Phase 2 Randomized Open-Label Study of BDC-1001 Monotherapy and Combination with Pertuzumab in HER2-Positive Metastatic Breast Cancer Post-Trastuzumab Deruxtecan

Trial ID: 2023-506038-65-00
Protocol: BBI-20231001
Sponsor: Bolt Biotherapeutics Inc.

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Diseases & Conditions

Breast cancer metastatic

Objectives

The primary objective of this Phase 2, multi-center, randomized, open-label trial is to evaluate the preliminary **anti-tumor activity** of **BDC-1001** as a single agent and in combination with **pertuzumab** in subjects with previously treated **HER2-positive metastatic breast cancer**. This objective is clinically relevant as it aims to assess the potential efficacy of BDC-1001, which could provide a new therapeutic option for patients who have limited treatment alternatives after prior therapies.

Secondary objectives include:

**Efficacy**: To evaluate the preliminary anti-tumor activity of BDC-1001 as a single agent and in combination with pertuzumab in subjects with previously treated HER2+ MBC.
**Safety**: To determine the safety and tolerability of BDC-1001 as a single agent and in combination with pertuzumab in subjects with previously treated HER2+ MBC.
**Pharmacokinetics (PK)**: To evaluate the exposure profile of BDC-1001 as a single agent and in combination with pertuzumab in subjects with previously treated HER2+ MBC.
**Anti-Drug Antibodies (ADA)**: To evaluate the immunogenicity of BDC-1001 as a single agent and in combination with pertuzumab in subjects with previously treated HER2+ MBC.

Participants

The clinical trial involves a total of **34 participants** diagnosed with **HER2-positive metastatic breast cancer**. The study population includes both male and female subjects, aged 18 years and older, who have previously undergone at least two lines of anti-HER2 therapies, including trastuzumab deruxtecan. Participants are required to have a histologically confirmed adenocarcinoma of the breast that is HER2-positive, as per the 2018 ASCO/CAP HER2 testing guidelines. The trial population was selected based on their ability to understand and sign the informed consent form, adequate organ function, and an ECOG performance status of 0 or 1. Additionally, participants must have measurable disease according to RECIST v1.1 criteria and an expected life expectancy of greater than 12 weeks. Lifestyle considerations such as the use of effective contraceptive measures are mandated for women of childbearing potential and their male partners. The trial also includes a vulnerable population, ensuring comprehensive representation within the study. Participants must agree to provide a biopsy prior to enrollment, or submit archival tumor tissue if a fresh biopsy is not feasible.

Plans and Procedures

The clinical trial is a Phase 2, multi-center, randomized, open-label study designed to evaluate the preliminary anti-tumor activity of **BDC-1001** as a single agent and in combination with **pertuzumab** in subjects with **human epidermal growth factor receptor 2-positive metastatic breast cancer** who have been previously treated with trastuzumab deruxtecan. The trial will involve the administration of BDC-1001 and pertuzumab as solutions for infusion, delivered intravenously. The study is expected to commence on October 20, 2023, and conclude by October 20, 2027, with a maximum treatment period of 24 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as adequate organ function, prior treatment history, and measurable disease according to RECIST v1.1 criteria. Following successful screening, participants will be randomized to receive either BDC-1001 alone or in combination with pertuzumab. Regular follow-up visits will be scheduled to monitor treatment response, safety, and any adverse events, with assessments including vital signs, laboratory values, and electrocardiograms. The primary endpoint is the objective response rate, while secondary endpoints include duration of response, disease control rate, progression-free survival, overall survival, and the incidence of treatment-emergent adverse events graded according to NCI CTCAE v5.0.

The expected length of participant involvement is up to 24 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The end-of-study visit will occur after the completion of the treatment period or upon early termination, during which final assessments will be conducted to evaluate the overall outcomes of the trial. Participants are required to adhere to contraceptive measures during the study and for a specified period after its completion to prevent pregnancy-related risks associated with the investigational treatments.

Treatment

The clinical trial involves the administration of **BDC-1001**, an investigational **antineoplastic agent** developed by Bolt Biotherapeutics, Inc. BDC-1001 is provided as a **solution for infusion** and is administered **intravenously**. The dosing regimen for BDC-1001 is set at a maximum daily dose of 20 mg/kg, with a total maximum dose of 20 mg/kg over a treatment period of up to 24 weeks. The active substance in BDC-1001 is of chemical origin, and the formulation is not specifically designed for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

In addition to BDC-1001, the trial includes the administration of **Pertuzumab**, a non-experimental treatment used as a comparator. Pertuzumab is also provided as a **solution for infusion** and is administered **intravenously**. The maximum daily dose for Pertuzumab is 420 mg, with a total maximum dose of 420 mg over the same 24-week treatment period. Pertuzumab is a protein-based therapeutic agent, and like BDC-1001, it is not formulated for pediatric use. The combination of BDC-1001 and Pertuzumab aims to evaluate the preliminary anti-tumor activity in subjects with **HER2-positive metastatic breast cancer** who have been previously treated with Trastuzumab Deruxtecan.

