Cediranib Maleate in Treating Patients With Malignant Mesothelioma That Cannot Be Removed By Surgery

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00309946
• Collaborator: (none)
• Enrollment: 51
• Location: 1
• Arm: 1
• Duration (Months): 57
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Advanced Malignant Mesothelioma; Epithelial Mesothelioma; Localized Malignant Mesothelioma; Recurrent Malignant Mesothelioma; Sarcomatous Mesothelioma	Drug: cediranib maleate	Phase 2

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:

1. 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:

1. 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:

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of AZD2171 (NSC#732208) in Patients With Malignant Mesothelioma
• Study Start Date: Dec 1, 2005
• Actual Primary Completion Date: Sep 1, 2010
• Actual Study Completion Date: Sep 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: cediranib maleate; Given orally; Other Names: AZD2171 Recentin

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637-1470

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Hedy Kindler, University of Chicago Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00309946
• Other Study ID Numbers: NCI-2009-00126; N01CM17102; CDR0000463521; 14203B
• First Posted: Apr 3, 2006
• Last Update Posted: Jul 31, 2014
• Last Verified: Oct 1, 2013

• Additional relevant MeSH terms: Mesothelioma; Mesothelioma, Malignant; Lung Neoplasms; Cediranib

Study Results

Participant Flow

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	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.
Period Title: Overall Study
STARTED	51
COMPLETED	50
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	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.
Overall Participants	51
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64
Sex: Female, Male (Count of Participants)
Female	9 17.6%
Male	42 82.4%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate, Complete (CR) or Partial (PR) Response
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	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.
Measure Participants	50
Number [percentage of participants]	5 9.8%

2. Secondary Outcome

Title	Changes in Laboratory Correlates
Description	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

Outcome Measure Data

Analysis Population Description

This outcome was not measured/assessed for any of the study subjects.

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	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.
Measure Participants	0

3. Secondary Outcome

Title	Pharmacogenomics by Correlating Genetic Polymorphisms With Drug Activity and Toxicity
Description	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

Outcome Measure Data

Analysis Population Description

This outcome was not measured/assessed for any of the study subjects.

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	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.
Measure Participants	0

