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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00389805
Recruitment Status : Completed
First Posted : October 19, 2006
Results First Posted : June 23, 2017
Last Update Posted : June 23, 2017
Eli Lilly and Company
Information provided by (Responsible Party):
University of California, Davis

October 18, 2006
October 19, 2006
January 20, 2017
June 23, 2017
June 23, 2017
March 2005
December 2006   (Final data collection date for primary outcome measure)
  • Number of Patients Experiencing a Dose-limiting Toxicity (Phase I) [ Time Frame: Up to 36 months ]
    Grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding, requirement for transfusion or lasting >7 days; febrile neutropenia; grade 3 neutropenia associated with infection; any other grade >/=3 non-hematologic toxicity considered by the investigator to be related to study drug.
  • Number of Participants Who Experience Adverse Events (Phase I) [ Time Frame: Throughout the entire study (up to 36 months). ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v3.0 (Phase I).
  • Number of Patients With Grade ≥ 3 Toxicity (Phase I) [ Time Frame: First cycle of treatment (3 weeks) ]
    Grade 3/4 toxicity occurring in a patient within 1 cycle.
  • Number of Patients Who Responded to Study Treatment (Phase II) [ Time Frame: From start of treatment until disease progression/recurrence. ]
    To determine the response rate of bortezomib in combination with pemetrexed in patients with advanced NSCLC. Response rate was assessed by CT scan. CT scans was performed at baseline and every two cycles (prior to 3rd and 5th cycle). The evaluation of response was based on standard RECIST criteria.
Not Provided
Complete list of historical versions of study NCT00389805 on Archive Site
  • Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) [ Time Frame: Up to 36 months ]
    Adverse events possibly related to treatment, graded according to the NCI CTCAE v3.0.
  • Maximum Tolerated Dose of Bortezomib in Combination With Pemetrexel (Phase I) [ Time Frame: Up to 36 months ]
  • Treatment Efficacy as Measured by RECIST (Phase I) [ Time Frame: Up to 36 months ]
    Response to therapy was evaluated every 2 cycles according to RECIST criteria.
  • Number of Participants With Toxicities (Phase II) [ Time Frame: Up to 36 months ]
    Each adverse event will be determined by using the NCI CTCAE, Version 3.0.
  • Analysis of Molecular Determinants in Tumor Samples (Phase II) [ Time Frame: Up to 36 months ]
    Expression of relevant molecular targets of the proteasome, which is inhibited by bortezomib.
  • Importance of Folate-associated Gene Expression and Response or Outcome (Phase II) [ Time Frame: Up to 36 months ]
    Overexpression of reduced folate carrier (RFC) protein is thought to contribute to decreased resistance to pemetrexed. Levels of expression will be studied by measuring mRNA transcripts using quantitative Reverse Transcriptase-Polymerase Chain Reaction in archival patient tumor specimens.
  • Effect of Bortezomib on Over Expression of NF-kB, BCL-2, and BCL-xL (Phase II) [ Time Frame: Up to 36 months ]
    Tumor levels of BCL-2, BCL-xL and BAX will be assessed by immunohistochemistry (IHC).
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Bortezomib and Pemetrexed Disodium in Treating Patients With Advanced Non-Small Cell Lung Cancer or Other Solid Tumors
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)

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.



  • 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 II)


  • 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.

Phase 1
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Lung Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Drug: bortezomib
  • Drug: pemetrexed disodium
  • Genetic: gene expression analysis
  • Genetic: mutation analysis
  • Genetic: protein expression analysis
  • Genetic: reverse transcriptase-polymerase chain reaction
  • Other: flow cytometry
  • Other: immunoenzyme technique
  • Other: immunohistochemistry staining method
Not Provided
Davies AM, Ho C, Metzger AS, Beckett LA, Christensen S, Tanaka M, Lara PN, Lau DH, Gandara DR. Phase I study of two different schedules of bortezomib and pemetrexed in advanced solid tumors with emphasis on non-small cell lung cancer. J Thorac Oncol. 2007 Dec;2(12):1112-6.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Not Provided
June 2007
December 2006   (Final data collection date for primary outcome measure)


  • 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


  • 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


  • 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
Sexes Eligible for Study: All
18 Years to 120 Years   (Adult, Senior)
Contact information is only displayed when the study is recruiting subjects
United States
H3E-US-X038 ( Other Identifier: Eli Lilly )
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Not Provided
University of California, Davis
University of California, Davis
Eli Lilly and Company
Study Chair: Angela Davies, MD University of California, Davis
University of California, Davis
April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP