A Phase II, Randomized, Double-Blind, Placebo-Controlled, 2-Arm, Multicenter Study Comparing Tivozanib Hydrochloride in Combination with Paclitaxel Versus Placebo in Combination with Paclitaxel in the Treatment of Subjects with Locally Recurrent and/or Metastatic Triple Negative Breast Cancer
This is a randomized, 2-arm, double-blind, placebo-controlled, 2-arm, multicenter study comparing tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel in subjects with locally recurrent or metastatic TnBC who have received no prior systemic therapy for advanced or mBC. The study is designed to compare PFS in subjects treated with tivozanib hydrochloride in combination with paclitaxel vs subjects treated with placebo in combination with paclitaxel. oRR, DoR, oS, safety and tolerability, pharmacokinetics, a hypoxia gene signature biomarker . additional exploratory objectives include evaluation of potential tumor biomarkers predictive of tumor sensitivity and/or resistance to tivozanib hydrochloride in combination with paclitaxel, and effectiveness of tivozanib hydrochloride in combination with paclitaxel in defined intrinsic molecular breast cancer subtypes.
Subjects will be stratified for eastern Cooperative oncology Group (eCoG) performance score (0 vs 1) and prior neoadjuvant or adjuvant taxane therapy (yes/no) and then randomized 2:1 to 1 of 2 treatment arms (tivozanib hydrochloride in combination with paclitaxel: placebo in combination with paclitaxel).
it is anticipated that enrollment in this study will be completed in approximately 15 months. Subjects will continue study treatment until disease progression or unacceptable toxicities occur, or if other withdrawal criteria are met.
Tivozanib hydrochloride or placebo (blinded) will be administered orally, at a dose of 1.5 mg/day, beginning on Day 1 of Cycle 1. Subjects will receive tivozanib hydrochloride or placebo once daily for 3 weeks followed by 1 week off treatment. one cycle is defined as 4 weeks. Cycles will be repeated every 4 weeks in the absence of disease progression or unacceptable toxicities.
The prescribed daily dose of tivozanib hydrochloride or placebo is to be taken, once per day, preferably in the morning, with water. only one capsule of tivozanib hydrochloride or placebo should be taken each day. if a dose is vomited or otherwise missed that day for any reason, the dose for that day should not be made up. The next dose should be taken as prescribed at the next scheduled time (ie one capsule is to be taken even if the previous dose was vomited or otherwise missed; additional dose(s) should not be taken at any time to make up for any missed dose(s)). Grapefruit and grapefruit juice should be avoided during the study.
Subjects will receive paclitaxel once weekly, beginning on Day 1 of Cycle 1. The next dose will be on Day 8 of Cycle 1 and the third dose will be on Day 15 of Cycle 1, followed by a 1 week rest (1 cycle [?] 4 weeks and should be in sync with tivozanib hydrochloride or placebo dosing). Cycles will be repeated every 4 weeks in the absence of disease progression or unacceptable toxicities. Paclitaxel will be administered via iV, over a 1 hour period, at a dose of 90 mg/m2. Weight should be monitored at each visit; recalculation of dose due to fluctuations in weight should be done according to institutional standards. Subjects should be pre-medicated with the following pre-treatment regimen or institutional standard of care:
iVRS will be used for randomization and drug management (, shipping to study sites and dispensing to subjects).
1. >= 18 year old females.
2. Unresectable, locally recurrent and/or metastatic TNBC with up to one line of non-taxane-containing chemotherapy for locally recurrent and/or metastatic disease
Note: There must be at least 21 days from the last dose of any previous non-taxane-containing
chemotherapy and the first dose of study drug. Toxicities from any previous therapy must also
have resolved to <= Grade 1 (except alopecia)
Note: For those subjects with no prior systemic therapy for locally recurrent and/or metastatic disease
(ie first-line locally recurrent and/or metastatic TNBC subjects), if they have received prior
neoadjuvant or adjuvant taxane therapy, they must not have progressed within 12 months of the
last dose of taxane.
3. Histologically or cytologically confirmed TNBC; Estrogen Receptor (ER), Progesterone Receptor
(PR) negative by immunohistochemistry (IHC) and Human Epithelial Receptor-2 (HER2) negative by
IHC or Fluorescence In Situ Hybridization (FISH). For ER and PR, a score of < 1% positive nuclei
will be considered negative. A HER2 IHC score of 0 or 1+ or a FISH ratio of < 1.8 is considered
negative. A HER2 IHC score of 2+ will be considered negative only if verified by FISH. Local
laboratory analysis will be used for eligibility; central laboratory confirmation will be performed
Note: If tumor tissue was previously tested for ER and/or PR in a laboratory with a
cutoff for negativity that was higher than 1% (eg < 5% or < 10% was considered
negative) or the actual percentage is not known, it should be retested and only subjects
with percent positive nuclei < 1% would be eligible.
4. Measurable disease per Response Evaluation Criteria in Solid Tumors [RECIST], 5. ECOG performance status of 0 or 1
6. A female is eligible to participate if she is of non-childbearing potential or has documentation of a
negative pregnancy test within 7 days prior to the start of the study treatment. Heterosexually active
pre-menopausal female subjects must agree to use adequate, highly effective contraceptive measures while on study and for 30 days after the last dose of study drug. Effective birth control includes
(a)intrauterine device (IUD) plus one barrier method;
(b) oral, implantable or injectible contraceptive
plus one barrier method; or
(c) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm).
7. Confirmed available archival tumor tissue. If tissue from more than one biopsy is available, the most recent is preferred.
8. Ability to give written informed consent.
9. Ability to comply with protocol requirements, including drug treatments and follow-up procedures.