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

Phase I/II Study of the Safety, Pharmacokinetics, and Preliminary Clinical Activity of BT5528 in Patients With Advanced Malignancies Associated With EphA2 Expression

INTRODUCTION

  • Org Study ID: BT5528-100
  • Secondary ID: N/A
  • NTC ID: NCT04180371
  • Sponsor: BicycleTx Limited

BRIEF SUMMARY

This clinical trial is evaluating a drug called BT5528 alone and in combination with nivolumab in participants with advanced solid tumors historically known for expression of EphA2. 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 about how effective BT5528 is for the treatment of ovarian cancer, urothelial/bladder cancer, lung cancer (NSCLC), triple-negative breast cancer, head and neck cancer (HNSCC), and gastric/upper gastrointestinal cancer.
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.

  • Overall Status
    Recruiting
  • Start Date
    November 7, 2019
  • Phase
    Phase 1, Phase 2
  • Study Type
    Interventional

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Part A-1 and A-2(escalations): Number of participants receiving BT5528 alone and in combination with nivolumab with treatment-emergent adverse events

Primary Outcome 1 - Timeframe: From Cycle 1 Day 1 (each cycle is 28 days) until 30 days post last dose

Primary Outcome 2 - Measure: Part A-1 and A-2 (escalations): Maximum tolerated dose (MTD) by the number of participants with dose limiting toxicities from BT5528 treatment alone and in combination with nivolumab

Primary Outcome 2 - Timeframe: At the end of Cycle 1 (each cycle is 28 days)

Primary Outcome 3 - Measure: Part B: Objective response rate by RECIST 1.1 in participants with solid tumors historically known for high expression of EphA2 tumor expression receiving BT5528 treatment

Primary Outcome 3 - Timeframe: 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 during study treatment)

Primary Outcome 4 - Measure: Part B: Duration of response by RECIST 1.1 in participants with solid tumors historically known for high expression of EphA2 receiving BT5528 treatment

Primary Outcome 4 - Timeframe: 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 during study treatment)

Primary Outcome 5 - Measure: Part B: Clinical benefit rate by RECIST 1.1 in participants with solid tumors historically known for high expression of EphA2 receiving BT5528 treatment

Primary Outcome 5 - Timeframe: 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 during study treatment)

Primary Outcome 6 - Measure: Part B: Time to tumor progression by RECIST 1.1 in participants solid tumors historically known for high expression of EphA2 receiving BT5528 treatment

Primary Outcome 6 - Timeframe: 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 during study treatment)

Primary Outcome 7 - Measure: Part B: Progression-free survival by RECIST 1.1 in participants solid tumors historically known for high expression of EphA2 receiving BT5528 treatment

Primary Outcome 7 - Timeframe: 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 during study treatment)

Primary Outcome 8 - Measure: Part B: PFS at 6 months by RECIST 1.1 in participants with solid tumors historically known for high expression of EphA2 receiving BT5528 treatment

Primary Outcome 8 - Timeframe: 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)

Primary Outcome 9 - Measure: Part B: Overall survival (OS) at 1 year in participants solid tumors historically known for high expression of EphA2 receiving BT5528 treatment

Primary Outcome 9 - Timeframe: From Cycle 1 Day 1 (each cycle is 28 days) until death or loss of follow-up or withdrawal of consent

CONDITION

  • Advanced Solid Tumor Historically Known for High EphA2 Expression
  • Urothelial Cancer
  • Ovarian Cancer
  • Non-small Cell Lung Cancer
  • Head and Neck Cancer
  • Triple Negative Breast Cancer
  • Gastric/Upper Gastrointestinal Cancer

ELIGIBILITY

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

- At least 18 years-of-age at the time of signature of the informed consent form

- 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

- All patients must have tumor tissue (fresh or archived) available for analysis of EphA2 tumor expression and other biomarkers. In the absence of available tumor tissue, patients must be willing to undergo a biopsy to provide fresh tumor samples

- Life expectancy ≥12 weeks after the start of BT5528 treatment according to the Investigator's judgment.

- Must be willing and able to comply with the protocol and study procedures.
Additional inclusion criteria for Phase I (dose escalation phase, with BT5528 alone or in combination with nivolumab):
Metastatic recurrent histologically confirmed malignant solid tumors historically known for high EphA2 tumor expression. Confirmation of EphA2 expression prior to enrollment is not required for participants with ovarian cancer and specific other individual tumor types.

