A study of tivozanib hydrochloride plus paclitaxel versus placebo plus paclitaxel in the treatment of breast cancer

• Register: EUCTR
• Last refreshed on: 19 May 2014
• Main ID: EUCTR2012-003507-35-IT
• Date of registration: 28/03/2013
• Prospective Registration: Yes
• Primary sponsor: AVEO Pharmaceuticals, Inc.
• Public title: A study of tivozanib hydrochloride plus paclitaxel versus placebo plus paclitaxel in the treatment of breast cancer
• Scientific title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled, 2-Arm, Multi-Center 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
• Date of first enrolment: 20/05/2013
• Target sample size: 147
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-003507-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: yes Other: no Number of treatment arms in the trial: 2

Countries of recruitment

Australia, Bahamas, Canada, Ghana, Italy, Korea, Democratic People's Republic of, Spain, Taiwan, Thailand, Ukraine

Contacts

• Name: Regulatory Affairs
• Affiliation: AVEO Pharmaceuticals, Inc.

• Name: Regulatory Affairs
• Affiliation: AVEO Pharmaceuticals, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. = 18 year old females
2. Subjects with unresectable locally recurrent or metastatic triple-negative breast cancer (TNBC)
3. Histologically or cytologically confirmed TNBC; Estrogen Receptor (ER), Progesterone Receptor (PR) and Human Epithelial Receptor-2 (HER2) negative by IHC. For ER and PR, a score of <1% positive nuclei will be considered negative. A HER2 IHC score of 0 or 1+ 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 retrospectively.
4. Measurable disease per Response Evaluation Criteria in Solid Tumors [RECIST], Version 1.1.
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. Sexually 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 last 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 more than one biopsy is available, the most recent is preferred.
8. Ability to give written informed consent and comply with protocol requirements, including drug treatments and follow-up procedures.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 103
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 44

Exclusion criteria:
1. Any prior systemic therapy (including chemotherapy, signal transduction inhibitors and monoclonal antibodies, immunotherapy, bevacizumab, any investigational or licensed drug that targets VEGF or VEGF receptors/pathway or are mammalian target of rapamycin [mTOR] inhibitors) for treatment of advanced or mBC.
2. Major surgical procedure within 4 weeks prior to administration of first dose of study drug; radiotherapy or minor surgical procedure within 2 weeks prior to administration of first dose of study drug; inadequate recovery from prior therapy or surgical procedure;
3. Untreated central nervous system metastases
Note: Subjects with previously treated (radiotherapy or surgery) brain metastasis that have been stable off steroids or enzyme-inducing anti-epileptic drugs for at least 3 months following prior treatment may be enrolled.
4. Any of the following hematologic and coagulation abnormalities:
• Hemoglobin < 9.0 g/dL;
• Absolute neutrophil count (ANC) < 1500 per mm3;
• Platelet count < 100,000 per mm3;
5. Any of the following serum chemistry and urinalysis abnormalities:
• Total bilirubin > 1.5 × ULN;
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN (or > 5 × ULN for subjects with liver metastasis);
• Alkaline phosphatase > 2.5 × ULN (or > 5 × ULN for subjects with liver or bone metastasis);
• Creatinine > 2.0 × ULN;
• Proteinuria > 2+ by urinalysis or urine dipstick.
6. Significant cardiovascular disease, including:
• Symptomatic Left Ventricular Dysfunction or Baseline left ventricular ejection fraction (LVEF) by multigated acquisition scan (MUGA) or echocardiogram (ECHO) of <50%;
• Uncontrolled hypertension: systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg documented on 2 consecutive measurements taken at least 24 hours apart;
• Myocardial infarction, or unstable angina within 6 months prior to administration of first dose of study drug;
• History of Class III or IV congestive heart failure, as defined by the New York Heart Association;
• History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation);
• Cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with anti-arrhythmic medication; and/or
• Coronary or peripheral artery bypass graft within 6 months of screening.
7. Severe peripheral neuropathy, defined as = Grade 2 (per CTCAE Version 4.0)
8. Non-healing wound, bone fracture, or skin ulcer
9. Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal condition with increased risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to administration of first dose of study drug.
10. Serious/active infection or infection requiring parenteral antibiotics
11. Significant arterial or venous thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug, including but not limited to:
• Deep vein thrombosis;
• Pulmonary embolism
• Cerebrovascular accident (CVA) or transient ischemic attack (TIA);
• Peripheral ischemia > Grade 2 (per CTCAE Version 4.0).
12. Significant bleeding disorders within 6 months prior to administration of first dose of study drug, including but not limited to:
• Hematemesis, hematochezia, melena or other gastrointestinal bleeding = Grade 2 (per CTCAE Version 4.0)

Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

Locally recurrent and/or metastatic triple negative breast cancer
MedDRA version: 14.1 Level: LLT Classification code 10006193 Term: Breast cancer NOS recurrent System Organ Class: 100000004864
MedDRA version: 14.1 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 100000004864

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Tivozanib hydrochloride
Product Code: AV-951
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Tivozanib Hydrochloride Monohydrate
CAS Number: 682745-41-1
Current Sponsor code: AV-951
Other descriptive name: Tivozanib Hydrochloride Monohydrate
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1.0-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: Tivozanib hydrochloride
Product Code: AV-951
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Tivozanib Hydrochloride Monohydrate
CAS Number: 682745-41-1
Current Sponsor code: AV-951
Other descriptive name: Tivozanib Hydrochloride Monohydrate
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1.5-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Trade Name: Paclitaxel Injection
Product Name: Paclitaxel Injection
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: PACLITAXEL
CAS Number: 33069-62-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 6-

Primary Outcome(s)

Secondary Objective: • To assess ORR (objective response rate) and duration of response (DoR) of subjects treated with tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel.
• To assess overall survival (OS) of subjects treated with tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel.
• To evaluate safety and tolerability of tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel.
• To assess the pharmacokinetics (PK) of tivozanib hydrochloride and paclitaxel when administered in combination.
• To evaluate the hypoxia signature as a predictive biomarker of tivozanib hydrochloride response and establish the optimal cut-off to identify biomarker positive and negative subgroups.
• To evaluate Quality of Life (QoL).

Primary end point(s): Progression free survival (PFS)

Main Objective: To compare progression free survival (PFS) of subjects treated with tivozanib hydrochloride in combination with paclitaxel vs subjects treated with placebo in combination with paclitaxel.

Timepoint(s) of evaluation of this end point: PFS is defined as the time from randomization to progression or death and will be evaluated throughout the duration of the study

Secondary Outcome(s)

Secondary end point(s): Objective response rate (ORR - the proportion of subjects with a best response of CR or PR) and overall survival (OS)

Timepoint(s) of evaluation of this end point: Throughout the duration of the study.

Final OS analysis will take place after all subjects have been lost to follow up or have died, or when 3 years have passed after the last subject was randomized, or when the 103rd OS event has occurred, whichever occurs first.

Secondary ID(s)

AV-951-12-204

NCT01745367

Source(s) of Monetary Support

AVEO PHARMACEUTICALS, INC.