Adverse Events

Time Frame	After completion of study treatment, patients are followed for up to 8 weeks.
Arm/Group Title	Treatment (Enzyme Inhibitor Therapy)
Arm/Group Description	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.
All Cause Mortality
	Treatment (Enzyme Inhibitor Therapy)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Enzyme Inhibitor Therapy)
	Affected / at Risk (%)	# Events
Total	31/51 (60.8%)
Blood and lymphatic system disorders
Lymphocyte count decreased	1/51 (2%)
Cardiac disorders
Atrial flutter	1/51 (2%)
Cardiac arrest	1/51 (2%)
Conduction disorder	1/51 (2%)
ECG QTc interval prolonged	1/51 (2%)
Hypertension	4/51 (7.8%)
Hypotension	1/51 (2%)
Mobitz (type) II atrioventricular block	1/51 (2%)
Pericardial effusion	1/51 (2%)
Sinus tachycardia	1/51 (2%)
Gastrointestinal disorders
Abdominal distension	1/51 (2%)
Anorexia	1/51 (2%)
Constipation	2/51 (3.9%)
Dehydration	2/51 (3.9%)
Diarrhea	2/51 (3.9%)
Small intestinal obstruction	1/51 (2%)
General disorders
Abdominal pain	1/51 (2%)
Chest wall pain	3/51 (5.9%)
Failure to thrive	1/51 (2%)
Fatigue	2/51 (3.9%)
Headache	1/51 (2%)
Intracranial hemorrhage	1/51 (2%)
Immune system disorders
Anaphylaxis	1/51 (2%)
Infections and infestations
Infection with unknown ANC: Blood	1/51 (2%)
Sepsis	1/51 (2%)
Metabolism and nutrition disorders
Alanine aminotransferase increased	1/51 (2%)
Aspartate aminotransferase increased	1/51 (2%)
Creatinine increased	1/51 (2%)
Hyperglycemia	1/51 (2%)
Hyperkalemia	1/51 (2%)
Hypoalbuminemia	1/51 (2%)
Hypoglycemia	1/51 (2%)
Hyponatremia	1/51 (2%)
Musculoskeletal and connective tissue disorders
Muscle weakness	1/51 (2%)
Nervous system disorders
Cognitive disturbance	1/51 (2%)
Confusion	2/51 (3.9%)
Depressed level of consciousness	1/51 (2%)
Dizziness	1/51 (2%)
Encephalopathy	1/51 (2%)
Peripheral motor neuropathy	1/51 (2%)
Seizure	2/51 (3.9%)
Renal and urinary disorders
Proteinuria	2/51 (3.9%)
Urinary retention	1/51 (2%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/51 (2%)
Bronchopulmonary hemorrhage	1/51 (2%)
Dyspnea	7/51 (13.7%)
Lung infection	1/51 (2%)
Pleural effusion	2/51 (3.9%)
Pneumothorax	1/51 (2%)
Pulmonary embolism	1/51 (2%)
Vascular disorders
Thromboembolic event	4/51 (7.8%)
Other (Not Including Serious) Adverse Events
	Treatment (Enzyme Inhibitor Therapy)
	Affected / at Risk (%)	# Events
Total	49/51 (96.1%)
Blood and lymphatic system disorders
Anemia	23/51 (45.1%)
Edema (limb)	5/51 (9.8%)
Epistaxis	6/51 (11.8%)
Hypotension	3/51 (5.9%)
Lymphocyte count decreased	14/51 (27.5%)
Platelet count decreased	8/51 (15.7%)
White blood cell count decreased	4/51 (7.8%)
Cardiac disorders
Hypertension	29/51 (56.9%)
Sinus tachycardia	4/51 (7.8%)
Endocrine disorders
Hypothyroidism	11/51 (21.6%)
Gastrointestinal disorders
Anorexia	28/51 (54.9%)
Constipation	13/51 (25.5%)
Dehydration	3/51 (5.9%)
Diarrhea	30/51 (58.8%)
Dry mouth	4/51 (7.8%)
Dysgeusia	5/51 (9.8%)
Dyspepsia	9/51 (17.6%)
Dysphagia	6/51 (11.8%)
Mucositis (oral)	12/51 (23.5%)
Nausea	17/51 (33.3%)
Pharyngolaryngeal pain	5/51 (9.8%)
Vomiting	9/51 (17.6%)
General disorders
Abdominal pain	8/51 (15.7%)
Arthralgia	4/51 (7.8%)
Back pain	10/51 (19.6%)
Chest wall pain	23/51 (45.1%)
Fatigue	35/51 (68.6%)
Headache	9/51 (17.6%)
Insomnia	5/51 (9.8%)
Oral pain	4/51 (7.8%)
Pain - Other	6/51 (11.8%)
Pain in extremity	6/51 (11.8%)
Weight loss	12/51 (23.5%)
Immune system disorders
Allergic rhinitis	4/51 (7.8%)
Metabolism and nutrition disorders
Alanine aminotransferase (ALT) increased	11/51 (21.6%)
Alkaline phosphatase (ALP) increased	9/51 (17.6%)
Aspartate aminotransferase (AST) increased	10/51 (19.6%)
Creatinine increased	6/51 (11.8%)
Hyperglycemia	26/51 (51%)
Hyperkalemia	7/51 (13.7%)
Hypoalbuminemia	20/51 (39.2%)
Hypocalcemia	4/51 (7.8%)
Hypoglycemia	4/51 (7.8%)
Hypomagnesemia	7/51 (13.7%)
Hyponatremia	18/51 (35.3%)
Musculoskeletal and connective tissue disorders
Muscle weakness	4/51 (7.8%)
Nervous system disorders
Anxiety	5/51 (9.8%)
Depression	4/51 (7.8%)
Peripheral sensory neuropathy	4/51 (7.8%)
Renal and urinary disorders
Hematuria	4/51 (7.8%)
Proteinuria	14/51 (27.5%)
Respiratory, thoracic and mediastinal disorders
Cough	12/51 (23.5%)
Dyspnea	15/51 (29.4%)
Voice changes	11/51 (21.6%)
Skin and subcutaneous tissue disorders
Nail loss	4/51 (7.8%)
Palmar-plantar erythrodysesthesia syndrome	5/51 (9.8%)
Rash (maculo-papular)	6/51 (11.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.