Melanoma
Conditions
Keywords
stage IV melanoma, recurrent melanoma
Brief summary
RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving erlotinib together with bevacizumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving erlotinib together with bevacizumab works in treating patients with stage IV melanoma.
Detailed description
OBJECTIVES: Primary * Determine the overall response rate, response duration, and frequency of progression-free survival at 6 months in patients with stage IV melanoma treated with erlotinib hydrochloride and bevacizumab. * Determine objective responses in patients treated with this regimen. Secondary * Determine the overall safety and tolerability of this regimen in these patients. * Evaluate tissue blocks for EGFR by monoclonal antibody H11 (DAKO) or fluorescence in situ hybridization(FISH)7p12-specific probe-overexpression or amplification in patients treated with this regimen. OUTLINE: This is a multicenter study. Patients receive oral erlotinib hydrochloride once daily on days 1-28 and bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo tissue collection to analyze EGFR by monoclonal antibody H11 (DAKO) or fluorescence in situ hybridization (FISH) 7p12-specific probe-overexpression or amplification. Biological markers AKT, MAPK, p27, p21, CD13, CD34, and factor VIII are also measured. After completion of study treatment, patients are followed periodically.
Interventions
BIOLOGICALbevacizumab
10mg/kg, slow IV infusion, Days 1 and 14
DRUGerlotinib hydrochloride
150mg PO qd
GENETICfluorescence in situ hybridization
Targeting multiple genetic aberrations in isolated tumor cells.
GENETICgene expression analysis
gene expression analysis
OTHERimmunologic technique
immunologic technique
OTHERlaboratory biomarker analysis
laboratory biomarker analysis
PROCEDUREbiopsy
biopsy
Sponsors
National Cancer Institute (NCI)
Vanderbilt-Ingram Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Measurable Stage IV melanoma * Easter Cooperative Oncology Group (ECOG) Performance Status must be 0-1 * Good organ function as demonstrated by, Creatinine \<2.mg/dl, AST or ALT \<5 times upper limit of normal for subjects with documented liver metastases; \<2.5 times the upper limit of normal (ULN) for subjects without evidence of liver metastases, bilirubin\<2.0mg/dl,, absolute neutrophil count (ANC)\>1500/ul, platelets\>75k/ul, hemoglobin (Hgb)\>9 (may be transfused to obtain) * Prior therapy: adjuvant interferon (IFN) allowed; no more than one prior regimen for advanced stage IV disease * Patients must have a life expectancy of \>3 months * Patients with brain metastases are eligible only if they fulfill the following: resected or stereotactic treatment a minimum of 3 months previously and no active CNS disease since then; brain metastases treated greater than 6 months ago without evidence of progression or hemorrhage, \<1cm in size per lesion (up to 3 lesions), and off all steroids * Patients may not have received other agents, either investigational or marketed, which act by either EGFr inhibition or anti-angiogenesis mechanisms. Other epidermal growth factor receptor (EGFR) inhibitors include (but are not limited to): Iressa, erbitux, CI-1033. Angiogenesis inhibitors include (but are not limited to): SU5416, SU6668, SU 0122348, CP547632, VEGF Trap, anti-integrin αVβ3. * Recovered from toxicity of major surgery (4 wks), chemotherapy or biologic therapy (4 wks), and/or radiation therapy (2 wks) * No active other malignancy within 12 months * No active systemic infection * Over age of 18 years and signed IRB approved informed consent
Exclusion criteria
* Subjects meeting any of the following criteria (3.2.2-3.2.16) are ineligible for study entry * Compromised renal or hepatic function as defined by Creatinine \>2.0mg/dl, aspartate transaminase (AST) or alanine transaminase (ALT) \>5 times upper limit of normal for subjects with documented liver metastases; \>2.5 times the upper limit of normal (ULN) for subjects without evidence of liver metastases * Patient may not be part of any other investigational studies * internationalized normal ratio (INR) \> 1.5 * Patients with PEG or G-tube are ineligible. * Major surgical procedure, open biopsy; or significant traumatic injury within 28 days, or anticipation of need for major surgical procedure during the course of the study * Any non-healing wound, ulcer, or bone fracture. * Any clinical evidence or history of a bleeding diathesis or coagulopathy. * Patients with a history of deep vein thrombosis or thromboembolic disease within the past 6 months. * History of acute myocardial infarction within 6 months. In addition, patients are ineligible if they have clinically significant cardiovascular disease ((e.g., uncontrolled hypertension \[blood pressure of \>160/110 mmHg on medication\], New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac dysrhythmia requiring medication, or peripheral vascular disease (Grade II or greater) * Patients with \> 1+ proteinuria will have 24-hour urine collection; for protein. Patients with ≥ 1gm protein/24 hrs will be excluded * If child bearing age must not be pregnant or nursing and use methods to prevent pregnancy * History or evidence upon physical examination of central nervous system (CNS) disease (e.g., primary brain tumor, seizures not controlled with standard medical therapy, or history of stroke) * Inability to comply with study and/or follow-up procedures * History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Response | At 6 months | Per Response Evaluation Criteria in Solid Tumor (RECIST): Progressive disease (PD): \>=20% increase in sum of longest diameter (LD) of target lesion(s), taking as reference smallest sum LD recorded since treatment started. Complete response (CR): disappearance of all target lesions. Partial response (PR): \>=30% decrease in sum of LD of target lesion(s), taking as reference baseline sum LD. Stable disease (SD): neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Disease Progression. | up to one year after off-study date | Time from on study date to date of progression in months, if the progression happened in the patient. Disease progression is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions with reference to the smallest sum LD since treatment began or the appearance of one or more new lesions. |
| Progression-free Survival at 6 Months | 6 months | Patients with Progression-free survival at 6 months |
| Number of Patients With Each Worst-grade Toxicity Response | Day 1 of each 28-day cycle for 6 cycles (168 days) | Number of patients with worst-grade toxicity at each of five grades following National Cancer Institute Common Toxicity Criteria with grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening/disabling, 5 = death. |
Countries
United States
Participant flow
Recruitment details
This study remained open from 09/15/2004 to 1/27/2006.
