HER2-positive Breast Cancer, Metastatic Breast Cancer
Conditions
Brief summary
This is an open-label, Phase 2 study to evaluate preliminary anti-tumor activity, safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of BDC-1001 administered as a single agent and in combination with pertuzumab in subjects with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) previously treated with trastuzumab deruxtecan (Enhertu®).
Detailed description
Eligible subjects will be randomly assigned in a 1:1 ratio to receive BDC-1001 as a single agent or BDC-1001 in combination with pertuzumab. Within each treatment arm, a Simon 2-stage design will be applied. Subjects will receive study treatment (i.e., BDC-1001 or BDC-1001 in combination with pertuzumab) for up to 24 months after Cycle 1 Day 1 (C1D1), until disease progression, unacceptable toxicity, or withdrawal for any reason. Bolt amended the protocol to transition any subjects still receiving BDC-1001 to continue receiving BDC-1001 in the Maintenance Phase. Subjects remaining on BDC-1001 will continue to receive BDC-1001 until a criterion for discontinuation has been met.
Interventions
DRUGBDC-1001
BDC-1001 is an immune-stimulating antibody conjugate (ISAC) designed to be delivered systemically (intravenously) and act locally by targeting HER2-expressing tumors and related metastatic disease for destruction by the innate and adaptive immune systems. BDC-1001 consists of an investigational biosimilar of the humanized monoclonal antibody (mAb) trastuzumab that is chemically conjugated to a toll-like receptor (TLR)7/8 agonist (payload) with an intervening non-cleavable, cell membrane impermeable linker.
DRUGPertuzumab
Pertuzumab is a monoclonal antibody that targets HER2 and prevents dimerization of HER2 with other members of the HER family (HER1, HER3, and HER4), thereby blocking ligand-activated downstream signaling.
Sponsors
Hoffmann-La Roche
Bolt Biotherapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Histologically confirmed adenocarcinoma of the breast that is HER2+ (IHC 3+ or gene amplification by ISH or NGS). * Have received 2 or more prior lines of anti-HER2-directed therapies, at least 1 in the metastatic setting and including trastuzumab deruxtecan. * Measurable disease as determined by RECIST v.1.1. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Have life expectancy of greater than 12 weeks per the Investigator. * All subjects must agree to have a biopsy prior to enrollment. If, in the judgment of the Investigator, a biopsy is not safely accessible or clinically feasible an archival tumor tissue sample must be submitted in lieu of a freshly collected specimen. Key
Exclusion criteria
* History of severe hypersensitivity to any ingredient of BDC-1001 or pertuzumab. * Previous treatment with a small molecule TLR7/8 agonist or TLR7/8 agonist that has been conjugated to tumor-targeting antibody such as ISACs within 12 months before starting study treatment. * Impaired cardiac function or history of clinically significant cardiac disease. * Human Immunodeficiency virus (HIV) infection, active hepatitis B infection, or hepatitis C infection. * Central nervous system metastases with the exception of disease that is asymptomatic, clinically stable, and has not required steroids for at least 28 days before starting study treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Per RECIST v1.1 as Assessed by Investigator | Up to approximately 1 year | Objective Response Rate (ORR) was defined as the proportion of participants with best overall response of confirmed Complete Response (CR) or Partial Response (PR) as determined by the treating Investigator using RECIST v1.1 criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) Per RECIST v1.1 as Assessed by Investigator | Up to approximately 1 year | Disease Control Rate (DCR) was the proportion of participants who achieved confirmed Complete Response (CR), Partial Response (PR), or Stable Disease (SD) lasting 23 or more weeks following the first dose of study treatment. |
| Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator | Up to approximately 1 year | Progression-free survival (PFS) was defined as the duration from the date of first study treatment administration (Cycle 1 Day 1) to the earliest date of documented PD per RECIST v1.1 or death. A death was considered a PFS event. |
| Overall Survival (OS) | Up to approximately 1 year | Overall Survival (OS) was defined as the duration from the date of first study treatment administration to the date of death, irrespective of cause. |
