Metastatic Breast Cancer
Conditions
Keywords
HER2 positive breast cancer, first line treatment, Dasatinib, SRC kinase, Trastuzumab resistance
Brief summary
This is a single-arm, open-label, phase I/II study. In the phase I, patients with Human Epidermal Growth Factor Receptor 2 (HER2) positive MBC will be treated with paclitaxel, trastuzumab and increasing doses of dasatinib to determine the Maximum Tolerated Dose (MTD), Dose Limiting Toxicity (DLT) and Recommended Phase II Dose (RPD) of the combination. Once the RPD has been identified, 48 patients will be treated at that dose to evaluate the efficacy and safety of the combination in the phase II.
Detailed description
Eligible patients will be enrolled and treated with 4-week cycles of trastuzumab 2 mg/kg IV weekly (following a loading dose of 4 mg/kg in cycle 1) and paclitaxel 80 mg/m2 weekly x 3 weeks followed by a rest period of 7 days. Dasatinib will be administered orally in two dose levels 100 and 140 mg once daily (a -1 dose level is included just in case dose de-escalation is needed). Treatment will be repeated on Day 1 of a 28-day cycle in all patients (both in the phase I as in the phase II) until radiographic or symptomatic progression or unacceptable toxicity occurs. Only in the phase I and in all patients included in every different dose level, the first cycle will last 38 days. Primary Objective: * To determine the maximum tolerated dose (MTD) and recommended phase II dose (RPD) of dasatinib in combination with fixed doses of trastuzumab and paclitaxel in HER2-positive MBC patients (Phase I). * To determine the efficacy, measured by objective response rate (ORR) in HER2-positive MBC patients with measurable disease (Phase II). Secondary Objective(s): * To characterize the safety of the combination (in both phase I and phase II). * To evaluate the Clinical Benefit Rate (CBR), Time to Progression (TTP), Progression Free Survival (PFS) and Response Duration (RD) (in the phase II). * To evaluate the pharmacokinetics (PK) of the combination (in the phase I and selected patients in the phase II if necessary). * To evaluate molecular characteristics that may be predictive of the activity (or lack of) and any correlation between the biological activity of the study treatment and the disease outcome. Exploratory objective: • To explore the correlation between the lymphocytosis and efficacy. Sample Size: Phase I: following the 3+3 rule, a minimum of 6 and a maximum of 12 patients will be recruited. Phase II:Assuming 10% drop-out rate, 48 patients are required to enter the study. The duration of the study, from first patient visit to last patient visit will be approximately 42 months.
Interventions
DRUGDasatinib
DRUGTrastuzumab
DRUGPaclitaxel
Sponsors
Bristol-Myers Squibb
Spanish Breast Cancer Research Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Female with histologically confirmed breast cancer with documented metastasis. 2. Patients must have Human Epidermal Growth Factor Receptor 2 (HER2) overexpression by immunohistochemistry (3+, HercepTest®; DAKO) or a positive fluorescence in situ hybridization for HER2 amplification evaluated by central laboratory. It is recommended that a formalin-fixed paraffin embedded (FFPE) tumor tissue block from the metastatic site (or the primary tumor, if metastatic site not available) required for HER2 testing are provided. 3. Patients can have measurable or non measurable disease for the Phase I part. For the Phase II only patients with measurable disease defined per RECIST 1.1 will be included. 4. Signed Written Informed Consent. 5. Target Population: 1. Patients with Performance Status (ECOG) of 0 or 1. 2. Number of previous therapies allowed or previous therapies may have included: * Chemotherapy: no prior chemotherapy for MBC is permitted. Patients treated with adjuvant chemotherapy regimens based on taxanes are allowed to be included if they are fully recovered of any taxane associated toxicity and a minimum of 12 months have elapsed from the end of this therapy. * Hormonal Therapy: patients may have had prior hormonal therapy. All hormonal agents must be discontinued at least 3 weeks prior to study entry. * Radiation Therapy: patients may have had prior radiation therapy that has not exceeded 25% of the bone marrow reserve. A minimum of 21 days must have elapsed between the last dose of radiation and registration into the study. Patients must have recovered from any acute toxic effects from radiation prior to registration. Lesions that have been irradiated cannot be included as sites of measurable disease for the phase II unless clear tumor progression, according to RECIST criteria, has been documented in these lesions since the end of radiation therapy. * Previous Surgery: previous surgery is permitted provided that wound healing has occurred. * Anti-HER2 Therapies: no prior anti-HER2 therapy for MBC is permitted. Patients treated with adjuvant anti-HER2 therapies (including but not limited to trastuzumab and lapatinib) are allowed to be included if a minimum of 12 months have elapsed from the end of this therapy. 3. Adequate Organ Function (...). 4. Ability to take oral medication (dasatinib must be swallowed whole). 5. Concomitant Medications i) Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy (discontinue St. Johns Wort at least 5 days before starting dasatinib) ii) Biphosphonates must not be initiated within 28 days prior to study therapy 6. Age and sex: f) Patient, age 18 years old. g) Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least 4 weeks after the last dose of study drug to minimize the risk of pregnancy. (...)