Pre-assignment details
36 patients consented to be in the study, two were determined not eligible.
Participants by arm
| Arm | Count |
|---|---|
| Therapeutic Intervention Patients receive pemetrexed disodium IV and oxaliplatin IV over 2 hours on day 1. Treatment repeats every 14 days for up to 4 courses. If patient progresses before receiving 4 courses of treatment, treatment will be discontinued and patient will proceed to surgery. | 34 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Disease progression | 29 |
| Overall Study | Other complicating illness | 3 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Therapeutic Intervention |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 17 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants |
| Age Continuous | 64 years STANDARD_DEVIATION 1 |
| Region of Enrollment United States | 34 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 34 / 34 |
| serious Total, serious adverse events | 10 / 34 |
Outcome results
Primary
Number of Patients With Response
Per Response Evaluation Criteria in Solid Tumor (RECIST): Progressive disease (PD): \>=20% increase in sum of longest diameter (LD) of target lesion(s), taking as reference smallest sum LD recorded since treatment started. Complete response (CR): disappearance of all target lesions. Partial response (PR): \>=30% decrease in sum of LD of target lesion(s), taking as reference baseline sum LD. Stable disease (SD): neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD.
Time frame: At 6 months
Population: Patients for whom a response could be determined. Three patients were not available for measurement of response: no data (2) and toxicity (1).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tarceva/Avastin | Number of Patients With Response | Complete Response | 0 participants |
| Tarceva/Avastin | Number of Patients With Response | Partial Response | 2 participants |
| Tarceva/Avastin | Number of Patients With Response | Stable Disease | 14 participants |
| Tarceva/Avastin | Number of Patients With Response | Progressive Disease | 15 participants |
Secondary
Number of Patients With Each Worst-grade Toxicity Response
Number of patients with worst-grade toxicity at each of five grades following National Cancer Institute Common Toxicity Criteria with grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening/disabling, 5 = death.
Time frame: Day 1 of each 28-day cycle for 6 cycles (168 days)
Population: Patients who received the study drug and who experienced a toxicity. Eleven patients did not experience any toxicity and are therefore not included in the analyzed population for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tarceva/Avastin | Number of Patients With Each Worst-grade Toxicity Response | No. of patients with worst-grade toxicity of 1 | 3 participants |
| Tarceva/Avastin | Number of Patients With Each Worst-grade Toxicity Response | No. of patients with worst-grade toxicity of 2 | 12 participants |
| Tarceva/Avastin | Number of Patients With Each Worst-grade Toxicity Response | No. of patients with worst-grade toxicity of 3 | 7 participants |
| Tarceva/Avastin | Number of Patients With Each Worst-grade Toxicity Response | No. of patients with worst-grade toxicity of 4 | 1 participants |
| Tarceva/Avastin | Number of Patients With Each Worst-grade Toxicity Response | No. of patients with worst-grade toxicity of 5 | 0 participants |
Secondary
Progression-free Survival at 6 Months
Patients with Progression-free survival at 6 months
Time frame: 6 months
Population: Those patients who were progression-free at 6 months from study entry. No date of progression was available for 7 patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tarceva/Avastin | Progression-free Survival at 6 Months | 7 participants |
Secondary
Time to Disease Progression.
Time from on study date to date of progression in months, if the progression happened in the patient. Disease progression is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions with reference to the smallest sum LD since treatment began or the appearance of one or more new lesions.
Time frame: up to one year after off-study date
Population: Patients with disease progression. Six patients were not available for determination to progression: no data (5) and toxicity (1).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tarceva/Avastin | Time to Disease Progression. | 3 Months |