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A Phase II, Multi-Centre, Randomized, Double-blind Trial to Evaluate the Therapeutic Benefit of Fulvestrant in Combination With ZACTIMA or Fulvestrant Plus Placebo in Postmenopausal Women With Bone Only or Bone Predominant, Hormone Receptor Positive Metastatic Breast Cancer

Phase 2
Open (Enrolling)
Metastatic Breast Cancer

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Trial Information

A Phase II, Multi-Centre, Randomized, Double-blind Trial to Evaluate the Therapeutic Benefit of Fulvestrant in Combination With ZACTIMA or Fulvestrant Plus Placebo in Postmenopausal Women With Bone Only or Bone Predominant, Hormone Receptor Positive Metastatic Breast Cancer

Tumor angiogenesis is associated with invasiveness and the metastatic potential of various
cancers. Vascular endothelial growth factor (VEGF), the most potent and specific angiogenic
factor, regulates normal and pathologic angiogenesis. The increased expression of VEGF has
been correlated with metastases, recurrence and poor prognosis in many cancers. It has been
shown the VEGF is involved in osteolysis in women with bone metastases. ZACTIMA is an agent
which targets VEGF. ZACTIMA is a new agent with novel method of action - it is a VEGF
inhibitor, epidermal growth factor (EGFR) inhibitor, tyrosine kinase inhibitor, as well as a
potential RET kinase activity inhibitor.

In summary, women with bone only, or bone predominant, metastatic breast cancer is an ideal
group to study anti-angiogenic therapies where angiogenesis could be a major factor in tumor
progression and where anti-angiogenic treatment with agents like ZACTIMA could be more

Inclusion Criteria:

1. Postmenopausal woman, defined as a woman fulfilling any one of the following

- Age greater than or equal to 60 years or

- Age greater than or equal to 45 years with amenorrhea more than 12 months with
an intact uterus or

- Follicle-stimulating hormone (FSH) levels in postmenopausal range or

- Having undergone a bilateral oophorectomy

2. Metastatic breast cancer with either radiologically confirmed bone only or
predominant metastases to bone not considered amenable to curative treatment.

3. Evidence of hormone sensitivity either ER+ and/or PgR+, as per institutional
standards, in the primary tumor.

4. Patients must fulfill one of the following RECIST criteria:

- Bone lesions, which are lytic, sclerotic or mixed (lytic + sclerotic), in the
absence of measurable disease as defined by RECIST criteria or

- Bone lesions, which are lytic, sclerotic or mixed (lytic + sclerotic), in the
presence of measurable disease as defined by RECIST criteria.

5. Patients must fulfill one of the following resistances to endocrine therapy criteria:

- Disease progression on tamoxifen or on an aromatase inhibitor as first or second
line therapy for metastatic disease or

- Development of metastatic disease while on treatment with tamoxifen or an
aromatase inhibitor in the adjuvant setting or

- Disease progression after discontinuation of prior adjuvant endocrine therapy.

Exclusion Criteria:

1. Previous treatment with fulvestrant or ZACTIMA.

2. History of hypersensitivity to active or inactive excipients of fulvestrant and/or

3. Has received greater than one line of systemic chemotherapy for metastatic breast

4. Has received chemotherapy within the past 14 days (+ 2 days).

5. Has received radiation therapy within the past 14 days (+ 2 days).

6. Has undergone major surgery within the past 21 days or has had major surgery
performed > 21 days prior to screening and the wound remains unhealed.

7. Has received LH-RH agonist within the past 4 months.

8. Prior treatment with VEGF inhibitors (prior use of AVASTIN permitted).

9. Current or previously active systemic malignancy within 3 years prior to
randomization (other than breast cancer, or adequately treated in-situ carcinoma of
the cervix, uteri, or basal or squamous cell carcinoma of the skin).

10. Presence of life-threatening metastatic visceral disease, defined as extensive
hepatic involvement, or any degree of brain or leptomeningeal involvement (past or
present), or symptomatic pulmonary lymphangetic spread. Patients with discrete
pulmonary parenchymal metastases are eligible, provided their respiratory function is
not compromised as a result of disease.

11. ECOG performance status of > 2.

12. Currently receiving (and are unwilling to discontinue) hormone replacement therapy.

13. Laboratory results sustained at:

- Platelets < 100 x 109 /L

- International normalized ratio (INR) > 1.6

- Total bilirubin > 1.5 times normal

- ALT or AST > 2.5 times normal range if no demonstrable liver metastases or > 5
times normal range in the presence of liver metastases. No more than three
retests within screening period are allowable.

14. Potassium level outside of normal range, despite supplementation; serum calcium (or
ionized or adjusted for albumin), or magnesium below the lower limit of the normal
range despite supplementation or creatinine clearance < 30mL/min.

15. History of:

- Bleeding diathesis (i.e. disseminated intravascular coagulation [DIC], clotting
factor deficiency) or

- Long-term anticoagulant therapy (other than anti-platelet therapy).

16. Any severe concomitant condition which makes it undesirable for the patient to
participate in the study or which would jeopardize compliance with the protocol, e.g.
severe renal or hepatic impairment or currently unstable or uncompensated respiratory
or cardiac conditions, ongoing or active infection, untreated primary
hyperparathyroidism, or psychiatric illness that would limit compliance with study

17. Anticipated life expectancy less than six months.

18. Non-approved/experimental drug treatment within previous 4 weeks before

19. Significant cardiovascular event (e.g., myocardial infarction, superior vena cava
syndrome), New York Heart Association (NYHA) classification of heart disease
(Appendix II) > Class II within 3 months before study entry, or presence of cardiac
disease that in the opinion of the investigator increases the risk of ventricular

20. History of arrhythmia (multifocal premature ventricular contractions (PVCs),
bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation)
which is symptomatic or requires treatment (NCI CTCAE Grade 3 or 4) or asymptomatic
sustained ventricular tachycardia. Atrial fibrillation, controlled on medication, is
not excluded.

21. Congenital long QT syndrome or 1st degree relative with unexplained sudden death
under 40 years of age.

22. QT prolongation with other medications that required discontinuation of that

23. Presence of left bundle branch block (LBBB).

24. QTc with Bazett's correction measurable at > 480msec on screening ECG. (Note: If a
patient has QTc > 480msec on screening ECG, the screen ECG may be repeated twice (at
least 24 hours apart). The average QTc from the three screening ECGs must be <
480msec in order for the patient to be eligible for the study). Patients who are
receiving a drug that has a risk of QTc prolongation (see Appendix III, Table 2) are
excluded if QTc is > 460msec.

25. Hypertension not controlled by medical therapy (systolic blood pressure > 160
millimeter of mercury (mmHg) or diastolic blood pressure > 100mmHg).

26. Concomitant medications that are potent inducers (rifampicin, rifabutin, phenytoin,
carbamazepine, phenobarbital and St. John's Wort) of CYP3A4 function.

27. Not accessible for treatment and follow up.

28. Failure to provide informed consent.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Significant change in NTx level defined as a ≥ 30% reduction in urinary NTx level from baseline.

Outcome Time Frame:

Week # 1-4, 12, and every 12 weeks until disease progression/recurrence

Safety Issue:


Principal Investigator

Mark Clemons, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

The Ottawa Hospital Regional Cancer Centre


Canada: Health Canada

Study ID:




Start Date:

August 2009

Completion Date:

June 2013

Related Keywords:

  • Metastatic Breast Cancer
  • Breast Cancer
  • Bone Metastases
  • Telopeptide
  • Zactima
  • Fulvestrant
  • Breast Neoplasms