Vorinostat, Paclitaxel, and Radiation Therapy in Treating Patients With Stage III Non-Small Cell Lung Cancer That Cannot Be Removed by Surgery

Condition(s) targeted: Lung Cancer

Intervention: paclitaxel (Drug); vorinostat (Drug); radiation therapy (Procedure)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Fred Hutchinson Cancer Research Center

Official(s) and/or principal investigator(s):
Patel Shilpen, MD, Principal Investigator, Affiliation: Fred Hutchinson Cancer Research Center

RATIONALE: Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving vorinostat together with paclitaxel and radiation therapy may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of vorinostat and to see how well it works when given together with paclitaxel and radiation therapy in treating patients with stage III non-small cell lung cancer that cannot be removed by surgery.

Official title: Phase I/II Clinical Trial Evaluating the Use of Vorinostat Combined With Paclitaxel and Radiotherapy in Patients With Inoperable Stage III Non-Small Cell Lung Cancer Unable to Tolerate Cisplatin

Study design: Treatment, Non-Randomized, Open Label

Primary outcome: Maximum tolerated dose of vorinostat

Secondary outcome:

Safety of vorinostat as evidenced by the number and percentage of patients that experience adverse events as categorized in the NCI CTCAE version 3.0

Efficacy of vorinostat, in terms of response rate, by CT scan

Duration of response in patients with responding disease

Progression-free survival on the date of the last tumor assessment

Overall survival time

Detailed description: OBJECTIVES:

Primary

- Determine the maximum tolerated dose (MTD) of vorinostat when administered in

combination with paclitaxel and thoracic radiotherapy in patients with locally advanced non-small cell lung cancer (NSCLC).

Secondary

- Assess the safety and toxicity of vorinostat when administered in combination with

paclitaxel and thoracic radiotherapy in patients with locally advanced NSCLC.

- Determine the radiological response rate, by CT scan, of vorinostat when administered in

combination with paclitaxel and thoracic radiotherapy in patients with locally advanced NSCLC.

- Describe the progression-free survival and overall survival of patients treated with

this regimen over 3 years of follow up.

OUTLINE: This is a phase I, dose-escalation study of vorinostat followed by a phase II study.

Patients receive paclitaxel IV over 1 hour once weekly and oral vorinostat once daily in weeks 1-7. Patients also undergo thoracic radiotherapy once daily, 5 days a week in weeks 1-7. Treatment continues in the absence of progressive disease or unacceptable toxicity.

After completion of study therapy, patients are followed at 30 days, 12 weeks, every 3 months for 2 years, and then every 6 months for 1 year.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed non-small cell lung cancer (NSCLC)

- Unresectable stage IIIA or IIIB (excluding malignant pleural effusion) disease

- At least one site of measurable disease, as defined by the modified RECIST criteria

- Unable to tolerate full-dose cisplatin as defined by 1 of the following criteria:

- Creatinine clearance < 50 mL/min

- Sensory hearing loss > grade 2

- Performance status ≥ 2

- Age ≥ 75 years

- Cardiac history, such as myocardial infarction within the past 6 months, angina,

or heart disease as defined by the New York Heart Association class III or IV

- Any other comorbid disease or condition that would increase the risk of toxicity

of cisplatin therapy

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- Life expectancy ≥ 12 weeks

- Not pregnant or breast feeding

- Negative pregnancy test

- Fertile patients must use effective double-barrier contraception

- Absolute neutrophil count ≥ 1,500/mcL

- Platelet count ≥ 100,000/mcL

- Hemoglobin ≥ 9 g/dL

- Prothrombin time or INR ≤ 1. 5 times upper limit of normal (ULN) (unless the patient is

receiving therapeutic anticoagulation)

- Partial thromboplastin time (PTT) ≤ 1. 2 times the ULN (unless the patient is receiving

therapeutic anticoagulation)

- K levels normal

- Mg levels normal

- Creatinine clearance ≥ 20 mL/min

- Serum total bilirubin ≤ 1. 5 times ULN

- AST and ALT ≤ 2. 5 times ULN

- Alkaline phosphatase ≤ 2. 5 times ULN

- No symptomatic neuropathy ≥ grade 2

- No known hypersensitivity to the components of study drug or its analogs or

paclitaxel

- No NYHA class III or IV congestive heart failure

- No myocardial infarction within the past 6 months

- QTc ≤ 0. 47 seconds

- No uncontrolled arrhythmia

- No "currently active" second malignancy except nonmelanoma skin cancer or carcinoma in

situ of the cervix

- Patients are not considered to have a "currently active" malignancy if they have

completed therapy for a prior malignancy, are disease free from prior malignancies for > 5 years or are considered by their physician to be at less than 30% risk of relapse

- No 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

PRIOR CONCURRENT THERAPY:

- More than 5 years since prior chemotherapy, radiotherapy, or biological therapy for

NSCLC

- More than 30 days since prior and no concurrent participation on a study with an

investigational compound or device

- No prior treatment with an HDAC inhibitor (e. g., romidespin [depsipeptide], NSC-

630176, MS 275, LAQ-824, belinostat [PXD-101], LBH589, MGCD0103, or CRA024781)

- More than 30 days since prior compounds with HDAC inhibitor-like activity for other

indications (e. g., valproic acid for epilepsy)

- No concurrent systemic steroids that have not been stabilized to the equivalent of ≤

10 mg/day prednisone during the past 30 days

- No concurrent chemotherapy, radiotherapy, biological therapy or investigational

anticancer therapy

- No concurrent other HDAC inhibitor (e. g., valproic acid)

- No concurrent prophylactic hematopoietic growth factors

Fred Hutchinson Cancer Research Center, Seattle, Washington 98195-6043, United States; Recruiting
Patel Shilpen, MD, Phone: 206-598-3300

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: March 2008
Last updated: October 25, 2008