Triple Negative Breast Cancer
Conditions
Brief summary
Primary Objective: To evaluate the tumor Objective Response Rate (ORR), according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) of SAR566658 in participants with anti-carbonic anhydrase 6 (CA6)-positive metastatic triple negative breast cancer (TNBC). Part 1: To select the SAR566658 dose based on ORR and safety of 2 dose levels of SAR566658. Part 2: Part 2a: To demonstrate the activity of SAR566658 based on ORR in participants overexpressing CA6 (membrane intensity of 2+, 3+ in greater than or equal to (\>=) 30% of tumor cells) treated at the selected dose in an expanded cohort, in addition to the participants treated in Part 1. - Part 2b: To assess the efficacy in participants with metastatic TNBC and mild CA6 expression. Secondary Objectives: To assess: * Disease Control Rate (DCR), Duration of Response (DOR), Progression-Free Survival (PFS), and Time To Progression (TTP). * The impact of ocular primary prophylaxis on the incidence of keratopathies. * The potential immunogenicity of SAR566658. * To evaluate the global safety profile.
Detailed description
The duration of the study for 1 participant included a screening period of up to 21 days prior to first study drug administration, 3-week treatment cycle(s) (until 30 days after last SAR566658 administration), and a follow-up period. Each participant was treated until radiological disease progression, unacceptable toxicity, or participant's refusal of further study treatment.
Interventions
DRUGSAR566658 (ACT14884)
Pharmaceutical form:Solution Route of administration: Intravenous
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
: * Measurable Metastatic TNBC. * Participants with CA6-positive disease. * Participants received at least 1 prior chemotherapy regimen but no more than 3 for advanced/metastatic disease. * Prior anticancer therapy must have contained anthracycline (eg, doxorubicin), if not contraindicated, and a taxane (eg, docetaxel, paclitaxel) in an adjuvant/neo-adjuvant or metastatic setting.
Exclusion criteria
* Eastern Cooperative Oncology Group (ECOG) performance status \>=2. * Participant less than 18 years old. * Pregnant or breast-feeding women. * Participants with reproductive potential who do not agree to use accepted and effective method of contraception during the study treatment period and for 6 months following discontinuation of study drug. * Wash out period of less than 3 weeks or 5 half-lives from previous antitumor chemotherapy, immunotherapy, or any investigational treatment. * History of brain metastasis (other than totally resected or previously irradiated and nonprogressive/relapsed), spinal cord compression or carcinomatous meningitis, or new evidence of brain leptomeningeal disease. * Prior treatment with eribulin as last prior therapy or prior maytansinoid treatments (DM1 or DM4 antibody-drug conjugates \[ADCs\]). * Known intolerance to infused protein products including other monoclonal antibodies and ADCs. * Poor bone marrow reserve and/or poor organ function. * Symptomatic peripheral neuropathy Grade \>=2. * Previous history of chronic corneal diseases (even if asymptomatic) or unresolved acute nonrecurrent corneal conditions. * Participants wearing contact lenses who are not willing to stop wearing them for the duration of the study. * Medical conditions requiring concomitant administration of strong Cytochrome P450 3A4 (CYP3A4) inhibitors, unless it could be discontinued at least 2 weeks before 1st administration of SAR566658. * Contraindications to the use of ophthalmic vasoconstrictor and/or corticosteroid. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Investigational Medicinal Product (IMP)-Related Predefined Safety Criteria Findings | Up to Cycle 2 (each cycle of 21 days) | Predefined safety criteria was defined as occurrence of following IMP-related treatment-emergent adverse event (TEAE) (based on National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] v4.03): Grade greater than or equal to (\>=) 3 TEAE from the System Organ Class (SOC) of eye disorders, Grade \>=3 peripheral neuropathy (Preferred Term), Grade \>=4 TEAE. Per NCI-CTCAE v4.03, Adverse Events (AE) were graded as follows: Grade 1: Mild; asymptomatic/mild symptoms; Grade 2: Moderate; minimal, local or non-invasive intervention indicated; Grade 3: Severe or medically significant; hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening consequences; Grade 5: Death related to AE. |
| Percentage of Participants With Objective Response | Baseline, every 6 weeks until radiological disease progression or study cut-off, whichever comes first (maximum number of cycles was 3, each cycle 21 days) | Objective Response in participants was defined as the participants with complete response (CR) and partial response (PR) as best response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). As per RECIST 1.1, CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Baseline, every 6 weeks until radiological disease progression or study cut-off, whichever comes first (maximum number of cycles was 3, each cycle 21 days) | DOR was defined as the time from the first documentation of objective tumor response (CR or PR) to the first radiological documentation of tumor progression or death (due to any cause), whichever comes first. As per RECIST 1.1, CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. |
