Study BT5528-100 in Patients With Advanced Solid Tumors Associated With EphA2 Expression

• ClinicalTrials.gov Identifier: NCT04180371
• Recruitment Status: Recruiting
• First Posted: November 27, 2019
• Last Update Posted: January 7, 2021
• Sponsor: Bicycle Tx Limited
• Information provided by (Responsible Party): Bicycle Tx Limited

Tracking Information

• First Submitted Date: November 19, 2019
• First Posted Date: November 27, 2019
• Last Update Posted Date: January 7, 2021
• Actual Study Start Date: November 7, 2019
• Estimated Primary Completion Date: December 31, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 6, 2021)

• Phase I: Number of participants receiving BT5528 alone and in combination with nivolumab with treatment-emergent adverse events [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until 30 days post last dose ]
  Safety reported as incidence of treatment-emergent adverse events
• Phase I: Maximum tolerated dose (MTD) by the number of participants with dose limiting toxicities from BT5528 treatment alone and in combination with nivolumab [ Time Frame: At the end of Cycle 1 (each cycle is 28 days) ]
  Maximum Tolerated Dose (MTD)
• Phase II: Objective response rate by RECIST 1.1 in participants with adenocarcinoma non-small cell lung cancer or other identified tumor subtypes positive for EphA2 tumor expression receiving BT5528 treatment alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months) ]
  Objective Response Rate (ORR)
• Phase II: Duration of response by RECIST 1.1 in participants with adenocarcinoma non-small cell lung cancer or other identified tumor subtypes positive for EphA2 tumor expression receiving BT5528 treatment alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Duration of Response (DOR)
• Phase II: Clinical benefit rate by RECIST 1.1 in participants with adenocarcinoma non-small cell lung cancer or other identified tumor subtypes positive for EphA2 tumor expression receiving BT5528 treatment alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Clinical benefit rate
• Phase II: Time to tumor progression by RECIST 1.1 in participants with adenocarcinoma non-small cell lung cancer or other identified tumor subtypes positive for EphA2 tumor expression receiving BT5528 treatment alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Time to Progression (TTP)
• Phase II: Progression free survival by RECIST 1.1 in participants with adenocarcinoma non-small cell lung cancer or other identified tumor subtypes positive for EphA2 tumor expression receiving BT5528 treatment alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Progression free survival (PFS)
• Phase II: PFS at 6 months by RECIST 1.1 in participants with adenocarcinoma non-small cell lung cancer or other identified tumor subtypes positive for EphA2 tumor expression receiving BT5528 treatment alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months) ]
  Progression free survival (PFS)
• Phase II: Overall survival at 1 year in participants with adenocarcinoma non-small cell lung cancer or other identified tumor subtypes which are positive for EphA2 tumor expression receiving BT5528 treatment alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until death or loss of follow-up or withdrawal of consent (assessed every 3 months for up to 1 year) ]
  Overall survival (OS)

Original Primary Outcome Measures (submitted: November 26, 2019)

• Phase I: Number of participants receiving BT5528 alone and in combination with nivolumab with treatment-emergent adverse events [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until 30 days post last dose ]
  Safety reported as incidence of treatment-emergent adverse events
• Phase I: Maximum tolerated dose (MTD) by the number of participants with dose limiting toxicities from BT5528 treatment alone and in combination with nivolumab [ Time Frame: At the end of Cycle 1 (each cycle is 28 days) ]
  Maximum Tolerated Dose (MTD)
• Phase II: Objective response rate by RECIST 1.1 in participants with selected solid tumor indications receiving BT5528 treatment alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months) ]
  Objective Response Rate (ORR)
• Phase II: Duration of response by RECIST 1.1 in participants with selected solid tumor indications receiving BT5528 treatment alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Duration of Response (DOR)
• Phase II: Clinical benefit rate by RECIST 1.1 in participants with selected solid tumor indications receiving BT5528 treatment alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Clinical benefit rate
• Phase II: Time to tumor progression by RECIST 1.1 in participants with selected solid tumor indications receiving BT5528 treatment alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Time to Progression (TTP)
• Phase II: Progression free survival by RECIST 1.1 in participants with selected solid tumor indications receiving BT5528 treatment alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Progression free survival (PFS)
• Phase II: Progression free survival at 6 months by RECIST 1.1 in participants with selected solid tumor indications receiving BT5528 treatment alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months) ]
  Progression free survival (PFS)
• Phase II: Overall survival at 1 year in participants with selected solid tumor indications receiving BT5528 treatment alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until death or loss of follow-up or withdrawal of consent (assessed every 3 months for up to 1 year) ]
  Overall survival (OS)

Current Secondary Outcome Measures (submitted: January 6, 2021)

