Bortezomib and Pemetrexed Disodium in Treating Patients With Advanced Non-Small Cell Lung Cancer or Other Solid Tumors

University of California (UC) Davis

Status and phase

Completed

Phase 2

Phase 1

Conditions

Unspecified Adult Solid Tumor, Protocol Specific

Lung Cancer

Treatments

Other: immunoenzyme technique

Drug: pemetrexed disodium

Genetic: protein expression analysis

Genetic: gene expression analysis

Other: immunohistochemistry staining method

Genetic: reverse transcriptase-polymerase chain reaction

Genetic: mutation analysis

Drug: bortezomib

Other: flow cytometry

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT00389805

H3E-US-X038 (Other Identifier)

200412739 (Other Identifier)

UCDCC#158

Details and patient eligibility

About

RATIONALE: Bortezomib and pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving bortezomib together with pemetrexed disodium may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of two different schedules of bortezomib when given together with pemetrexed disodium and to see how well they work in treating patients with advanced non-small cell lung cancer or other solid tumors.

Full description

OBJECTIVES:

Primary

Determine the safety, including dose-limiting toxicities, and feasibility of combining bortezomib with pemetrexed disodium in patients with advanced non-small cell lung cancer (NSCLC) or other solid tumors. (Phase I)
Determine the response rate in patients with advanced NSCLC treated with this regimen. (Phase II)

Secondary

Compare the toxicity of 2 different schedules of bortezomib and pemetrexed disodium in patients with advanced solid tumors. (Phase I)
Determine the maximum tolerated dose (MTD) of bortezomib when administered with pemetrexed disodium in 2 different treatment schedules in these patients. (Phase I)
Determine, preliminarily, the efficacy of the combination of bortezomib and pemetrexed disodium in patients with advanced solid tumors. (Phase I)
Assess the overall survival and progression-free survival of these patients. (Phase II)
Evaluate the frequency and severity of toxicities associated with this regimen. (Phase II)

Tertiary

Perform laboratory correlative studies on tumor tissue and blood samples to investigate potential predictors of response. (Phase II)

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

Phase I: Patients will be accrued, in an alternating fashion, to 1 of 2 treatment groups.
- Group I: Patients receive pemetrexed disodium IV on day 1 and bortezomib IV on days 1, 4, 8, and 11.
- Group II: Patients receive pemetrexed disodium IV on day 1 and bortezomib IV on days 1 and 8.

In both groups, treatment repeats every 21 days in the absence of unacceptable toxicity or disease progression.

Cohorts of 3-6 patients per group receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Phase II: Patients receive pemetrexed disodium bortezomib (at the MTD) as in either group I or group II of the phase I portion of the study. Selection of the treatment schedule is based upon observed toxicity, safety, tolerability, efficacy, and clinical practicality.

Blood is drawn at baseline and prior to courses 2 and 3 for correlative and molecular studies.

Tumor tissue and blood samples from patients enrolled in the phase II portion of the study are examined for various biological markers. Immunohistochemistry is used to measure BCL-2 gene, BCL-xL gene, BAX gene, and p27. Reverse transcriptase-polymerase chain reaction is used to assay the expression of thymidylate synthase, folsyl-polyglutamate synthase, and reduced folate carrier. Levels of plasminogen-activator inhibitor 1 gene, vascular endothelial growth factor, and osteopontin are measured by immunoenzyme techniques. The nuclear expression of NF-kB and p27 in blood is compared before and after study treatment by flow cytometry.

After completion of study treatment, patients in phase I are followed for 30 days and patients in phase II are followed periodically.

Enrollment

27 patients

Sex

All

Ages

18 to 120 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Cytologically or histologically confirmed diagnosis of 1 of the following:
- Advanced solid tumor that progressed after standard therapy or for which no effective curative therapy exists (phase I)
- Stage IIIB (pleural effusion) or IV non-small cell lung cancer (NSCLC) (phase II)
  - Disease must have progressed or recurred after 1 platinum-based therapy regimen
  - NSCLC that has progressed or recurred after first-line therapy for stage IIIA or IIIB disease allowed
Measurable disease
- Disease in previously irradiated sites is considered measurable if there is clear disease progression following radiotherapy
- Evaluable disease (bone metastases, pleural fluid, ascites) allowed (phase I)
No symptomatic brain metastasis or disease requiring steroids and anticonvulsants
- Asymptomatic, previously treated (surgical resection or radiotherapy) brain metastases allowed provided patient is neurologically stable and has been off steroids and anticonvulsants for ≥ 4 weeks

PATIENT CHARACTERISTICS:

Zubrod performance status 0-2 (phase I) or 0-1 (phase II)
Life expectancy ≥ 3 months
Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 50 mL/min
Bilirubin normal
AST ≤ 2.5 times upper limit of normal
Granulocyte count ≥ 1,500/mm³
Platelet count of ≥ 100,000/mm³
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 3 months after completion of study treatment
No pre-existing neuropathy ≥ grade 2
No other prior malignancy except for the following (phase II):
- Adequately treated basal cell or squamous cell skin cancer
- In situ cervical cancer
- Adequately treated stage I or II cancer currently in complete remission
- Any other cancer from which the patient has been disease free for > 5 years
No hypersensitivity to bortezomib, boron, or mannitol
No cardiovascular complications, including any of the following:
- Myocardial infarction within the past 6 months
- New York Heart Association class III-IV heart failure
- Uncontrolled angina
- Severe uncontrolled ventricular arrhythmias
- Electrocardiographic (ECG) evidence of acute ischemia or active conduction system abnormalities
  - Any ECG abnormality at screening must be documented as not medically relevant

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
No prior bortezomib or pemetrexed disodium
Any number of prior chemotherapy regimens allowed (phase I)
More than 4 weeks since prior chemotherapy (6 weeks for mitomycin C) and recovered
More than 2 weeks since prior radiotherapy and recovered
No nonsteroidal anti-inflammatory drugs (NSAIDs) or salicylates 2 days prior and 2 days after (5 days pre and post for long-acting NSAIDs) administration of pemetrexed disodium
No concurrent anticonvulsants that are metabolized by the cytochrome P450 pathway