Clinical trial NCT00389805: Bortezomib and Pemetrexed Disodium in Treating Patients With Advanced Non-Small Cell Lung Cancer or Other Solid Tumors
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Lung Cancer
Unspecified Adult Solid Tumor, Protocol Specific
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
Lead sponsor: University of California, Davis
Sponsor class: OTHER
Collaborators: name: Eli Lilly and Company
First posted: 2006-10-19
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility 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

Primary outcomes:
measure: Number of Patients Experiencing a Dose-limiting Toxicity (Phase I)
timeFrame: Up to 36 months
measure: Number of Participants Who Experience Adverse Events (Phase I)
timeFrame: Throughout the entire study (up to 36 months).
measure: Number of Patients With Grade ≥ 3 Toxicity (Phase I)
timeFrame: First cycle of treatment (3 weeks)
measure: Number of Patients Who Responded to Study Treatment (Phase II)
timeFrame: From start of treatment until disease progression/recurrence.
Secondary outcomes:
measure: Number of Patients With Toxicity by NCI CTC v3.0 (Phase I)
timeFrame: Up to 36 months
measure: Maximum Tolerated Dose of Bortezomib in Combination With Pemetrexel (Phase I)
timeFrame: Up to 36 months
measure: Number of Participants With Response to Therapy as Measured by RECIST (Phase I)
timeFrame: Up to 36 months
measure: Number of Participants With Toxicities (Phase II)
timeFrame: Up to 36 months
measure: Analysis of Molecular Determinants in Tumor Samples (Phase II)
timeFrame: Up to 36 months
measure: Importance of Folate-associated Gene Expression and Response or Outcome (Phase II)
timeFrame: Up to 36 months
measure: Effect of Bortezomib on Over Expression of NF-kB, BCL-2, and BCL-xL (Phase II)
timeFrame: Up to 36 months
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California Davis Cancer Center
state: California
Study officials:
affiliation: University of California, Davis
name: Angela Davies, MD
role: STUDY_CHAIR
References:
citation: 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.