Lung Cancer, Unspecified Adult Solid Tumor, Protocol Specific
Conditions
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
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.
Interventions
DRUGbortezomib
DRUGpemetrexed disodium
GENETICgene expression analysis
GENETICmutation analysis
GENETICprotein expression analysis
GENETICreverse transcriptase-polymerase chain reaction
OTHERflow cytometry
OTHERimmunoenzyme technique
OTHERimmunohistochemistry staining method
Sponsors
Eli Lilly and Company
University of California, Davis
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Experiencing a Dose-limiting Toxicity (Phase I) | 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) | 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) | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Analysis of Molecular Determinants in Tumor Samples (Phase II) | Up to 36 months | Expression of relevant molecular targets of the proteasome, which is inhibited by bortezomib. |
| Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Up to 36 months | Adverse events possibly related to treatment, graded according to the NCI CTCAE v3.0. |
| Effect of Bortezomib on Over Expression of NF-kB, BCL-2, and BCL-xL (Phase II) | Up to 36 months | Tumor levels of BCL-2, BCL-xL and BAX will be assessed by immunohistochemistry (IHC). |
| Importance of Folate-associated Gene Expression and Response or Outcome (Phase II) | 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. |
| Maximum Tolerated Dose of Bortezomib in Combination With Pemetrexel (Phase I) | Up to 36 months | — |
| Number of Participants With Response to Therapy as Measured by RECIST (Phase I) | Up to 36 months | 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. |
| Number of Participants With Toxicities (Phase II) | Up to 36 months | Each adverse event will be determined by using the NCI CTCAE, Version 3.0. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A Pemetrexed on day 1 and bortezomib days 1, 4, 8, and 11 every 21 days | 15 |
| Arm B Pemetrexed on day 1 and bortezomib days 1 and 8 every 21 days | 12 |
| Total | 27 |
Baseline characteristics
| Characteristic | Arm A | Arm B | Total |
|---|---|---|---|
| Age, Continuous | 62 years | 59 years | 60 years |
| Region of Enrollment United States | 15 participants | 12 participants | 27 participants |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 14 Participants |
| Sex: Female, Male Male | 9 Participants | 4 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 15 | 12 / 12 |
| serious Total, serious adverse events | 0 / 15 | 0 / 12 |
Outcome results
Primary
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).
Time frame: Throughout the entire study (up to 36 months).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Number of Participants Who Experience Adverse Events (Phase I) | 15 Participants |
| Arm B | Number of Participants Who Experience Adverse Events (Phase I) | 12 Participants |
Primary
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.
Time frame: Up to 36 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Number of Patients Experiencing a Dose-limiting Toxicity (Phase I) | 3 Participants |
| Arm B | Number of Patients Experiencing a Dose-limiting Toxicity (Phase I) | 0 Participants |
Primary
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.
Time frame: From start of treatment until disease progression/recurrence.
Population: The Phase II study was not conducted.
Primary
Number of Patients With Grade ≥ 3 Toxicity (Phase I)
Grade 3/4 toxicity occurring in a patient within 1 cycle.
Time frame: First cycle of treatment (3 weeks)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A | Number of Patients With Grade ≥ 3 Toxicity (Phase I) | Anemia | 1 participants |
| Arm A | Number of Patients With Grade ≥ 3 Toxicity (Phase I) | Increased transaminases | 1 participants |
| Arm A | Number of Patients With Grade ≥ 3 Toxicity (Phase I) | Thrombocytopenia | 0 participants |
| Arm A | Number of Patients With Grade ≥ 3 Toxicity (Phase I) | Fatigue | 2 participants |
| Arm A | Number of Patients With Grade ≥ 3 Toxicity (Phase I) | Neutropenia | 12 participants |
| Arm B | Number of Patients With Grade ≥ 3 Toxicity (Phase I) | Fatigue | 0 participants |
| Arm B | Number of Patients With Grade ≥ 3 Toxicity (Phase I) | Neutropenia | 1 participants |
| Arm B | Number of Patients With Grade ≥ 3 Toxicity (Phase I) | Anemia | 0 participants |
| Arm B | Number of Patients With Grade ≥ 3 Toxicity (Phase I) | Thrombocytopenia | 1 participants |
| Arm B | Number of Patients With Grade ≥ 3 Toxicity (Phase I) | Increased transaminases | 0 participants |
Secondary
Analysis of Molecular Determinants in Tumor Samples (Phase II)
Expression of relevant molecular targets of the proteasome, which is inhibited by bortezomib.
Time frame: Up to 36 months
Population: The Phase II study was not conducted.
Secondary
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).
Time frame: Up to 36 months
Population: The Phase II study was not conducted.
Secondary
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.
Time frame: Up to 36 months
Population: The Phase II study was not conducted.
Secondary
Maximum Tolerated Dose of Bortezomib in Combination With Pemetrexel (Phase I)
Time frame: Up to 36 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Maximum Tolerated Dose of Bortezomib in Combination With Pemetrexel (Phase I) | 1.3 Mg/m^2 |
| Arm B | Maximum Tolerated Dose of Bortezomib in Combination With Pemetrexel (Phase I) | 1.6 Mg/m^2 |
Secondary
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.
Time frame: Up to 36 months
Population: All patients for whom response evaluation measurements were recorded at baseline and after 2 cycles.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Number of Participants With Response to Therapy as Measured by RECIST (Phase I) | Complete Response (CR) | 0 Participants |
| Arm A | Number of Participants With Response to Therapy as Measured by RECIST (Phase I) | Partial Response (PR) | 1 Participants |
| Arm A | Number of Participants With Response to Therapy as Measured by RECIST (Phase I) | Stable Disease (SD) | 7 Participants |
| Arm A | Number of Participants With Response to Therapy as Measured by RECIST (Phase I) | Progressive Disease (PD) | 7 Participants |
| Arm B | Number of Participants With Response to Therapy as Measured by RECIST (Phase I) | Progressive Disease (PD) | 5 Participants |
| Arm B | Number of Participants With Response to Therapy as Measured by RECIST (Phase I) | Complete Response (CR) | 0 Participants |
| Arm B | Number of Participants With Response to Therapy as Measured by RECIST (Phase I) | Stable Disease (SD) | 6 Participants |
| Arm B | Number of Participants With Response to Therapy as Measured by RECIST (Phase I) | Partial Response (PR) | 1 Participants |
Secondary
Number of Participants With Toxicities (Phase II)
Each adverse event will be determined by using the NCI CTCAE, Version 3.0.
Time frame: Up to 36 months
Population: The Phase II study was not conducted.
Secondary
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.
Time frame: Up to 36 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Constipation | 5 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Edema | 4 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Increased transaminases | 12 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Fatigue | 15 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Cough | 5 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Fever | 3 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Thrombocytopenia | 0 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Infection | 6 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Dehydration | 4 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Nausea +/- vomiting | 10 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Anorexia | 4 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Neuropathy | 4 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Diarrhea | 2 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Rash | 6 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Anemia | 1 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Renal impairment | 5 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Dizziness | 5 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Weakness | 0 participants |
| Arm A | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Neutropenia | 12 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Weakness | 2 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Neutropenia | 1 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Anemia | 0 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Thrombocytopenia | 1 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Increased transaminases | 5 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Anorexia | 6 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Constipation | 3 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Cough | 4 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Dehydration | 1 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Diarrhea | 3 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Dizziness | 4 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Edema | 4 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Fatigue | 11 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Fever | 3 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Infection | 4 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Nausea +/- vomiting | 6 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Neuropathy | 6 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Rash | 5 participants |
| Arm B | Number of Patients With Toxicity by NCI CTC v3.0 (Phase I) | Renal impairment | 1 participants |