Vorinostat in Combination With Palliative Radiotherapy for Patients With Non-Small Cell Lung Cancer
Condition: Non-Small Cell Lung Cancer (NSCLC)
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Vorinostat; Radiotherapy
Intervention description: 200 mg, 300 mg, 400 mg, once per RT fraction; Standard fractionation of 3.0 Gy per day over 2 weeks, to a total dose of 30 Gy, will be utilized for all patients. All patients will be treated one time per day, 5 days per week unless interruption is clinically indicated.
Intervention MeSH terms: Vorinostat
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a dose escalation study that will assess the safety of Vorinostat, a Histone
      Deacetylase (HDAC) inhibitor, in combination with palliative radiotherapy in patients with
      advanced or metastatic Non-Small Cell Lung Cancer (NSCLC). Vorinostat has been approved for
      use in patients with cutaneous T-cell lymphomas, but several pre-clinical studies suggest
      activity in lung cancer cell lines. Several HDAC inhibitors,including Vorinostat, may enhance
      the effect of radiotherapy, and this study will seek to confirm this.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Eligibility Criteria

          -  Patients must have histologically or cytologically confirmed NSCLC. Patients must have
             metastatic disease, stage IIIB with malignant pleural effusion, or be otherwise
             unsuitable for potentially curative therapy due to bulk of disease or comorbid medical
             illness. There must be disease apparent on imaging which offers a medical indication
             for radiation therapy. Palliative radiotherapy would be offered as appropriate
             standard therapy outside of a study setting. (NOTE: Radiotherapy utilized in this
             regimen is the same as that which would be offered as standard treatment outside of
             this study). Indications for palliative radiation include pain, pathologic fracture or
             risk of fracture, lymphovascular obstruction, bronchial obstruction, neural
             impingement, dyspnea, or bleeding.

          -  There must be a measurable tumor target (visible, palpable, or radiographically
             evident) for palliative radiation. The target for radiotherapy must be in the thoracic
             region (i.e., there must be normal lung tissue at the same anatomic level).

          -  Previous systemic therapy for NSCLC is allowed, as long as all prior therapy was
             completed at least two weeks before enrollment. Patients treated with nitrosurea or
             radioisotope may not be enrolled unless such treatment was at least 6 weeks prior to
             enrollment. Patients must have no previous exposed to HDAC inhibitors (patients
             previously treated with valproic acid are eligible if the exposure was greater than 30
             days prior to enrollment).

          -  Age ≥18 years. Because no dosing or adverse event data are currently available on the
             use of vorinostat alone, or in combination radiation in patients <18 years of age,
             children are excluded from this study.

          -  ECOG performance status ≤3

          -  Life expectancy of greater 3 months.

          -  Patients must have normal organ and marrow function as defined below, all laboratory
             values to be obtained within 2 weeks prior to enrollment:

          -  absolute neutrophil count ≥1,500/mcL

          -  platelets ≥100,000/mcL

          -  hemoglobin ≥9 g/ dL

          -  serum bilirubin <1.5 times the upper limit of normal (ULN) serum AST, ALT, ALP <2.5
             times ULN

          -  serum Creatinine <1.5 times ULN

          -  serum Potassium, Magnesium, Calcium - within normal range

          -  The effects of radiation on the developing human fetus are known to be teratogenic.
             For this reason, women of child-bearing potential and sexually active men must agree
             to use adequate contraception (hormonal or barrier method of birth control;
             abstinence) prior to study entry and for the duration of study participation. Should a
             woman become pregnant or suspect she is pregnant while participating in this study,
             she should inform her treating physician immediately.

          -  Ability to understand and the willingness to sign a written informed consent document.

          -  Ability to swallow a capsule

          -  Patients must have had a CT scan of the chest, abdomen, and pelvis (or PET/CT of the
             body), as well as an MRI or contrasted CT of the brain within 30 days of enrollment

        Exclusion Criteria:

          -  Patients with known, untreated brain metastases will be excluded from this clinical
             trial because of their poor prognosis and because they often develop progressive
             neurologic dysfunction that would confound the evaluation of neurologic and other
             adverse events. Patients who have received whole brain radiotherapy within 2 weeks of
             enrollment will also be excluded.

          -  Patients treated on an investigational drug trial within 30 days of study enrollment.

          -  Patients with active grade 2 or greater acute toxicity related to prior
             cancer-directed therapy

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to vorinostat, or patients with a history of an unanticipated severe
             normal tissue reaction to previous radiation treatment.

          -  Patients with congenital long QT-syndrome will be excluded, as a known side effect of
             vorinostat is prolongation of QT interval. Patients on anti-arrhythmic medications or
             other medications known to lead to prolonged QT interval will be exclude unless an ECG
             has been obtained documenting a normal QT interval within 90 days prior to enrollment.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection (fever >38ºC within 48 hours of enrollment), symptomatic congestive heart
             failure (i.e., NYHA class 3 or greater), unstable angina pectoris, coronary
             angioplasty within 6 months prior to enrollment, or cardiac arrhythmia. Additionally,
             patients with suspected or confirmed poor compliance, mental instability, or prior or
             current alcohol or drug abuse deemed by the investigator to be likely to affect their
             ability to sign the informed consent, or undergo study procedures will be excluded.

          -  Pregnant women are excluded from this study because radiation has the potential for
             teratogenic or abortifacient effects. Because there is an unknown but potential risk
             for adverse events in nursing infants secondary to treatment of the mother with
             vorinostat, breastfeeding should be discontinued if the mother is treated. Women of
             childbearing potential must have a negative pregnancy test prior to enrollment.

          -  Patients with active HIV or viral hepatitis.

          -  Patients in whom primary radiation therapy, with potentially curative intent, is
             indicated will be excluded.