Sorafenib and Letrozole, Anastrozole, or Exemestane in Treating Postmenopausal Women With Estrogen Receptor-Positive and/or Progesterone Receptor-Positive Metastatic Breast Cancer

Phase II Randomized Study of Sorafenib Compared to Placebo When Administered in Combination With Aromatase Inhibitors for Postmenopausal Women With Metastatic Breast Cancer

RATIONALE: Sorafenib may stop the growth of tumor cells by blocking blood flow to the tumor and by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Aromatase inhibition therapy using letrozole, anastrozole, or exemestane may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether sorafenib is more effective than a placebo when given together with letrozole, anastrozole, or exemestane in treating metastatic breast cancer.

PURPOSE: This randomized phase II trial is studying how well sorafenib works compared with a placebo when given together with letrozole, anastrozole, or exemestane in treating postmenopausal women with estrogen receptor-positive and/or progesterone receptor-positive metastatic breast cancer.

Study Overview

• Status: Terminated
• Conditions: Breast Cancer
• Intervention / Treatment: Other: placebo; Drug: sorafenib tosylate; Drug: anastrozole; Drug: exemestane; Drug: letrozole

Detailed Description

OBJECTIVES:

Primary

• To compare the progression-free survival of postmenopausal women with estrogen receptor- and/or progesterone receptor-positive metastatic breast cancer treated with sorafenib tosylate vs placebo and letrozole, anastrozole, or exemestane.

Secondary

• To compare the overall survival and time to treatment failure of patients treated with these regimens.
• To compare the objective tumor response rate and duration of response in patients treated with these regimens.
• To assess the adverse event profile of sorafenib tosylate in combination with aromatase inhibitors in these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to prior aromatase inhibitor therapy (yes vs no) and line of endocrine therapy for metastatic disease (first-line vs second-line). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral sorafenib tosylate twice daily and oral letrozole, anastrozole, or exemestane once daily on days 1-28.
• Arm II: Patients receive oral placebo twice daily and oral letrozole, anastrozole, or exemestane once daily on days 1-28.

In both arms, treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed periodically for up to 5 years.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 55259
      • Mayo Clinic in Arizona
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic in Florida
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed adenocarcinoma of the breast

  • Metastatic disease

• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques (i.e., MRI or CT scan of chest, abdomen and pelvis) or ≥ 10 mm by spiral CT scan

  • Non-measurable disease allowed, defined as all other lesions (or sites of disease), including small lesions (longest diameter < 20 mm by conventional techniques or < 10 mm by spiral CT scan)
• Must have objective evidence of progression within the past 3 months
• No human epidermal growth factor receptor 2 (HER2)/neu overexpression, defined as gene amplification by fluorescence in situ hybridization or 3+ overexpression by immunohistochemistry, or unknown HER2/neu status

• No active brain metastases

  • Patients with neurological symptoms must undergo a contrast CT scan or MRI of the brain to exclude active brain metastasis
  • Patients with treated brain metastases allowed provided they have no evidence of disease and have been off definitive therapy (including steroids) for the past 3 months

• Hormone receptor status:

  • Estrogen receptor- and/or progesterone receptor-positive disease

PATIENT CHARACTERISTICS:

• Female
• The Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Postmenopausal
• Hemoglobin ≥ 9.0 g/dL
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT and AST ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver involvement)
• INR ≤ 1.5
• PTT within normal limits
• Creatinine ≤ 1.5 times ULN
• Not nursing, pregnant, or able to become pregnant
• No significant traumatic injury within the past 4 weeks
• No history of bleeding diathesis or uncontrolled coagulopathy
• No serious, nonhealing wound, ulcer, or bone fracture

• No clinically significant cardiac disease, including any of the following:

  • New York Heart Association class III-IV congestive heart failure
  • Unstable angina (i.e., anginal symptoms at rest) or new-onset angina (i.e., began within the past 3 months)
  • Myocardial infarction within the past 6 months
• No cardiac ventricular arrhythmias requiring antiarrhythmic therapy
• No uncontrolled hypertension (systolic BP > 150 mm Hg or diastolic BP > 90 mm Hg), despite optimal medical management
• No thrombolic, embolic, venous, or arterial events (e.g., cerebrovascular accident including transient ischemic attacks) within the past 6 months
• No pulmonary hemorrhage or bleeding event > grade 2 within the past 4 weeks
• No other hemorrhage or bleeding event ≥ grade 3 within the past 4 weeks
• No active clinically serious infection > grade 2
• No known HIV infection
• No chronic hepatitis B or C infection
• No previous or concurrent cancer that is distinct in primary site or histology from breast cancer except carcinoma in situ of the cervix, treated basal cell skin cancer, superficial bladder tumors (i.e., Ta and Tis), or any cancer curatively treated within the past 5 years
• No known or suspected allergy to sorafenib tosylate or other agents used in this study

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No major surgery or open biopsy within the past 4 weeks
• No more than 1 prior regimen of endocrine therapy for metastatic breast cancer, provided that the patient has not received an aromatase inhibitor within the past 12 months
• No more than 1 prior regimen of chemotherapy for metastatic disease

• More than 2 weeks since prior radiotherapy, except if to a non-target lesion only or single-dose radiotherapy for palliation

  • Prior radiotherapy to a target lesion(s) is permitted only if there has been clear progression of the lesion since radiotherapy was completed
• Concurrent anticoagulation treatment (e.g., warfarin or heparin) allowed
• No concurrent Hypericum perforatum (St. John's wort), rifampin, bevacizumab, or any other drugs (licensed or investigational) that target vascular endothelial growth factor (VEGF) or VEGF receptors
• No concurrent cytochrome P450 enzyme-inducing anti-epileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients receive oral sorafenib tosylate twice daily and oral letrozole, anastrozole, or exemestane once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: sorafenib tosylate; given orally; Drug: anastrozole; given orally; Drug: exemestane; given orally; Drug: letrozole; given orally
Active Comparator: Arm II; Patients receive oral placebo twice daily and oral letrozole, anastrozole, or exemestane once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.	Other: placebo; given orally; Drug: anastrozole; given orally; Drug: exemestane; given orally; Drug: letrozole; given orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Progression-free survival was defined as the time from randomization to the earliest date of documentation of disease progression or death due to any cause. In the case of a participant started treatment and then never return for any evaluations, the participant was censored for progression 1 day post-randomization.	Time from randomization to disease progression or death (up to 5 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Survival time was defined as the time from randomization to death due to any cause.	Time from randomization to death (up to 5 years)
Time to Treatment Failure	Time to treatment failure was defined as the time from the date of the randomization to the date at which the patient was removed from treatment due to progression, adverse events, or refusal.	Time from randomization to treatment failure (up to 5 years)
Objective Tumor Response Rate	A confirm response was defined as either a complete response (CR) or partial response (PR) noted as the objective status on 2 consecutive evaluation at least 4 weeks apart. The confirmed response rate was estimated within each treatment group by the number of confirmed responses divided by the total number of participants randomized.	Up to 5 years
Duration of Response	Duration of response was defined for all patients who have achieved a confirmed response as the date at which the patient's earliest best objective status was first noted to be either a CR or PR to the earliest date progression was documented.	Up to 5 years
Adverse Event	Number of participants that experienced adverse events (grade 3 and above) as measured by NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Adverse events were assessed every week during first 6 weeks of therapy, every 4 weeks on months 1 to 6, every 12 weeks on months 7 and beyond and at the end of treatment.	Time from randomization to end of treatment

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Vivek Roy, MD, Mayo Clinic; Principal Investigator: Donald W Northfelt, M.D., Mayo Clinic; Principal Investigator: Timothy J Hobday, M.D., Mayo Clinic

Study record dates

Study Major Dates

• Study Start: December 1, 2007
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: December 13, 2007
• First Submitted That Met QC Criteria: December 13, 2007
• First Posted (Estimate): December 14, 2007

Study Record Updates

• Last Update Posted (Estimate): February 5, 2016
• Last Update Submitted That Met QC Criteria: January 7, 2016
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: stage IV breast cancer; recurrent breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protein Kinase Inhibitors; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Sorafenib; Letrozole; Anastrozole; Exemestane
• Other Study ID Numbers: RC0731 (Other Identifier: Mayo Clinic Cancer Center); P30CA015083 (U.S. NIH Grant/Contract); 07-005768 (Other Identifier: Mayo Clinic IRB)