Clinical trial NCT04131543: Phase II Study With Cabozantinib in Patients With RET Positive NSCLC
Official title: "Phase II Study to Evaluate the Activity and Safety of Cabozantinib in Pretreated, Advanced RET-rearranged Non-small Cell Lung Cancer Patients: CRETA Trial"
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Non Small Cell Lung Cancer
Lead sponsor: University of Bologna
Sponsor class: OTHER
Collaborators: name: AOU S.Orsola Malpighi-Unit of Oncologic Molecular and Transplantations Pathology
name: Bioikos Ambiente Srl
name: Ipsen
name: Mipharm SpA
First posted: 2019-10-18
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single-arm, ope label clinical trial
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: 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

Primary outcomes:
measure: Response Rate (RR)
timeFrame: From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
Secondary outcomes:
measure: Toxicity (frequency of adverse events)
timeFrame: From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
measure: Progression-Free Survival (PFS)
timeFrame: From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
measure: Overall survival (OS)
timeFrame: From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
measure: Duration of response (DOR
timeFrame: From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
measure: Disease Control Rate(DCR)
timeFrame: From the start of treatment ( Baseline) to the progression of Disease (PD) or trial discontinuation whichever occurs first, assessed up to 24 months
Other outcomes:
measure: RET aberration
timeFrame: On the start of treatment (Baseline) and through study completion, an average of 1 year
measure: RET-rearrangment on tumor tissue
timeFrame: At the start of treatment (baseline)
Locations:
city: Bologna
country: Italy
facility: OU di Oncologia Medica- Azienda ospedaliero-Universitaria S. Orsola Malpighi
city: Catania
country: Italy
facility: U.O di Oncologia Medica Policlinico V.Emanuele-G.Rodolico
city: Genova
country: Italy
facility: Oncologia Medica 2 -Policlinico San Martino
city: Milano
country: Italy
facility: S.S. di Oncologia Medica toraco-polmonare - Fondazione IRCCS - Istituto Nazionale Tumori
city: Napoli
country: Italy
facility: U.O.C Pneumologia ad Indirizzo Oncologico -AORN Ospedali dei Colli Monaldi-Cotugno-CTO
city: Padova
country: Italy
facility: UOC di Oncologia Medica 2 - IOV Istituto Oncologico Veneto
city: Parma
country: Italy
facility: UOC di Oncologia Medica- Azienda Ospidaliero Universitaria di Parma
city: Perugia
country: Italy
facility: US di Oncologia Medica - A.O. di Perugia
city: Pisa
country: Italy
facility: UO Pneumologia - A.O.U Pisana
city: Roma
country: Italy
facility: S.C. di Oncologia Medica - IFO - Istituto Regina Elena
city: Udine
country: Italy
facility: UOC di Oncologia Medica - Azienda Sanitaria Universitaria Integrata di Udine
Study officials:
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