Combination of Gemcitabine and Imatinib Mesylate in Pemetrexed-pretreated Patients With Pleural Mesothelioma

Study Overview
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Brief Summary
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This is a phase II, monocentric study of the combination of gemcitabine and imatinib mesylate in pemetrexed-pretreated patients with MPM expressing PDGFR-beta and/or C-kit by Immunohistochemistry (IHC). Treatment will be done until disease progression, or patient refusal or withdrawal of patient consent, or unacceptable toxicity

Detailed Description
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Pemetrexed-pretreated patients with MPM expressing PDGFR-beta and/or C-kit by IHC will receive chemotherapy as follow : Gemcitabine 1000 mg/m2, i.v., days 3 and 10 of a 21-days schedule; Imatinib mesylate 400 mg/die orally on days 1-5 and 8-12 of a 21-days schedule. Treatment repeats every 21 days in the absence of disease progression, patient refusal or withdrawal of patient consent, or unacceptable toxicity. The molecular profile of patients enrolled will be evaluated with Ion Personal Genome Machine (PGM) Torrent Next-generation Sequencing platform in order to individuate potential predictive biomarkers and to improve the understanding of the molecular biology of these rare tumors. A correlation among the molecular profiles identified, clinical characteristics, and survival data of patients will be done

Official Title
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A Phase II Study of the Combination of Gemcitabine and Imatinib Mesylate in Pemetrexed-pretreated Patients With Malignant Pleural Mesothelioma

Conditions
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Mesothelioma, Malignant

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Imatinib mesylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of > 18 years. Histologically proven malignant mesothelioma of the pleura or of the peritoneum, expressing PDGFR-beta and/or C-kit by immunohistochemistry. Locally advanced disease, unsuitable for curative surgical resection, or metastatic disease. Confirmed progression of the disease according to modified RECIST-criteria, documented after a pemetrexed-based chemotherapy. Eastern Cooperative Oncology group (ECOG) Performance Status of 0, 1 or 2. Life expectancy of at least 3 months. Written informed consent. Exclusion Criteria: Co-existing tumors of different histologic origin, except non melanomatous localized skin cancer and/or in situ cervical carcinoma. A history of earlier tumors of different histologic origin being in complete remission for less than 5 years. Unresolved toxicity from prior antitumor treatment(s). Primary peritoneal mesothelioma. Any of the following abnormal baseline hematological values: Hb < 9 g/dL White blood count (WBC) < 3 x 109/L Neutrophils < 1.5 x 109/L Platelets < 100 x 109/L Serum bilirubin > 2.5 mg/dL Alanine transaminase (ALAT) and Aspartate transaminase (ASAT) > 3 x upper normal limit (UNL) (unless due to liver metastases) Serum creatinine > 1.5 mg/dL. Symptomatic and/or unstable pre-existing brain metastases. To be enrolled in the study, subjects must have confirmation of stable disease by MRI or computer tomography (CT) scan within 4 weeks from day 1 of cycle 1 of treatment and have central nervous system (CNS) metastases well controlled by steroids, anti - epileptics or other symptom-relieving medications. Clinically relevant cardiovascular disease, i.e., myocardial infarction or other severe coronary artery diseases within the prior 6 months, cardiac arrythmia requiring medication, uncontrolled hypertension, overt cardiac failure or non compensated chronic heart disease in New York Heart Association (NYHA) class II or more. History of psychiatric disabilities, potentially interfering with the capability of giving adequate informed consent. Pregnant or lactating women or inability/unwillingness to practice a medically approved method of contraception during study period (including 3 months following the end of treatment) Uncontrolled active infections. Any condition which, in the judgement of the Investigator, would place the patient at undue risk or interfere with the results of the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine & Imatinib mesylate<br>Gemcitabine 1000 mg/m2, i.v., days 3 and 10 of a 21-days schedule; Imatinib mesylate 400 mg/die orally on days 1-5 and 8-12 of a 21-days schedule. | Drug: Gemcitabine<br>* infusion drug<br>* Other names: Gemzar;Drug: Imatinib mesylate<br>* oral drug<br>* Other names: Glivec;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| anti-tumor activity of Imatinib mesylate in combination with Gemcitabine | assess the anti-tumor activity of Imatinib mesylate in combination with Gemcitabine, in terms of 3-months progression-free survival (PFS) rate | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| anti-tumor activity of Imatinib mesylate in combination with Gemcitabine in terms of Response Evaluation Criteria In Solid Tumors (RECIST) criteria | assess anti-tumor activity of Imatinib Mesylate (IM) in combination with GEM, in terms of objective response rate according to RECIST criteria (Modified RECIST criteria for MPM), and duration of response | 16 weeks | 
| anti-tumor activity of Imatinib mesylate in combination with Gemcitabine in terms of overall survival (OS). | assess anti-tumor activity of IM in combination with GEM, in terms of overall survival (OS). | 30 months | 
| safety profile of the combination according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3 | determine the safety profile of the combination according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3 | 16 weeks | 
| molecular profile of patients | evaluate the molecular profile of patients enrolled with Ion PGM Torrent Next-generation Sequencing platform correlating the molecular profiles identified with clinical characteristics and survival data of patients. | baseline |