Exclusion criteria
1. Sex and reproductive status: 1. WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after the last dose of study drug 2. Women who are pregnant or breastfeeding. 3. Women with a positive pregnancy test 2. Target Disease Exceptions: a) Central nervous system (CNS) metastases which are not well controlled. Eligible patients must be asymptomatic, cannot be receiving steroids or anticancer treatment, and must be enrolled at least 1 month after the end of the radiotherapy treatment 3. Medical History and Concurrent Diseases 1. No malignancy \[other than the one treated in this study\] which required radiotherapy or systemic treatment within the past 5 years. 2. Concurrent medical condition which may increase the risk of toxicity, including: Pleural or pericardial effusion of any grade. 3. Cardiac Symptoms; any of the following should be considered for exclusion: i) Uncontrolled angina, congestive heart failure or myocardial infarction (MI) within (6 months) ii). Patients with intercurrent cardiac dysfunction or left ventricular ejection fraction (LVEF) \< 50%. iii) Diagnosed congenital long QT syndrome. iv) Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes). v) Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (450 msec). vi) Patients with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration. d) History of significant bleeding disorder unrelated to cancer, including: i) Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease). ii) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies). iii) Ongoing or recent (≤ 3 months) significant gastrointestinal bleeding. 4. Allergies and Adverse Drug Reactions a) Patients with known allergy to any of the study drugs or their components. 5. Prohibited Treatments and/or Therapies a) Category I drugs that are generally accepted to have a risk of causing Torsades de Pointes including: (Patients must discontinue drug 7 days prior to starting dasatinib) i) quinidine, procainamide, disopyramide ii) amiodarone, sotalol, ibutilide, dofetilide iii) erythromycin, clarithromycin iv) chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide v) cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine. b) Concurrent anti-cancer therapy c) Potent CYP3A4 inhibitors 6. Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicity (DLT) Within the First Cycle of Dasatinib in Combination With Trastuzumab and Paclitaxel (Phase I) | Up to cycle 1 | DLT was defined as the occurrence of any of the following adverse events or abnormal laboratory value (graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03), assessed as possibly, probably or definitively related to study drugs, occurring within the first cycle of study treatment: Need of any dose modification within the first cycle due to toxicity, grade 3 or 4 neutropenia complicated with fever ≥38.5° C or infection, grade 4 neutropenia (absolute neutrophil count (ANC)\<0.5x1000000000/L) of at least 7 days duration, grade 3 thrombocytopenia complicated by hemorrhage, grade 4 thrombocytopenia, any grade 4 non-hematologic toxicity, grade 3 non-hematologic toxicities except nausea, vomiting, or diarrhea that can be controlled by appropriate medical intervention or prophylaxis, inability to resume dosing for cycle 2 at the current dose level within 14 days due to treatment related toxicity. |
| Maximum Tolerated Dose (MTD) of Dasatinib in Combination With Trastuzumab and Paclitaxel (Phase I) | Up to cycle 1 | MTD is determined by testing increasing doses of dasatinib on dose escalation cohorts 3 to 6 patients per dose level. MTD reflects the highest dose tested in which a DLT is experienced by 0 out of 3 or 1 out of 6 patients among the dose levels |
| Recommended Phase II Dose (RP2D) of Dasatinib in Combination With Trastuzumab and Paclitaxel (Phase I). | Up to cycle 1 | The RP2D was decided by the investigators taken into consideration the information obtained in the study and based on the MTD. To define the RP2D, information about toxicity observed during the full treatment were taken into consideration (relative dose intensity and toxicity observed). |
| Objective Response Rate (ORR) | Through study treatment, an average of 24 months | Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. ORR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) out of the patients who had measurable disease at baseline. Per RECIST, Complete Response (CR) is defined as the disappearance of all target lesions; Partial Response (PR) is defined as an \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Duration (RD) | Through study treatment, an average of 24 months | Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. RD is defined as the time from the date when the measurement criteria are met for complete response (CR) or partial response (PR) (whichever status is recorded first) until the date of first observation of disease progression or death occurred. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions. For responding patients not known to have died as of the data cut-off date and who do not have progression, RD will be censored at the date of last visit with adequate assessment. For responding patients who receive subsequent anticancer therapy (after discontinuation from the study treatment) prior to progression, RD will be censored at the date of last visit with adequate assessment prior to the initiation of post-discontinuation anticancer therapy. |
| Dasatinib Maximun Plasma Concentration (Cmax) Value (Pharmacokinetics (PK) Phase I) | Cycle 1 day 2 and day 18 | To assess the influence of the concomitant administration of paclitaxel and trastuzumab on dasatinib PKs, we compared dasatinib exposures alone (first PK occasion: day 2 of cycle 1) or combined (second PK occasion: day 18 on cycle 1). The mean profiles of dasatinib plasma concentrations were determined by dose and PK occasion. |
| Dasatinib Area Under the Plasma Concentration-time Curve (AUC) Value (Pharmacokinetics (PK) Phase I) | Cycle 1 day 2 and day 18 | To assess the influence of the concomitant administration of paclitaxel and trastuzumab on dasatinib PKs, we compared dasatinib exposures alone (first PK occasion: day 2 of cycle 1) or combined (second PK occasion: day 18 on cycle 1). The area under the plasma concentration-time curve from time zero to 8 hours post dose (AUC0-8) were calculated in all treated patients, as the dasatinib plasmatic half-life is very short and concentrations at 24 hours post dose could only be quantified in some patients. |
| Phosphorylated SRC (p-SRC) Protein Expression Change in Peripheral Blood Mononuclear Cells After 8 Hours of Treatment (Phase II) | Cycle 1 day 1 at 0 hours and at 8 hours | Sequential peripheral blood mononuclear cells (PBMCs) on Cycle 1 Day 1 before treatment and 8 hours (h) after treatment (0h and 8h) were assessed to explore changes in the expression of p-SRC proteins measured by enzyme-linked immunosorbent assay (ELISA). For ELISA analyses, a duplicate of 100 µg of the extract was used to detect p-SRC (Tyr416). ELISA is a plate-based assay technique designed for detecting and quantifying proteins. The instrumentation used for protein signal-detection is an absorbance spectrophotometer (AS), which measures Absorbance (A). A is the quantity of light absorbed by a sample. As different compounds absorb light at different wavelengths, an AS can be used to distinguish compounds by analyzing the pattern of wavelengths absorbed by a given sample. Additionally, the amount of light absorbed is directly proportional to the concentration of absorbing compounds in that sample, so an AS can also be used to determine concentrations of compounds in the sample. |
| Phosphorylated AKT (p-AKT) Protein Expression Change in Peripheral Blood Mononuclear Cells After 8 Hours of Treatment (Phase II) | Cycle 1 day 1 at 0 hours and at 8 hours | Sequential peripheral blood mononuclear cells (PBMCs) on Cycle 1 Day 1 before treatment and 8 hours (h) after treatment (0h and 8h) were assessed to explore changes in the expression of p-AKT proteins measured by enzyme-linked immunosorbent assay (ELISA). For ELISA analyses, a duplicate of 100 µg of the extract was used to detect p-AKT (Ser473). ELISA is a plate-based assay technique designed for detecting and quantifying proteins. The instrumentation used for protein signal-detection is an absorbance spectrophotometer (AS), which measures Absorbance (A). A is the quantity of light absorbed by a sample. As different compounds absorb light at different wavelengths, an AS can be used to distinguish compounds by analyzing the pattern of wavelengths absorbed by a given sample. Additionally, the amount of light absorbed is directly proportional to the concentration of absorbing compounds in that sample, so an AS can also be used to determine concentrations of compounds in the sample. |
| Phosphorylation Status of Phosphorylated SRC (p-SRC) in Skin After Treatment (Phase I) | Cycle 1 day 1 at 0 hours and at 8 hours, cycle 1 day 4 and cycle 2 day 1 | p-SRC was analyzed in the skin biopsies taken at cycle 1 day 1 at 0 hours and 8 hours, cycle 1 day 4 and cycle 2 day 1, only in patients accepting to participate. A semi-quantitative H-score (or histo score) determined by the estimation of the percentage of tumour cells positively stained with low, medium, or high staining intensity. The final score is determined after applying a weighting factor to each estimate. The formula used is H-score = (low %) × 1 + (medium %) × 2 + (high %) × 3, and the results ranged from minimum 0 to maximum 300. Aim: to confirm the mechanism of action identified in preclinical models where the combination of dasatinib and trastuzumab show a statistically significant reduction in the phosphorylated levels of SRC. |
| The Number of Participants Who Experienced Adverse Events (AE) | Through study treatment, an average of 24 months | Safety was assessed by standard clinical (blood pressure, pulse and body temperature, electrocardiogram (ECG), left ventricular ejection fraction (LVEF)) and laboratory tests (hematology: hemoglobin, platelet count, red blood cells (RBC), white blood cells (WBC) with differential (neutrophils) and absolute lymphocyte count, and serum chemistry: alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, creatinine, sodium, potassium, magnesium, phosphate and calcium). Adverse events grade were defined by the NCI CTCAE v 4.03. |
| Phosphorylation Status of Phosphorylated AKT (p-AKT) in Skin After Treatment (Phase I) | Cycle 1 day 1 at 0 hours and at 8 hours and cycle 2 day 1 | p-AKT was analyzed in the skin biopsies taken at cycle 1, day 1 at 0 hours and 8 hours, and cycle 2 day 1, only in patients accepting to participate. A semi-quantitative H-score (or histo score) determined by the estimation of the percentage of tumour cells positively stained with low, medium, or high staining intensity. The final score is determined after applying a weighting factor to each estimate. The formula used is H-score = (low %) × 1 + (medium %) × 2 + (high %) × 3, and the results ranged from minimum 0 to maximum 300. Aim: to confirm the mechanism of action identified in preclinical models where the combination of dasatinib and trastuzumab show a statistically significant reduction in the phosphorylated levels of AKT |
| Phosphorylation Status of Phosphorylated AKT (p-AKT) in Skin After Treatment (Phase II) | Cycle 1 day 1 at 0 hours and at 8 hours | p-AKT was analyzed in the skin biopsies taken at cycle 1, day 1 at 0 hours and 8 hours, only in patients accepting to participate. A semi-quantitative H-score (or histo score) determined by the estimation of the percentage of tumour cells positively stained with low, medium, or high staining intensity. The final score is determined after applying a weighting factor to each estimate. The formula used is H-score = (low %) × 1 + (medium %) × 2 + (high %) × 3, and the results ranged from minimum 0 to maximum 300. Aim: to confirm the mechanism of action identified in preclinical models where the combination of dasatinib and trastuzumab show a statistically significant reduction in the phosphorylated levels of AKT |