| Duration of Response (DOR) Per RECIST v1.1 as Assessed by Investigator | Up to approximately 1 year | Duration of Response (DOR) was calculated for participants who achieved confirmed CR or PR. For such participants, DOR is defined as the duration from the start date of CR or PR (whichever response status is observed first) and subsequently confirmed, to the earliest of documented date of PD per RECIST v 1.1 or death. Of the 8 participants with response assessments, there were no participants with PR or CR. Because there were no responses of PR or CR, the DOR cannot be calculated. |
| Number of Participants Who Had Any Treatment Emergent Adverse Event (TEAE) Related to Study Treatment | Continuously from first dose of study treatment through end of treatment and Safety Follow-Up. Up to approximately 1 year. | Treatment Emergent Adverse Events (TEAE) was defined as any AE that started on or after the first administration of study treatment. TEAEs were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. |
| Number of Participants With Any Treatment Emergent Serious Adverse Event (SAE) Related to Study Treatment | Continuously from first dose of study treatment through end of treatment and Safety Follow-Up. Up to approximately 1 year. | Treatment Emergent Adverse Events (TEAE) was defined as any AE that started on or after the first administration of study treatment. TEAEs were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. A Serious Adverse Event (SAE) was defined as an AE event that resulted in death, was life-threatening, required or prolongs hospitalization, caused persistent or significant disability or incapacity, resulted in congenital anomalies or birth defects, or was an important medical event. |
| Number of Participants With at Least 1 Treatment Emergent Adverse Event (TEAE) | Continuously from first dose of study treatment through end of treatment and Safety Follow-Up. Up to approximately 1 year | Treatment Emergent Adverse Events (TEAE) was defined as any AE that started on or after the first administration of study treatment. TEAEs were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. |
Countries
Spain, United States
Participant flow
Pre-assignment details
Participants were enrolled at study sites in the United States and Spain.
Participants by arm
| Arm | Count |
|---|---|
| BDC-1001 Single Agent Participants received BDC-1001 administered intravenously (IV) every 2 weeks | 6 |
| BDC-1001 in Combination With Pertuzumab Participants received BDC-1001 administered intravenously (IV) every 2 weeks, in combination with pertuzumab administered intravenously (IV) as a fixed non-weight-based dose of 840-mg IV loading dose and then 420-mg IV maintenance dose every 3 weeks. | 5 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Progressive Disease | 1 | 0 |
| Overall Study | Study Terminated by Sponsor | 2 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | BDC-1001 Single Agent | BDC-1001 in Combination With Pertuzumab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 6 | 0 / 5 |
| other Total, other adverse events | 6 / 6 | 5 / 5 |
| serious Total, serious adverse events | 2 / 6 | 2 / 5 |
Outcome results
Primary
Objective Response Rate (ORR) Per RECIST v1.1 as Assessed by Investigator
Objective Response Rate (ORR) was defined as the proportion of participants with best overall response of confirmed Complete Response (CR) or Partial Response (PR) as determined by the treating Investigator using RECIST v1.1 criteria.
Time frame: Up to approximately 1 year
Population: Three of the 11 participants did not have response assessments.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BDC-1001 Single Agent | Objective Response Rate (ORR) Per RECIST v1.1 as Assessed by Investigator | 0 Participants |
| BDC-1001 in Combination With Pertuzumab | Objective Response Rate (ORR) Per RECIST v1.1 as Assessed by Investigator | 0 Participants |
Secondary
Disease Control Rate (DCR) Per RECIST v1.1 as Assessed by Investigator
Disease Control Rate (DCR) was the proportion of participants who achieved confirmed Complete Response (CR), Partial Response (PR), or Stable Disease (SD) lasting 23 or more weeks following the first dose of study treatment.
Time frame: Up to approximately 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BDC-1001 Single Agent | Disease Control Rate (DCR) Per RECIST v1.1 as Assessed by Investigator | 0 Participants |
| BDC-1001 in Combination With Pertuzumab | Disease Control Rate (DCR) Per RECIST v1.1 as Assessed by Investigator | 0 Participants |
Secondary
Duration of Response (DOR) Per RECIST v1.1 as Assessed by Investigator
Duration of Response (DOR) was calculated for participants who achieved confirmed CR or PR. For such participants, DOR is defined as the duration from the start date of CR or PR (whichever response status is observed first) and subsequently confirmed, to the earliest of documented date of PD per RECIST v 1.1 or death. Of the 8 participants with response assessments, there were no participants with PR or CR. Because there were no responses of PR or CR, the DOR cannot be calculated.
Time frame: Up to approximately 1 year
Population: DOR was not assessed as there were no participants with CR or PR.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BDC-1001 Single Agent | Duration of Response (DOR) Per RECIST v1.1 as Assessed by Investigator | 0 Participants |
| BDC-1001 in Combination With Pertuzumab | Duration of Response (DOR) Per RECIST v1.1 as Assessed by Investigator | 0 Participants |
Secondary
Number of Participants Who Had Any Treatment Emergent Adverse Event (TEAE) Related to Study Treatment
Treatment Emergent Adverse Events (TEAE) was defined as any AE that started on or after the first administration of study treatment. TEAEs were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
Time frame: Continuously from first dose of study treatment through end of treatment and Safety Follow-Up. Up to approximately 1 year.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BDC-1001 Single Agent | Number of Participants Who Had Any Treatment Emergent Adverse Event (TEAE) Related to Study Treatment | 3 Participants |
| BDC-1001 in Combination With Pertuzumab | Number of Participants Who Had Any Treatment Emergent Adverse Event (TEAE) Related to Study Treatment | 5 Participants |
Secondary
Number of Participants With Any Treatment Emergent Serious Adverse Event (SAE) Related to Study Treatment
Treatment Emergent Adverse Events (TEAE) was defined as any AE that started on or after the first administration of study treatment. TEAEs were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. A Serious Adverse Event (SAE) was defined as an AE event that resulted in death, was life-threatening, required or prolongs hospitalization, caused persistent or significant disability or incapacity, resulted in congenital anomalies or birth defects, or was an important medical event.
Time frame: Continuously from first dose of study treatment through end of treatment and Safety Follow-Up. Up to approximately 1 year.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BDC-1001 Single Agent | Number of Participants With Any Treatment Emergent Serious Adverse Event (SAE) Related to Study Treatment | 0 Participants |
| BDC-1001 in Combination With Pertuzumab | Number of Participants With Any Treatment Emergent Serious Adverse Event (SAE) Related to Study Treatment | 0 Participants |
Secondary
Number of Participants With at Least 1 Treatment Emergent Adverse Event (TEAE)
Treatment Emergent Adverse Events (TEAE) was defined as any AE that started on or after the first administration of study treatment. TEAEs were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
Time frame: Continuously from first dose of study treatment through end of treatment and Safety Follow-Up. Up to approximately 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BDC-1001 Single Agent | Number of Participants With at Least 1 Treatment Emergent Adverse Event (TEAE) | 6 Participants |
| BDC-1001 in Combination With Pertuzumab | Number of Participants With at Least 1 Treatment Emergent Adverse Event (TEAE) | 5 Participants |
Secondary
Overall Survival (OS)
Overall Survival (OS) was defined as the duration from the date of first study treatment administration to the date of death, irrespective of cause.
Time frame: Up to approximately 1 year
Population: All treated participants are included
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BDC-1001 Single Agent | Overall Survival (OS) | Surviving at last contact before data cut off | 4 Participants |
| BDC-1001 Single Agent | Overall Survival (OS) | Died due to any cause | 2 Participants |
| BDC-1001 in Combination With Pertuzumab | Overall Survival (OS) | Surviving at last contact before data cut off | 5 Participants |
| BDC-1001 in Combination With Pertuzumab | Overall Survival (OS) | Died due to any cause | 0 Participants |
Secondary
Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator
Progression-free survival (PFS) was defined as the duration from the date of first study treatment administration (Cycle 1 Day 1) to the earliest date of documented PD per RECIST v1.1 or death. A death was considered a PFS event.
Time frame: Up to approximately 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BDC-1001 Single Agent | Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator | 0.986 Months |
| BDC-1001 in Combination With Pertuzumab | Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator | 1.955 Months |