and in combination with nivolumab
Cohort A-1 and A-2 and C: Progression free survival time to assess preliminary anti-tumor activity of BT8009 as a monotherapy and in combination with nivolumab [Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death for up to three years]
Duration of time from start of study 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 treatment alone and in combination with nivolumab
Cohort A-1 and A-2 and C: Progression free survival rate at 6 months to assess preliminary anti-tumor activity of BT8009 as a monotherapy and in combination with nivolumab [Every 8 weeks after cycle 1 day 1 for 6 months (each cycle is 28 days)]
Proportion of participants with advanced solid tumor malignancies associated with Nectin-4 expression or advanced solid tumor malignancies having renal insufficiency receiving BT8009 as monotherapy and in combination with nivolumab and without disease progression at 6 months from the start of study drug administration according to RECIST 1.1 criteria
Cohort A-1 and A-2 and C: Overall survival rate to assess preliminary anti-tumor activity of BT8009 as a monotherapy and in combination with nivolumab [Every 3 months for up to 1 year]
Proportion of participants with advanced solid tumor malignancies associated with Nectin-4 expression or advanced solid tumor malignancies having renal insufficiency receiving BT8009 as monotherapy and in combination with nivolumab who experience death within 1 year from start of study drug administration.
Cohort B1 and B2 (expansion): Number of participants with treatment emergent adverse events receiving BT8009 alone and in combination with nivolumab to assess safety and tolerability [From cycle 1 day 1 until 30 days after the end of treatment (each cycle is 28 days) or approximately 1 year]
Number of participants with advanced solid tumor malignancies associated with Nectin-4 expression receiving BT8009 alone or in combination with nivolumab who experience treatment-emergent adverse events using CTCAE v5.0 criteria.
All cohorts: Plasma concentrations of BT8009 and MMAE to determine its PK parameters [From Cycle 1 Day 1 through end of treatment (each cycle is 28 days) or for up to 1 year]
Plasma concentrations of BT8009 and MMAE from all participants taking BT8009 alone and in combination with nivolumab
All cohorts: Number of participants positive for anti-drug antibodies (ADA) to determine incidence of ADA [From Cycle 1 Day 1 through end of treatment (each cycle is 28 days) or for up to 1 year]
Number of participants positive for anti-drug antibodies (ADA) from all participants receiving BT8009 alone and in combination with nivolumab

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria

Life expectancy ≥12 weeks
Must have exhausted all standard treatment options, including appropriate targeted therapies, for example, EGFR or ALK therapies for relevant oncogene driver NSCLC patients; or available MMAE-containing ADC treatment in urothelial carcinoma; or patients for which no standard therapy is considered appropriate or to provide clinical benefit, as assessed by the Investigator.
Part A cohorts: Patients with the following tumor histology:

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 tumor that recurred after or has been refractory to prior therapy (fresh tumor biopsy or an archived sample testing positive for Nectin-4 expression)

Part B-1 and B-2 Nectin-4 basket monotherapy and combination cohorts: patients with solid tumor advanced, recurrent disease confirmed as Nectin-4 positive who must have failed at least one prior line of therapy and radiologically progressed on most recent line of therapy.
Part C renal insufficiency cohort: Patients with solid tumor, advanced disease who have renal insufficiency.

Key Exclusion Criteria (all patients)

Clinically relevant troponin elevation
Uncontrolled diabetes
Uncontrolled, symptomatic brain metastases
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).
Systemic IV anti-infective treatment, or fever within the last 14 days prior to first dose of BT8009.

Parts A-2 and B-2 Nivolumab Combination Cohorts Exclusion Criteria

Prior organ transplant (including allogeneic)
Active systemic infection requiring therapy
History of interstitial lung disease

Other protocol-defined Inclusion/Exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sarah Cannon Research Institute at HealthONE	Denver	Colorado	United States	80218
2	Ocala Oncology Center	Ocala	Florida	United States	34474
3	Norton Cancer Institute, Downtown	Louisville	Kentucky	United States	40202
4	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89169
5	University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
6	Thomas Jefferson University, Sidney Kimmel Cancer Center	Philadelphia	Pennsylvania	United States	19107
7	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37203
8	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
9	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
10	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G IZ5
11	Institut Bergonie	Bordeaux		France	33076
12	Centre Leon Berard	Lyon		France	69373
13	Institut Gustave Roussy	Villejuif		France	94805
14	Ospedale San Raffaele	Milan		Italy	20132
15	Vall d'Hebron Institute of Oncology	Barcelona		Spain	08035
16	Hospital Clinic de Barcelona	Barcelona		Spain	08036
17	START Madrid Fundacion Jimenez Diaz	Madrid		Spain	28040
18	Next Oncology - Hospital Quironsalud Madrid	Madrid		Spain	28223
19	Sarah Cannon Research Institute UK	London		United Kingdom	W1G 6AD
20	The Christie NHS Foundation Trust	Manchester		United Kingdom	M20 4BX