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Study of the Combination of Tivantinib Plus Pemetrexed and Carboplatin

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ClinicalTrials.gov Identifier: NCT02049060
Recruitment Status : Completed
First Posted : January 29, 2014
Last Update Posted : January 22, 2021
Sponsor:
Information provided by (Responsible Party):
Armando Santoro, MD, Istituto Clinico Humanitas

Tracking Information
First Submitted Date  ICMJE May 24, 2013
First Posted Date  ICMJE January 29, 2014
Last Update Posted Date January 22, 2021
Actual Study Start Date  ICMJE January 2013
Actual Primary Completion Date May 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 28, 2014)
To determine the dose limiting toxicities (DLTs) of Tivantinib [ Time Frame: 18 months ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 20, 2016)
  • To determine the pharmacokinetics profile of Tivantinib in combination with Carboplatin and Pemetrexed [ Time Frame: 18 months ]
    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 with PFS [ Time Frame: 18 months ]
    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 with RECIST [ Time Frame: 18 months ]
    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 ]
    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 ]
    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 ]
    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 ]
    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
Original Secondary Outcome Measures  ICMJE
 (submitted: January 28, 2014)
  • To determine the pharmacokinetics profile of Tivantinib in combination with Carboplatin and Pemetrexed [ Time Frame: 18 months ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of the Combination of Tivantinib Plus Pemetrexed and Carboplatin
Official Title  ICMJE Phase I-Ib Study of the Combination of Tivantinib Plus 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
Brief Summary 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.
Detailed Description

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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Malignant Pleural Mesothelioma
  • Nonsquamous Nonsmall Cell Neoplasm of Lung
Intervention  ICMJE Drug: Tivantinib

•- 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

Other Name: ARQ 197
Study Arms  ICMJE Experimental: Tivantinib+carboplatino+pemetrexed

•- 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

Intervention: Drug: Tivantinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 20, 2016)
31
Original Estimated Enrollment  ICMJE
 (submitted: January 28, 2014)
35
Actual Study Completion Date  ICMJE December 2017
Actual Primary Completion Date May 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients must be diagnosed with MPM or non squamous NSCLC.
  2. Inoperable disease according to local surgeon, not previously treated with chemotherapy; patients relapsed/progressed after previous surgery will be also evaluable for inclusion.
  3. Age > 18.
  4. ECOG Performance Status 0-1 and life expectancy of at least 12 weeks.
  5. Measurable and/or evaluable lesions according to modified RECIST criteria [51].
  6. Written informed consent.
  7. Patients must be accessible for treatment and follow up. Patients registered on this trial must be treated and followed at the participating center.
  8. Patients must use effective contraception during the study lasting at least one month after the end of treatment for both sexes.
  9. 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:

  1. Any prior chemotherapy (including intracavitary administration).
  2. 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
  3. Serious non-healing wound or ulcer.
  4. Evidence of bleeding diathesis or coagulopathy.
  5. Uncontrolled hypertension.
  6. 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.
  7. Current treatment with anticoagulants for therapeutic purposes.
  8. Treatment with any investigational drug within 30 days prior to enrolment.
  9. Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of basal cell carcinoma or cervical cancer in situ
  10. 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.
  11. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02049060
Other Study ID Numbers  ICMJE ONC-2011-001
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: not planned
Responsible Party Armando Santoro, MD, Istituto Clinico Humanitas
Study Sponsor  ICMJE Armando Santoro, MD
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Armando Santoro, MD Istituto Clinico Humanitas
PRS Account Istituto Clinico Humanitas
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP