A phase II, open label, single arm study to assess the efficacy of cabozantinib in patients with advanced/metastatic non-small cell lung cancer harboring MET exon14 alterations, who developed acquired resistance to tepotinib or capmatinib

JRCT ID: jRCT2051240082

Registered date:03/07/2024

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: non-small cell lung cancer
• Date of first enrollment: 01/08/2024
• Target sample size: 30
• Study type: Interventional
• Intervention(s): The study drug (cabozantinib) will be administered orally at a dose of 60 mg once daily (fasting) on consecutive days and continued until the study drug (cabozantinib) meets the criteria for discontinuation.

Outcome(s)

• Primary Outcome: Response rate (according to the central review committee)
• Secondary Outcome: Progression-free survival, disease control rate, safety, overall survival

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1) Patients whose written consent has been obtained
2) Patients who are at least 18 years of age at the time of consent
3) Patients with histologically or cytologically confirmed non-small cell lung cancer
4) Patients with locally advanced or metastatic disease not amenable to surgery or curative radiation therapy
5) Patients with MET gene exon 14 mutations as determined by a companion diagnostic or comprehensive genomic profiling test (CGP test) approved for use in determining the indication for a target therapy prior to tepotinib or capmatinib
6) Patients with one or more non-irradiated measurable lesions with a maximum diameter of at least 10 mm (or 15 mm for lymph nodes) as accurately measured by CT or MRI scan during the screening period and confirmed disease progression by radiological imaging
7) Patients with radiographic confirmation of disease progression after best response CR, PR, or SD (any duration of CR, PR, or SD) with tepotinib or capmatinib. Patients whose best response is PD are not eligible for enrollment.
8) Patients who have received or are intolerant to at least one regimen of platinum-based chemotherapy with or without immune checkpoint inhibitors or the combination of nivolumab and ipilimumab*1
*1 Patients who received platinum therapy as adjuvant chemotherapy and relapse within 6 months from the date of completion of the therapy are eligible even if they have not received any of the above drugs.
9) Patients who have received or are intolerant to docetaxel therapy
10) Patients with an ECOG performance status of 0 to 1 and expected to survive at least 12 weeks
11) Patients with recovery to baseline or Grade 1 (CTCAE v.5.0) or less of prior therapy-related toxicity, unless clinically insignificant and stable on supportive care (patients with immune checkpoint inhibitor irAE that is stable on replacement therapy may be included even if Grade 2 or higher) Grade 2 or higher may be included. Patients with peripheral sensory neuropathy caused by docetaxel can be included even if they are Grade 2.)
12) Patients with adequate bone marrow and organ function to meet the following laboratory and measurement values within 14 days prior to enrollment:
a. SPO2 >= 92 % at rest (room air)
b. Absolute neutrophil count (ANC) >= 1500/mm3
c. Platelet count >= 100,000/mm3
d. Hemoglobin >= 9 g/ dL
e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 x upper limit of normal (institutional)
f. Total bilirubin <= 1.5 x upper limit of normal (Institution). Subjects with Gilbert's syndrome <= 3 mg/dL
g. HbA1c <= 8%.
h. Serum creatinine <= 2.0 x upper limit of normal (Institution) or calculated creatinine clearance >= 30 mL/min using the Cockroft-Gault formula
i. Urine protein/urine creatinine ratio (UPCR) <= 1 or 24-hour urine protein < 1 g
13) For women of childbearing potential, patients who use appropriate contraceptive measures, are not lactating, and have a negative pregnancy test result prior to initiation of treatment with the study drug (cabozantinib). Or, patients who meet one of the following criteria at the time of screening and can be judged to be non-pregnant
-Postmenopausal women aged 51 years or older who have been amenorrheic for at least 12 months after discontinuation of all exogenous hormone therapy.
-Women under 50 years of age who are considered postmenopausal if they have been amenorrheic for 12 months or longer since discontinuation of exogenous hormone therapy and have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels within the postmenopausal range of the provider's reference values.
-Women whose records confirm that they have undergone permanent sterilization by hysterectomy, bilateral oophorectomy or bilateral tubectomy (tubal ligation is not acceptable).
14) Male subjects must be willing to use a barrier contraceptive method (e.g., condom)

