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

CHU de Caen

Groupe Francais de Pneumo-Cancerologie

European Lung Cancer Working Party

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

Trial Contact Information

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

Sponsor Name Pending

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

Trial Contact Information

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

University of Chicago Cancer Research Center

Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center

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

Trial Contact Information

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

6.	Phase II Study of Bevacizumab, Pemetrexed and Carboplatin as First-Line Therapy in Malignant Pleural Mesothelioma

Phase	Type	Status	Age Range (yrs)	Sponsor	Protocol IDs
Phase II	Treatment	Approved-not yet active	18 and over	Other	ONC-2006-003 EUDRACT 2006-004429-27, NCT00407459

Trial Description

Summary

The primary objective is to assess antitumor activity of the combination of bevacizumab, pemetrexed and carboplatin, in terms of time to progression.

Further Study Information

Secondary endpoints are to evaluate:

• the objective response rate (RR) of the combination;

• the toxicity and the safety profile of the combination;

• the duration of response (RD) and time to treatment failure (TTF);

• the overall survival (OS)

Eligibility Criteria

Inclusion Criteria:

• Histologically proven malignant pleural mesothelioma, inoperable, non previously treated with chemotherapy including intracavitary administration;

• PS 0-1;

• measurable and/or evaluable lesions according to RECIST criteria;

• adequate organ function.

Exclusion Criteria:

• uncontrolled hypertension;

• evidence of bleeding diathesis or coagulopathy;

• pregnancy or breast-feeding.

Trial Lead Organizations/Sponsors

Istituto Clinico Humanitas

Armando Santoro

Principal Investigator

Armando Santoro, MD		Ph: +39 02 8224 Ext.4080
		Email: armando.santoro@humanitas.it

Giovanni L Ceresoli, MD		Ph: +39 02 8224 Ext.4559
		Email: giovanni_luca.ceresoli@humanitas.it

Trial Contact Information

7.	Phase II Study of Bortezomib and Cisplatin as First-Line Treatment in Patients With Malignant Mesothelioma

Phase	Type	Status	Age Range (yrs)	Sponsor	Protocol IDs
Phase II	Treatment	Active	18 and over	Other, Pharmaceutical / Industry	EORTC-08052 JJPRD-26866138CAN2012, EUDRACT-2006-000009-51, 08052, NCT00458913

Alternate Title

Bortezomib and Cisplatin as First-Line Therapy in Treating Patients With Malignant Mesothelioma

Objectives

1. Determine the activity and safety of bortezomib and cisplatin as first-line treatment in patients with malignant mesothelioma.
2. Validate the use of progression-free survival rate as a primary endpoint for the design of phase II mesothelioma trials.

Entry Criteria

Disease Characteristics:

• Histologically confirmed pleural malignant mesothelioma, meeting 1 of the following criteria:
  
  • Recurrent disease after radical surgery
  • Disease not considered suitable for radical treatment

   

• Measurable or evaluable disease

   

• No clinical evidence of brain or leptomeningeal metastases

   

Prior/Concurrent Therapy:

• See Disease Characteristics
• No prior systemic chemotherapy for mesothelioma
• No other concurrent antineoplastic agents except medications that may have antineoplastic activity but are taken for other reasons (e.g., megestrol acetate, cyclooxygenase-2 inhibitors, or bisphosphonates)
• No other concurrent experimental agents

Patient Characteristics:

• WHO performance status 0-1
• Life expectancy > 12 weeks
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Absolute neutrophil count > 1,500/mm³
• Platelet count > 100,000/mm³
• Creatinine clearance > 60 mL/min OR > 50 mL/min
• ALT and AST < 2.5 times upper limit of normal (ULN) (< 5 times ULN if liver metastases present)
• Bilirubin < 1.5 times ULN
• No concurrent secondary malignancy except carcinoma in situ of the cervix or adequately treated basal cell skin cancer
• No other malignancy treated within the past 5 years
  
  • Melanoma, breast cancer, or hypernephroma treated within the past 5 years and without recurrence are allowed

• No uncontrolled or severe cardiovascular disease, including any of the following:
  
  • Myocardial infarction within the past 6 months
  • New York Heart Association class III-IV heart failure
  • Uncontrolled angina
  • Clinically significant pericardial disease or cardiac amyloidosis

• No preexisting peripheral neuropathy
• No known or suspected allergy or intolerance to boron, mannitol, or heparin, if an indwelling catheter is used
• No psychological, familial, sociological, or geographical condition that would preclude protocol compliance

Trial Contact Information

Trial Lead Organizations

European Organization for Research and Treatment of Cancer

Mary O'Brien, MD, Protocol chair		Ph: 44-20-8661-3276 Email: mary.o'brien@rmh.nhs.uk

8.	Phase II Study of Pazopanib Hydrochloride in Patients With Malignant Pleural Mesothelioma

Phase	Type	Status	Age Range (yrs)	Sponsor	Protocol IDs
Phase II	Biomarker/Laboratory analysis, Treatment	Active	18 and over	NCI	NCCTG-N0623 N0623, NCT00459862

Alternate Title

Pazopanib in Treating Patients With Malignant Pleural Mesothelioma

Objectives

Primary

1. Determine the effect of pazopanib hydrochloride on the proportion of patients with malignant pleural mesothelioma who are progression-free at 6 months based on the RECIST criteria.
2. Determine the clinical toxicities of this drug in this patient population.

Secondary

1. Determine the objective tumor response status in these patients as measured by the RECIST criteria or the modified RECIST criteria.
2. Determine the response rate in patients treated with this drug.
3. Determine the effect of this drug on overall survival and time to progression in these patients.
4. Assess predictive markers of activity of this drug in these patients.
5. Assess serologic markers of target inhibition by this drug in these patients.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed malignant pleural mesothelioma
  
  • Measurable disease
  • No progressive disease inside or outside of any prior radiation field

   

• No symptomatic, untreated, or uncontrolled CNS metastases
  
  • Patients with CNS metastases treated with whole brain radiation (WBRT) may be enrolled after completion of WBRT
    
    • Patients may begin study therapy as early as the next day after completion of WBRT

   

Prior/Concurrent Therapy:

• See Disease Characteristics
• No more than 1 prior systemic therapy for malignant pleural mesothelioma
• No ancillary therapy considered investigational within the past 4 weeks
• No major surgery (i.e., laparotomy) or open biopsy within the past 4 weeks*
• No minor surgery within the past 2 weeks*
• Prior palliative radiotherapy allowed
  
  • No prior palliative radiotherapy to the chest except for a maximum of 3 fractions of radiotherapy for superior vena cava syndrome

• No concurrent therapeutic warfarin
  
  • Low molecular-weight heparin or prophylactic low-dose warfarin allowed

• No other concurrent chemotherapy, immunotherapy, hormonal therapy, or radiotherapy
• No concurrent medications that act through the CYP450 system
• No concurrent combination antiretroviral therapy for HIV-positive patients

 [Note: *Insertion of a vascular access device is not considered major or minor surgery]

Patient Characteristics:

• ECOG performance status 0-2
• Life expectancy ≥ 12 weeks
• ANC ≥1,500/mm³
• Platelet count ≥ 100,000/mm³
• WBC ≥ 3,000/mm³
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN
• Alkaline phosphatase ≤ 2.5 times ULN
• Creatinine ≤ 1.5 times ULN or creatinine clearance ≥ 50 mL/min
• Proteinuria ≤ 1+ on 2 consecutive dipsticks taken ≥ 1 week apart
• PT/INR/PTT ≤ 1.2 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective nonhormonal contraception
• No uncontrolled infection
• No uncontrolled blood pressure (BP) (defined as systolic BP > 140 mm Hg and/or diastolic BP > 90 mm Hg in spite of adequate anti-hypertensive therapy)
• No condition that impairs ability to swallow and retain study drug tablets including, but not limited to, any of the following:
  
  • Gastrointestinal tract disease resulting in an inability to take oral medication
  • Requirement for IV alimentation
  • Prior surgical procedures affecting absorption
  • Active peptic ulcer disease

• No other severe underlying disease that, in the judgment of the investigator, would limit study compliance
• No other primary malignancy except for carcinoma in situ of the cervix or nonmelanomatous skin cancer, unless that prior malignancy was diagnosed and definitively treated ≥ 5 years ago with no subsequent evidence of recurrence
  
  • Patients with a history of low-grade (Gleason score ≤ 6) localized prostate cancer are eligible even if diagnosed within the past 5 years

• No history of allergic reactions attributed to compounds of similar chemical or biological composition to pazopanib hydrochloride or other agents used in the study
• None of the following concurrent severe and/or uncontrolled medical conditions:
  
  • Serious or nonhealing wound, ulcer, or bone fracture
  • Abdominal fistula, diverticulosis, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days
  • Poorly controlled diabetes
  • Interstitial pneumonia
  • Extensive and symptomatic interstitial fibrosis of the lung

• No cardiovascular illness or complication, including any of the following:
  
  • Any history of cerebrovascular accident within the past 6 months
  • History of myocardial infarction (prior electrocardiographic evidence of myocardial injury)
  • History of cardiac arrhythmia (prior electrocardiographic evidence of abnormal heart rhythm)
  • Admission for unstable angina
  • Cardiac angioplasty or stenting within the past 12 months
  • NYHA class III-IV heart failure
    
    • Asymptomatic NYHA class II heart failure allowed

  • QTc prolongation (defined as a QTc interval ≥ 500 msecs) or other significant electrocardiogram abnormalities
  • Venous thrombosis within the past 12 weeks

• No symptomatic, untreated, or uncontrolled seizure disorder
• No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit study compliance
• No significant traumatic injury within the past 4 weeks

Trial Contact Information

Trial Lead Organizations

North Central Cancer Treatment Group

Julian Molina, MD, PhD, Protocol chair		Ph: 507-538-7623 Email: cancerclinicaltrials@mayo.edu
Nicholas Reuter, MD, Protocol co-chair		Ph: 320-229-4907; 877-229-4907 Email: schosp@cloudnet.com

9.	Study of NGR-hTNF as Single Agent in Patients Affected by Advanced or Metastatic Malignant Pleural Mesothelioma

Phase	Type	Status	Age Range (yrs)	Sponsor	Protocol IDs
Phase II	Treatment	Active	Over 18	Pharmaceutical / Industry	NGR010 EUDRACT Number: 2006-005993-39, NCT00484276

Trial Description

Summary

The main objective of the trial is to document the progression free survival (PFS) in advanced or metastatic malignant pleural mesothelioma patients treated with NGR-hTNF as single agent.

Safety will be established by clinical and laboratory assessment according to NCI-CTC criteria.

Further Study Information

This is a phase II, open-label, non-randomized study that will be conducted in patients affected by advanced or metastatic malignant pleural mesothelioma previously treated with no more than one systemic therapeutic regimen , that will be conducted using Simon's two-stage design method.

Eligibility Criteria

Inclusion Criteria:

• Patients >18 years affected by malignant pleural mesothelioma previously treated with no more than one systemic therapeutic regimen

• Histologically or cytological confirmed malignant pleural mesothelioma of any of the following subtype: epithelial, sarcomatous, mixed

• Prior intrapleural cytotoxic agents including bleomycin not considered systemic chemotherapy

• ECOG Performance status 0 - 2

• Adequate baseline bone marrow, hepatic and renal function, defined as follows:

• Neutrophils > 1.5 x 109/L and platelets > 100 x 109/L

• Bilirubin < 1.5 x ULN

• AST and/or ALT < 2.5 x ULN in absence of liver metastasis

• AST and/or ALT < 5 x ULN in presence of liver metastasis

• Serum creatinine < 1.5 x ULN

• Absence of any conditions in which hypervolemia and its consequences (e.g. increased stroke volume, elevated blood pressure) or haemodilution could represent a risk for the patient (take as reference "Technical data sheet human albumin" specifically used in Pharmacy Department for NGR-hTNF dilution)

• Patients may have had prior therapy providing the following conditions are met:

• Chemotherapy and radiotherapy: wash-out period of 28 days

• Surgery: wash-out period of 14 days

• Normal cardiac function and absence of uncontrolled hypertension

• Patients must give written informed consent to participate in the study

Exclusion Criteria:

• Concurrent anticancer therapy

• Patients may not receive any other investigational agents while on study

• Clinical signs of CNS involvement

• Patients with active or uncontrolled systemic disease/infections or with serious illness or medical conditions, which is incompatible with the protocol

• Known hypersensitivity/allergic reaction to human albumin preparations or to any of the excipients

• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol

• Pregnancy or lactation. Patients - both males and females - with reproductive potential (i.e. menopausal for less than 1-year and not surgically sterilized) must practice effective contraceptive measures throughout the study. Women of childbearing potential must provide a negative pregnancy test (serum or urine) within 14 days prior to registration

Trial Lead Organizations/Sponsors

MolMed S.p.A.

Federico Caligaris-Cappio

Principal Investigator

Federico Caligaris-Cappio, MD

Ph: +39 02 2643 Ext.2529

Trial Contact Information

10.	Phase I Study Using Sunitinib Plus Radiation Therapy for Cancer Patients

Phase	Type	Status	Age Range (yrs)	Sponsor	Protocol IDs
Phase I	Treatment	Active	18 and over	Other	06C.549 NCT00437372

Trial Description

Summary

This study is using the combination of radiation and antiangiogenic agents (agents that destroy existing blood vessels) seems to be an approach to tumor cure.

Further Study Information

The combination of ionizing radiation and antiangiogenic agents seems to be a counterintuitive approach to tumor cure because oxygen is a potent radiosensitizer and a reduction in oxygen concentration would be expected following a reduction in tumor vasculature after antiangiogenic treatment.

Eligibility Criteria

Inclusion Criteria:

• Minimum 2 week course of radiation therapy

• Solid tumors of the central nervous system, head and neck, thorax, and pelvis

Exclusion Criteria:

• Major surgery or radiation therapy within 4 weeks starting study treatment

• Grade 3 hemorrhage within 4 weeks

Trial Lead Organizations/Sponsors

Kimmel Cancer Center at Thomas Jefferson University - Philadelphia

Adam P Dicker, MD, Ph

Principal Investigator

Adam P Dicker, MD, PhD

Principal Investigator

Adam P Dicker, Md, PhD		Ph: 215-955-6527
		Email: adam.dicker@jeffersonhospital.org

Trial Contact Information

11.	Oxaliplatin and Paclitaxel Plus Bevacizumab in Advanced Peritoneal Carcinomatosis

Phase	Type	Status	Age Range (yrs)	Sponsor	Protocol IDs
Phase I	Treatment	Active	Not specified	Other	2006-1068 NCT00491855

Trial Description

Summary

Primary Objectives:

1. To establish acceptable dosages of paclitaxel, oxaliplatin and bevacizumab in a regimen of intravenous bevacizumab followed by continuous intravenous infusion of paclitaxel on day 1, intraperitoneal oxaliplatin on day 2, and intraperitoneal paclitaxel on day 8 once every 3 weeks in patients with advanced peritoneal carcinomatosis.

2. To assess toxicity profile.

3. To assess clinical responses.

Further Study Information

THE STUDY DRUGS:

Paclitaxel is designed to block cancer cells from dividing, which may cause them to die.

Oxaliplatin is designed to keep new cancer cells from growing

Bevacizumab is designed to prevent or slow down the growth of cancer cells by blocking the growth of blood vessels.

SCREENING TESTS:

Before you can receive the study drugs on this study, you will have "screening tests" to help the doctor decide if you are eligible to take part in this study. The following tests will be performed:

• You will have either a computed tomography (CT) scan or magnetic resonance imaging (MRI) scan to measure the status of the disease.

• Blood (about 1 tablespoon) and urine will be collected for routine tests. This routine blood draw will include a pregnancy test for women who are able to have children. To be eligible to take part in this study, the pregnancy test must be negative.

• You will have an electrocardiogram (ECG -- a test that measures the electrical activity of the heart).

• Your complete medical history will be recorded.

• You will have a physical exam.

STUDY DRUG DOSE LEVELS:

Up to 12 study drug dose levels will be tested in this study. Participants will be enrolled in groups of 3. The first 3 participants will be enrolled at the lowest dose level. If there are no intolerable side effect seen, the next 3 participants will be enrolled into the next higher dose level. This will continue until acceptable dose levels of the study drugs are found. The dose level that you are assigned to will depend on when you enroll on this study. You will receive the same dose level for the entire study unless you develop side effects, in which case doses of the drugs will be decreased by your doctor.

DRUG ADMINISTRATION:

If you agree to participate in this study, you will have a catheter placed in your abdomen before receiving study drug. A catheter is a sterile flexible tube that will be placed while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form.

On Day 1, you will receive bevacizumab followed by paclitaxel through a needle in your vein over 24 hours.

On Day 2, after you have completed the paclitaxel infusion, you will be given about 1 quart of fluid containing oxaliplatin into the abdomen through the catheter over 15 minutes.

On Day 8, you will be given about 1 quart of fluid containing paclitaxel into the abdomen through the catheter over 15 minutes.

Every 21 days is called a study "cycle."

STUDY VISITS:

During each cycle, you will see your doctor in his office to make sure that you are still eligible to receive study drugs.

• Blood (about 1 tablespoon) will be drawn for routine tests each day during hospitalization and then once a week as an outpatient.

• A urine sample will be collected once each cycle for routine tests.

• You will also have a repeat CT or MRI scan (to check disease status) once every 3 cycles.

LENGTH OF STUDY:

You may receive up to 6 cycles of study drugs. You will be taken off study if the disease gets worse or intolerable side effects occur.

END-OF-STUDY VISIT:

If you are taken off study, you will be asked to have an end-of-study visit. At this visit, the following tests will be performed:

• Blood (about 1 tablespoon) and urine will be collected for routine tests.

• You will also have a repeat CT or MRI scan (to check disease status).

This is an investigational study. Paclitaxel, oxaliplatin, and bevacizumab are FDA-approved drugs, but their use in this study is investigational. The costs of these drugs (paclitaxel, oxaliplatin and bevacizumab) will be the responsibility of you and/or your insurance provider. You should be aware that bevacizumab might not be paid for by your insurance company and is expensive. Up to 72 patients will take part in this study. All will be enrolled at M. D. Anderson.

Eligibility Criteria

Inclusion Criteria:

1. Patients must have advanced peritoneal carcinomatosis: they have either a disease where there is no established standard of care therapy or have failed one or more prior therapy. These include, but not limited to, recurrent epithelial ovarian cancer, advanced endometrial cancer, advanced gastric cancer, advanced colorectal cancer, and advanced primary peritoneal mesothelioma without significant chest involvement. Previous intraperitoneal therapy with different agents is allowed as long as their diseases have progressed.

2. Patients must have ECOG performance status < or = 2 (0-2).

3. Patients must have normal organ and marrow function as defined below: Absolute neutrophil count > or = 1,500/mcL Platelets > or = 100,000/mcL Total bilirubin < or = 2.0 and ALT <2.5 X the institutional upper limit of normal; Creatinine < or = 2.0 mg/dL or creatinine clearance > or = 40mL/min/1.73m2.

4. Patients must be able to understand and the willingness to sign an IRB-approved written informed consent document.

5. Patients must have evidence of peritoneal carcinomatosis that is evaluable by CT or MRI.

6. In the clinical judgment of the investigator, patients must have adequate potential intraperitoneal fluid distribution with no gross fluid loculations and adhesions that would significantly affect intraperitoneal drug distribution. This determination may be made based on documented clinical, imaging or laboratory assessment.

7. Patients must have PT/PTT within 1.2 x the institutional upper limit of normal or < 3 x the institutional upper limit of normal on anticoagulants.

8. Patients must have resting blood pressure no greater than 140 mmHg(systolic) or 90 mmHg (diastolic) for eligibility. Initiation or adjustment of blood pressure medication is permitted prior to study entry.

Exclusion Criteria:

1. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (NYHA Class III or IV), unstable angina pectoris, symptomatic cardiac arrhythmia, active bleeding, active thrombosis, or psychiatric illness/social situations that would limit compliance with study requirements.

2. History of allergic reactions to the study drugs or their analogs.

3. Failure to recover from any prior surgery within 4 weeks of study entry.

4. Pregnant or lactating. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment. Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry, for the duration of study participation and for at least 3 months after the last treatment.

5. Any treatment specific for tumor control within 3 weeks of study drugs; or within 2 weeks if cytotoxic agents were given weekly (within 6 wks for nitrosoureas or mitomycin C), or within 5 half-lives for target agents with half lives and pharmacodynamic effects lasting less than 5 days (that include but are not limited to erlotinib, sorafenib, sunitinib, bortezomib, and other similar agents); or failure to recover from the toxic effect of any therapy prior to study entry.

6. Serious non-healing wound, ulcer, bone fracture (including abdominal fistula, gastrointestinal perforation or intra-abdominal abscess), or history of bleeding diathesis or coagulopathy.

7. History of radiotherapy to the abdominal and pelvic regions or history of multiple abdominal surgeries that contraindicates this protocol therapy.

8. Urine dipstick for proteinuria >/= 2+ (patients discovered to have >/= 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate </= 1g of protein in 24 hours to be eligible).

9. Grade 2 or greater neuropathy, and history of brain or leptomeningeal metastases that significantly increase risks of intracranial bleeding.

10. All types of solid tumors are included. However, patients with significant metastases outside of abdomen and pelvis as well as any mass greater than 4 cm are excluded.

Trial Lead Organizations/Sponsors

M. D. Anderson Cancer Center at University of Texas

Siqing Fu, MD, PhD

Principal Investigator

Siqing Fu, MD, PhD

Ph: 713-792-7960

Trial Contact Information

12.	A Study To Find the Best Dose of SU011248 When Given With Pemetrexed, Pemetrexed and Cisplatin Or Pemetrexed and Carboplatin in Patients With Advanced Solid Tumors

Phase	Type	Status	Age Range (yrs)	Sponsor	Protocol IDs
Phase I	Treatment	Active	18 and over	Pharmaceutical / Industry	A6181084 NCT00528619

Trial Description

Summary

This study will assess the maximum tolerated dose, overall safety and antitumor activity of SU011248 in combination with pemetrexed, pemetrexed and cisplatin or pemetrexed and carboplatin in patients with advanced solid tumors.

Eligibility Criteria

Inclusion Criteria:

• Patients with a diagnosis of a solid cancer which is not responsive to standard therapy or for which no standard therapy exists.

• Patient has a good performance status (ECOG 0 or 1).

Exclusion Criteria:

• Prior treatment with either pemetrexed or SU011248.

• Coughing up blood within 4 weeks before starting study treatment (small amounts okay).

• Hypertension that cannot be controlled by medications.

Trial Lead Organizations/Sponsors

Pfizer Incorporated

Pfizer CT.gov Call Center

Study Director

Pfizer Oncology Clinical Trial Information Service		Ph: 1-877-369-9753
		Email: PfizerCancerTrials@emergingmed.com

Trial Contact Information

13.	Phase I Study of Sorafenib Tosylate, Pemetrexed Disodium, and Cisplatin in Patients With Advanced Solid Tumors

Phase	Type	Status	Age Range (yrs)	Sponsor	Protocol IDs
Phase I	Treatment	Active	18 and over	NCI, Pharmaceutical / Industry	UMN-2007LS086 UMN-2007LS086, 0712M22703, BAYER-UMN-2007LS086, NCT00703638

Alternate Title

Sorafenib, Pemetrexed, and Cisplatin in Treating Patients With Advanced Solid Tumors

Objectives

Primary

1. To determine the maximum tolerated dose of sorafenib tosylate when given in combination with pemetrexed disodium and cisplatin in patients with advanced non-squamous cell solid tumor malignancy including, but not limited to, breast, lung, colon, pancreatic, prostate, or head and neck cancer or sarcoma.

