Mesothelioma Antiangiogenesis Clinical Trials

1.	Mesothelioma Avastin Plus Pemetrexed-Cisplatin Study

Phase	Type	Status	Age Range (yrs)	Sponsor	Protocol IDs
Phase III, Phase II	Treatment	Active	18 to 75	Other	IFCT-GFPC-ELCWP-0701 NCT00651456

Trial Description

Summary

Our hypothesis is that the addition of bevacizumab to the standard chemotherapy treatment of MPM will improve overall survival and quality of life beyond that achieved with chemotherapy alone.

Further Study Information

A phase II trial associating the reference chemotherapy (pemetrexed plus cisplatin) with bevacizumab is needed to ensure that no specific toxicity is induced by this association, and that this triplet have interesting activity. As pleural mesothélioma is a rare tumor, a phase III trial, using the survival data from the phase II part study, will be able to include a sufficient number of patients, in a reasonable period of time, to answer the question of efficacy of the anti-angiogenic triplet, providing the efficacy outcomes could be considered as favorable, at the end of the phase II part of the study.

Eligibility Criteria

Inclusion Criteria:

• Malignant, histologically proved, non resectable pleural Mesothelioma

• In case of pleural effusion, a talc pleurodesis, although not recommended, is allowed in accordance with current local practice, at the time of diagnostic thorascopy, with inclusion CT scan performed after pleurodesis.

• ECOG Performance status 0-2

• Mesothelioma with only pleural effusion without uni- or bidimensionally measurable disease will be eligible (adapted RECIST criteria)

• At least 18 years of age, less than 76 years of age

• Radiation therapy of thoracocentis tract (3 x 7Gy) performed before beginning medical study treatment, and the interval between thoracoscopic procedure and radiation will not exceed 28 days

Exclusion Criteria:

• Prior chemotherapy

• Brain metastasis

• History of cerebral vascular accident (CVA) or transient ischemic attack

Trial Lead Organizations/Sponsors

French Thoracic Oncology Intergroup Center

Gilles Robinet, Dr

Study Director

Arnaud Scherpereel, Dr

Study Director

Gérard Zalcman, Pr

Ph: 33-2-31-06-44-76

Franck Morin
		Email: franck.morin@ifct.fr

2.	A Study of VEGF-Antisense Oligonucleotide in Combination With Pemetrexed and Cisplatin for the Treatment of Advanced Malignant Mesothelioma

Phase	Type	Status	Age Range (yrs)	Sponsor	Protocol IDs
Phase II, Phase I	Biomarker/Laboratory analysis, Treatment	Approved-not yet active	18 to 90	Other	18M-07-2 NCT00668499

Trial Description

Summary

This will be a single institution non-randomized phase I/II trial for patients with malignant mesothelioma stage II and above, who have not received prior chemotherapy for their disease.

The purpose of this phase is to select a dose of VEGF-AS (antiangiogenesis drug)to be given with standard doses of pemetrexed followed by cisplatin on day 1 of a 21-day cycle.

Further Study Information

The Study Objectives in Phase I are:

To determine the safety of the combination of VEGF-Antisense Oligonucleotide (VEGF-AS, Veglin™) plus Pemetrexed and Cisplatin in subjects with advanced Malignant Mesothelioma,.via a dose escalation protocol. To determine the Maximum Tolerated Dose (MTD) and Dose Limiting Toxicity (DLT) of VEGF-AS plus Premetrexed and Cisplatin. To determine the time to disease progression To determine the objective response rate of the combination of VEGF-AS plus Pemetrexed and Cisplatin for the treatment of advanced malignant mesothelioma

The study Objectives in Phase II are:

To further characterize the toxicity experienced by patients with malignant mesothelioma treated with VEGF-AS plus Cisplatin and Pemetrexed.

To determine median and overall survival.

The Laboratory objectives are:

To measure plasma VEGF levels before, during, and after therapy as a correlate of outcome. To determine the pharmacokinetic profile of VEGF-AS plus Pemetrexed and Cisplatin.

Eligibility Criteria

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed malignant pleural mesothelioma, epithelial, sarcomatoid, or mixed subtype

• Patients must have measurable disease,using RECIST criteria.Pleural effusions and ascites are not considered measurable lesions.

• Patients with pleural mesothelioma must be IMIG stage ≥II

• Age greater than or equal to 18 years.

• ECOG performance status less than or equal to 2 and an estimated survival of at least 3 months

• Patients must have adequate organ and marrow function as defined below:

Absolute neutrophil count greater than or equal to1,500 Platelets greater than or equal to 100,000 Total bilirubin less than or equal to2.0x the upper limits of institutional normal AST/ALT less than or equal to 2.0x the upper limits of institutional normal Creatinine Clearance greater than 50ml/min

• The effects of VEGF-AS on the developing human fetus are unknown.

• Pemetrexed may cause fetal harm when administered to a pregnant woman and is classified pregnancy category D. There are no studies of pemetrexed in pregnant women. Cisplatin is also categorized as FDA Pregnancy Category D. There is positive evidence of human fetal risk. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

• Ability to understand and the willingness to sign a written informed consent.

• Patients with history of prior cured malignancy > 5 years since the completion of treatment may be accrued provided that other eligibility criteria are met.

Exclusion Criteria:

• Patients who have had chemotherapy for Mesothelioma prior to study entry

• Patients who have had radiation therapy within 3 weeks prior to entering the study. All patients should have recovered from all toxicities of prior therapy.

• Patients receiving therapy with other investigational agents at the time of study enrollment.

• Patients with uncontrolled brain metastases

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant and nursing women are excluded from this study

• Patients who had any major surgery within 4 weeks

Trial Lead Organizations/Sponsors

USC/Norris Comprehensive Cancer Center and Hospital

Barbara J. Gitlitz

Principal Investigator

Gina Tse, RN		Ph: 323/865-0514
		Email: Tse_G@ccnt.usc.edu

Charlean Ketchens, RN		Ph: 323/226-2452
		Email: Ketchens_C@ccnt.usc.edu

3.	Phase II Study of AZD2171 in Patients With Malignant Pleural, Peritoneal, or Tunica Vaginalis Mesothelioma That is Not Amenable to Curative Surgery

Phase	Type	Status	Age Range (yrs)	Sponsor	Protocol IDs
Phase II	Biomarker/Laboratory analysis, Treatment	Active	18 and over	NCI	UCCRC-14203B NCI-7103, 7103, NCT00309946

Alternate Title

AZD2171 in Treating Patients With Malignant Mesothelioma That Cannot Be Removed By Surgery

Objectives

Primary

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.

Secondary

1. Determine the progression-free survival of patients treated with AZD2171.
2. Determine the toxicity experienced by patients treated with AZD2171.
3. Determine median and overall survival of patients treated with AZD2171.

Tertiary

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.

Entry Criteria

Disease Characteristics:

• 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
  
   

Prior/Concurrent Therapy:

• 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

Patient Characteristics:

• ECOG performance status (PS) 0-1 OR Karnofsky PS 70-100%
• Life expectancy > 3 months
• WBC ≥ 3,000/mm³
• Absolute neutrophil count ≥ 1,500/mm³
• Hemoglobin ≥ 8 g/dL
• Platelets ≥ 100,000/mm³
• Total bilirubin normal
• AST/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 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

Trial Contact Information

Trial Lead Organizations

University of Chicago Cancer Research Center

Hedy Kindler, MD, Principal investigator		Ph: 773-702-0360; 888-824-0200

4.	Cisplatin, Pemetrexed and Bevacizumab for Untreated Malignant Mesothelioma

Phase	Type	Status	Age Range (yrs)	Sponsor	Protocol IDs
Phase II	Treatment	Active	18 and over	Other	AVF3442S NCT00295503

Trial Description

Summary

To estimate the time to progression of cancer in patients with previously untreated mesothelioma receiving cisplatin, pemetrexed and bevacizumab

Further Study Information

Secondary endpoints will include:

objective response rate

overall survival

In addition, the objective of the analysis of the correlative science data is to determine any association between tumor expression of VEGF/KDR complex and/or the presence of sv40 (as detected by PCR amplification) and objective response.

