Tivozanib in Combination With Paclitaxel in Patients With Locally Recurrent or Metastatic Triple Negative Breast Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Study Comparing Tivozanib Hydrochloride in Combination With Paclitaxel v Placebo in Combination With Paclitaxel in Locally Recurrent and/or Metastatic Triple Negative Breast Cancer

Conditions
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Triple Negative Breast Cancer

Intervention / Treatment
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* Drug: Tivozanib Hydrochloride
* Drug: paclitaxel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Placebo in combination with paclitaxel<br>Placebo orally once daily on a 3 weeks on/1 week off schedule with 90 mg/m2 of paclitaxel administered intravenously 3 weeks on (Day 1, Day 8 and Day 15)/1 week off (4 weeks = 1 Cycle). | Drug: paclitaxel<br> <br> * Other names: PTX;Drug: Placebo<br> <br> |
| Experimental: Tivo in combination with paclitaxel<br>1.5 mg tivozanib hydrochloride orally once daily on a 3 weeks on/1 week off schedule with 90 mg/m2 of paclitaxel administered intravenously 3 weeks on (Day 1, Day 8 and Day 15)/1 week off (4 weeks = 1 Cycle). | Drug: Tivozanib Hydrochloride<br> <br> * Other names: Tivozanib;Drug: paclitaxel<br> <br> * Other names: PTX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | approximately 24 months | 
| 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. | approximately 24 months | 
| 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. | approximately 24 months | 
| 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. | approximately 24 months | 
| 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. | 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 | 
| 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. | approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tivozanib hydrochloride, triple negative breast cancer, paclitaxel, pharmacokinetics, biomarkers, metastatic breast cancer, mBC, TNBC