| Progression Free Survival (PFS) | Baseline, every 6 weeks until radiological disease progression or study cut-off, whichever comes first (maximum number of cycles was 3, each cycle 21 days) | PFS was defined as the time interval between the date of first study treatment administration and the date of documented tumor progression or death (due to any cause), whichever comes first. As per RECIST 1.1, progression was defined as at least a 20% increase in the sum of diameters of target lesions. |
| Time to Tumor Progression (TTP) | Baseline, every 6 weeks until radiological disease progression or study cut-off, whichever comes first (maximum number of cycles was 3, each cycle 21 days) | TTP was defined as the time interval between the date of first study treatment administration and the date of the first radiologically documented tumor progression. As per RECIST 1.1, progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. |
| Number of Participants With Keratopathies (Corneal Toxicity) | Up to 30 days after last drug administration (maximum number of cycles was 3, each cycle 21 days) | Keratopathy is an eye disorder that involves a blister-like swelling of the cornea (the clear layer in front of the iris and pupil). All participants received ocular primary prophylaxis in each eye in order to prevent the occurrence of keratopathies at the time of each infusion (vasoconstrictor, ophthalmic topical steroid, and cold mask on eyes) and steroid eye drops for an additional 2 days following SAR566658 administration. |
| Number of Participants With Positive Anti-SAR566658 Antibodies Response | Up to 3 treatment cycles, each cycle 21 days | — |
| Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events (SAE) | Up to 30 days after last drug administration (maximum number of cycles was 3, each cycle 21 days) | AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAEs were defined as AEs that developed or worsened in grade or became serious during the on-treatment period (the time from the first treatment administration to the last treatment administration +30 days). An SAE is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a medically important event. |
| Percentage of Participants With Disease Control | Baseline, every 6 weeks until radiological disease progression or study cut-off, whichever comes first (maximum number of cycles was 3, each cycle 21 days) | Disease control in participants was defined as the participants with CR, PR and stable disease (SD) with a duration of at least 3 months. As per RECIST 1.1, CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of diameters of target lesions) taking as reference the smallest sum diameters while on study. |
Countries
Belgium, Czechia, Italy, Netherlands, Spain
Participant flow
Recruitment details
The study was conducted at 13 sites in 5 countries from 23 March 2017 to 07 September 2018.
Pre-assignment details
A total of 23 participants who met all of the inclusion criteria and none of the exclusion criteria were enrolled in the study and included in Part 1. The study was prematurely terminated due to safety reasons, hence Part 2 was not conducted and no analysis was performed.
Participants by arm
| Arm | Count |
|---|---|
| SAR566658 90 mg/m^2 Participants received SAR566658 90 mg/m\^2 as intravenous infusion on Day 1 and Day 8 of each 21-day treatment cycle (maximum number of cycles received was 3). | 11 |
| SAR566658 120 mg/m^2 Participants received SAR566658 120 mg/m\^2 as intravenous infusion on Day 1 and Day 8 of each 21-day treatment cycle (maximum number of cycles received was 3). | 12 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 |
| Overall Study | Disease progression | 7 | 9 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | SAR566658 120 mg/m^2 | Total | SAR566658 90 mg/m^2 |
|---|---|---|---|
| Age, Continuous | 50.33 years STANDARD_DEVIATION 15.3 | 53.39 years STANDARD_DEVIATION 13.61 | 56.73 years STANDARD_DEVIATION 11.23 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 23 Participants | 11 Participants |
| Sex: Female, Male Female | 12 Participants | 23 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 | 0 / 11 | 0 / 12 |
| other Total, other adverse events | 11 / 11 | 12 / 12 |
| serious Total, serious adverse events | 1 / 11 | 6 / 12 |
Outcome results
Primary
Number of Participants With Investigational Medicinal Product (IMP)-Related Predefined Safety Criteria Findings
Predefined safety criteria was defined as occurrence of following IMP-related treatment-emergent adverse event (TEAE) (based on National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] v4.03): Grade greater than or equal to (\>=) 3 TEAE from the System Organ Class (SOC) of eye disorders, Grade \>=3 peripheral neuropathy (Preferred Term), Grade \>=4 TEAE. Per NCI-CTCAE v4.03, Adverse Events (AE) were graded as follows: Grade 1: Mild; asymptomatic/mild symptoms; Grade 2: Moderate; minimal, local or non-invasive intervention indicated; Grade 3: Severe or medically significant; hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening consequences; Grade 5: Death related to AE.
