This is a prospective, open-label, mono-centric, phase I-Ib trial of Tivantinib in combination with Pemetrexed and Carboplatin as first-line therapy in patients with advanced or metastatic cancer suitable for a Carboplatin and Pemetrexed regimen as part of their specific therapy.
This is a prospective, open-label, mono-centric, phase I-Ib trial of Tivantinib in combination with Pemetrexed and Carboplatin as first-line therapy in patients with advanced or metastatic cancer suitable for a Carboplatin and Pemetrexed regimen as part of their specific therapy.This trial will be conducted to determine the maximum tolerated dose (MTD), safety/tolerability, pharmacokinetics and preliminary anti-tumor activity of escalating doses of Tivantinib in combination with standard fixed doses of Carboplatin and Pemetrexed. The dose-escalation stage will be followed by an expansion stage at the MTD to better define toxicity and clinical activity. MTD is defined as the highest dose level at which \< 33% of 6 patients experience a DLT. Eligible patients will be enrolled and treated according to the following 3 + 3 design starting from cohort 0: * 1 level: Tivantinib 120 mg p.o. BID + Carboplatin AUC 5 i.v. day 1 every 3 weeks + Pemetrexed 500 mg/mq i.v. day 1 every 3 weeks 0 level: Tivantinib 240 mg p.o. BID + Carboplatin AUC 5 i.v. day 1 every 3 weeks + Pemetrexed 500 mg/mq i.v. day 1 every 3 weeks * 1 level: Tivantinib 360 mg p.o. BID + Carboplatin AUC 5 i.v. day 1 every 3 weeks + Pemetrexed 500 mg/mq i.v. day 1 every 3 weeks If the frequency of DLTs encountered at dose-level +1 will not fulfil the MTD definition, then Tivantinib 360 mg bid in combination with Carboplatin AUC 5 and Pemetrexed 500 mg/mq will be accepted as the recommended dose for phase IItrials. Treatment will be continued on the basis of tumor assessment. Patients with stable disease, complete or partial response will continue treatment until progressive disease, unacceptable toxicity, patient or physician decision. For chemotherapy agents, however, a maximum of 6 cycles will be administered. Tivantinib will be continued until progressive disease, unacceptable toxicity, patient or physician decision. Toxicity will be graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3. Following the dose-escalation phase of the study, additional patients (in order to reach a total of 13 patients with MPM and 18 patients with NSCLC treated at MTD/recommended dose for phase Ib trials) will be accrued to the expansion stage of this trial, to assess the preliminary anti-tumor activity of Tivantinib in combination with Carboplatin (AUC 5) and Pemetrexed (500 mg/mq) primarily.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
31
•- 1 level: Tivantinib 120 mg p.o. BID + Carboplatin AUC 5 i.v. day 1 every 3 weeks + Pemetrexed 500 mg/mq i.v. day 1 every 3 weeks •0 level: Tivantinib 240 mg p.o. BID + Carboplatin AUC 5 i.v. day 1 every 3 weeks + Pemetrexed 500 mg/mq i.v. day 1 every 3 weeks •+ 1 level: Tivantinib 360 mg p.o. BID + Carboplatin AUC 5 i.v. day 1 every 3 weeks + Pemetrexed 500 mg/mq i.v. day 1 every 3 weeks
Istituto Clinico Humanitas
Rozzano, Milan, Italy
To determine the dose limiting toxicities (DLTs) of Tivantinib
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.
Time frame: 18 months
To determine the pharmacokinetics profile of Tivantinib in combination with Carboplatin and Pemetrexed
To determine the pharmacokinetics profile of Tivantinib in combination with Carboplatin (AUC 5) and Pemetrexed (500 mg/mq).
Time frame: 18 months
To assess the preliminary anti-tumor activity of Tivantinib with PFS
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
Time frame: 18 months
To assess the preliminary anti-tumor activity of Tivantinib with RECIST
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.
Time frame: 18 months
To evaluate dynamic changes in blood levels
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)
Time frame: 18 months
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To evaluate the expression of biomarkers
To evaluate the expression of phospho-c-Met, total c-Met, and downstream markers of c-Met signaling pathway in patients' tumor tissue samples
Time frame: 18 months
To dermine the MTD of combination
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.
Time frame: 18 month
To assess the preliminary anti-tumor activity of tivantinib
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
Time frame: 18 month