Triple Negative Breast Cancer
Conditions
Keywords
Tivozanib hydrochloride, triple negative breast cancer, paclitaxel, pharmacokinetics, biomarkers, metastatic breast cancer, mBC, TNBC
Brief summary
This is a phase 2 multicenter, double-blind, randomized, placebo-controlled, two-arm study for subjects with locally recurrent or metastatic triple negative breast cancer.
Detailed description
This is a phase 2 multicenter, double-blind, randomized, placebo-controlled, two-arm study for subjects with locally recurrent or metastatic triple negative breast cancer. Patients will be randomized 2:1 to either tivozanib hydrochloride and weekly paclitaxel or placebo and weekly paclitaxel. Subjects will be stratified based on Eastern Cooperative Oncology Group (ECOG) performance score (0 vs 1) and line of treatment (first vs second). All subjects will be evaluated for progression free survival and overall survival as well as safety and tolerability. Biomarker and pharmacokinetic (PK) analysis are also included in study. This study will determine whether tivozanib hydrocholoride combined with weekly paclitaxel improves clinical outcomes in patients with triple negative breast cancer.
Interventions
Sponsors
Astellas Pharma Inc
AVEO Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Locally recurrent or metastatic TNBC, defined as ER/PR \<1%, HER2 0-1+, or 2+ with negative FISH * Measurable disease per RECIST version 1.1 * ECOG performance status of 0 or 1 * Confirmed available archival tumor tissue.
Exclusion criteria
* More than 1 prior systemic chemotherapy for treatment of locally recurrent or metastatic breast cancer (neoadjuvant and adjuvant therapy is allowed provided the subject did not progress within 12 months of taxane based therapy * Prior treatment with VEGF pathway targeted agent * Major surgery within 4 weeks or minor surgery or radiotherapy within 2 weeks of first dose of study drug * Known history of central nervous system metastasis (subjects with previously treated (radiotherapy or surgery) brain metastasis that have been stable off steroids or enzyme-inducing antiepileptic drugs for at least 3 months following prior treatment may be enrolled) * Significant hematologic, gastrointestinal, thromboembolic, vascular, bleeding, or coagulation disorders * Significant serum chemistry or urinalysis abnormalities * Significant cardiovascular disease, including: uncontrolled hypertension; myocardial infarction or unstable angina within 6 months prior to administration of first dose of study drug; and symptomatic left ventricular dysfunction or baseline left ventricular ejection fraction (LVEF) by multigated acquisition scan (MUGA) or ECHO. * Severe peripheral neuropathy ≥ Grade 2 * Currently active second primary malignancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Progression-free Survival (PFS) of Subjects | approximately 24 months | PFS is defined as the time from randomization to progressive disease (PD) or death. The PFS comparison was performed for subjects treated with tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Overall Survival (OS) of Subjects | approximately 24 months | OS measures how long subjects, who undergo a certain treatment regimen, live compared to subjects who are in a control group (i.e., taking either another drug or an inactive treatment, known as a placebo). OS comparison was performed for subjects treated with tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel. |
| Safety and Tolerability of Tivozanib Hydrochloride in Combination With Paclitaxel vs Placebo in Combination With Paclitaxel | approximately 24 months | Number of subjects with serious and non-serious adverse events. |
| Comparison of Objective Response Rate (ORR) and Duration of Response (DoR) of Subjects | approximately 24 months | ORR is defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period. DoR is defined as the length of time that a tumor continues to respond to treatment without the cancer growing or spreading. The ORR and DoR comparison was performed for subjects treated with tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel. |
| Identification of Hypoxia Gene Signature | Cycle 1, Day 1: Pre-dose and 2, 4 and 24 hours post dose; Cycle 1, Day 8: Pre-dose; Cycle 1, Day 21: Pre-dose and 2, 4, 24, 48, and 96 hours post dose; Cycle 2 (Day 1): Pre-dose | Evaluation of hypoxia gene signature as a predictive biomarker of tivozanib hydrochloride response and establish the optimal cut-off to identify biomarker positive and negative subgroups. The genes comprising the hypoxia gene signature was analyzed in tumor tissue from subjects. |
| Measurement of Subjects' Quality of Life (QoL) | approximately 24 months | The Functional Assessment of Cancer Therapy-Breast (FACT-B) and Euro Quality of Life - 5 Dimensions (EQ-5D) questionnaires was used throughout the study to measure subjects' health-related QoL. |
| Pharmacokinetics (PK) of Tivozanib Hydrochloride and Paclitaxel When Administered in Combination | approximately 24 months | PK is defined as the study of the bodily absorption, distribution, metabolism, and excretion of drugs. |
Countries
Australia, Canada, Germany, Italy, South Korea, Spain, Taiwan, The Bahamas, Ukraine, United States
Participant flow
Recruitment details
Participants who met all the inclusion and none of the exclusion criteria were enrolled
Pre-assignment details
All participants underwent inclusion and exclusion criteria assessment and all eligible subjects signed the informed consent before undergoing any study related procedures. The study was terminated prior to completing enrollment, hence descriptive statistical analyses were performed for a limited set of data.
