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Whole Brain Radiotherapy (WBRT) With Sorafenib for Breast Cancer Brain Metastases (BCBM): A Phase I Study

Phase 1
18 Years
Open (Enrolling)
Breast Cancer, Brain Metastases

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Trial Information

Whole Brain Radiotherapy (WBRT) With Sorafenib for Breast Cancer Brain Metastases (BCBM): A Phase I Study

Inclusion Criteria:

- Histologically-confirmed metastatic adenocarcinoma of the breast (Confirmation will
be done at MSKCC)

- Age ≥18 years.

- Radiologic evidence of new and/or progressive brain metastasis (>10 mm in longest
dimension) by MR imaging of the Brain

- Life expectancy of >12 weeks.

- ECOG Performance of 0 to 2 Stable corticosteroid dose (not exceeding more than 16 mg
daily) for ≥ 5 days.

- No limit to prior therapies with last anti-cancer treatment ≥ 2 weeks from initiation
of protocol based therapy provided all toxicities (other than alopecia) have resolved
to ≤Grade 1 or baseline.

- Planned WBRT based on number (≥ 3 lesions) and/or size (≥ 1 cm) of BMs. Patients
who require additional clinically indicated stereotactic radiosurgery (SRS) in
addition to WBRT will also be eligible.

Patients with prior SRS will also be eligible, provided that there are new, non-irradiated
measurable brain lesions.

- Prior hormonal therapy for locally advanced or metastatic disease is allowed but this
must have been discontinued prior to enrollment. No washout period will be required.

- Adequate bone marrow, liver, and renal function as assessed by the following:

- Granulocyte count ≥ 1,000/μL, platelet count ≥ 100,000/μL, and hemoglobin ≥ 10 g/dL
(hematologic parameters must be assessed at least 14 days after a prior transfusion,
if any)

- Serum bilirubin ≤ 1.5 mg/dL; AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN except
for: Patients with hepatic metastases: ALT and AST ≤ 5 × ULN; patients with hepatic
and/or bone metastases:

alkaline phosphatase ≤ 5 × ULN and patients with Gilbert's disease: serum bilirubin < 5

- Serum creatinine ≤ 1.5 mg/dL or creatinine clearance of ≥ 60 mL/min based on a
24-hour urine collection

- Women of childbearing potential must have a negative serum pregnancy test performed
within 7 days prior to enrollment and must agree to use adequate contraception prior
to enrollment and for the duration of study participation. 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.

- Patients must be able to swallow and retain oral medication.

Exclusion Criteria:

- Leptomeningeal metastases, hemorrhagic metastases, presence of midline shift

- Contraindications to sorafenib

- Prior treatment with any agent that targets vascular endothelial growth factor (VEGF)
or VEGF receptors (VEGFR) (licensed or investigational including sorafenib), except

- Craniotomy or any other major surgery, open biopsy, or significant traumatic injury
within 4 weeks of enrollment.

- Serious, non-healing wound, ulcer, or bone fracture.

- Uncontrolled seizures

- Use of cytochrome P450 enzyme-inducing anti-epileptic drugs (such as phenytoin,
carbamazepine, or phenobarbital) is not allowed.

- Cardiac disease:

Congestive heart failure >class II New York Heart Association (NYHA) (See Appendix B, or

- Unstable angina (anginal symptoms at rest), or new-onset angina (begun within the
last 3 months), or myocardial infarction within the 6 months prior to enrollment, or

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. Thrombolic,
embolic, venous, or arterial events such as a cerebrovascular accident including
transient ischemic attacks within the past 6 months.

- Evidence or history of bleeding diathesis or coagulopathy at the time of enrollment.

- Pulmonary hemorrhage/bleeding event >National Cancer Institute Common Terminology for
Adverse Events (NCI-CTCAE, version 4.0) Grade 2 within 4 weeks of enrollment.

- Any other hemorrhage/bleeding event ≥NCI-CTCAE Grade 3 within 4 weeks of enrollment.

- Therapeutic anticoagulation with Vitamin-K antagonists (e.g., warfarin) or with
heparins and heparinoids. However, prophylactic anticoagulation as described below is

- Low dose warfarin (1 mg orally, once daily) with PT-INR ≤ 1.5 x ULN is permitted.
Infrequent bleeding or elevations in PT-INR have been reported in some subjects
taking warfarin while on sorafenib or capecitabine therapy. Therefore, subjects
taking concomitant warfarin should be monitored regularly for changes in PT, PT-INR
or clinical bleeding episodes.

- Low dose aspirin (≤ 100 mg daily). Active clinically serious infection >NCI-CTCAE
Grade 2.

- Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C (the
safety and effectiveness of sorafenib in this patient population have not been

- Previous or concurrent cancer that is distinct in primary site or histology from
breast cancer within 5 years prior to enrollment EXCEPT cervical cancer in situ,
treated basal cell carcinoma, superficial bladder tumors [Ta and Tis].

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 before

- Concurrent anti-cancer therapy (chemotherapy, hormonal therapy, radiation therapy
(other than that specified by the protocol), surgery, immunotherapy, biologic therapy
including trastuzumab, lapatinib, bevacizumab, tyrosine kinase inhibitors other than
sorafenib or tumor embolization

- Women who are pregnant or breast-feeding.

- Use of any investigational drug within 28 days or 5 half-lives, whichever is longer,
preceding enrollment. For the purposes of this study, bevacizumab will not be
considered investigational therapy.

- Inability to comply with protocol and /or not willing or not available for follow-up

- Any condition which in the investigator's opinion makes the patient unsuitable for
the study participation.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose

Outcome Description:

Dose-escalation Phase: The proposed three dose levels of sorafenib during dose escalation are 200 mg, 400mg, and 600 mg administered daily orally. The dose-escalation phase is for 3-6 patients to be treated at each dose level. Assuming 3 dose levels during this phase, it will require a minimum of 2 and a maximum of 18 patients.

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Andrew Seidman, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

November 2012

Completion Date:

November 2014

Related Keywords:

  • Breast Cancer
  • Brain Metastases
  • Whole Brain Radiotherapy (WBRT)
  • Sorafenib (BAY 43-9006)
  • 12-046
  • Breast Neoplasms
  • Neoplasm Metastasis
  • Neoplasms, Second Primary
  • Brain Neoplasms



Memorial Sloan Kettering Cancer CenterNew York, New York  10021