• Phase I: Objective response rate by RECIST 1.1 in participants with advanced solid tumors with high EphA2 levels receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Objective Response Rate (ORR)
• Phase I: Duration of response by RECIST 1.1 in participants with advanced solid tumors with high EphA2 levels receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Duration of Response (DOR)
• Phase I: Clinical benefit rate by RECIST 1.1 in participants with advanced solid tumors with high EphA2 levels receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Clinical benefit rate
• Phase I: Time to tumor progression by RECIST 1.1 in participants with advanced solid tumors with high EphA2 levels receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Time to progression (TTP)
• Phase I: Progression free survival time by RECIST 1.1 in participants with advanced solid tumors with high EphA2 levels receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Progression free survival (PFS)
• Phase I: Progression free survival at 6 months by RECIST 1.1 in participants with advanced solid tumors with high EphA2 levels receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months) ]
  Progression free survival (PFS)
• Phase I: Overall survival time at 12 months in participants with advanced solid tumors with high EphA2 levels receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until death or loss of follow-up or withdrawal of consent (assessed every 3 months up to 12 months ]
  Overall survival (OS)
• Phase II: Determination of the number of participants with non-small cell lung cancer or other identified tumor subtypes positive for EphA2 tumor expression receiving BT5528 alone and in combination with nivolumab with treatment-emergent adverse events [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until 30 days post last dose ]
• All phases: Determine the plasma concentrations of BT5528 in plasma from all participants taking BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1,and end of each cycle (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or withdrawal of consent(assessed up to 12 months ]
• All phases: Determine the plasma concentrations of MMAE in plasma from all participants taking BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1,and end of each cycle (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or withdrawal of consent(assessed up to 12 months ]
• All phases: Number of participants positive for anti-drug antibodies (ADA) from all participants receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1,and end of each cycle (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or withdrawal of consent(assessed up to 12 months ]

Original Secondary Outcome Measures (submitted: November 26, 2019)

• Phase I: Objective response rate by RECIST 1.1 in participants with advanced solid tumors with high EphA2 levels receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Objective Response Rate (ORR)
• Phase I: Duration of response by RECIST 1.1 in participants with advanced solid tumors with high EphA2 levels receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Duration of Response (DOR)
• Phase I: Clinical benefit rate by RECIST 1.1 in participants with advanced solid tumors with high EphA2 levels receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Clinical benefit rate
• Phase I: Time to tumor progression by RECIST 1.1 in participants with advanced solid tumors with high EphA2 levels receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Time to progression (TTP)
• Phase I: Progression free survival time by RECIST 1.1 in participants with advanced solid tumors with high EphA2 levels receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months ]
  Progression free survival (PFS)
• Phase I: Progression free survival at 6 months by RECIST 1.1 in participants with advanced solid tumors with high EphA2 levels receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months) ]
  Progression free survival (PFS)
• Phase I: Overall survival time at 12 months in participants with advanced solid tumors with high EphA2 levels receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until death or loss of follow-up or withdrawal of consent (assessed every 3 months up to 12 months ]
  Overall survival (OS)
• Phase II: Determination of the number of participants with non-small cell lung cancer receiving BT5528 alone and in combination with nivolumab with treatment-emergent adverse events [ Time Frame: From Cycle 1 Day 1 (each cycle is 28 days) until 30 days post last dose ]
• All phases: Maximum observed plasma concentration (Cmax) of BT5528 in plasma from all participants taking BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1,and end of each cycle (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or withdrawal of consent(assessed up to 12 months ]
• All phases: Minimum observed plasma concentration (Cmin) of BT5528 in plasma from all participants taking BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1,and end of each cycle (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or withdrawal of consent(assessed up to 12 months ]
• All phases: Area under the plasma concentration versus time curve (AUC) of BT5528 in plasma from all participants taking BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1,and end of each cycle (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or withdrawal of consent(assessed up to 12 months ]
• All phases: Biological terminal half-life (t1/2) of BT5528 in plasma from all participants taking BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1,and end of each cycle (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or withdrawal of consent(assessed up to 12 months ]
• All phases: Number of participants positive for anti-drug antibodies (ADA) from all participants receiving BT5528 alone and in combination with nivolumab [ Time Frame: From Cycle 1,and end of each cycle (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or withdrawal of consent(assessed up to 12 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study BT5528-100 in Patients With Advanced Solid Tumors Associated With EphA2 Expression
• Official Title: Phase I/II Study of the Safety, Pharmacokinetics, and Preliminary Clinical Activity of BT5528 in Patients With Advanced Malignancies Associated With EphA2 Expression

Brief Summary

This clinical trial is evaluating a drug called BT5528 alone and in combination with nivolumab in participants with advanced solid tumors that are identified as positive for EphA2 expression. The main goals of this study are to:

• Find the recommended dose of BT5528 that can be given safely to participants alone and in combination with nivolumab
• Learn more about the side effects of BT5528
• Learn more about BT5528 therapy alone and in combination with nivolumab.

Detailed Description

BT5528 consists of a bicyclic peptide (Bicycle®) which binds to EphA2, and is covalently attached to a spacer and a protease cleavable peptide linker attached to MMAE.

