Advanced Malignant Mesothelioma, Epithelial Mesothelioma, Localized Malignant Mesothelioma, Recurrent Malignant Mesothelioma, Sarcomatous Mesothelioma
Conditions
Brief summary
This phase II trial is studying how well cediranib maleate works in treating patients with malignant mesothelioma that cannot be removed by surgery. Cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor
Detailed description
We conducted a multi-center phase II trial of cediranib in patients with unresectable, histologically-confirmed malignant mesothelioma (MM) who had received \<=1 prior regimen of chemotherapy. The primary endpoint was objective response rate. Initial cediranib dosing was 45 mg daily during a 28-day cycle. Due to substantial toxicity, the starting dose was subsequently lowered to 30 mg daily. Pretreatment evaluation included a medical history and physical exam, complete blood count and differential, chemistry panel, pregnancy test, and a computed tomography (CT) scan of the chest, abdomen, and pelvis if relevant. A history and physical exam were repeated every 14 days and laboratory evaluations including a complete blood count with differential, serum chemistry panel, and urinalysis were repeated every 7 days. Patients were provided with a blood pressure monitoring device and a diary to record their blood pressure readings twice daily. Patients received a minimum of 2 cycles unless unacceptable toxicity or rapid clinical progression of disease occurred. Response was evaluated by CT imaging every two cycles. Confirmatory scans were to be obtained at least 4 weeks after initial documentation of an objective complete or partial response. Cediranib was administered orally once daily on days 1 through 28 of a 28-day cycle. Cediranib was initially dosed at 45 mg daily, but due to substantial rates of toxicity the protocol was amended in June 2007 to decrease the starting dose to 30 mg daily. Cediranib was taken 1 hour (h) before or 2 h after meals. Only one dose modification was permitted. When the starting cediranib dose was 45 mg, dose level-1 was 30 mg daily. After the protocol amendment, dose level-1 was 20 mg daily. Further dose reductions were allowed at the discretion of the investigator only if the patient had received clinical benefit from cediranib for \>3 months. Patients undergo blood collection periodically during study for biomarker and optional pharmacogenomic correlative studies. After completion of study treatment, patients are followed for up to 8 weeks. Adverse effects were graded according to National Cancer Institute Common Toxicity Criteria version 3.0. The dose was reduced for grade 3 or greater non-hematologic toxicity attributable to cediranib or grade 4 hematologic toxicity if the toxicity lasted for \>5 days and did not resolve to \<=grade 2. Maximal antihypertensive therapy was defined as taking 4 antihypertensive agents for \>2 weeks at full dosage. For patients on antihypertensive therapy who had an elevation in systolic blood pressure (SBP) \>=140 mmHg or diastolic blood pressure (DBP) \>=90 mmHg on 2 separate readings during a 48 h period, the dose of cediranib was maintained without interruption while the dosage of current antihypertensive therapy was increased or an additional antihypertensive agent was started. If 2 readings reported a SBP \>=180 mmHg or a DBP \>=105 mmHg during a 1 week period, cediranib was held and there was either an increase in the dosage of current antihypertensive therapy or an additional antihypertensive agent was added. Resumption of cediranib was allowed only after the blood pressure was \<140/90 mmHg. If 2 blood pressure readings recorded an SBP \>=160 mmHg or a DBP \>=105 mmHg 1 h apart during a 48 hour period in a patient already on maximal antihypertensive therapy, cediranib was held and treatment was resumed at 1 dose level lower when the blood pressure was \<160/105. PRIMARY OBJECTIVE: I. Determine the objective response rate in patients with malignant pleural, peritoneal, or tunica vaginalis mesothelioma that is not amenable to curative surgery who are treated with AZD2171 (cediranib maleate). SECONDARY OBJECTIVES: I. Determine the progression-free survival of patients treated with AZD2171. II. Determine the toxicity experienced by patients treated with AZD2171. III. Determine median and overall survival of patients treated with AZD2171. TERTIARY OBJECTIVES: I. Generate preliminary data regarding potential utility of pharmacogenomic and plasma/serum biomarkers of angiogenesis as predictive or prognostic markers for future investigations of this drug in malignant mesothelioma.
Interventions
DRUGcediranib maleate
Given orally
Sponsors
National Cancer Institute (NCI)
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
* Histologically or cytologically confirmed malignant pleural, peritoneal, or tunica vaginalis mesothelioma * Epithelial, sarcomatoid, or mixed subtype * International Mesothelioma Interest Group stage II-IV disease (for patients with pleural mesothelioma) * Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR \> 10 mm by spiral CT scan * Pleural effusion and ascites are not considered measurable lesions * Disease not amenable to curative surgery * No known brain metastases * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 OR Karnofsky PS 70-100% * Life expectancy \> 3 months * White blood cell (WBC) ≥ 3,000/mm³ * Absolute neutrophil count ≥ 1,500/mm³ * Hemoglobin ≥ 8 g/dL * Platelets ≥ 100,000/mm³ * Total bilirubin normal * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 times upper limit of normal(ULN) * Creatinine normal OR creatinine clearance \> 60 mL/min * Fertile patients must use effective contraception * Not pregnant or nursing * Negative pregnancy test * No history of allergic reactions to compounds of similar chemical or biologic composition to AZD2171 * Mean corrected QT interval (QTc) ≤ 500 msec (with Bazett's correction) by EKG * No history of long QT syndrome * Proteinuria ≤ 1+ on two consecutive dipsticks taken ≥ 1 week apart * No other concurrent malignancy * No New York Heart Association class III or IV cardiac disease * No uncontrolled intercurrent illness including, but not limited to, any of the following: * Hypertension * Ongoing or active infection * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Psychiatric illness or social situations that would limit study compliance * No more than 1 prior cytotoxic chemotherapy * Prior intrapleural cytotoxic agents (including bleomycin) do not count towards prior cytotoxic chemotherapy * At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered * No prior radiotherapy to the only site of measurable disease * At least 4 weeks since prior radiotherapy and recovered * At least 4 weeks since prior major surgery and recovered * More than 30 days since prior participation in an investigational trial * No prior treatment with a vascular endothelial growth factor (VEGF) inhibitor * No other concurrent investigational agents * No concurrent commercial agents for the malignancy * No concurrent medication that may markedly affect renal function (e.g., vancomycin, amphotericin, or pentamidine) * No concurrent hematopoietic growth factors except epoetin alfa * No concurrent palliative radiotherapy * No combination antiretroviral therapy for HIV-positive patients * No concurrent drugs or biologics with proarrhythmic potential
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate, Complete (CR) or Partial (PR) Response | Every 8 weeks | Evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee. To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat assessments that should be performed no less than 4 weeks after the criteria for response are first met. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Laboratory Correlates | Baseline, days 15 and 29 of course 1, and then every 28 days | Examined using paired t-test or Wilcoxon signed-ranks test. |
| Pharmacogenomics by Correlating Genetic Polymorphisms With Drug Activity and Toxicity | Week 1 of course 1 | Focus on variants of genes in the pathway targeted by cediranib maleate, including kdr/flk-1 (the specific target of cediranib maleate) and the genes that encode Vascular endothelial growth factor A (VEGF-A) or HIF1α. If additional information relevant to other genes of interest in the pathway becomes available the samples will be utilized for such analysis as well. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Enzyme Inhibitor Therapy) Initial cediranib maleate dosing was 45 mg (once daily) during a 28-day cycle. Courses repeated every 28 days in the absence of disease progression or unacceptable toxicity. Due to substantial toxicity, the starting dose was subsequently lowered to 30 mg daily. | 51 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Treatment (Enzyme Inhibitor Therapy) |
|---|---|
| Age, Continuous | 64 years |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 49 / 51 |
| serious Total, serious adverse events | 31 / 51 |
Outcome results
Primary
Objective Response Rate, Complete (CR) or Partial (PR) Response
Evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee. To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat assessments that should be performed no less than 4 weeks after the criteria for response are first met.
Time frame: Every 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Objective Response Rate, Complete (CR) or Partial (PR) Response | 5 percentage of participants |
Secondary
Changes in Laboratory Correlates
Examined using paired t-test or Wilcoxon signed-ranks test.
Time frame: Baseline, days 15 and 29 of course 1, and then every 28 days
Population: This outcome was not measured/assessed for any of the study subjects.
Secondary
Pharmacogenomics by Correlating Genetic Polymorphisms With Drug Activity and Toxicity
Focus on variants of genes in the pathway targeted by cediranib maleate, including kdr/flk-1 (the specific target of cediranib maleate) and the genes that encode Vascular endothelial growth factor A (VEGF-A) or HIF1α. If additional information relevant to other genes of interest in the pathway becomes available the samples will be utilized for such analysis as well.
Time frame: Week 1 of course 1
Population: This outcome was not measured/assessed for any of the study subjects.