Eligibility Criteria

Inclusion criteria

5.2.1 Patients must have histologically proven malignant mesothelioma (epithelial, sarcomatoid, or mixed subtype) not amenable to curative surgery or radiotherapy. Eligible sites of origin include the pleura, peritoneum, and tunica vaginalis.

5.2.2 Patient's disease must not be amenable to curative treatment with surgery. Evidence of gross unresectability will include but not be limited to direct extension into the chest wall, mediastinal or hilar lymphadenopathy, pulmonary or cardiac function that is inadequate to tolerate resection, and sarcomatoid or mixed histology.

5.2.3 Patients must be > 18 years old 5.2.4 Patients must have measurable disease.

Adequate organ function and functional status

Exclusion Criteria:

a. General Medical Concerns 5.3.1 Patients must not be pregnant or breast feeding. 5.3.2 No "currently active" second malignancy other than non-melanoma skin cancer. Patients are not considered to have a "currently active" second malignancy if they have completed therapy and have a less than 30% risk of relapse.

5.3.3 No uncontrolled intercurrent illness including but not limited to: active infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, or psychiatric/social situations that would limit compliance with study requirements.

5.3.4 No HIV positive patients receiving combination anti-retroviral therapy because of possible pharmacokinetic interactions with study medications.

5.3.5 History of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab or other agents used in the study.

5.3.6 Inability to interrupt aspirin or other non-steroidal medication for a 5 day period.

c. Bevacizumab-Specific Concerns

Subjects meeting any of the following criteria are ineligible for study entry:

5.3.7 Patients with brain metastases are excluded 5.3.8 History of myocardial infarction or CVA (stroke) within 6 months of study entry.

5.3.9 Evidence of bleeding diathesis or coagulopathy. Patients on therapeutic doses of coumadin are eligible as long as the INR is maintained in the range of 2-3 and there is no evidence of active bleeding.

5.3.10 Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during the course of the study 5.3.11 Urine protein:creatinine ratio less than 1.0 at screening 5.3.12 Serious, non-healing wound, ulcer, or bone fracture

Trial Lead Organizations/Sponsors

Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas

Jonathan E Dowell, MD

Principal Investigator

Jonathan E Dowell, MD		Ph: 214-648-4180
		Email: jonathan.dowell@utsouthwestern.edu

Erin Fenske		Ph: 214-648-7097
		Email: erin.fenske@utsouthwestern.edu

5.	Phase II Study of Sunitinib Malate in Patients With Advanced Malignant Pleural Mesothelioma

Phase	Type	Status	Age Range (yrs)	Sponsor	Protocol IDs
Phase II	Treatment	Active	18 and over	NCI	CAN-NCIC-IND183 NCIC-183, NCT00392444, IND183

Alternate Title

Sunitinib in Treating Patients With Advanced Malignant Pleural Mesothelioma

Objectives

1. Assess the efficacy of sunitinib malate, in terms of response rate (complete and partial), in patients with malignant pleural mesothelioma.
2. Assess the toxicity, safety, and tolerability of this drug in these patients.
3. Assess the duration of response or stable disease, stable disease rate, progression-free survival, and median and overall survival rates.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed malignant pleural mesothelioma
  • Advanced or metastatic disease incurable by standard therapies
  
  
   
• Measurable disease, defined as at least 1 unidimensionally measurable lesion ≥ 20 mm by conventional teachniques or ≥ 10 mm by spiral CT scan
  • No sole site of disease in a previously irradiated area unless there has been subsequent evidence of progression
  • Low-dose, palliative radiotherapy allowed
  
  
   
• Meets 1 of the following criteria for prior cytotoxic chemotherapy treatment:
  • Previously treated with 1 platinum-based chemotherapy regimen
  • Previously untreated (i.e., no prior cytotoxic chemotherapy)
  
  
   
• No known brain metastases
  
   

Prior/Concurrent Therapy:

• See Disease Characteristics
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
• At least 7 days since prior and no concurrent CYP3A4 inhibitors, including any of the following:
  • Azole antifungals (e.g., ketoconazole, itraconazole, miconazole)
  • Verapamil
  • Clarithromycin
  • HIV protease inhibitors (e.g., indinavir, saquinavir, ritonavir, atazanavir, or nelfinavir)
  • Erythromycin
  • Delavirdine
  • Diltiazem
• At least 12 days since prior and no concurrent CYP3A4 inducers, including any of the following:
  • Rifampin
  • Phenytoin
  • Rifabutin
  • Hypericum perforatum (St. John’s wort)
  • Carbamazepine
  • Efavirenz
  • Phenobarbital
  • Tipranavir
• At least 4 weeks since prior major surgery and recovered
• At least 4 weeks since prior radiotherapy and recovered
• At least 12 months since prior coronary/peripheral artery bypass graft or stenting
• No prior surgical procedures affecting absorption
• No prior radiotherapy that involved ≥ 30% of functioning bone marrow
• No prior treatment with any other antiangiogenic agents or multitargeted tyrosine kinase inhibitors, including any of the following:
  • Bevacizumab
  • Sorafenib tosylate
  • Pazopanib
  • Thalidomide
  • AZD2171
  • Vandetanib
  • AMG706
  • Vatalanib
  • VEGF Trap
• No prior angiogenesis inhibitors except epidermal growth factor receptor inhibitors or other noncytotoxic therapy
• No other concurrent anticancer therapy or treatment with other investigational anticancer agents
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent therapeutic doses of coumadin-derivative anticoagulants (e.g., warfarin)
  • Doses ≤ 2 mg/day for prophylaxis of thrombosis or low molecular weight heparin for patients with an INR < 1.5 are allowed
• No concurrent agents with proarrhythmic potential, including any of the following:
  • Terfenadine
  • Quinidine
  • Procainamide
  • Disopyramide
  • Sotalol
  • Probucol
  • Bepridil
  • Haloperidol
  • Risperidone
  • Indapamide
  • Flecainide

Patient Characteristics:

• ECOG performance status 0-1
• Life expectancy ≥ 12 weeks
• Platelet count ≥ 100,000/mm³
• Absolute granulocyte count ≥ 1,500/mm³
• Bilirubin normal
• AST and ALT ≤ 2.5 times upper limit of normal
• Calcium ≤ 3 mmol/L
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Patients must reside within a 1.5 hour drive from participating center
• Able to take oral medication
• No other malignancy within the past 5 years except adequately treated nonmelanoma skin cancer, curatively treated in-situ carcinoma of the cervix, or any other curatively treated solid tumor
• No known history of allergic reactions attributed to compounds of similar chemical or biologic composition to sunitinib malate
• No QTc prolongation (i.e., QTc interval ≥ 500 msec) or other significant ECG abnormalities
• No New York Heart Association (NYHA) class III or IV heart failure
• Patients with the following histories allowed provided they are asymptomatic with respect to cardiac function and LVEF is normal by MUGA at baseline:
  • Anthracycline exposure
  • Central thoracic radiation that included the heart
  • NYHA class II cardiac function
• No uncontrolled hypertension (i.e., systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg)
• No cardiac disease within the past 12 months, including any of the following:
  • Myocardial infarction
  • Cardiac arrhythmia
  • Stable/unstable angina
  • Symptomatic congestive heart failure
• No pulmonary embolism within the past 12 months
• No cerebrovascular accident or transient ischemic attack within the past 12 months
• No bowel obstruction or any condition that would impair the ability to swallow and retain sunitinib malate, including any of the following:
  • Gastrointestinal tract disease resulting in an inability to take oral medication
  • Requirement for IV alimentation
  • Active peptic ulcer disease
• No serious illness or medical condition that would preclude study treatment including, but not limited to, any of the following:
  • History of significant neurologic or psychiatric disorder that would impair the ability to obtain consent or limit compliance with study requirements
  • Active uncontrolled infection
  • Any other medical condition that might be aggravated by treatment
  • Serious or nonhealing wound, ulcer, or bone fracture
  • Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days
• No pre-existing hypothyroidism unless euthyroid on medication

Trial Contact Information

Trial Lead Organizations

NCIC-Clinical Trials Group

Scott Laurie, MD, FRCPC, Protocol chair		Ph: 613-737-7700 ext. 70173; 888-627-5346