Bortezomib, Paclitaxel, Carboplatin and Radiation Therapy for Non-Small Cell Lung Cancer

National Cancer Institute (NCI)

Status and phase: Completed; Phase 2; Phase 1

Conditions: Stage IIIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer

Treatments: Drug: paclitaxel; Drug: carboplatin; Drug: bortezomib; Radiation: 3-dimensional conformal radiation therapy

Study type: Interventional

Funder types: NIH

Identifiers

NCT00093756

CDR0000390108

N0321 (Other Identifier)

NCCTG-N0321

U10CA025224 (U.S. NIH Grant/Contract)

NCI-2009-00643 (Registry Identifier)

Details and patient eligibility

About

This phase I/II trial (phase I closed to accrual as of 09/29/2009) is studying the side effects and best dose of bortezomib, paclitaxel, and carboplatin when given with radiation therapy and to see how well they work in treating patients with stage IIIA or stage IIIB non-small cell lung cancer that cannot be removed by surgery. Bortezomib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Bortezomib may increase the effectiveness of paclitaxel and carboplatin by making tumor cells more sensitive to the drugs. Radiation therapy uses high-energy x-rays to damage tumor cells. Giving bortezomib, paclitaxel, and carboplatin together with radiation therapy may kill more tumor cells.

Full description

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of bortezomib, paclitaxel, and carboplatin when administered with fractionated radiotherapy in patients with unresectable stage IIIA or IIIB non-small cell lung cancer. (Phase I) (closed to accrual as of 09/29/2009) II. Determine the 1-year survival of patients treated with this regimen. (Phase II)

SECONDARY OBJECTIVES:

I. Determine the tolerability of this regimen in these patients. (Phase II) II. Determine the response rate, progression-free survival, and overall survival of patients treated with this regimen. (Phase II) III. Correlate p27 expression in tumor tissue with survival, time to progression, and response in patients treated with this regimen. (Phase II)

OUTLINE: This is a multicenter, phase I (closed to accrual as of 09/29/2009), dose-escalation study of bortezomib, paclitaxel, and carboplatin followed by a phase II study.

PHASE I: (closed to accrual as of 09/29/2009) Patients receive bortezomib IV on days 1, 4, 8, and 11. Patients also receive paclitaxel IV over 3 hours followed by carboplatin IV over 30 minutes on day 2. Patients undergo radiotherapy once daily on days 1-5, 8-12, 15-19. Treatment repeats every 3 weeks up to 2 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of bortezomib, paclitaxel, and carboplatin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

PHASE II: Patients receive bortezomib, paclitaxel, and carboplatin as in phase I at the MTD. Patients also undergo radiotherapy as in phase I. Patients are followed up periodically for up to 5 years from the time of registration.

Enrollment: 52 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

• Histologically or cytologically confirmed non-small cell lung cancer (NSCLC)
• Locally advanced stage IIIA or IIIB disease that is considered unresectable
• No stage IV disease
• Requires radiotherapy
• Performance status (PS) - Eastern Cooperative Oncology Group (ECOG) 0-1
• At least 12 weeks
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• aspartate aminotransferase (AST) ≤ 3 times ULN
• Creatinine ≤ 1.5 times ULN
• No New York Heart Association class III or IV heart disease
• Forced expiratory volume (FEV) FEV_1 ≥ 1 L OR 35% of predicted
• Weight loss < 10% within the past 3 months
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No peripheral neuropathy ≥ grade 2
• No other severe underlying disease that would preclude study participation
• No uncontrolled infection
• No unhealed wound within the past 2 weeks
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, adequately treated noninvasive carcinomas (carcinoma in situ), or localized prostate cancer
• No concurrent prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF)
• No prior systemic chemotherapy for NSCLC*
• No prior radiotherapy to the chest
• More than 2 weeks since prior major surgery

Contraindications

• Any of the following:

  • Pregnant wome
  • Nursing women
  • Men or women of childbearing potential or their sexual partners who are unwilling to employ adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device [IUD], or abstinence, etc.) as this regimen may be harmful to a developing fetus or nursing child NOTE: This study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown.

• Any of the following prior therapies:

  • Prior radiation therapy to the chest
  • Prior systemic chemotherapy for NSCLC (phase II portion)

• New York Heart Association classification III or IV (see Appendix II).

• Any other severe underlying diseases which are, in the judgment of the investigator, inappropriate for entry into this study.

• uncontrolled infection.

• Major surgery or unhealed wound ≤ 2 weeks prior to registration.

• Prior history of malignancy ≤ 5 years, except for adequately treated basal cell or squamous cell skin cancer, adequately treated noninvasive carcinomas (carcinoma in situ), or localized prostate cancer.

• Peripheral neuropathy ≥grade 2

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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52 participants in 1 patient group

Treatment (bortezomib, paclitaxel, carboplatin)

Experimental group

Description:

PHASE I: Cohorts of 3-6 patients receive escalating doses of study medications until the maximum tolerated dose (MTD) is determined. PHASE II: Patients receive as in phase I at the MTD. Patients also undergo radiotherapy as in phase I. 3-dimensional conformal radiation therapy bortezomib: Given IV paclitaxel: Given IV carboplatin: Given IV

Treatment:

Radiation: 3-dimensional conformal radiation therapy

Drug: paclitaxel

Drug: carboplatin

Drug: bortezomib