Time frame: Up to Cycle 2 (each cycle of 21 days)
Population: Analysis was performed on participants evaluable for predefined safety criteria population which included participants treated in the study and had completed 2 cycles, or who experienced predefined safety criteria.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SAR566658 90 mg/m^2 | Number of Participants With Investigational Medicinal Product (IMP)-Related Predefined Safety Criteria Findings | Grade>=3 related TEAE from SOC Eye disorders | 2 Participants |
| SAR566658 90 mg/m^2 | Number of Participants With Investigational Medicinal Product (IMP)-Related Predefined Safety Criteria Findings | Grade>=3 related peripheral neuropathy | 0 Participants |
| SAR566658 90 mg/m^2 | Number of Participants With Investigational Medicinal Product (IMP)-Related Predefined Safety Criteria Findings | Grade>=4 related TEAE | 0 Participants |
| SAR566658 120 mg/m^2 | Number of Participants With Investigational Medicinal Product (IMP)-Related Predefined Safety Criteria Findings | Grade>=3 related TEAE from SOC Eye disorders | 2 Participants |
| SAR566658 120 mg/m^2 | Number of Participants With Investigational Medicinal Product (IMP)-Related Predefined Safety Criteria Findings | Grade>=3 related peripheral neuropathy | 0 Participants |
| SAR566658 120 mg/m^2 | Number of Participants With Investigational Medicinal Product (IMP)-Related Predefined Safety Criteria Findings | Grade>=4 related TEAE | 0 Participants |
Primary
Percentage of Participants With Objective Response
Objective Response in participants was defined as the participants with complete response (CR) and partial response (PR) as best response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). As per RECIST 1.1, CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Baseline, every 6 weeks until radiological disease progression or study cut-off, whichever comes first (maximum number of cycles was 3, each cycle 21 days)
Population: Analysis was performed on all-treated population which included participants who actually received at least 1 dose or any partial dose of SAR566658.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SAR566658 90 mg/m^2 | Percentage of Participants With Objective Response | 9.1 percentage of participants |
| SAR566658 120 mg/m^2 | Percentage of Participants With Objective Response | 8.3 percentage of participants |
Secondary
Duration of Response (DOR)
DOR was defined as the time from the first documentation of objective tumor response (CR or PR) to the first radiological documentation of tumor progression or death (due to any cause), whichever comes first. As per RECIST 1.1, CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions.
Time frame: Baseline, every 6 weeks until radiological disease progression or study cut-off, whichever comes first (maximum number of cycles was 3, each cycle 21 days)
Population: Data for this outcome measure was not collected and analyzed due to early termination of the study.
Secondary
Number of Participants With Keratopathies (Corneal Toxicity)
Keratopathy is an eye disorder that involves a blister-like swelling of the cornea (the clear layer in front of the iris and pupil). All participants received ocular primary prophylaxis in each eye in order to prevent the occurrence of keratopathies at the time of each infusion (vasoconstrictor, ophthalmic topical steroid, and cold mask on eyes) and steroid eye drops for an additional 2 days following SAR566658 administration.
Time frame: Up to 30 days after last drug administration (maximum number of cycles was 3, each cycle 21 days)
Population: Analysis was performed on all treated population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SAR566658 90 mg/m^2 | Number of Participants With Keratopathies (Corneal Toxicity) | 3 Participants |
| SAR566658 120 mg/m^2 | Number of Participants With Keratopathies (Corneal Toxicity) | 5 Participants |
Secondary
Number of Participants With Positive Anti-SAR566658 Antibodies Response
Time frame: Up to 3 treatment cycles, each cycle 21 days
Population: Data for this outcome measure was not collected and analyzed due to early termination of the study.
Secondary
Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events (SAE)
AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAEs were defined as AEs that developed or worsened in grade or became serious during the on-treatment period (the time from the first treatment administration to the last treatment administration +30 days). An SAE is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a medically important event.
Time frame: Up to 30 days after last drug administration (maximum number of cycles was 3, each cycle 21 days)
Population: Analysis was performed on all treated population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SAR566658 90 mg/m^2 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events (SAE) | Any TEAE | 11 Participants |
| SAR566658 90 mg/m^2 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events (SAE) | Any treatment emergent SAE | 1 Participants |
| SAR566658 90 mg/m^2 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events (SAE) | Any TEAE leading to treatment discontinuation | 3 Participants |
| SAR566658 120 mg/m^2 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events (SAE) | Any TEAE | 12 Participants |
| SAR566658 120 mg/m^2 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events (SAE) | Any treatment emergent SAE | 6 Participants |
| SAR566658 120 mg/m^2 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events (SAE) | Any TEAE leading to treatment discontinuation | 3 Participants |
Secondary
Percentage of Participants With Disease Control
Disease control in participants was defined as the participants with CR, PR and stable disease (SD) with a duration of at least 3 months. As per RECIST 1.1, CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of diameters of target lesions) taking as reference the smallest sum diameters while on study.
Time frame: Baseline, every 6 weeks until radiological disease progression or study cut-off, whichever comes first (maximum number of cycles was 3, each cycle 21 days)
Population: Data for this outcome measure was not collected and analyzed due to early termination of the study.
Secondary
Progression Free Survival (PFS)
PFS was defined as the time interval between the date of first study treatment administration and the date of documented tumor progression or death (due to any cause), whichever comes first. As per RECIST 1.1, progression was defined as at least a 20% increase in the sum of diameters of target lesions.
Time frame: Baseline, every 6 weeks until radiological disease progression or study cut-off, whichever comes first (maximum number of cycles was 3, each cycle 21 days)
Population: Data for this outcome measure was not collected and analyzed due to early termination of the study.
Secondary
Time to Tumor Progression (TTP)
TTP was defined as the time interval between the date of first study treatment administration and the date of the first radiologically documented tumor progression. As per RECIST 1.1, progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study.
Time frame: Baseline, every 6 weeks until radiological disease progression or study cut-off, whichever comes first (maximum number of cycles was 3, each cycle 21 days)
Population: Data for this outcome measure was not collected and analyzed due to early termination of the study.