Phase II Study With Cabozantinib in Patients With RET Positive NSCLC

Study Overview
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Brief Summary
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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

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

Conditions
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Non Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Cabozantinib 20 MG
* Drug: Cabozantinib 40 MG
* Drug: Cabozantinib 60 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Ability to understand and willingness to sign informed consent prior to initiation of any study procedures. Pathologically (histology or cytology) confirmed diagnosis of non- small cell lung carcinoma. 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. Male or female and = 18 years of age Life expectancy = 12 weeks Have progressed after or during at least one standard anticancer treatment 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 Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 1 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) 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 Recovered (i.e., = Grade 1 toxicity) from effects of prior anticancer therapy, except alopecia No radiologic or clinical evidence of acute or chronic pancreatitis 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. 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. Ability to comply with protocol requirement. Exclusion criteria: 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. Previous treatment with cabozantinib. Gastrointestinal disorders likely to interfere with absorption of the study drug. Subjects with gastrointestinal disorders associated with a high risk of perforation of fistula formation. Subjects with active peptic ulcer or with a history of clinically ¿significant GI bleeding within 6 months before the first dose of study treatment. Patients requiring full-dose anticoagulation therapy any time prior to enrollment. Current use of aspirin, clopidogrel, ticlopidine. Patients with tumors invading major pulmonary vessels and/or with cavitating pulmonary lesions. 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. Subjects with clinical or radiological signs of pulmonary hemorrhage within 3 months before the first dose of study treatment. 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). History of congenital platelet function defect. Patient unable to swallow tablets Corrected QT interval greater than 500 ms (Fridericia formula) 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. 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. 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) 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. Rare hereditary problems of

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single-arm, ope label clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cabozantinib<br>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. | Drug: Cabozantinib 20 MG<br>* 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.<br>* Other names: CABOMETYX;Drug: Cabozantinib 40 MG<br>* 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.<br>* Other names: CABOMETYX;Drug: Cabozantinib 60 MG<br>* 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.<br>* Other names: CABOMETYX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (RR) | 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) | 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) | 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) | 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 | 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) | 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 |