- Exhausted all appropriate treatment options per local guidelines
Additional inclusion criteria for Phase II (dose expansion phase, with BT5528 alone):
Participants with metastatic recurrent disease histologically confirmed to be non-small cell lung cancer, ovarian cancer, triple-negative breast cancer (TNBC), gastric/upper gastrointestinal (GI) cancer, head and neck (H&N) cancer, urothelial cancer are eligible and must have failed or are ineligible for all appropriate treatment options per local guidelines and must have evidence of radiographic progression on the most recent line of therapy

- Patients with urothelial cancer who have previously received treatment with enfortumab vedotin (EV) are eligible to the study. Patients who received EV and showed disease progression within 6 months of treatment start are planned for less than 50% of total patients enrolled in the cohort
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

- Prior toxicities must have resolved to Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 (except alopecia which can be Grade 2)

- Current treatment with strong inhibitors or inducers of CYP3A4 or strong inhibitors of P-gp

- Known sensitivity to any of the ingredients of the investigational product or monomethyl auristatin E (MMAE)

- 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

- Major surgery (excluding placement of vascular access) within 4 weeks of first dose of BT5528 study treatment and must have recovered adequately prior to starting study therapy

- Receipt of live vaccine within 30 days of study treatment

- Untreated CNS metastases or leptomeningeal disease

- Uncontrolled hypertension (systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg that is not responsive to intervention) at screening or prior to initiation of study drug.
History or current evidence of 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:
(a) Patients with history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure or symptoms of New York Heart Association Class III-IV documented within 6 months prior to first dose of BT5528 or: (i) Mean resting corrected QT interval (QTcF) >470 msec (ii) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval (iii) Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting electrocardiograms (ECGs), e.g., complete left bundle branch block, third degree heart block
Known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS). Note: Well controlled HIV will be allowed if the patient meets all the following criteria at inclusion:
CD4+ T-cell (CD4+) counts ≥350 cells/uL;

- HIV viral load <400 copies/mL - Without a history of opportunistic infection within the last 12 months. - On established antiretroviral therapy (ART) for at least 4 weeks. Use of anti-retroviral therapy is permitted, but should be discussed with the Medical Monitor on a case-by-case basis. - Patients with a positive hepatitis B surface antigen and/or anti-hepatitis B core antibody. Patients with a negative polymerase chain reaction (PCR) assay are permitted with appropriate antiviral therapy - Active hepatitis C infection with positive viral load if hepatitis C virus (HCV) antibody positive (if antibody is negative then viral load not applicable). Patients who have been treated for hepatitis C infection can be included if they have documented sustained virologic response of ≥12 weeks. - Thromboembolic events and/or bleeding disorders 3 months (e.g., deep vein thrombosis [DVT] or pulmonary embolism [PE]) prior to first dose - Prior history of pneumonitis with presence of residual symptoms - History of another malignancy within 3 years before the first dose of BT5528, or any evidence of residual disease from a previously diagnosed malignancy (excluding adequately treated with curative intent basal cell carcinoma, squamous cell of the skin, cervical intraepithelial neoplasia/cervical carcinoma in situ or melanoma in situ or ductal carcinoma in situ of the breast). - Systemic anti-infective treatment or fever within the last 14 days prior to first dose of BT5528 study treatment - Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.
Additional Exclusion Criteria (BT5528 in combination with nivolumab):
Prior intolerance to immune checkpoint inhibitor

- Known hypersensitivity to checkpoint inhibitor therapy

- 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
Additional Exclusion Criteria Part B Monotherapy cohort:
• Patients with leptomeningeal disease

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Hendrik-Tobias Arkenau, MD, PhD

Role: Study Chair

Affiliation: Sarah Cannon Research Institute UK

Overall Contact

Name: Hendrik-Tobias Arkenau, MD, PhD

Phone: 617-945-8155

Email: clinicalstudies@bicycletx.com

LOCATION

Facility Status Contact
Facility: California Cancer Associates for Research and Excellence, Inc.
Encinitas, California 92024
United States
Status: Recruiting Contact: Principal Investigator
Alberto Bessudo, MD

Facility: University of California, San Diego (UCSD) - Medical Center
La Jolla, California 92037
United States
Status: Recruiting Contact: Principal Investigator
Shumei Kato, MD

Facility: University of California - Irvine Medical Center
Orange, California 92868
United States
Status: Recruiting Contact: Principal Investigator
Misako Nagasaka, MD

