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Phase I/II Study of Two Different Schedules of Bortezomib (VELCADE, PS-341) and Pemetrexed (ALIMTA) in Advanced Solid Tumors, With Emphasis on Non-Small Cell Lung Cancer (NSCLC)

Phase 1/Phase 2
18 Years
Not Enrolling
Lung Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Phase I/II Study of Two Different Schedules of Bortezomib (VELCADE, PS-341) and Pemetrexed (ALIMTA) in Advanced Solid Tumors, With Emphasis on Non-Small Cell Lung Cancer (NSCLC)



- 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)


- 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


- 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

- 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

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

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.

PROJECTED ACCRUAL: A total of 86 patients will be accrued for this study.

Inclusion Criteria


- 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

- Disease must have progressed or recurred after 1 platinum-based therapy

- 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


- 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


- 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

- No concurrent anticonvulsants that are metabolized by the cytochrome P450 pathway,
including any of the following:

- Enzyme-inducing drugs

- Primidone

- Carbamazepine

- Phenobarbital

- Phenytoin

- Enzyme-inhibiting drugs

- Oxcarbazepine

- Topiramate

- Zonisamide

- Valproic acid

Type of Study:


Study Design:

Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Response rate (Phase II)

Safety Issue:


Principal Investigator

Angela Davies, MD

Investigator Role:

Study Chair

Investigator Affiliation:

University of California, Davis


United States: Federal Government

Study ID:




Start Date:

March 2005

Completion Date:

Related Keywords:

  • Lung Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • recurrent non-small cell lung cancer
  • stage IIIB non-small cell lung cancer
  • stage IV non-small cell lung cancer
  • unspecified adult solid tumor, protocol specific
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms
  • Neoplasms



University of California Davis Cancer Center Sacramento, California  95817