| Phosphorylation Status of Phosphorylated ERK (p-ERK) in Skin After Treatment (Phase I) | Cycle 1 day 1 at 0 hours and at 8 hours, cycle 1 day 4 at 8 hours and cycle 2 day 1 at 8 hours | p-ERK was analyzed in the skin biopsies taken at cycle 1 day 1 at 0 hours and 8 hours, cycle 1 day 4 at 8 hours, and cycle 2 day 1 at 8 hours, only in patients accepting to participate. A semi-quantitative H-score (or histo score) determined by the estimation of the percentage of tumour cells positively stained with low, medium, or high staining intensity. The final score is determined after applying a weighting factor to each estimate. The formula used is H-score = (low %) × 1 + (medium %) × 2 + (high %) × 3, and the results ranged from minimum 0 to maximum 300. Aim: to confirm the mechanism of action identified in preclinical models where the combination of dasatinib and trastuzumab show a statistically significant reduction in the phosphorylated levels of ERK |
| Phosphorylation Status of Phosphorylated ERK (p-ERK) in Skin After Treatment (Phase II) | Cycle 1 day 1 at 0 hours and at 8 hours | Phosphorylated extracellular signal-regulated kinases (p-ERK) 1 and 2 expression were analyzed in the skin biopsies taken at the cycle 1 day 1 at 0 hours and 8 hours, only in patients accepting to participate. A semi-quantitative H-score (or histo score) determined by the estimation of the percentage of tumour cells positively stained with low, medium, or high staining intensity. The final score is determined after applying a weighting factor to each estimate. The formula used is H-score = (low %) × 1 + (medium %) × 2 + (high %) × 3, and the results ranged from minimum 0 to maximum 300. Aim: to confirm the mechanism of action identified in preclinical models where the combination of dasatinib and trastuzumab show a statistically significant reduction in the phosphorylated levels of ERK |
| Number of Participants With Correlation Between Lymphocytosis and Efficacy. | Cycle 1 | Efficacy (ORR, CBR, TTP, RD and PFS) was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria, and were correlated Lymphocytes, that were measured in the weekly hematology analyses performed within the first cycle. |
| Phosphorylation Status of Phosphorylated SRC (p-SRC) in Skin After Treatment (Phase II) | Cycle 1 day 1 at 0 hours and at 8 hours | p-SRC was analyzed in the skin biopsies taken at cycle 1 day 1 at 0 hours and 8 hours, only in patients accepting to participate. A semi-quantitative H-score (or histo score) determined by the estimation of the percentage of tumour cells positively stained with low, medium, or high staining intensity. The final score is determined after applying a weighting factor to each estimate. The formula used is H-score = (low %) × 1 + (medium %) × 2 + (high %) × 3, and the results ranged from minimum 0 to maximum 300. Aim: to confirm the mechanism of action identified in preclinical models where the combination of dasatinib and trastuzumab show a statistically significant reduction in the phosphorylated levels of SRC. |
| To Evaluate the Clinical Benefit Rate (CBR) | Through study treatment, an average of 24 months | Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CBR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) plus stable disease lasting at least 6 months out of the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Time to Progression (TTP) | Through study treatment, an average of 24 months | TTP is defined as the time from the date of the first dose to the first date of objectively determined progressive disease. For patients not known to have objectively-determined progressive disease, TTP will be censored at the date of the last objective progression-free assessment. For patients who receive subsequent systemic anticancer therapy (after discontinuation from the study treatment) prior to objective disease progression, TTP will be censored at the date of last objective progression-free assessment prior to the initiation of post-discontinuation systemic anticancer therapy. |
| Progression Free Survival (PFS) | Through study treatment, an average of 24 months | PFS is defined as the time from the date of the first dose to the first date of objectively determined progressive disease or death from any cause. For patients not known to have died as of the data cut-off date and who do not have objectively-determined progressive disease, PFS will be censored at the date of the last objective progression-free assessment. For patients who receive subsequent systemic anticancer therapy (after discontinuation from the study treatment) prior to objective disease progression or death, PFS will be censored at the date of last objective progression-free assessment prior to the initiation of post-discontinuation systemic anticancer therapy. |
Countries
Spain
Participant flow
Recruitment details
Ten patients were enrolled at the phase I receiving at least one cycle of the combination. Six patients were included at Dose Level (DL) 1 and four patients at DL 2. One patient at DL 1 and two patients at DL 2 had a DLT. Twenty-seven patients were included at the phase II.
Participants by arm
| Arm | Count |
|---|---|
| Dasatinib 100mg + Trastuzumab 2mg/kg + Paclitaxel 80mg/m2 Cohort 1: Eligible patients were enrolled and treated with 4-week cycles of trastuzumab 2 mg/kg IV weekly (following a loading dose of 4 mg/kg in cycle 1) and paclitaxel 80 mg/m2 weekly x 3 weeks followed by a rest period of 7 days. Dasatinib 100mg was administered orally once daily (QD). Treatment was repeated on Day 1 of a 28-day cycle until radiographic or symptomatic progression or unacceptable toxicity occured. Only in the phase I, the first cycle lasted 38 days. | 6 |
| Dasatinib 140mg + Trastuzumab 2mg/kg + Paclitaxel 80mg/m2 Cohort 2: Eligible patients were enrolled and treated with 4-week cycles of trastuzumab 2 mg/kg IV weekly (following a loading dose of 4 mg/kg in cycle 1) and paclitaxel 80 mg/m2 weekly x 3 weeks followed by a rest period of 7 days. Dasatinib 140mg was administered orally once daily (QD). Treatment was repeated on Day 1 of a 28-day cycle until radiographic or symptomatic progression or unacceptable toxicity occured. Only in the phase I, the first cycle lasted 38 days. | 4 |
| PhaseII Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 Phase II with recommended Phase II Dose (RP2D) Dasatinib 100mg: Eligible patients were enrolled and treated with 4-week cycles of trastuzumab 2 mg/kg IV weekly (following a loading dose of 4 mg/kg in cycle 1) and paclitaxel 80 mg/m2 weekly x 3 weeks followed by a rest period of 7 days. Dasatinib 100mg was administered orally once daily (QD). Treatment was repeated on Day 1 of a 28-day cycle until radiographic or symptomatic progression or unacceptable toxicity occured. Two patients from phase I with measurable disease and RP2D were included in the phase II analyses. | 29 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Phase I | Adverse Event | 2 | 2 | 0 | 0 |