Facility: Sarah Cannon Research Institute at HealthONE
Denver, Colorado 80218
United States
Status: Recruiting Contact: Principal Investigator
Gerald Falchook, MD, MS

Facility: Florida Cancer Specialists
Sarasota, Florida 34232
United States
Status: Recruiting Contact: Principal Investigator
Judy Wang, MD

Facility: Dana Farber Cancer Institute
Boston, Massachusetts 02215
United States
Status: Recruiting Contact: Principal Investigator
Julia Rotow, MD

Facility: Barbara Ann Karmanos Cancer Institute
Detroit, Michigan 48201
United States
Status: Recruiting Contact: Principal Investigator
Hirva Mamdani, MD

Facility: Stephenson Cancer Center (Oklahoma University)
Oklahoma City, Oklahoma 73104
United States
Status: Recruiting Contact: Principal Investigator
Babar Bashir, MD

Facility: Sidney Kimmel Cancer Center at Thomas Jefferson University
Philadelphia, Pennsylvania 19107
United States
Status: Recruiting Contact: Principal Investigator
Matthews Cara, MD

Facility: Women and Infants Hospital
Providence, Rhode Island 02905
United States
Status: Recruiting Contact: Principal Investigator
Meredith McKean, MD, MPH

Facility: Tennessee Oncology, PLLC
Nashville, Tennessee 37203
United States
Status: Recruiting Contact: Principal Investigator
Vivek Subbiah, MD

Facility: MD Anderson Cancer Center
Houston, Texas 77030
United States
Status: Recruiting Contact: Principal Investigator
Alexander Spira, MD

Facility: Virginia Cancer Specialists
Fairfax, Virginia 22031
United States
Status: Recruiting Contact: Principal Investigator
Smitha Menon, MD

Facility: Froedtert Hospital and the Medical College of Wisconsin
Milwaukee, Wisconsin 53226
United States
Status: Recruiting Contact: Principal Investigator
Dr. Nuria Kotecki

Facility: Institut Jules Bordet
Brussels, 1070
Belgium
Status: Recruiting Contact: Principal Investigator
Jean-Pascal Machiels, MD,PhD

Facility: Cliniques Universitaires Saint-Luc
Bruxelles, 9000
Belgium
Status: Recruiting Contact: Principal Investigator
Hans Prenen, MD, PhD

Facility: Antwerp University Hospital (UZA)
Edegem, 21565
Belgium
Status: Recruiting Contact: Principal Investigator
Dr. Sylvie Rottey

Facility: Universitair Ziekenhuis Gent (UZ)
Gent, 3722
Belgium
Status: Recruiting Contact: Principal Investigator
Joo-Hwan Park, MD

Facility: Gachon University Gil Medical Center
Incheon, 8035
Korea, Republic of
Status: Recruiting Contact: Principal Investigator
Sang Wun Kim, MD

Facility: Severance Hospital, Yonsei University Health System
Seoul, 28040
Korea, Republic of
Status: Recruiting Contact: Principal Investigator
Elena Garralda Cabanas, MD

Facility: Hospital Universitario Vall d'Hebron
Barcelona, 28050
Spain
Status: Recruiting Contact: Principal Investigator
Bernard Doger de Speville, MD

Facility: Hospital Fundación Jimenez Diaz
Madrid, CB2 0QQ
Spain
Status: Recruiting Contact: Principal Investigator
Emiliano Calvo Aller, MD

Facility: Centro Integral Oncologico Clara Campal
Madrid, W1G 6AD
Spain
Status: Recruiting Contact: Principal Investigator
Bristi Basu, MD

Facility: Cambridge University Hospitals NHS Foundation Trust
Cambridge, M20 4BX
United Kingdom
Status: Recruiting Contact: Principal Investigator
Elisa Fontana, MD

Facility: Sarah Cannon Research Institute UK
London, NE7 7DN
United Kingdom
Status: Recruiting Contact: Principal Investigator
Louise Carter, MBBS, PhD

Facility: The Christie NHS Foundation Trust
Manchester,
United Kingdom
Status: Recruiting Contact: Principal Investigator
Dr. Alistair Greystoke

Facility: Sir Bobby Robson Cancer Trials Research Centre, The Northern Center for Cancer Care, Freeman Hospital
Newcastle Upon Tyne,
United Kingdom
Status: Recruiting Contact: N/A