Clinical Trials /

Whole Brain Radiotherapy (WBRT) With Sorafenib for Breast Cancer Brain Metastases (BCBM)

NCT01724606

Description:

Sorafenib is a new type of anti-cancer drug. It belongs to a new class of medications known as tyrosine kinase inhibitors. Sorafenib is thought to work against cancer in many ways. It helps decrease blood supply to the tumor. It also blocks some proteins that help the tumor cells to grow." Sorafenib is approved by the Food and Drug administration (FDA) for treatment for other cancers like liver and kidney cancer. Sorafenib has also been studied in the treatment of breast cancer that has spread but is not specifically approved for the treatment of breast cancer. It has been studied both as a single agent and also in combination with other anti-cancer therapies for breast cancer. In laboratory models and in some patients with other cancers, sorafenib has been studied in tumors in the brain. In this study, sorafenib will be given together with whole brain radiation therapy (WBRT). Overall this research study is designed to answer 2 main questions: 1. What dose of sorafenib should be used together with WBRT? 2. What are the side effects of sorafenib and WBRT when given together?

Related Conditions:
  • Breast Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 12-046
  • NCT ID: NCT01724606

Conditions

  • Breast Cancer
  • Brain Metastases

Interventions

DrugSynonymsArms
SorafenibRadiotherapy with Sorafenib

Purpose

Sorafenib is a new type of anti-cancer drug. It belongs to a new class of medications known as tyrosine kinase inhibitors. Sorafenib is thought to work against cancer in many ways. It helps decrease blood supply to the tumor. It also blocks some proteins that help the tumor cells to grow." Sorafenib is approved by the Food and Drug administration (FDA) for treatment for other cancers like liver and kidney cancer. Sorafenib has also been studied in the treatment of breast cancer that has spread but is not specifically approved for the treatment of breast cancer. It has been studied both as a single agent and also in combination with other anti-cancer therapies for breast cancer. In laboratory models and in some patients with other cancers, sorafenib has been studied in tumors in the brain. In this study, sorafenib will be given together with whole brain radiation therapy (WBRT). Overall this research study is designed to answer 2 main questions: 1. What dose of sorafenib should be used together with WBRT? 2. What are the side effects of sorafenib and WBRT when given together?

Trial Arms

NameTypeDescriptionInterventions
Radiotherapy with SorafenibExperimentalThis is a single institution, open label, prospective, phase I clinical trial using standard 3+3 design. Histologically confirmed metastatic adenocarcinoma of the breast with radiologic evidence of new and/or progressive brain metastases (BM) with a clinical indication for WBRT will be enrolled.
  • Sorafenib

Eligibility Criteria

        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.

          -  Karnofsky Performance Status (KPS) of ≥70%

          -  If a patient is on corticosteroids, he/she must be on a non-escalating corticosteroid
             dose (not exceeding more than 16 mg daily of Dexamethasone oral) 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 (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.

          -  No limit to prior therapies with last anti-cancer treatment ≥2 weeks from initiation
             of WBRT. Please note: there is no washout period required for trastuzumab and
             pertuzumab.

          -  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.

          -  Continuation of trastuzumab and pertuzumab are allowed for those patients already on
             trastuzumab and pertuzumab therapy.

          -  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 mg/dL

          -  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 Please
             note: leptomeningeal metastases may be allowed if it is limited to cranial metastasis
             (MRI spine should be completed, within 4 weeks of enrollment, to show that no other
             leptomeningeal metastases is present) and is not the only metastasis present in the
             brain.'

          -  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
             bevacizumab.

          -  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.

          -  Congenital long QT syndrome or taking drugs known to prolong the QT interval ( See
             Appendix D or http://www. Azcert.org )

          -  Subjects taking any drugs with a known risk of causing torsades de pointes.

          -  Grade 3 hypertension ( SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg despite maximal medical
             therapy)

          -  ≥ Grade 2 Lipase increased (>1.5 x ULN),

          -  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
             allowed:

          -  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
             studied).

          -  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, squamous cell carcinoma (SCC), as long as it is other
             than SCC involving skin of the head and/or neck, and 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 for more than one day, or rifampin [rifampicin], and/or
             rifabutin) within 28 days before randomization.

          -  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
             assessments.

          -  Any condition which in the investigator's opinion makes the patient unsuitable for the
             study participation.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose
Time Frame:1 year
Safety Issue:
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.

Secondary Outcome Measures

Measure:CNS progression-free survival
Time Frame:1 year
Safety Issue:
Description:CNS-PFS is defined as the interval between the date of study entry and the date of intracranial tumor progression or death from any cause. We will evaluate this during follow-up MRI scans that will be performed as a standard of care using the Macdonald criteria.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • Whole Brain Radiotherapy (WBRT)
  • Sorafenib (BAY 43-9006)
  • 12-046

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