Secondary

1. To characterize the quantitative and qualitative toxicities of this regimen in these patients.
2. To obtain preliminary information about the antitumor activity of this regimen in these patients.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed non-hematologic malignancy including, but not limited to, any of the following:
  
  • Breast cancer
  • Lung cancer
  • Colon cancer
  • Pancreatic cancer
  • Prostate cancer
  • Head and neck cancer
  • Sarcoma

   

• No squamous cell lung cancer

   

• Advanced disease
  
  • Must have failed or become intolerant to prior standard therapy and is no longer likely to respond to such therapy
    
    • Patients with mesothelioma do not have to meet prior therapy requirements in order to be enrolled on the study since the combination of cisplatin and pemetrexed disodium is considered current standard first-line therapy for mesothelioma

   

• Measurable or nonmeasurable disease as defined by RECIST criteria

   

• Previously treated stable brain metastases allowed

   

• No clinically significant third-space fluid, such as pleural effusion or ascites
  
  • Third-space fluid allowed provided it can be completely drained

   

• Hormone receptor status not specified

   

Prior/Concurrent Therapy:

• At least 3 weeks since prior systemic therapy (6 weeks for bevacizumab) and recovered
• At least 3 months since prior pemetrexed disodium or cisplatin
• No prior sorafenib tosylate
• More than 4 weeks since prior major surgery or open biopsy
• No NSAIDs or salicylates for 2 days before, during, and for 2 days after pemetrexed disodium administration
  
  • No NSAIDs or salicylates with a long half-life (e.g., naproxen, piroxicam, diflunisal, albumetone) for 5 days before, during, and for 2 days after pemetrexed disodium administration

• No concurrent Hypericum perforatum (St. John's wort) or rifampin
• Concurrent anti-coagulation treatment with warfarin or heparin allowed

Patient Characteristics:

• Menopausal status not specified
• ECOG performance status 0-2
• ANC ≥ 1.5 x 10⁹/L
• Platelet count ≥ 100 x 10⁹/L
• Hemoglobin ≥ 9 g/dL
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 3 times ULN (5 times ULN if liver has tumor involvement)
• AST and ALT ≤ 3 times ULN (5 times ULN if liver has tumor involvement)
• Serum creatinine ≤ 1.5 mg/dL
• Creatinine clearance > 45 mL/min
• INR < 1.5 OR PT/PTT normal
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception during and for 2 weeks after completion of study treatment
• Able to take folic acid and vitamin B₁₂
• Able to take oral medications without crushing, dissolving, or chewing tablets
• No malabsorption problem
• No other condition that impairs the patient‘s ability to swallow whole pills
• No New York Heart Association class III-IV congestive heart failure
• No unstable angina (anginal symptoms at rest) or new onset angina within the past 3 months
• No myocardial infarction within the past 6 months
• No cardiac ventricular arrhythmias requiring anti-arrhythmic therapy
• No uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg or diastolic BP > 90 mm Hg despite optimal medical management
• No thrombolic or embolic events, such as cerebrovascular accident or transient ischemic attacks, within the past 6 months
• No pulmonary hemorrhage/bleeding event ≥ CTCAE grade 2 within the past 4 weeks
• No other hemorrhage/bleeding event ≥ CTCAE grade 3 within the past 4 weeks
• No evidence or history of bleeding diathesis or coagulopathy
• No known or suspected allergy to sorafenib tosylate, pemetrexed disodium, cisplatin, or any agent given in the course of this study
• No known HIV infection or chronic hepatitis B or C infection
• No active clinically serious infection > CTCAE grade 2
• No serious nonhealing wound, ulcer, or bone fracture
• No significant traumatic injury within the past 4 weeks
• No peripheral neuropathy ≥ CTCAE grade 2
• No second primary malignancy except in situ carcinoma of the cervix or breast or other in situ malignancies, adequately treated basal cell carcinoma of the skin, or other malignancy treated at least 3 years ago with no evidence of recurrence

Trial Contact Information

Trial Lead Organizations

Masonic Cancer Center at University of Minnesota

Priya Kumar, MD, Principal investigator		Ph: 612-625-7667; 888-226-2376