| Phase I | Physician Decision | 3 | 1 | 0 | 0 |
| Phase II | Adverse Event | 0 | 0 | 0 | 6 |
| Phase II | Death | 0 | 0 | 0 | 1 |
| Phase II | Not finished treatment | 0 | 0 | 0 | 1 |
| Phase II | Physician Decision | 2 | 0 | 0 | 5 |
| Phase II | Protocol Violation | 0 | 0 | 0 | 1 |
| Phase II | Withdrawal by Subject | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Dasatinib 140mg + Trastuzumab 2mg/kg + Paclitaxel 80mg/m2 | Total | Dasatinib 100mg + Trastuzumab 2mg/kg + Paclitaxel 80mg/m2 | PhaseII Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 |
|---|---|---|---|---|
| Age, Continuous | 49.43 years | 48.48 years | 44.44 years | 49.18 years |
| Eastern Cooperative Oncology Group (ECOG) status ECOG 0 | 3 Participants | 23 Participants | 2 Participants | 18 Participants |
| Eastern Cooperative Oncology Group (ECOG) status ECOG 1 | 1 Participants | 16 Participants | 4 Participants | 11 Participants |
| Hormonal Receptor Estrogen Receptor Negative | 2 Participants | 10 Participants | 1 Participants | 7 Participants |
| Hormonal Receptor Estrogen Receptor Positive | 2 Participants | 29 Participants | 5 Participants | 22 Participants |
| Hormonal Receptor Progesterone Receptor Negative | 3 Participants | 21 Participants | 2 Participants | 16 Participants |
| Hormonal Receptor Progesterone Receptor Positive | 1 Participants | 18 Participants | 4 Participants | 13 Participants |
| Menopausal Status Perimenopausal | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Menopausal Status Postmenopausal | 2 Participants | 21 Participants | 2 Participants | 17 Participants |
| Menopausal Status Premenopausal | 1 Participants | 17 Participants | 4 Participants | 12 Participants |
| Race/Ethnicity, Customized Caucasian | 4 Participants | 37 Participants | 5 Participants | 28 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Spain | 4 Participants | 39 Participants | 6 Participants | 29 Participants |
| Sex: Female, Male Female | 4 Participants | 39 Participants | 6 Participants | 29 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 4 | 1 / 29 |
| other Total, other adverse events | 6 / 6 | 4 / 4 | 29 / 29 |
| serious Total, serious adverse events | 1 / 6 | 2 / 4 | 6 / 29 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Dasatinib in Combination With Trastuzumab and Paclitaxel (Phase I)
MTD is determined by testing increasing doses of dasatinib on dose escalation cohorts 3 to 6 patients per dose level. MTD reflects the highest dose tested in which a DLT is experienced by 0 out of 3 or 1 out of 6 patients among the dose levels
Time frame: Up to cycle 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Maximum Tolerated Dose (MTD) of Dasatinib in Combination With Trastuzumab and Paclitaxel (Phase I) | 100 mg |
Primary
Number of Participants With Dose Limiting Toxicity (DLT) Within the First Cycle of Dasatinib in Combination With Trastuzumab and Paclitaxel (Phase I)
DLT was defined as the occurrence of any of the following adverse events or abnormal laboratory value (graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03), assessed as possibly, probably or definitively related to study drugs, occurring within the first cycle of study treatment: Need of any dose modification within the first cycle due to toxicity, grade 3 or 4 neutropenia complicated with fever ≥38.5° C or infection, grade 4 neutropenia (absolute neutrophil count (ANC)\<0.5x1000000000/L) of at least 7 days duration, grade 3 thrombocytopenia complicated by hemorrhage, grade 4 thrombocytopenia, any grade 4 non-hematologic toxicity, grade 3 non-hematologic toxicities except nausea, vomiting, or diarrhea that can be controlled by appropriate medical intervention or prophylaxis, inability to resume dosing for cycle 2 at the current dose level within 14 days due to treatment related toxicity.
Time frame: Up to cycle 1
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Number of Participants With Dose Limiting Toxicity (DLT) Within the First Cycle of Dasatinib in Combination With Trastuzumab and Paclitaxel (Phase I) | 1 Participants |
| Phase I: Dasatinib 140mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Number of Participants With Dose Limiting Toxicity (DLT) Within the First Cycle of Dasatinib in Combination With Trastuzumab and Paclitaxel (Phase I) | 2 Participants |
Primary
Objective Response Rate (ORR)
Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. ORR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) out of the patients who had measurable disease at baseline. Per RECIST, Complete Response (CR) is defined as the disappearance of all target lesions; Partial Response (PR) is defined as an \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Through study treatment, an average of 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Objective Response Rate (ORR) | 23 Participants |
Primary
Recommended Phase II Dose (RP2D) of Dasatinib in Combination With Trastuzumab and Paclitaxel (Phase I).
The RP2D was decided by the investigators taken into consideration the information obtained in the study and based on the MTD. To define the RP2D, information about toxicity observed during the full treatment were taken into consideration (relative dose intensity and toxicity observed).
Time frame: Up to cycle 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Recommended Phase II Dose (RP2D) of Dasatinib in Combination With Trastuzumab and Paclitaxel (Phase I). | 100 mg |
Secondary
Dasatinib Area Under the Plasma Concentration-time Curve (AUC) Value (Pharmacokinetics (PK) Phase I)
To assess the influence of the concomitant administration of paclitaxel and trastuzumab on dasatinib PKs, we compared dasatinib exposures alone (first PK occasion: day 2 of cycle 1) or combined (second PK occasion: day 18 on cycle 1). The area under the plasma concentration-time curve from time zero to 8 hours post dose (AUC0-8) were calculated in all treated patients, as the dasatinib plasmatic half-life is very short and concentrations at 24 hours post dose could only be quantified in some patients.
