Carboplatin, Paclitaxel, and Radiation Therapy With or Without Thalidomide in Patients With Stage III Non-small Cell Lung Cancer

National Cancer Institute (NCI)

Status and phase: Terminated; Phase 3

Conditions: Lung Cancer

Treatments: Drug: carboplatin; Drug: paclitaxel; Radiation: radiation therapy; Drug: thalidomide

Study type: Interventional

Funder types: NIH

Identifiers

NCT00004859

E3598 (Other Identifier)

NCI-2012-02943

CDR0000067510 (Registry Identifier)

U10CA021115 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

This randomized phase III trial is studying carboplatin, paclitaxel, radiation therapy, and thalidomide to see how well they work compared to carboplatin, paclitaxel, and radiation therapy alone in treating patients with newly diagnosed stage III non-small cell lung cancer. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Thalidomide may stop the growth of non-small cell lung cancer by stopping blood flow to the tumor. It is not yet known if combination chemotherapy plus radiation therapy is more effective with or without thalidomide.

Full description

OBJECTIVES:

I. Compare the survival and time to progression of patients with stage IIIA or IIIB non-small cell lung cancer when treated with carboplatin, paclitaxel, and chemoradiotherapy with or without thalidomide.

II. Evaluate the toxicity of the thalidomide-containing regimen and compare response rates of the two groups.

III. Determine whether the inactivation of p16, Death-associated protein kinase (DAP-kinase), O6-methylguanine-DNA methyltransferase (MGMT) gene, or tissue-inhibitor of metalloproteinase 3 (TIMP-3) genes can be used to predict survival in these patients treated with this regimen.

IV. Determine whether the detection of a methylation biomarker in serum can be used to predict survival in these patients treated with this regimen.

OUTLINE: This is a randomized study. Patients are stratified according to disease histology (squamous vs nonsquamous), performance status (0 vs 1), disease stage (IIIA vs IIIB), and time of randomization (before addition of chemoradiotherapy vs after). Patients are randomized to one of two treatment arms.

ARM A: Patients receive paclitaxel intravenously (IV) over 3 hours immediately followed by carboplatin IV over 15-30 minutes on days 1 and 22. Treatment continues every 22 days in the absence of unacceptable toxicity or disease progression.

ARM B: Patients receive paclitaxel and carboplatin as in arm A. Patients also receive oral thalidomide and oral low-dose aspirin daily beginning on day 1 for up to 24 months in the absence of disease progression.

Beginning between days 43-50, patients in both arms with stable or responding disease receive chemoradiotherapy comprising paclitaxel IV over 1 hour and carboplatin IV over 15-30 minutes once weekly for 6 weeks and radiotherapy (RT) 5 days a week for 6 weeks. Arm B patients continue oral thalidomide.

Patients are followed every 2 months for 2 years and then every 6 months for 3 years.

Enrollment: 589 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Histologically confirmed newly diagnosed non-small cell bronchogenic carcinoma

  • Squamous cell
  • Adenocarcinoma
  • Large cell undifferentiated
  • Bronchoalveolar
  • Non-small cell carcinoma not otherwise stated

• Unresectable stage IIIA

  • Mediastinal lymph node enlargement of at least 1 cm but less than 2 cm on computed tomography (CT) scans must have mediastinotomy or thoracoscopy to rule out resectability

OR

• Stage IIIB disease without significant pleural effusion

  • Seen on CT scan only (not seen on chest x-ray) or does not reaccumulate after 1 thoracentesis and is cytologically negative
  • Metastases to contralateral, mediastinal, or supraclavicular nodes allowed

• Bidimensionally measurable or evaluable disease

• 18 and over

• ECOG performance status 0-1

• Adequate hematopoietic, hepatic, and renal function obtained <=4 weeks prior to registration:

  • Platelet count at least 100,000/mm^3
  • White Blood Cell (WBC) count at least 4,000/mm^3 OR absolute neutrophil count at least 2,000/mm^3
  • Bilirubin normal
  • Serum glutamic oxaloacetic transaminase (SGOT) no greater than 2.5 times upper limit of normal
  • Creatinine no greater than 1.5 mg/dL OR creatinine clearance at least 60 mL/min

• Fertile patients must use 2 methods of effective contraception for 4 weeks prior to, during, and for 4 weeks after study therapy

• Concurrent filgrastim (G-CSF) allowed for persistent neutropenia

Exclusion criteria

• Positive pregnancy test,pregnant or nursing
• Uncontrolled high blood pressure, unstable angina, congestive heart failure, or myocardial infarction within the prior year
• Serious cardiac arrhythmias requiring medication
• Prior radiotherapy to only area of measurable or active tumor
• Less than 5 years since prior chemotherapy
• Other active malignancies
• Serious uncontrolled active infection
• Evidence of greater than grade 1 neuropathy by history or physical examination
• History of seizure disorders
• Contraindication to daily low-dose (81 mg/day) aspirin

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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589 participants in 2 patient groups

Arm A (Paclitaxel + Carboplatin + RT)

Active Comparator group

Description:

Induction chemotherapy dosing: Paclitaxel, 225 mg/m² (3 hour infusion) Day 1. Carboplatin, area under the plasma drug concentration versus time curve (AUC) =6.0, 15-30 min IV infusion immediately following paclitaxel, Day 1 Concurrent chemotherapy / radiotherapy dosing: Paclitaxel, 45 mg/m2, administered weekly during radiotherapy over one hour. Carboplatin, AUC=2, 15- 30 minutes IV infusion immediately following paclitaxel; administered weekly during radiotherapy Radiation therapy started between days 43-50 from day 1 of cycle 1. The primary tumor and areas of known nodal disease received 60 Gy at 2.0 Gy fractions, 5 fractions/week for 30 fractions over 6 weeks to the post chemotherapy tumor volume as seen on computed tomography (CT). The initial 50 Gy was delivered to target volume (TV). The final 10 Gy was delivered to a reduced volume targeting defined by TV

Treatment:

Radiation: radiation therapy

Drug: paclitaxel

Drug: carboplatin

Arm B (Paclitaxel + Carboplatin + RT+ Thalidomide)

Experimental group

Description:

paclitaxel, carboplatin, and radiotherapy are same as those in Arm A. thalidomide: Induction chemotherapy dosing, oral daily, starting Day 1 for 24 months or until disease progression. Concurrent chemotherapy / radiotherapy dosing, oral daily, begin with 200 mg thalidomide as a single dose at bedtime. The dose is then increased by 100 mg every week as tolerated up to a total dose of 1000 mg.

Treatment:

Drug: thalidomide

Radiation: radiation therapy

Drug: paclitaxel

Drug: carboplatin