Phase II Study With Cabozantinib in Patients With RET Positive NSCLC (CRETA)

October 17, 2019 updated by: Andrea Ardizzoni, University of Bologna

"Phase II Study to Evaluate the Activity and Safety of Cabozantinib in Pretreated, Advanced RET-rearranged Non-small Cell Lung Cancer Patients: CRETA Trial"

This study is aimed to explore the antitumor activity, safety and efficacy profile of cabozantinib in pretreated, advanced RET-rearranged non-small cell lung cancer patients

Study Overview

Study Type

Interventional

Enrollment (Anticipated)

25

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Bologna, Italy, 40138
        • Recruiting
        • OU di Oncologia Medica- Azienda ospedaliero-Universitaria S. Orsola Malpighi
        • Contact:
        • Contact:
        • Principal Investigator:
          • Andrea Ardizzoni, DM
        • Sub-Investigator:
          • Francesco Gelsomino, DM
        • Sub-Investigator:
          • Karim Rihawi, DM
      • Catania, Italy, 95125
        • Not yet recruiting
        • U.O di Oncologia Medica Policlinico V.Emanuele-G.Rodolico
        • Contact:
        • Principal Investigator:
          • Hector Soto Parra, DM
      • Genova, Italy, 16132
        • Not yet recruiting
        • Oncologia Medica 2 -Policlinico San Martino
        • Contact:
        • Principal Investigator:
          • Carlo Genova, DM
      • Milano, Italy, 20133
      • Napoli, Italy, 80131
        • Not yet recruiting
        • U.O.C Pneumologia ad Indirizzo Oncologico -AORN Ospedali dei Colli Monaldi-Cotugno-CTO
        • Contact:
        • Principal Investigator:
          • Danilo Rocco, DM
      • Padova, Italy, 35128
        • Not yet recruiting
        • UOC di Oncologia Medica 2 - IOV Istituto Oncologico Veneto
        • Contact:
        • Contact:
        • Principal Investigator:
          • Giulia Pasello, DM
      • Parma, Italy, 43126
        • Not yet recruiting
        • UOC di Oncologia Medica- Azienda Ospidaliero Universitaria di Parma
        • Contact:
        • Contact:
        • Principal Investigator:
          • Marcello Tiseo, DM
      • Perugia, Italy, 06132
        • Not yet recruiting
        • US di Oncologia Medica - A.O. di Perugia
        • Contact:
        • Principal Investigator:
          • Fausto Roila, DM
      • Pisa, Italy, 56126
        • Not yet recruiting
        • UO Pneumologia - A.O.U Pisana
        • Contact:
        • Principal Investigator:
          • Antonio Chella, DM
      • Roma, Italy, 00144
        • Not yet recruiting
        • S.C. di Oncologia Medica - IFO - Istituto Regina Elena
        • Contact:
        • Contact:
        • Principal Investigator:
          • Sabrina Vari, DM
      • Udine, Italy, 33100
        • Not yet recruiting
        • UOC di Oncologia Medica - Azienda Sanitaria Universitaria Integrata di Udine
        • Contact:
        • Principal Investigator:
          • Ciro Rossetto, DM

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Locally advanced, relapsed or metastatic non-small cell lung cancer - stage IIIB/IV according to 7th International Association for the Study of Lung Cancer (IASLC) classification
  2. Ability to understand and willingness to sign informed consent prior to initiation of any study procedures.
  3. Pathologically (histology or cytology) confirmed diagnosis of non- small cell lung carcinoma.
  4. RET gene rearrangement by local laboratory analysis with an approved standard method (FISH or Next Generation Sequencing Panel). An archival tumor sample must be available for central laboratory confirmation.
  5. Male or female and = 18 years of age
  6. Life expectancy = 12 weeks
  7. Have progressed after or during at least one standard anticancer treatment
  8. Have measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1); clear radiological evidence of disease progression after first-line therapy must be documented; no previous radiotherapy on the only site of measurable or evaluable disease, unless that site had subsequent evidence of progression
  9. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 1
  10. Subjects must have adequate organ function including the following:

    • Absolute neutrophil count > 1.5 x 10^9/L
    • Platelet count > 100 x 10^9/L
    • Haemoglobin > 90 g/L
    • ALT < 2.5 times the upper limit of normal (ULN)
    • AST < 2.5 times ULN
    • Total bilirubin <1.5 times ULN
    • Creatinine <1.5 times ULN concurrent with creatinine clearance > 50 ml/min (measured or calculated by Cockcroft and Gault equation, confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN)
    • Lipase < 2.0 times the upper limit of normal (ULN)
  11. Stable medical condition, including the absence of acute exacerbations of chronic illnesses, serious infections, or major surgery within 4 weeks before registration, and otherwise noted in other inclusion/exclusion criteria
  12. Recovered (i.e., = Grade 1 toxicity) from effects of prior anticancer therapy, except alopecia
  13. No radiologic or clinical evidence of acute or chronic pancreatitis
  14. For Females: must be postmenopausal (defined as amenhorrea = 12 consecutive months) before the screening visit, or are surgically sterile. If they are of childbearing potential, a negative serum pregnancy test obtained within 3 days before starting study treatment has to be documented; furthermore, patients must agree to adopt 2 effective methods of contraception, at the same time, from the time of signing the informed consent form (ICF) through 4 months after the last dose of study drug.
  15. For Males: even if surgically sterilized (i.e. post-vasectomy status) agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug.
  16. Ability to comply with protocol requirement.

Exclusion criteria:

  1. Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before randomization. Systemic treatment with radionuclides within 6 weeks before randomization. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
  2. Previous treatment with cabozantinib.
  3. Gastrointestinal disorders likely to interfere with absorption of the study drug.
  4. Subjects with gastrointestinal disorders associated with a high risk of perforation of fistula formation.
  5. Subjects with active peptic ulcer or with a history of clinically ¿significant GI bleeding within 6 months before the first dose of study treatment.
  6. Patients requiring full-dose anticoagulation therapy any time prior to enrollment.
  7. Current use of aspirin, clopidogrel, ticlopidine.
  8. Patients with tumors invading major pulmonary vessels and/or with cavitating pulmonary lesions.
  9. Major surgery within the last four weeks. Complete wound healing from major surgery must have occurred 1 month before randomization and from minor surgery at least 10 days before randomization. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
  10. Subjects with clinical or radiological signs of pulmonary hemorrhage within 3 months before the first dose of study treatment.
  11. Symptomatic CNS or leptomeningeal lesions, not previously treated with radiotherapy.

    Untreated central nervous system (CNS) or leptomeningeal metastases are allowed if asymptomatic. Patients with symptomatic CNS or leptomeningeal lesions will be allowed to participate in this study if previously treated with radiotherapy and on stable dose of corticosteroids and/or anticonvulsants for > 10 days or not requiring such medication.

    Radiotherapy must have been completed a minimum of 4 weeks prior to registration, and patients must have recovered from AEs related to radiotherapy to < grade 1 (except alopecia).

  12. History of congenital platelet function defect.
  13. Patient unable to swallow tablets
  14. Corrected QT interval greater than 500 ms (Fridericia formula)
  15. Clinically significant, uncontrolled heart diseases:

    • Unstable angina within 6 months prior to screening
    • Myocardial infarction within 6 months prior to screening
    • History of documented congestive heart failure
    • Uncontrolled hypertension defined by a Systolic Blood Pressure , with or without antihypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening
    • Ventricular arrhythmias, Supraventricular and nodal arrhythmias not controlled with medication
    • Congenital history of QT syndrome.
  16. Diagnosed with or treated for another malignancy within 3 years before the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type may be enrolled in the study if they have undergone complete resection and no evidence of active disease is present.
  17. Any type of systemic anticancer agent within 3 weeks of first dose of study treatment, or within 5 half- lives of the agent whichever is shorter (subjects on LHRH or GnRH agonists may be maintained on these agents)
  18. Any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with subject's safety, provision of informed consent, or compliance to study procedures.
  19. Rare hereditary problems of