Time frame: Cycle 1 day 2 and day 18
Population: Two participant samples for cycle 1 day 18 could not be obtained.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Dasatinib Area Under the Plasma Concentration-time Curve (AUC) Value (Pharmacokinetics (PK) Phase I) | Day 2 Dasatinib alone | 530.6 ng·h/mL | Standard Deviation 237.1 |
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Dasatinib Area Under the Plasma Concentration-time Curve (AUC) Value (Pharmacokinetics (PK) Phase I) | Day 18 Dasatinib in combination P and T | 248.1 ng·h/mL | Standard Deviation 156.7 |
| Phase I: Dasatinib 140mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Dasatinib Area Under the Plasma Concentration-time Curve (AUC) Value (Pharmacokinetics (PK) Phase I) | Day 2 Dasatinib alone | 1159.2 ng·h/mL | Standard Deviation 128.3 |
| Phase I: Dasatinib 140mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Dasatinib Area Under the Plasma Concentration-time Curve (AUC) Value (Pharmacokinetics (PK) Phase I) | Day 18 Dasatinib in combination P and T | 1047.3 ng·h/mL | Standard Deviation 682.8 |
Secondary
Dasatinib Maximun Plasma Concentration (Cmax) Value (Pharmacokinetics (PK) Phase I)
To assess the influence of the concomitant administration of paclitaxel and trastuzumab on dasatinib PKs, we compared dasatinib exposures alone (first PK occasion: day 2 of cycle 1) or combined (second PK occasion: day 18 on cycle 1). The mean profiles of dasatinib plasma concentrations were determined by dose and PK occasion.
Time frame: Cycle 1 day 2 and day 18
Population: Two participant samples for cycle 1 day 18 could not be obtained.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Dasatinib Maximun Plasma Concentration (Cmax) Value (Pharmacokinetics (PK) Phase I) | Day 2 Dasatinib alone | 191.0 ng/mL | Standard Deviation 92.1 |
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Dasatinib Maximun Plasma Concentration (Cmax) Value (Pharmacokinetics (PK) Phase I) | Day 18 Dasatinib in combination P and T | 78.4 ng/mL | Standard Deviation 51.1 |
| Phase I: Dasatinib 140mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Dasatinib Maximun Plasma Concentration (Cmax) Value (Pharmacokinetics (PK) Phase I) | Day 2 Dasatinib alone | 422.3 ng/mL | Standard Deviation 56.4 |
| Phase I: Dasatinib 140mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Dasatinib Maximun Plasma Concentration (Cmax) Value (Pharmacokinetics (PK) Phase I) | Day 18 Dasatinib in combination P and T | 314.4 ng/mL | Standard Deviation 153.6 |
Secondary
Number of Participants With Correlation Between Lymphocytosis and Efficacy.
Efficacy (ORR, CBR, TTP, RD and PFS) was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria, and were correlated Lymphocytes, that were measured in the weekly hematology analyses performed within the first cycle.
Time frame: Cycle 1
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Number of Participants With Correlation Between Lymphocytosis and Efficacy. | 0 Participants |
| Phase I: Dasatinib 140mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Number of Participants With Correlation Between Lymphocytosis and Efficacy. | 0 Participants |
| PhaseII Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Number of Participants With Correlation Between Lymphocytosis and Efficacy. | 0 Participants |
Secondary
Phosphorylated AKT (p-AKT) Protein Expression Change in Peripheral Blood Mononuclear Cells After 8 Hours of Treatment (Phase II)
Sequential peripheral blood mononuclear cells (PBMCs) on Cycle 1 Day 1 before treatment and 8 hours (h) after treatment (0h and 8h) were assessed to explore changes in the expression of p-AKT proteins measured by enzyme-linked immunosorbent assay (ELISA). For ELISA analyses, a duplicate of 100 µg of the extract was used to detect p-AKT (Ser473). ELISA is a plate-based assay technique designed for detecting and quantifying proteins. The instrumentation used for protein signal-detection is an absorbance spectrophotometer (AS), which measures Absorbance (A). A is the quantity of light absorbed by a sample. As different compounds absorb light at different wavelengths, an AS can be used to distinguish compounds by analyzing the pattern of wavelengths absorbed by a given sample. Additionally, the amount of light absorbed is directly proportional to the concentration of absorbing compounds in that sample, so an AS can also be used to determine concentrations of compounds in the sample.
Time frame: Cycle 1 day 1 at 0 hours and at 8 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylated AKT (p-AKT) Protein Expression Change in Peripheral Blood Mononuclear Cells After 8 Hours of Treatment (Phase II) | 0.04 Absorbance 450 nm | Standard Deviation 0.09 |
Secondary
Phosphorylated SRC (p-SRC) Protein Expression Change in Peripheral Blood Mononuclear Cells After 8 Hours of Treatment (Phase II)
Sequential peripheral blood mononuclear cells (PBMCs) on Cycle 1 Day 1 before treatment and 8 hours (h) after treatment (0h and 8h) were assessed to explore changes in the expression of p-SRC proteins measured by enzyme-linked immunosorbent assay (ELISA). For ELISA analyses, a duplicate of 100 µg of the extract was used to detect p-SRC (Tyr416). ELISA is a plate-based assay technique designed for detecting and quantifying proteins. The instrumentation used for protein signal-detection is an absorbance spectrophotometer (AS), which measures Absorbance (A). A is the quantity of light absorbed by a sample. As different compounds absorb light at different wavelengths, an AS can be used to distinguish compounds by analyzing the pattern of wavelengths absorbed by a given sample. Additionally, the amount of light absorbed is directly proportional to the concentration of absorbing compounds in that sample, so an AS can also be used to determine concentrations of compounds in the sample.
