Study of the Combination of Vorinostat and Radiation Therapy for the Treatment of Patients With Brain Metastases

NCT00838929 | Completed Phase 1 Results DMC

• 3 other identifiers: 08D.5222008-19JT 1331
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 2

Brief 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).

Conditions

Brain Metastases

Keywords

brain metastases; radiation; vorinostat; lung cancer; breast cancer

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) of Vorinostat and Radiotherapy in Patients With Brain Metastases.

  To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Vorinostat and radiotherapy in patients with brain metastases. The maximum tolerated dose (MTD) will be one dose below the DLT occurring in at least 1 out of 3 subjects. 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

  Weekly during treatment On Last day of treatment (30 days after last drug dose) Follow-up (every 3 months)

Study Arms (3)

Vorinostat (200 mg) and radiation

EXPERIMENTAL

Cohort 1: Patients receive 200 mg of Vorinostat and radiation

Drug: Vorinostat; Radiation: Radiation Therapy

Vorinostat (300 mg) and radiation

EXPERIMENTAL

Cohort 2: Patients receive 300 mg of vorinostat and radiation

Drug: Vorinostat; Radiation: Radiation Therapy

Vorinostat (400 mg) and radiation

EXPERIMENTAL

Cohort 3: Patients receive 400 mg of vorinostat and radiation

Drug: Vorinostat; Radiation: Radiation Therapy

Interventions

Vorinostat DRUG

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

Also known as: Zolinza

Vorinostat (200 mg) and radiation; Vorinostat (300 mg) and radiation; Vorinostat (400 mg) and radiation

Radiation Therapy RADIATION

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.

Also known as: Radiation oncology, Radiotherapy, XRT

Vorinostat (200 mg) and radiation; Vorinostat (300 mg) and radiation; Vorinostat (400 mg) and radiation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients requiring a 3 week course of fractionated whole brain radiation therapy for brain metastases.
• Age \> or = 18
• Histological or cytological diagnosis of a malignancy.
• 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.
• Radiographic evidence of brain metastasis.
• Measurable disease preferred but not required for eligibility
• Patient must have performance status of \< or = 2 on the ECOG Performance Scale.
• Life expectancy of \> or = 3 months
• Resolution of all acute toxic effects of prior chemotherapy or radiotherapy or surgical procedures to NCI CTCAE Version 3.0 grade \< or = 1.
• 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

You may not qualify if:

• Previous cranial irradiation (whether whole or partial brain, single fraction or multiple fractions) within the previous six months.
• 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.
• 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).
• 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.
• Patients with markedly elevated intracranial pressure.
• 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.
• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
• An extended QTc interval on baseline EKG examination. Normal values: male \< 430ms, female \<450 ms.
• 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
• Uncontrolled hypertension defined as systolic blood pressure \> 150 mmHg or diastolic pressure \> 90 mmHg, despite optimal medical management.
• Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
• Active clinically serious infection \> CTCAE Grade 2
• NCI CTCAE grade 3 hemorrhage within 4 weeks of starting the study treatment.
• Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
• Pulmonary hemorrhage/bleeding event \> or = CTCAE Grade 2 within 4 weeks of first dose of study drug.

Sponsors & Collaborators

• Sidney Kimmel Cancer Center at Thomas Jefferson University: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (2)

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

The University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Related Links

• Kimmel Cancer Center at Thomas Jefferson University, an NCI-Designated Cancer Center

MeSH Terms

Conditions

Brain Neoplasms; Lung Neoplasms; Breast Neoplasms

Interventions

Vorinostat; Radiotherapy; Radiation

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids; Therapeutics; Physical Phenomena

Results Point of Contact

• Title: Wenyin Shi, MD, PhD
• Organization: Thomas Jefferson University

Wenyin.Shi.@jefferson.edu

215-955-4111

Study Officials

• Wenyin Shi, MD, PhD

  Thomas Jefferson Universtiy

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 6, 2009
• First Posted: February 9, 2009
• Study Start: March 1, 2009
• Primary Completion: January 1, 2012
• Study Completion: March 1, 2015
• Last Updated: May 4, 2025
• Results First Posted: November 1, 2013

Record last verified: 2025-05

Locations

US (2)