Participants by arm
| Arm | Count |
|---|---|
| Placebo in Combination With Paclitaxel Participants received placebo orally once daily with 90 mg/m2 of paclitaxel administered intravenously beginning on Day 1 for 3 weeks followed by 1 week off treatment. | 8 |
| Tivozanib Hydrochloride in Combination With Paclitaxel Participants received 1.5 mg tivozanib hydrochloride orally once daily with 90 mg/m2 of paclitaxel administered intravenously beginning on Day 1 for 3 weeks followed by 1 week off treatment. | 22 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Other Reasons Unspecified | 0 | 2 |
| Overall Study | Termination of The Study by The Sponsor | 6 | 18 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo in Combination With Paclitaxel | Tivozanib Hydrochloride in Combination With Paclitaxel | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 20 Participants | 24 Participants |
| Age, Continuous | 61.3 years STANDARD_DEVIATION 16.02 | 54.5 years STANDARD_DEVIATION 10.06 | 56.3 years STANDARD_DEVIATION 12.02 |
| Body Mass Index | 30.6 kg/m^2 STANDARD_DEVIATION 10.67 | 182.3 kg/m^2 STANDARD_DEVIATION 708.53 | 144.4 kg/m^2 STANDARD_DEVIATION 613.48 |
| Race/Ethnicity, Customized Asian | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Black | 0 participants | 5 participants | 5 participants |
| Race/Ethnicity, Customized Dominican | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 8 participants | 14 participants | 22 participants |
| Sex: Female, Male Female | 8 Participants | 22 Participants | 30 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 | — / — | — / — |
| other Total, other adverse events | 8 / 8 | 19 / 21 |
| serious Total, serious adverse events | 1 / 8 | 1 / 21 |
Outcome results
Primary
Comparison of Progression-free Survival (PFS) of Subjects
PFS is defined as the time from randomization to progressive disease (PD) or death. The PFS comparison was performed for subjects treated with tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel.
Time frame: approximately 24 months
Population: The study was terminated prior to completing enrollment; due to low enrollment, no data was collected for this outcome measure.
Secondary
Comparison of Objective Response Rate (ORR) and Duration of Response (DoR) of Subjects
ORR is defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period. DoR is defined as the length of time that a tumor continues to respond to treatment without the cancer growing or spreading. The ORR and DoR comparison was performed for subjects treated with tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel.
Time frame: approximately 24 months
Population: The study was terminated prior to completing enrollment; due to low enrollment, no data was collected for this outcome measure.
Secondary
Comparison of Overall Survival (OS) of Subjects
OS measures how long subjects, who undergo a certain treatment regimen, live compared to subjects who are in a control group (i.e., taking either another drug or an inactive treatment, known as a placebo). OS comparison was performed for subjects treated with tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel.
Time frame: approximately 24 months
Population: The study was terminated prior to completing enrollment; due to low enrollment, no data was collected for this outcome measure.
Secondary
Identification of Hypoxia Gene Signature
Evaluation of hypoxia gene signature as a predictive biomarker of tivozanib hydrochloride response and establish the optimal cut-off to identify biomarker positive and negative subgroups. The genes comprising the hypoxia gene signature was analyzed in tumor tissue from subjects.
Time frame: Cycle 1, Day 1: Pre-dose and 2, 4 and 24 hours post dose; Cycle 1, Day 8: Pre-dose; Cycle 1, Day 21: Pre-dose and 2, 4, 24, 48, and 96 hours post dose; Cycle 2 (Day 1): Pre-dose
Population: The study was terminated prior to completing enrollment; due to low enrollment, no data was collected for this outcome measure.
Secondary
Measurement of Subjects' Quality of Life (QoL)
The Functional Assessment of Cancer Therapy-Breast (FACT-B) and Euro Quality of Life - 5 Dimensions (EQ-5D) questionnaires was used throughout the study to measure subjects' health-related QoL.
Time frame: approximately 24 months
Population: The study was terminated prior to completing enrollment; due to low enrollment, no data was collected for this outcome measure.
Secondary
Pharmacokinetics (PK) of Tivozanib Hydrochloride and Paclitaxel When Administered in Combination
PK is defined as the study of the bodily absorption, distribution, metabolism, and excretion of drugs.
Time frame: approximately 24 months
Population: The study was terminated prior to completing enrollment; due to low enrollment, no data was collected for this outcome measure.
Secondary
Safety and Tolerability of Tivozanib Hydrochloride in Combination With Paclitaxel vs Placebo in Combination With Paclitaxel
Number of subjects with serious and non-serious adverse events.
Time frame: approximately 24 months
Population: Descriptive statistical analyses were performed for a limited set of data (disposition, demographics, and adverse events).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tivozanib Hydrochloride in Combination With Paclitaxel | Safety and Tolerability of Tivozanib Hydrochloride in Combination With Paclitaxel vs Placebo in Combination With Paclitaxel | Subjects with serious adverse events | 1 Participants |
| Tivozanib Hydrochloride in Combination With Paclitaxel | Safety and Tolerability of Tivozanib Hydrochloride in Combination With Paclitaxel vs Placebo in Combination With Paclitaxel | Subjects with non-serious adverse events | 19 Participants |
| Placebo in Combination With Paclitaxel | Safety and Tolerability of Tivozanib Hydrochloride in Combination With Paclitaxel vs Placebo in Combination With Paclitaxel | Subjects with serious adverse events | 1 Participants |
| Placebo in Combination With Paclitaxel | Safety and Tolerability of Tivozanib Hydrochloride in Combination With Paclitaxel vs Placebo in Combination With Paclitaxel | Subjects with non-serious adverse events | 8 Participants |