Time frame: Cycle 1 day 1 at 0 hours and at 8 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylated SRC (p-SRC) Protein Expression Change in Peripheral Blood Mononuclear Cells After 8 Hours of Treatment (Phase II) | 0.36 Absorbance 450 nm | Standard Deviation 0.378 |
Secondary
Phosphorylation Status of Phosphorylated AKT (p-AKT) in Skin After Treatment (Phase I)
p-AKT was analyzed in the skin biopsies taken at cycle 1, day 1 at 0 hours and 8 hours, and cycle 2 day 1, only in patients accepting to participate. A semi-quantitative H-score (or histo score) determined by the estimation of the percentage of tumour cells positively stained with low, medium, or high staining intensity. The final score is determined after applying a weighting factor to each estimate. The formula used is H-score = (low %) × 1 + (medium %) × 2 + (high %) × 3, and the results ranged from minimum 0 to maximum 300. Aim: to confirm the mechanism of action identified in preclinical models where the combination of dasatinib and trastuzumab show a statistically significant reduction in the phosphorylated levels of AKT
Time frame: Cycle 1 day 1 at 0 hours and at 8 hours and cycle 2 day 1
Population: Skin biopsies could only be obtained in 5 participants at cycle 1 day 1 at 0 hours and 8 hours and cycle 2 day 1.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated AKT (p-AKT) in Skin After Treatment (Phase I) | H-score Cycle 1, day 1, 0 hours | 65 score on a scale |
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated AKT (p-AKT) in Skin After Treatment (Phase I) | H-score Cycle 1, day 1, 8 hours | 20 score on a scale |
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated AKT (p-AKT) in Skin After Treatment (Phase I) | H-score Cycle 1, day 4, 8 hours | 10 score on a scale |
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated AKT (p-AKT) in Skin After Treatment (Phase I) | H-score Cycle 2, day 1, 8 hours | 13 score on a scale |
Secondary
Phosphorylation Status of Phosphorylated AKT (p-AKT) in Skin After Treatment (Phase II)
p-AKT was analyzed in the skin biopsies taken at cycle 1, day 1 at 0 hours and 8 hours, only in patients accepting to participate. A semi-quantitative H-score (or histo score) determined by the estimation of the percentage of tumour cells positively stained with low, medium, or high staining intensity. The final score is determined after applying a weighting factor to each estimate. The formula used is H-score = (low %) × 1 + (medium %) × 2 + (high %) × 3, and the results ranged from minimum 0 to maximum 300. Aim: to confirm the mechanism of action identified in preclinical models where the combination of dasatinib and trastuzumab show a statistically significant reduction in the phosphorylated levels of AKT
Time frame: Cycle 1 day 1 at 0 hours and at 8 hours
Population: Skin biopsies could only be obtained in 6 participants at cycle 1 day 1 at 0 hours and 8 hours.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated AKT (p-AKT) in Skin After Treatment (Phase II) | H-score 0 hours | 70 score on a scale |
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated AKT (p-AKT) in Skin After Treatment (Phase II) | H-score 8 hours | 20 score on a scale |
Secondary
Phosphorylation Status of Phosphorylated ERK (p-ERK) in Skin After Treatment (Phase I)
p-ERK was analyzed in the skin biopsies taken at cycle 1 day 1 at 0 hours and 8 hours, cycle 1 day 4 at 8 hours, and cycle 2 day 1 at 8 hours, only in patients accepting to participate. A semi-quantitative H-score (or histo score) determined by the estimation of the percentage of tumour cells positively stained with low, medium, or high staining intensity. The final score is determined after applying a weighting factor to each estimate. The formula used is H-score = (low %) × 1 + (medium %) × 2 + (high %) × 3, and the results ranged from minimum 0 to maximum 300. Aim: to confirm the mechanism of action identified in preclinical models where the combination of dasatinib and trastuzumab show a statistically significant reduction in the phosphorylated levels of ERK
Time frame: Cycle 1 day 1 at 0 hours and at 8 hours, cycle 1 day 4 at 8 hours and cycle 2 day 1 at 8 hours
Population: Skin biopsies could only be obtained in 5 participants at cycle 1 day 1 at 0 hours and 8 hours, cycle 1 day 4 at 8 hours and cycle 2 day 1 at 8 hours.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated ERK (p-ERK) in Skin After Treatment (Phase I) | H-score Cycle 1, day 1, 0 hours | 63 score on a scale |
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated ERK (p-ERK) in Skin After Treatment (Phase I) | H-score Cycle 1, day 1, 8 hours | 20 score on a scale |
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated ERK (p-ERK) in Skin After Treatment (Phase I) | H-score Cycle 1, day 4, 8 hours | 14 score on a scale |
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated ERK (p-ERK) in Skin After Treatment (Phase I) | H-score Cycle 2, day 1, 8 hours | 11 score on a scale |
Secondary
Phosphorylation Status of Phosphorylated ERK (p-ERK) in Skin After Treatment (Phase II)
Phosphorylated extracellular signal-regulated kinases (p-ERK) 1 and 2 expression were analyzed in the skin biopsies taken at the cycle 1 day 1 at 0 hours and 8 hours, only in patients accepting to participate. A semi-quantitative H-score (or histo score) determined by the estimation of the percentage of tumour cells positively stained with low, medium, or high staining intensity. The final score is determined after applying a weighting factor to each estimate. The formula used is H-score = (low %) × 1 + (medium %) × 2 + (high %) × 3, and the results ranged from minimum 0 to maximum 300. Aim: to confirm the mechanism of action identified in preclinical models where the combination of dasatinib and trastuzumab show a statistically significant reduction in the phosphorylated levels of ERK
Time frame: Cycle 1 day 1 at 0 hours and at 8 hours
Population: Skin biopsies could only be obtained in 6 participants at cycle 1 day 1 at 0 hours and 8 hours.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated ERK (p-ERK) in Skin After Treatment (Phase II) | H-score 0 hours | 60 score on a scale |
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated ERK (p-ERK) in Skin After Treatment (Phase II) | H-score 8 hours | 16 score on a scale |
Secondary
Phosphorylation Status of Phosphorylated SRC (p-SRC) in Skin After Treatment (Phase I)
p-SRC was analyzed in the skin biopsies taken at cycle 1 day 1 at 0 hours and 8 hours, cycle 1 day 4 and cycle 2 day 1, only in patients accepting to participate. A semi-quantitative H-score (or histo score) determined by the estimation of the percentage of tumour cells positively stained with low, medium, or high staining intensity. The final score is determined after applying a weighting factor to each estimate. The formula used is H-score = (low %) × 1 + (medium %) × 2 + (high %) × 3, and the results ranged from minimum 0 to maximum 300. Aim: to confirm the mechanism of action identified in preclinical models where the combination of dasatinib and trastuzumab show a statistically significant reduction in the phosphorylated levels of SRC.
Time frame: Cycle 1 day 1 at 0 hours and at 8 hours, cycle 1 day 4 and cycle 2 day 1
Population: Skin biopsies could only be obtained in 5 participants at cycle 1 day 1 at 0 hours and 8 hours, cycle 1 day 4 and cycle 2 day 1.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated SRC (p-SRC) in Skin After Treatment (Phase I) | H-score Cycle 1, day 1, 0 hours | 103 score on a scale |
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated SRC (p-SRC) in Skin After Treatment (Phase I) | H-score Cycle 1, day 1, 8 hours | 28 score on a scale |
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated SRC (p-SRC) in Skin After Treatment (Phase I) | H-score Cycle 1, day 4 | 14 score on a scale |
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated SRC (p-SRC) in Skin After Treatment (Phase I) | H-score Cycle 2, day 1 | 20 score on a scale |
Secondary
Phosphorylation Status of Phosphorylated SRC (p-SRC) in Skin After Treatment (Phase II)
p-SRC was analyzed in the skin biopsies taken at cycle 1 day 1 at 0 hours and 8 hours, only in patients accepting to participate. A semi-quantitative H-score (or histo score) determined by the estimation of the percentage of tumour cells positively stained with low, medium, or high staining intensity. The final score is determined after applying a weighting factor to each estimate. The formula used is H-score = (low %) × 1 + (medium %) × 2 + (high %) × 3, and the results ranged from minimum 0 to maximum 300. Aim: to confirm the mechanism of action identified in preclinical models where the combination of dasatinib and trastuzumab show a statistically significant reduction in the phosphorylated levels of SRC.
Time frame: Cycle 1 day 1 at 0 hours and at 8 hours
Population: Skin biopsies could only be obtained in 6 participants at cycle 1 day 1 at 0 hours and 8 hours.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated SRC (p-SRC) in Skin After Treatment (Phase II) | H-score 0 hours | 105 score on a scale |
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Phosphorylation Status of Phosphorylated SRC (p-SRC) in Skin After Treatment (Phase II) | H-score 8 hours | 27 score on a scale |
Secondary
Progression Free Survival (PFS)
PFS is defined as the time from the date of the first dose to the first date of objectively determined progressive disease or death from any cause. For patients not known to have died as of the data cut-off date and who do not have objectively-determined progressive disease, PFS will be censored at the date of the last objective progression-free assessment. For patients who receive subsequent systemic anticancer therapy (after discontinuation from the study treatment) prior to objective disease progression or death, PFS will be censored at the date of last objective progression-free assessment prior to the initiation of post-discontinuation systemic anticancer therapy.
Time frame: Through study treatment, an average of 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Progression Free Survival (PFS) | 23.9 months |
Secondary
Response Duration (RD)
Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. RD is defined as the time from the date when the measurement criteria are met for complete response (CR) or partial response (PR) (whichever status is recorded first) until the date of first observation of disease progression or death occurred. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions. For responding patients not known to have died as of the data cut-off date and who do not have progression, RD will be censored at the date of last visit with adequate assessment. For responding patients who receive subsequent anticancer therapy (after discontinuation from the study treatment) prior to progression, RD will be censored at the date of last visit with adequate assessment prior to the initiation of post-discontinuation anticancer therapy.
Time frame: Through study treatment, an average of 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Response Duration (RD) | 18.4 months |
Secondary
The Number of Participants Who Experienced Adverse Events (AE)
Safety was assessed by standard clinical (blood pressure, pulse and body temperature, electrocardiogram (ECG), left ventricular ejection fraction (LVEF)) and laboratory tests (hematology: hemoglobin, platelet count, red blood cells (RBC), white blood cells (WBC) with differential (neutrophils) and absolute lymphocyte count, and serum chemistry: alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, creatinine, sodium, potassium, magnesium, phosphate and calcium). Adverse events grade were defined by the NCI CTCAE v 4.03.
Time frame: Through study treatment, an average of 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | The Number of Participants Who Experienced Adverse Events (AE) | 6 Participants |
| Phase I: Dasatinib 140mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | The Number of Participants Who Experienced Adverse Events (AE) | 4 Participants |
| PhaseII Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | The Number of Participants Who Experienced Adverse Events (AE) | 29 Participants |
Secondary
Time to Progression (TTP)
TTP is defined as the time from the date of the first dose to the first date of objectively determined progressive disease. For patients not known to have objectively-determined progressive disease, TTP will be censored at the date of the last objective progression-free assessment. For patients who receive subsequent systemic anticancer therapy (after discontinuation from the study treatment) prior to objective disease progression, TTP will be censored at the date of last objective progression-free assessment prior to the initiation of post-discontinuation systemic anticancer therapy.
Time frame: Through study treatment, an average of 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | Time to Progression (TTP) | 23.9 months |
Secondary
To Evaluate the Clinical Benefit Rate (CBR)
Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CBR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) plus stable disease lasting at least 6 months out of the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Through study treatment, an average of 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I: Dasatinib 100mg/Trastuzumab 2mg/kg/Paclitaxel 80mg/m2 | To Evaluate the Clinical Benefit Rate (CBR) | 24 Participants |