Exclude criteria

1) Persons involved in the planning and conduct of this clinical trial (investigator coordinating physician and employees or staff of the implementing medical institution)
2) Patients being treated with any of the following
a. Patients who have been treated with the study drug (cabozantinib)
b. Patients who have received any cytotoxic chemotherapy, study drug or other anticancer therapy (except immune checkpoint inhibitors) within 14 days prior to enrollment in a therapeutic or investigational setting
c. Patients who have received an immune checkpoint inhibitor within 28 days prior to enrollment
d. Patients who have undergone major surgery (e.g., surgery of the gastrointestinal tract, resection or biopsy of brain metastases) within 60 days prior to enrollment. However, patients with complete wound healing within 1 month prior to enrollment for major surgery or within 10 days prior to enrollment for minor surgery (e.g., vascularization, simple resection, tooth extraction, etc.) are excluded. Patients with prolonged complications related to surgery are not eligible.
e. Patients who received radiotherapy for bone metastases within 2 weeks prior to enrollment or other external radiation therapy within 4 weeks prior to enrollment. radionuclide treatment to the whole body within 6 weeks prior to enrollment. or ongoing clinically significant complications from prior radiotherapy.
f. Patients receiving concomitant medications*1,*2 (including natural or botanical supplements) known to have potent inhibitory or inducing effects on cytochrome P4503A4 (CYP3A4). Or patients who are unable to discontinue these drugs prior to enrollment.
1 Strong inducers of CYP3A4: Dexamethasone (1.5 mg/day or less is acceptable), phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St. John's Wort, etc.
2) Strong inhibitors of CYP3A4: ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, grapefruit, seville orange, etc.
3) Patients with known brain metastases or extradural lesions, unless adequately treated with radiotherapy and/or surgery and stable for at least 4 weeks prior to enrollment. Patients must be free of neurological symptoms and not receiving corticosteroid therapy at the time of enrollment.
4) Patients receiving treatment with oral anticoagulants (e.g., warfarin, direct thrombin inhibitors, factor Xa inhibitors) or platelet inhibitors
Note: The use of low-dose aspirin (<=100 mg/day), low-dose warfarin (<1 mg/day), and low-dose low molecular weight heparin (LMWH) for cardiac protection is acceptable. Anticoagulation with therapeutic doses of LMWH is acceptable if there is no imaging evidence of brain metastases, the patient is stable for at least 12 weeks prior to enrollment, and no thromboembolism or anticoagulation complications have occurred.
5) Patients receiving chronic treatment with corticosteroids or other immunosuppressive agents (except for inhaled or topical corticosteroids or corticosteroids with a daily dose equivalent of 10 mg prednisone or less). Subjects with brain metastases requiring systemic corticosteroids are also ineligible.
6) Patients with serious chronic diseases that are poorly controlled including, but not limited to, the following
a. Cardiovascular disorders
i. symptomatic congestive heart failure, unstable angina, severe arrhythmia.
ii. uncontrolled hypertension with sustained blood pressure greater than 150 mmHg systolic or 100 mmHg diastolic despite optimal antihypertensive therapy
iii. stroke (including TIA), myocardial infarction, or other ischemic event or thromboembolism (e.g., deep vein thrombosis, pulmonary embolism) occurring within 6 months prior to enrollment
b. Gastrointestinal disorders, including those associated with a high risk of perforation or fistula formation
i. tumors invading the gastrointestinal tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or biliary tract, or gastropyloric obstruction
ii. abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months prior to enrollment
Note: Complete healing of an intra-abdominal abscess must be confirmed prior to enrollment.
c. history of clinically significant hematuria, hematemesis, hemoptysis greater than 0.5 teaspoon (2.5 ml), or other significant bleeding (e.g., pulmonary hemorrhage) within 3 months prior to enrollment
d. development of cavitating lung lesions or known endobronchial disease
e. involvement of major pulmonary vessels
f. other clinically significant disease including
i. active infection requiring systemic therapy, human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related disease, active chronic hepatitis B or C
ii. serious wounds/ulcers/fractures that do not heal
iii. malabsorption syndrome
iv. Noncompensated/symptomatic hypothyroidism
v. Moderate to severe hepatic dysfunction (Child-Pugh B or C)
vi. need for hemodialysis or peritoneal dialysis
vii. history of solid organ transplantation
7) Patients with a QT interval (QTcF) greater than 500 msec within 14 days prior to enrollment.
*If the QTcF exceeds 500 msec, two additional ECGs must be performed on the same day; subjects shall be eligible in this regard if the average of three consecutive results is less than 500 msec.
8) Pregnant or lactating women
9) Patients unable to swallow tablets or capsules
10) Patients with pre-existing known allergy or hypersensitivity to any component of the study drug (cabozantinib)
11) Patients diagnosed with other malignancies within 2 years prior to enrollment (except superficial skin cancer or localized low-grade tumors considered cured that have not received systemic therapy)
12) Patients with a history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis requiring steroid therapy, or evidence of active ILD
13) Patients who are unable to comply with the study procedures, restrictions and requirements and are determined by the investigator (subinvestigator) to be inappropriate to participate in the study.

Related Information

• Primary Sponsor: Takeda Masayuki
• Source(s) of Monetary Support: Japan Agency for Medical Research and Development