Phase III Trial Comparing Capecitabine in Combination With Sorafenib or Placebo in the Treatment of Locally Advanced or Metastatic HER2-Negative Breast Cancer
Diagnosis: Breast: Metastatic
NCT ID: NCT01234337
(View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 11-299
The objective of this phase-III trial is to compare the efficacy and safety of sorafenib in combination with capecitabine versus capecitabine in combination with placebo in the treatment of subjects with locally advanced or metastatic HER2-negative breast cancer who are resistant to or have failed prior taxane and an anthracycline or for whom further anthracycline therapy is not recommended. A signed informed consent form After signing consent there can be up to 28days before starting the treatment during which time a number of tests will be carried out which will include tumor evaluations and medical history. The following tests and evaluations will have to be done within 7 days of the start of treatment,on Day 1 of every cycle and at the end of study: Patient will have a complete physical exam, electrocardiogram, blood tests, urinalysis, patient quality of life questionnaires and vital signs. The treatment period will be divided into 21-day (3-week) cycles. Subject will be checked for side effects for safety assessment on weekly basis for the first 6 weeks (Day 1, Day 8, Day 15, etc [+/- 3 days]) and then every 3 weeks thereafter (ie, Day 1 of subsequent cycles [+/- 3 days]).Capecitabine (1,000 mg/m2) is to be administered twice a day (every 12 hours) orally from Day 1 to Day 14 of each 21-day (3 weeks) cycle. Sorafenib or matching placebo (1 tablet in the morning followed by 2 tablets in the evening approximately 12 hours apart) is to be administered daily orally from Day 1 to Day 21 of each 21 day (3 weeks) cycle. Subjects will be followed for overall survival.
Massachusetts General Hospital, Dana Farber Cancer Institute at Faulkner Hospital, Dana-Farber Cancer Institute, Brigham and Women's Hospital
Steven Isakoff, MD, PhD,
Massachusetts General Hospital
Erica Mayer, MD,
Dana-Farber Cancer Institute
Massachusetts General Hospital:
Cancer Trials Call Center, 877-789-6100
Dana-Farber Cancer Institute:
Breast Cancer Nursing Team, 617-632-3478
- Age ≥ 18 years.
- Subject has histologically or cytologically confirmed HER2-negative adenocarcinoma of
the breast. HER2 status should be determined by an accredited laboratory
- Locally advanced or metastatic disease. Locally advanced disease must not be
amenable to resection with curative intent. Must have measurable or non measurable
disease (but radiologically evaluable) according to RECIST 1.1.
- All computer tomography (CT; with contrast) and magnetic resonance imaging (MRI) used
to document disease must have been done ≤ 4 weeks before randomization. Bone scans
(if clinically indicated) must have been done ≤ 8 weeks prior to randomization
- Subjects are resistant to or have failed prior taxane and an anthracycline OR
resistant to or have failed prior taxane AND for whom further anthracycline therapy
is not indicated.
- Treatment failure is defined as:
- Documented tumor progression >4 and 12 months after the last dose of therapy
when given in the metastatic setting OR
- Recurrence > 6 and less than or equal to 12 months of the last taxane or
anthracycline dose when given in the adjuvant or neo-adjuvant setting.
Note: Subjects who relapse beyond 12 months after the last taxane or anthracycline dose
given in the adjuvant, neo-adjuvant, or metastatic setting may be considered eligible for
the study provided that further anthracycline therapy and further taxane therapy have both
been considered and ruled out due to:
- Cumulative dose of anthracycline (240-400 mg/m2 doxorubicin to 300cc-550 mg/m2
doxorubicin equivalents) OR
- Intolerance before enrollment in this study as defined as:
- Anthracycline - (1) cardiotoxicity regardless of dose; or (2) severe/life-threatening
toxicity (eg, hypersensitivity) during prior treatment
- Taxane - (1) severe/life-threatening toxicity (eg, fatigue, hypersensitivity) during
prior treatment; or (2) unacceptable peripheral neuropathy following prior treatment
- Subject must have received no more than one chemotherapy treatment for
- Prior hormonal therapy for locally advanced or metastatic breast cancer is
allowed. Subjects who are refractory to hormonal therapy are allowed.
- Prior neo-adjuvant or adjuvant chemotherapy is allowed.
- Subject must have discontinued prior chemotherapy, prior radiation therapy, or
prior hormonal therapy for locally advanced or metastatic disease greater than
or equal to 4 weeks (28 days). Start of study treatment is allowed within less
than 28 days of the prior therapy provided that 5 half-lives of the prior
treatment drug(s) have elapsed before start of treatment.
- Adequate bone marrow, liver, and renal function within 7 days prior to
randomization as assessed by serum blood tests and all acute toxic effects of
any prior treatment have resolved to NCI-CTCAE v4.0 Grade 1 or less at the time
of signing the Informed Consent Form (ICF).
- Women of childbearing potential must have a negative serum pregnancy test
performed within 7 days prior to randomization.
- Subjects (men and women) of childbearing potential must agree to use adequate
contraception beginning at the signing of the ICF until at least 30 days after
the last dose of study drug.
- Subject must be able to swallow and retain oral medication
- HER2-positive breast cancer.
- Unknown hormone receptor status (estrogen and progesterone receptor).
- Subjects with bilateral breast cancer or a history of two distinct breast cancers are
- Subjects with inflammatory breast carcinoma are excluded
- Subjects who have received no prior taxane and anthracycline for the treatment of
breast cancer (either in adjuvant, neo-adjuvant or metastatic setting).
- Prior use of any licensed or investigational drug that targets VEGF or VEGFR (eg,
bevacizumab, brivanib, sunitinib, vatalinib).
- Prior use of sorafenib or capecitabine
- Subjects considered by the treating investigator to be appropriate candidates for
hormonal therapy as current treatment for metastatic breast cancer are excluded.
- Subjects with seizure disorder requiring medication
- Subjects with active brain metastases or leptomeningeal disease.
- Radiation to any measurable target lesions less than or equal to 4 weeks prior to
- Major surgery, open biopsy, or significant traumatic injury 4 weeks before signing
- Evidence or history of bleeding diathesis or coagulopathy., Uncontrolled hypertension
, Active or clinically significant cardiac disease, Subjects with thrombotic,
embolic, venous, or arterial events such as cerebrovascular accident (including
transient ischemic attacks) within 6 months before randomization
- Subject with any pulmonary hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 3 or
higher within 4 weeks before randomization;
- Subjects with an infection of NCI-CTCAE v4.0 Grade 2 or higher.
- Subjects with a history of human immunodeficiency virus infection or current chronic
or active hepatitis B or C infection.
- Presence of a non-healing wound, non-healing ulcer, or bone fracture
- Subjects who have used strong CYP3A4 inducers (eg, phenytoin, carbamazepine,
phenobarbital, St. John's Wort [Hypericum perforatum], dexamethasone at a dose of
greater than 16 mg daily, or rifampin [rifampicin], and/or rifabutin) within 28 days
- Subjects with any previously untreated or concurrent cancer that is distinct in
primary site or histology from breast cancer except cervical cancer in-situ, treated
basal cell carcinoma, or superficial bladder tumor. Subjects with a history of two
distinct breast cancers are excluded
- Subjects with a history of dihydopyrimidine dehydrogenase (DHPD) deficiency or severe
and unexpected reactions to fluropyrimidine
- Women who are pregnant or breast-feeding.
- Any condition which, in the investigator's opinion, makes the subject unsuitable for