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Cabozantinib
Cabozantinib will be administered orally at a (starting) dose of 60 mg once daily. The drug is taken continuously over a period of 28 days (4 weeks), which constitutes one treatment cycle. In all subjects, dose reductions and delays to manage toxicity. Cabozantinib should be taken in fasting condition with no food for at least 2 hours before and 1 hour after taking the tablets. A high fat meal significantly increased the median tmax to 6 hours from 4 hours (fasted). The treatment will be continued until disease progression, intolerable toxicity, patient refusal or Investigator's decision or any criterion for withdrawal from the trial or trial drug is fulfilled.
Cabozantinib will be administered orally at a (starting) dose of 60 mg once daily. The drug is taken continuously over a period of 28 days (4 weeks), which constitutes one treatment cycle. In all subjects, dose reductions (40mg 20mg) and delays to manage toxicity.
Other Names:
  • CABOMETYX
Cabozantinib will be administered orally at a (starting) dose of 60 mg once daily. The drug is taken continuously over a period of 28 days (4 weeks), which constitutes one treatment cycle. In all subjects, dose reductions (40mg 20mg) and delays to manage toxicity.
Other Names:
  • CABOMETYX
Cabozantinib will be administered orally at a (starting) dose of 60 mg once daily. The drug is taken continuously over a period of 28 days (4 weeks), which constitutes one treatment cycle. In all subjects, dose reductions and delays to manage toxicity. Cabozantinib should be taken in fasting condition with no food for at least 2 hours before and 1 hour after taking the tablets. A high fat meal significantly increased the median tmax to 6 hours from 4 hours (fasted). The treatment will be continued until disease progression, intolerable toxicity, patient refusal or Investigator's decision or any criterion for withdrawal from the trial or trial drug is fulfilled.
Other Names:
  • CABOMETYX

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Response Rate (RR)
Time Frame: From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
Exact binomial method will be used to estimate the response rate (CR+PR) and its 95% confidence interval.Proportion of patients presenting Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) based on the Investigator's assessment according to standard RECIST criteria v1.1. Patients with no tumor assessment after baseline will be classified as non-responders.
From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Toxicity (frequency of adverse events)
Time Frame: From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
the assessment of safety will be based mainly on the frequency of adverse events; toxicity will be measured according to NCI Common Toxicity Criteria Adverse Event (CTCAE), version 4.03.
From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
Progression-Free Survival (PFS)
Time Frame: From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
PFS will be calculated from the first treatment intake to the date of progressive disease, or death.
From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
Overall survival (OS)
Time Frame: From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
OS will be calculated from the first treatment intake to death from any cause.
From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
Duration of response (DOR
Time Frame: From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
DOR will be calculated from the first treatment intake to the date of disease progression or death.
From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
Disease Control Rate(DCR)
Time Frame: From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
DCR will be measured as the sum of complete and partial responses + stable disease.
From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
RET aberration
Time Frame: On the start of treatment (Baseline) and through study completion, an average of 1 year
Detection of RET aberration on DNA extracted from circulating tumor cells (CTCs) isolated in blood at baseline (optional)
On the start of treatment (Baseline) and through study completion, an average of 1 year
RET-rearrangment on tumor tissue
Time Frame: At the start of treatment (baseline)
Archival tumor tissue (FFPE tumor block or 7-10 unstained slides) will be assessed for determination of RET-rearrangment on tumor cells by using A FISH evaluation of the translocation will be performed using a break-apart probe for the 10p11 locus.
At the start of treatment (baseline)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 7, 2019

Primary Completion (Anticipated)

August 7, 2020

Study Completion (Anticipated)

August 7, 2022

Study Registration Dates

First Submitted

September 26, 2019

First Submitted That Met QC Criteria

October 17, 2019

First Posted (Actual)

October 18, 2019

Study Record Updates

Last Update Posted (Actual)

October 18, 2019

Last Update Submitted That Met QC Criteria

October 17, 2019

Last Verified

October 1, 2019

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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