The Phase I/II multi-center, open-label trial will evaluate BT5528 administered once-weekly as a single agent and in combination with nivolumab. The Phase I portion is a dose escalation primarily designed to assess the safety and tolerability of BT5528 and to determine a recommended Phase II dose (RP2D). Following selection of a recommended Phase II dose (RP2D), a dose expansion portion will be initiated with the primary objective of evaluating the clinical activity of BT5528.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Advanced Solid Tumor Identified as Positive for EphA2 Tumor Expression by Central Laboratory (Phase 1)
• Non Small Cell Lung Cancer Identified as Positive for EphA2 Tumor Expression by Central Laboratory (Phase 2)

Intervention

• Drug: BT5528
  Participants will receive a 60-minute intravenous infusion of BT5528 once a week (Days 1, 8, 15, and 22) or every other week (Days 1 and 15) on a 4-week cycle at the selected dose.
• Drug: Nivolumab
  Participants will receive nivolumab at 480mg intravenous infusion every 4 weeks.
  Other Name: Opdivo

Study Arms

• Experimental: Phase I - Dose escalation (BT5528)
  Cohorts of participants will receive increasing doses of BT5528. It is expected that up to 48 participants will participate in this dose escalation arm.
  Intervention: Drug: BT5528
• Experimental: Phase I - Dose escalation combination (BT5528 & nivolumab)
  Cohorts of participants will receive increasing doses of BT5528 and a standard dose of nivolumab. It is expected that up to 24 participants will participate in this dose escalation combination arm.
  Interventions:

  • Drug: BT5528
  • Drug: Nivolumab
• Experimental: Phase II - Dose expansion 1 (BT5528)
  A cohort of participants will receive the selected dose of BT5528 as a monotherapy. It is expected that up to 40 patients with non-small cell lung cancer (NSCLC) with EGFR mutation and confirmed EphA2 tumor expression will participate in this dose expansion arm.
  Intervention: Drug: BT5528
• Experimental: Phase II - Dose expansion combination (BT5528 & nivolumab)
  A cohort of participants will receive the selected dose of BT5528 in combination with a standard dose of nivolumab. It is expected that up to 14 participants with non-small cell lung cancer without EGFR mutation and confirmed EphA2 tumor expression will participate in this dose expansion arm.
  Interventions:

  • Drug: BT5528
  • Drug: Nivolumab
• Experimental: Phase II - Dose expansion 2 (BT5528)
  A cohort of participants will receive the selected dose of BT5528 as a monotherapy. It is expected that up to 40 patients with NSCLC without EGFR mutation and confirmed EphA2 tumor expression will participate in this dose expansion arm.
  Intervention: Drug: BT5528

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 5, 2020): 166
• Original Estimated Enrollment (submitted: November 26, 2019): 152
• Estimated Study Completion Date: December 31, 2023
• Estimated Primary Completion Date: December 31, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

General Inclusion:

• 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
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• Acceptable renal, hepatic, hematologic and coagulation functions
• Negative pregnancy test for women of childbearing potential
• Male participants with female partners of childbearing potential and female participants of childbearing potential are required to follow highly effective contraception
• Availability of archived tumor samples or willingness to provide fresh tumor biopsy during screening for EphA2 assessment

Additional inclusion criteria for Phase I (dose escalation phase, with BT5528 alone or in combination with nivolumab):

• Metastatic recurrent histologically confirmed malignant solid tumors confirmed to have EphA2 tumor expression
• Exhausted all appropriate treatment options per local guidelines

Additional inclusion criteria for Phase II (dose expansion phase, with BT5528 alone or in combination with nivolumab):

• Participants with metastatic recurrent disease histologically confirmed to be adenocarcinoma subtype of NSCLC (adeno-NSCLC) are eligible and must have exhausted all appropriate treatment options per local guidelines including progression on or after platinum-based chemotherapy and appropriate therapies for driver mutations (if applicable).
• Confirmed EphA2 tumor expression

Exclusion criteria (all participants):

• Chemotherapy treatments within 14 days prior to first dose of study treatment, other anticancer treatments, treatment within 28 days or 5 half-lives, whichever is the shorter
• Experimental treatments within 4 weeks of first dose of BT5528
• Current treatment with strong inhibitors or inducers of CYP3A4 or strong inhibitors of P-gp
• Uncontrolled, symptomatic brain metastases
• 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 specific cardiovascular criteria
• Thromboembolic events and/or bleeding disorders 3 months (e.g., deep vein thrombosis [DVT] or pulmonary embolism [PE]) prior to first dose

Additional Exclusion Criteria (BT5528 in combination with nivolumab):

• Prior organ transplant (including allogeneic)
• Diagnosis of clinically relevant immunodeficiency
• Active systemic infection requiring therapy
• More than 10 mg daily prednisone equivalent or other strong immunosuppressant
• History of autoimmune disease except alopecia or vitiligo
• History of interstitial lung disease

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Bicycle Tx Limited; 617-945-8155; clinicalstudies@bicycletx.com

• Listed Location Countries: United Kingdom, United States

Administrative Information

• NCT Number: NCT04180371
• Other Study ID Numbers: BT5528-100
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Bicycle Tx Limited
• Study Sponsor: Bicycle Tx Limited
• Collaborators: Not Provided

Investigators

• Study Chair: Johanna Bendell; Tennessee Oncology

• PRS Account: Bicycle Tx Limited
• Verification Date: January 2021