Study of the Combination of Vorinostat and Radiation Therapy for the Treatment of Patients With Brain Metastases
Condition: Brain Metastases
MeSH terms: Neoplasm Metastasis; Brain Neoplasms
Intervention: Vorinostat; Radiation Therapy
Intervention description: All doses given for 3 weeks
Dose level -2 - 50 mg PO qd (to be used in de-escalation if toxicity occurs) Dose level -1 - 100 mg PO qd (to be used in de-escalation if toxicity occurs) Dose level I - 200 mg PO qd (initial starting dose) Dose level II - 300 mg PO qd Dose level III - 400 mg PO qd; Patients will take Vorinostat daily during radiation therapy, they will be recommended to swallow the capsule 60-90 minutes prior to estimate time of radiation.
Intervention MeSH terms: Vorinostat
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: brain metastases; radiation; vorinostat; lung cancer; breast cancer

Summary:

      Vorinostat in combination with radiation therapy can be administered safely and will be
      tolerated in patients with brain metastases, while providing an assessment of the anti-tumor
      activity of this combination.

      This is a multi-center, open-label, non-randomized Phase I study in patients with brain
      metastases. Patients will be administered oral Vorinostat and radiation therapy and will be
      treated for 3 weeks. Patients will be enrolled in cohorts and will be treated at sequentially
      rising dose levels of Vorinostat combined with radiation therapy. We will initially enter 3
      subjects at each dose. If none of the three experiences a dose-limiting toxicity we will
      proceed to the next dose. If one of the three experiences that level of toxicity, we will
      accrue 3 more subjects at that dose. If at any time there are two or more dose-limiting
      toxicities (in the 3-6 subjects) on a given dose, we will drop down to a lower dose. Dose
      escalation will continue until the MTD of Vorinostat and radiation therapy is established.
      The MTD will then be one dose below the DLT occurring in at least 1 out of 3 subjects (2 out
      of 6 patients).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients requiring a 3 week course of fractionated whole brain radiation therapy for
             brain metastases.

          2. Age > or = 18

          3. Histological or cytological diagnosis of a malignancy.

          4. Patients who have only 1-3 metastases are frequently treated with stereotactic
             radiation. Nonetheless, if the treating physician decides that whole brain
             radiotherapy is the appropriate treatment such patients would be eligible to enroll
             upon in the study.

          5. Radiographic evidence of brain metastasis.

          6. Measurable disease preferred but not required for eligibility

          7. Patient must have performance status of < or = 2 on the ECOG Performance Scale.

          8. Life expectancy of > or = 3 months

          9. Resolution of all acute toxic effects of prior chemotherapy or radiotherapy or
             surgical procedures to NCI CTCAE Version 3.0 grade < or = 1.

         10. Adequate organ function as defined by the following criteria:

               -  Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase
                  [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase
                  [SGPT]) < or = 2.5 x local laboratory upper limit of normal (ULN), or AST and ALT
                  < or = 5 x ULN if liver function abnormalities are due to underlying malignancy

               -  Total serum bilirubin < or = 1.5 x ULN

               -  Absolute neutrophil count (ANC) > or = 1500/µL

               -  Platelets > or = 100,000/µL

               -  Hemoglobin > or = 9.0 g/dL

               -  Serum calcium < or = 12.0 mg/dL

               -  Serum creatinine < or = 1.5 x ULN

               -  Potassium level within normal limits.

               -  Magnesium level within normal limits.

         11. Female patient of childbearing potential has a negative serum pregnancy test β-hCG
             within 72 hours prior to receiving the first dose of Vorinostat .

         12. Female patient is either post menopausal, free from menses for > or = 2 years,
             surgically sterilized, or willing to use 2 adequate barrier methods of contraception
             to prevent pregnancy, starting with Visit 1.

         13. Male patient agrees to use an adequate method of contraception for the duration of the
             study.

         14. Ability to understand and the willingness to sign a written informed consent. A signed
             informed consent must be obtained prior to any study specific procedures.

         15. INR < 1.5 or a PT/PTT within normal limits. Patients receiving anti-coagulation
             treatment with an agent such as warfarin or heparin may be allowed to participate. For
             patients on warfarin, the INR should be measured prior to initiation of Vorinostat and
             monitored at least weekly, or as defined by the local standard of care, until INR is
             stable.

         16. Patient is available for study related assessments, and management at the treating
             institution, for the duration of the study.

        Exclusion Criteria:

          1. Previous cranial irradiation (whether whole or partial brain, single fraction or
             multiple fractions) within the previous six months.

          2. Patient who has had chemotherapy within 21 days, non-cranial radiotherapy within 10
             days, or who has not recovered from adverse events due to agents administered more
             than 30 days earlier.

          3. Patient is currently participating or has participated in a study with an
             investigational compound or device within 14 days of initial dosing with study
             drug(s).

          4. Patient has had prior treatment with an HDAC inhibitor (e.g., romidepsin
             (Depsipeptide), NSC-630176, MS 275, LAQ-824, belinostat (PXD-101), LBH589, MGCD0103,
             CRA024781, etc). Patients who have received compounds with HDAC inhibitor-like
             activity, such as valproic acid, as anti-tumor therapy should not enroll in this
             study. Patients who have received such compounds for other indications, e.g. valproic
             acid for epilepsy, may enroll after a 30-day washout period under neurological
             supervision.

          5. Patients with markedly elevated intracranial pressure.

          6. Cardiac disease: Congestive heart failure > class II NYHA. Patients must not have
             unstable angina (anginal symptoms at rest) or new onset angina (began within the last
             3 months) or myocardial infarction within the past 6 months.

          7. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

          8. An extended QTc interval on baseline EKG examination. Normal values: male < 430ms,
             female <450 ms.

          9. Concomitant use of medications known to extend the QTc interval: Quinidine,
             Procainamide, Disopyramide, Dofetilide, Ibutilide, Sotalol, Amiodarone, Bepridil,
             Cisapride, Macrolides, Erythromycin, Clarithromycin, Fluoroquinolones, Sparfloxacin,
             Antiprotozoals, Pentamidine, Antimalarials, Halofantrine, Chloroquine, Phenothiazine
             neuroleptics, Thioridazine, Chlorpromazine, Mesoridazine, Butyrophenone neuroleptics,
             Droperidol, Haloperidol, Diphenylpiperidine neuroleptics, Pimozide, Arsenic trioxide,
             Methadone, Cesium, Licorice, Zhigancao

         10. Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic
             pressure > 90 mmHg, despite optimal medical management.

         11. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.

         12. Active clinically serious infection > CTCAE Grade 2

         13. NCI CTCAE grade 3 hemorrhage within 4 weeks of starting the study treatment.

         14. Thrombolic or embolic events such as a cerebrovascular accident including transient
             ischemic attacks within the past 6 months.

         15. Pulmonary hemorrhage/bleeding event > or = CTCAE Grade 2 within 4 weeks of first dose
             of study drug.

         16. Serious non-healing wound, ulcer, or bone fracture.

         17. Evidence or history of bleeding diathesis or coagulopathy

         18. Major surgery, open biopsy or significant traumatic injury within 4 weeks of first
             study drug.

         19. Use of St. John's Wort or rifampin (rifampicin).

         20. Any condition that impairs patient's ability to swallow whole pills.

         21. Any malabsorption problem.

         22. Pregnancy or breastfeeding. Female subjects must be surgically sterile or be
             postmenopausal, or must agree to use effective contraception during the period of
             therapy. All female subjects with reproductive potential must have a negative
             pregnancy test (serum or urine) prior to enrollment. Male subjects must be surgically
             sterile or must agree to use effective contraception during the period of therapy. The
             definition of effective contraception will be based on the judgment of the principal
             investigator or a designated associate.

         23. Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or study
             drug administration, or may interfere with the interpretation of study results, and in
             the judgment of the investigator would make the subject inappropriate for entry into
             this study.

         24. Documented history of cranial hemorrhage

         25. Patient has an active infection or has received intravenous antibiotics, antiviral, or
             antifungal agents within 2 weeks prior to the start of the study drug.

         26. Patient has uncontrolled inter-current illness or circumstances that could limit
             compliance with the study, including, but not limited to the following: active
             infection, acute or chronic graft versus host disease, symptomatic congestive heart
             failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric conditions.

         27. Patient has a history or current evidence of any condition, therapy, or lab
             abnormality that might confound the results of the study, interfere with the patient's
             participation for the full duration of the study or is not in the best interest of the
             patient to participate.

         28. Patient has a history of a gastrointestinal surgery or other procedures that might, in
             the opinion of the investigator, interfere with the absorption or swallowing of the
             study drugs.

         29. Patient has known hypersensitivity to the components of study drug or its analogs.

         30. Patient has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         31. Patient is, at the time of signing informed consent, a regular user (including
             "recreational use") of any illicit drugs, substance abuse or had a recent history
             (within the last year) of drug or alcohol abuse.

         32. Patient is pregnant or breast feeding, or expecting to conceive or father children
             within the projected duration of the study.