Lung CancerPhase 1/2NCT00389805
Bortezomib and Pemetrexed Disodium in Treating Patients With Advanced Non-Small Cell Lung Cancer or Other Solid Tumors
A Phase 1/2 study testing bortezomib, pemetrexed disodium and gene expression analysis in people with Lung Cancer and Unspecified Adult Solid Tumor, Protocol Specific, run by University of California, Davis at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 120 years
- Conditions the study is for
- Lung Cancer, Unspecified Adult Solid Tumor, Protocol Specific
- What is being tested?
- bortezomib, pemetrexed disodium and gene expression analysis
- How many people
- 27 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2005to Jun 2007
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 120 years
- All sexes
- No healthy volunteers
- Adult, Older adult
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
Trial locations and contacts
1 site in 1 country.
United States1 site
University of California Davis Cancer Center
Sacramento, California, 95817
About this study
Official title: 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.
Read the detailed 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.
- Being tested
- bortezomib, pemetrexed disodium, gene expression analysis, mutation analysis, protein expression analysis
- Keywords
- 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
- Medical subject headings
- Lung Neoplasms, Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
bortezomibDrug
pemetrexed disodiumDrug
gene expression analysisGenetic
mutation analysisGenetic
protein expression analysisGenetic
reverse transcriptase-polymerase chain reactionGenetic
flow cytometryOther
immunoenzyme techniqueOther
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Patients Experiencing a Dose-limiting Toxicity (Phase I)
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.
Measured: Up to 36 months
Number of Participants Who Experience Adverse Events (Phase I)
Number of participants with treatment-related adverse events as assessed by CTCAE v3.0 (Phase I).
Measured: Throughout the entire study (up to 36 months).
Number of Patients With Grade ≥ 3 Toxicity (Phase I)
Grade 3/4 toxicity occurring in a patient within 1 cycle.
Measured: First cycle of treatment (3 weeks)
Number of Patients Who Responded to Study Treatment (Phase II)
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.
Measured: From start of treatment until disease progression/recurrence.
Secondary outcomes (7)
Number of Patients With Toxicity by NCI CTC v3.0 (Phase I)
Adverse events possibly related to treatment, graded according to the NCI CTCAE v3.0.
Measured: Up to 36 months
Maximum Tolerated Dose of Bortezomib in Combination With Pemetrexel (Phase I)
Measured: Up to 36 months
Number of Participants With Response to Therapy as Measured by RECIST (Phase I)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Best overall response is the best response recorded from the start of the treatment until disease progression/recurrence.
Measured: Up to 36 months
Number of Participants With Toxicities (Phase II)
Each adverse event will be determined by using the NCI CTCAE, Version 3.0.
Measured: Up to 36 months
Analysis of Molecular Determinants in Tumor Samples (Phase II)
Expression of relevant molecular targets of the proteasome, which is inhibited by bortezomib.
Measured: Up to 36 months
Importance of Folate-associated Gene Expression and Response or Outcome (Phase II)
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.
Measured: Up to 36 months
Effect of Bortezomib on Over Expression of NF-kB, BCL-2, and BCL-xL (Phase II)
Tumor levels of BCL-2, BCL-xL and BAX will be assessed by immunohistochemistry (IHC).
Measured: Up to 36 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Oct 2006 (estimated)
- Study startMar 2005
- Primary completionDec 2006
- Study completionJun 2007
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Lung CancerStudies of the same condition, open and under way.
- More trials run by University of California, DavisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 27 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, Davis
- Sponsor type
- University, hospital or other
- Collaborators
- Eli Lilly and Company
- Responsible party
- Sponsor
- Investigators
- Angela Davies, MD, Study chair, University of California, Davis
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00389805
- Sponsor's protocol ID
- UCDCC#158
- Other IDs
- 200412739, H3E-US-X038
- Status last verified
- Sep 2017
- First submitted
- 18 Oct 2006
- Last updated
- 31 Oct 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
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. doi: 10.1097/JTO.0b013e31815ba7d0.
PubMed 18090584
Study at a glance
From the registry record, last updated by the sponsor on 31 Oct 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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)
- ClinicalTrials.gov ID
- NCT00389805
- Acronym / sponsor ID
- UCDCC#158
- Keywords
- 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
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 27 participants (actual)
- Lead sponsor
- University of California, DavisUniversity, hospital or other
- Collaborators
- Eli Lilly and Company
- Study start
- Mar 2005
- Primary completion
- Dec 2006 (actual)
- Study completion
- Jun 2007 (actual)
- First posted
- 19 Oct 2006 (estimated)
- Results
- Posted 23 Jun 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 18 to 120 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| bortezomib | Drug | – |
| pemetrexed disodium | Drug | – |
| gene expression analysis | Genetic | – |
| mutation analysis | Genetic | – |
| protein expression analysis | Genetic | – |
| reverse transcriptase-polymerase chain reaction | Genetic | – |
| flow cytometry | Other | – |
| immunoenzyme technique | Other | – |
| immunohistochemistry staining method | Other | – |
Primary outcome
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.
7 secondary outcomes
Number of Patients With Toxicity by NCI CTC v3.0 (Phase I)
Time frame: Up to 36 months
Maximum Tolerated Dose of Bortezomib in Combination With Pemetrexel (Phase I)
Time frame: Up to 36 months
Number of Participants With Response to Therapy as Measured by RECIST (Phase I)
Time frame: Up to 36 months
Number of Participants With Toxicities (Phase II)
Time frame: Up to 36 months
Analysis of Molecular Determinants in Tumor Samples (Phase II)
Time frame: Up to 36 months
Importance of Folate-associated Gene Expression and Response or Outcome (Phase II)
Time frame: Up to 36 months
Effect of Bortezomib on Over Expression of NF-kB, BCL-2, and BCL-xL (Phase II)
Time frame: Up to 36 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Oct 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 18090584Davies 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. doi: 10.1097/JTO.0b013e31815ba7d0.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Angela Davies, MD study chair
University of California, Davis
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing bortezomib, pemetrexed disodium and gene expression analysis in people with Lung Cancer and Unspecified Adult Solid Tumor, Protocol Specific, run by University of California, Davis at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Oct 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 Jun 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Patients Experiencing a Dose-limiting Toxicity (Phase I) (time frame: Up to 36 months). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00389805, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Oct 2018.