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Study of the Combination of Tivantinib Plus Pemetrexed and Carboplatin

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02049060
Recruitment Status : Unknown
Verified February 2017 by Armando Santoro, MD, Istituto Clinico Humanitas.
Recruitment status was:  Active, not recruiting
First Posted : January 29, 2014
Last Update Posted : February 10, 2017
Sponsor:
Information provided by (Responsible Party):
Armando Santoro, MD, Istituto Clinico Humanitas

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.

Condition or disease Intervention/treatment Phase
Malignant Pleural Mesothelioma Nonsquamous Nonsmall Cell Neoplasm of Lung Drug: Tivantinib Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 31 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : January 2013
Actual Primary Completion Date : May 2016
Estimated Study Completion Date : December 2017


Arm Intervention/treatment
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

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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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).

  2. 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

  3. 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.

  4. 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)

  5. 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

  6. 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.

  7. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02049060


Locations
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Italy
Istituto Clinico Humanitas
Rozzano, Milan, Italy, 20089
Sponsors and Collaborators
Armando Santoro, MD
Investigators
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Principal Investigator: Armando Santoro, MD Istituto Clinico Humanitas
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Responsible Party: Armando Santoro, MD, Principal Investigators, Istituto Clinico Humanitas
ClinicalTrials.gov Identifier: NCT02049060    
Other Study ID Numbers: ONC-2011-001
First Posted: January 29, 2014    Key Record Dates
Last Update Posted: February 10, 2017
Last Verified: February 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: not planned
Keywords provided by Armando Santoro, MD, Istituto Clinico Humanitas:
MPM
NSCLC
Additional relevant MeSH terms:
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Mesothelioma
Lung Neoplasms
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Mesothelial
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases