Primary Outcome Measure:
- To determine the dose limiting toxicities (DLTs) of Tivantinib [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
1.To determine the dose limiting toxicities (DLTs) of Tivantinib given orally twice daily on a continuous schedule in combination with Carboplatin and Pemetrexed administered intra-venous every 3 weeks.
Secondary Outcome Measures:
- To determine the pharmacokinetics profile of Tivantinib in combination with Carboplatin and Pemetrexed [ Time Frame: 18 months ] [ Designated as safety issue: No ]
To determine the pharmacokinetics profile of Tivantinib in combination with Carboplatin (AUC 5) and Pemetrexed (500 mg/mq)
- To assess the preliminary anti-tumor activity of Tivantinib [ Time Frame: 18 months ] [ Designated as safety issue: No ]
To assess the preliminary anti-tumor activity of Tivantinib in combination with Carboplatin (AUC 5) and Pemetrexed (500 mg/mq), in terms of 3-months progression-free survival rate for malignant pleural mesothelioma patients and 5-months progression-free survival rate for NSCLC patients
- To assess the preliminary anti-tumor activity of Tivantinib [ Time Frame: 18 months ] [ Designated as safety issue: No ]
To assess the preliminary anti-tumor activity of Tivantinib in combination with Carboplatin (AUC 5) and Pemetrexed (500 mg/mq), in terms of objective response rate according to “response criteria evaluation criteria in solid tumors” (Modified RECIST criteria for Malignant Pleural Mesothelioma), and duration of response.
- To evaluate dynamic changes in blood levels [ Time Frame: 18 months ] [ Designated as safety issue: No ]
To evaluate dynamic changes in blood levels of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and soluble c-Met, in patients treated with Tivantinib in combination with Carboplatin (AUC 5) and Pemetrexed (500 mg/mq)
- To evaluate the expression of biomarkers [ Time Frame: 18 months ] [ Designated as safety issue: No ]
To evaluate the expression of phospho-c-Met, total c-Met, and downstream markers of c-Met signaling pathway in patients’ tumor tissue samples
- To dermine the MTD of combination [ Time Frame: 18 month ] [ Designated as safety issue: Yes ]
To determine the MTD of the combination, defined as the highest dosage cohort at which no more than one of six patients experiences a DLT during the first treatment cycle, considering the level +1 as the maximum level to explore. This will be the recommended dose for a subsequent phase II study.
- To assess the preliminary anti-tumor activity of tivantinib [ Time Frame: 18 month ] [ Designated as safety issue: No ]
To assess the preliminary anti-tumor activity of Tivantinib in combination with Carboplatin (AUC 5) and Pemetrexed (500 mg/mq), in terms of 3-months progression-free survival rate for malignant pleural mesothelioma patients and 5-months progression-free survival rate for NSCLC patients
Eligibility Criteria
- Inclusion Criteria:
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- Patients must be diagnosed with MPM or non squamous NSCLC.
- Inoperable disease according to local surgeon, not previously treated with chemotherapy; patients relapsed/progressed after previous surgery will be also evaluable for inclusion.
- Age > 18
- ECOG Performance Status 0-1 and life expectancy of at least 12 weeks.
- Measurable and/or evaluable lesions according to modified RECIST criteria [51].
- Written informed consent.
- Patients must be accessible for treatment and follow up. Patients registered on this trial must be treated and followed at the participating center.
- Patients must use effective contraception during the study lasting at least one month after the end of treatment for both sexes.
- Laboratory requirements:
- Neutrophils >1.5 x 109/L and Platelets >100 x 109/L
- Total bilirubin <1.5 time the upper-normal limits (UNL) of the Institutional normal values, AST (SGOT) and ALT (SGPT) < 2.5 x UNL, or <5 x UNL in case of liver metastases, alkaline phosphatase <2.5 x UNL, < 5 x UNL in case of liver metastases, <10 x UNL in case of bone metastases.
- Creatinine clearance >50 mL/min
- Exclusion Criteria:
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- Any prior chemotherapy (including intracavitary administration).
- 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 CNS metastases well controlled by steroids, anti – epileptics or other symptom-relieving medications
- Serious non-healing wound or ulcer.
- Evidence of bleeding diathesis or coagulopathy.
- Uncontrolled hypertension.
- Clinically significant (i.e. active) cardiovascular disease, for example cerebrovascular accidents (<6 months), myocardial infarction (< 6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication.
- Current treatment with anticoagulants for therapeutic purposes.
- Treatment with any investigational drug within 30 days prior to enrolment.
- Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of basal cell carcinoma or cervical cancer in situ
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study.
- Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study.