Efficacy

Efficacy in this clinical trial will be assessed using several key endpoints. The primary endpoint is the **objective response rate** according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints include the duration of response, disease control rate, progression-free survival, and overall survival. Additionally, the incidence of treatment-emergent adverse events (AEs) and serious adverse events (SAEs) will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Changes from baseline in vital signs, laboratory values, and electrocardiograms (ECGs) will also be monitored.

Pharmacokinetic parameters such as Cmin and Cmax values will be obtained throughout the study and compared to the pharmacokinetic data from the Phase 1 single-agent BDC-1001 study using a population approach. The incidence of anti-drug antibodies will be evaluated as well. These efficacy parameters will be measured and collected at various timepoints throughout the trial, ensuring a comprehensive analysis of the treatment's impact on subjects with **Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer**. The trial is designed to provide a thorough evaluation of the anti-tumor activity of BDC-1001 both as a single agent and in combination with pertuzumab.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Be able to understand and sign the informed consent form.
Be age 18 years or older at the time of informed consent.
All subjects must agree to have a biopsy prior to enrollment. If, in the judgement of the Investigator, a biopsy is not safely accessible or clinically feasible an archival tumor tissue must be submitted in lieu of a freshly collected specimen.
Histologically confirmed adenocarcinoma of the breast that is HER2+ (per 2018 ASCO/CAP HER2 testing guidelines) by Clinical Laboratory Improvement Amendments (CLIA) certified laboratory assessment
Have received 2 or more prior lines of anti- human epidermal growth factor receptor 2 (HER2)-directed therapies, at least 1 of them is in the metastatic setting and 1 of the prior therapies needs to be trastuzumab deruxtecan (ENHERTU®). Prior neo-adjuvant or adjuvant therapy that resulted in relapse within 12 months of completion of therapy will be considered a line of treatment for metastatic disease
Have experienced disease progression on or been otherwise unsuitable for (eg, did not tolerate) the most recent therapy
Have measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria
Have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
Have expected life expectancy of greater than 12 weeks per the Investigator
Adequate organ function defined as per protocol.
Women of childbearing potential should agree not to donate eggs and must use a highly effective contraceptive measure (a method that can achieve a failure rate of less than 1% per year) during treatment and until 7 months after the end treatment. Highly effective, alternative non-hormonal contraceptive measures are preferred.
Potent men that are partners of women of childbearing potential must be willing to use condoms in combination with a second highly effective method of female contraception (as above) during the study and agree not to donate sperm from Screening through 7 months after completion of study. A male partner will be considered as potent unless surgically sterilized (with documentation of sterility).

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Exclusion Criteria

Central nervous system metastases with the exception of disease that is asymptomatic, clinically stable (without evidence of progression for at least 4 weeks by repeating imaging during study Screening), and has not required steroids for at least 28 days before starting study treatment.
Cardiac disease as described in the protocol.
Pulmonary disease including idiopathic pulmonary fibrosis, interstitial lung disease, pneumonitis requiring steroids, or symptomatic pleural effusion within 6 months before starting study treatment OR ongoing requirement for supplemental oxygen
Hepatic disease resulting in symptomatic ascites, encephalopathy, coagulopathy, esophageal/gastric varices, or persistent jaundice
Arterial thrombotic event, stroke, or transient ischemia attack within 6 months before starting study treatment
Bleeding diathesis or uncontrolled bleeding within 7 days before starting study treatment
Bone marrow transplant or solid organ transplant
Infection included in the protocol.
Autoimmune disease requiring systemic disease-modifying or immunosuppressive therapy within 2 years before starting study treatment. Exceptions include disease managed with only replacement therapies (eg, thyroxine, etc.)
Malignancy within 2 years before starting study treatment other than the disease under study. Exceptions include indolent or definitively treated disease not expected to require treatment during the study, affect the safety of subjects, or affect the endpoints of the trial
Any medical condition requiring corticosteroids (> 10 mg daily oral prednisone or equivalent) or other systemic immunosuppressive therapy within 28 days before starting study treatment. Exceptions include inhaled or topical steroids
Residual toxicity from previous treatment as described in the protocol
Prior anticancer therapies as described in protocol.
History of severe hypersensitivity to any ingredient of BDC-1001 or pertuzumab
Received live/attenuated virus vaccine within 28 days before starting study treatment
Major surgery within 28 days of starting study treatment
Radiation therapy within 2 weeks of C1D1
Actively enrolled in another clinical study, unless it is an observational (noninterventional) clinical study or the follow-up component of an interventional study
Subject is a lactating mother or pregnant as confirmed by pregnancy tests within 7 days prior to start of study treatment
Subject is unwilling or unable to follow protocol requirements.
Uncontrolled pleural effusion, pericardial effusion, or recurrent ascites drainage.
Any condition that, in the opinion of the Investigator, would interfere with evaluation of BDC-1001 and pertuzumab or interpretation of the subject’s safety or study results