| Eligibility |
Inclusion Criteria:
1. Male or female subjects = 18 years old.
2. Written informed consent approved by the Independent Ethics Committee (IEC), prior to
the performance of any trial activities.
3. Histologically or cytologically confirmed diagnosis of DTC, including the following
subtypes:
(Note: results of a previous biopsy will be accepted):
1. Papillary thyroid carcinoma (PTC) including histological variants of PTC such as
follicular variant, tall cell, columnar cell, cribriform-morular, solid, oxyphil,
Warthin-like, trabecular, tumor with nodular fasciitis-like stroma, Hürthle cell
variant of papillary carcinoma, poorly differentiated.
2. Follicular thyroid carcinoma (FTC) including histological variants of FTC such as
Hürthle cell, clear cell, insular, and poorly differentiated.
4. Measurable disease according to RECIST 1.1 on computed tomography/magnetic resonance
imaging (CT/MRI) performed within 28 days prior to first dose of study treatment.
5. Must have been previously treated with or deemed ineligible for treatment with
Iodine-131 for DTC.
6. Must have been previously treated and experienced documented radiographic progression
per RECIST 1.1 with one or two of the following vascular endothelial growth factor
(VEGF) targeting TKI agents for DTC:
1. Lenvatinib first-line or,
2. Sorafenib first-line or,
3. Two prior vascular endothelial growth factor receptor (VEGFR) TKIs.
7. Recovery to baseline or = Grade 1 (Common Terminology Criteria for Adverse Events
Version 5 [CTCAE v 5.0]) from toxicities related to any prior treatments, unless AEs
are clinically nonsignificant and/or stable on supportive therapy.
8. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
9. Adequate organ and bone marrow function based upon meeting all of the following
laboratory criteria within 10 days before first dose of study treatment:
1. Absolute neutrophil count = 1500/mm3 (= 1.5 GI/L) without receipt of granulocyte
colony-stimulating factor support within 2 weeks before screening laboratory
sample collection.
2. Platelets = 100,000/mm3 (= 100 GI/L) without receipt of transfusion within 2
weeks before screening laboratory sample collection
3. Hemoglobin = 9 g/dL (= 90 g/L) without receipt of transfusion within 2 weeks
before screening laboratory sample collection
4. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline
phosphatase (ALP) = 3 × upper limit of normal (ULN). ALP = 5 × ULN if the subject
has documented bone metastases
5. Bilirubin = 1.5 × the upper limit of normal (ULN). For subjects with known
Gilbert's disease = 3 × ULN
6. Serum creatinine = 2.0 × ULN or calculated creatinine clearance = 30 mL/min (=
0.5 mL/sec) using the Cockcroft-Gault
7. Urine protein/creatinine ratio (UPCR) = 1 mg/mg (= 113.2 mg/mmol)
10. Female subjects of childbearing potential (WOCBP) must provide a negative urine
pregnancy test at screening, and must agree to use a medically accepted and highly
effective birth control method (i.e. those with a failure rate less than 1%; for the
duration of the study treatment and for 4 months after the final dose of cabozantinib.
- A woman is considered of childbearing potential ( i.e. fertile) following menarche
and until becoming post-menopausal unless permanently sterile. Women will be
considered post-menopausal if they have been amenorrhoeic for 12 months without an
alternative medical cause. The following age-specific requirements apply:
1. Amenorrheic for =1 year in the absence of chemotherapy and/or hormonal treatments
2. Luteinizing hormone (LH) and/or follicle stimulating hormone and/or estradiol
levels in the post-menopausal range
3. Radiation induced oophorectomy with last menses >1 year ago
4. Chemotherapy induced menopause with >1 year interval since last menses
5. Surgical sterilization (bilateral oophorectomy or hysterectomy)
6. Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy)
7. Women =50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, or underwent surgical sterilization (bilateral oophorectomy,
bilateral salpingectomy or hysterectomy).
11. Non-sterile males must be willing to use a highly effective method of birth control
for the duration of the study treatment and for 4 months after the final dose of
cabozantinib.
A sterile male is defined as:
1. One for whom azoospermia has been previously demonstrated in a semen sample
examination as definitive evidence of infertility.
2. Males with known "low sperm counts" (consistent with "sub-fertility") are not to
be considered sterile for purposes of this study.
12. Capable of understanding and complying with the protocol requirements and signed
informed consent.
Exclusion Criteria:
1. Prior treatment with any of the following:
1. Cabozantinib.
2. Selective small-molecule BRAF kinase inhibitor (eg, vemurafenib, dabrafenib).
3. Immune checkpoint inhibitor therapy (eg, PD-1 or PD-L1 targeting agent).
4. Systemic chemotherapy regimen (given as a single agent or in combination with
another chemotherapy agent).
2. Receipt of any type of small molecule kinase inhibitor (including investigational
kinase inhibitor) within 2 weeks or 5 half-lives of the agent, whichever is longer,
before first dose of study treatment.
3. Receipt of any type of anticancer antibody (including investigational antibody) within
4 weeks before first dose of study treatment.
4. Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation
therapy within 4 weeks before first dose of study treatment. Patients with clinically
relevant ongoing complications from prior radiation therapy that have not completely
resolved are not eligible (eg, radiation esophagitis or other inflammation of the
viscera).
5. Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
before first dose of study treatment. Eligible subjects must be neurologically
asymptomatic and without corticosteroid treatment at the time of inclusion.
6. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin
and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel), except for the
following allowed anticoagulants:
1. Low-dose aspirin for cardioprotection (per local applicable guidelines) and
low-dose low molecular weight heparins (LMWH).
2. Anticoagulation with therapeutic doses of LMWH in subjects without known brain
metastases who are on a stable dose of LMWH for at least 6 weeks before first
dose of study treatment and who have had no clinically significant hemorrhagic
complications from the anticoagulation regimen or the tumor.
7. The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
a. Cardiovascular disorders: i. Congestive heart failure class 3 or 4 as defined by
the New York Heart Association, unstable angina pectoris, serious cardiac arrhythmias.
ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic or > 100 mm
Hg diastolic despite optimal antihypertensive treatment.
iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction, or
other ischemic event, or thromboembolic event (eg, deep venous thrombosis [DVT],
pulmonary embolism) within 6 months before first dose of study treatment. Note:
Patients with a more recent diagnosis of DVT are allowed if stable, asymptomatic, and
treated with LMWH for at least 6 weeks before first dose of study treatment.
b. Gastrointestinal disorders (eg, malabsorption syndrome or gastric outlet
obstruction) including those associated with a high risk of perforation or fistula
formulation: i. Tumors invading the GI tract, active peptic ulcer disease,
inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis,
symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of
the pancreatic or biliary duct, or gastric outlet obstruction.
ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess
within 6 months before first dose of study treatment. Note: Complete healing of an
intra-abdominal abscess must be confirmed prior to the first dose of study treatment.
c. Clinically significant hematemesis or hemoptysis of > 0.5 teaspoon (> 2.5 mL) of
red blood or history of other significant bleeding within 3 months before the first
dose of study treatment.
d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation. e.
Lesions invading major pulmonary blood vessels. f. Other clinically significant
disorders such as: i. Active infection requiring systemic treatment, infection with
human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome-related
illness, or chronic hepatitis B (HBV) or C (HCV) infection.
ii. Serious non-healing wound/ulcer/bone fracture. iii. Malabsorption syndrome. iv.
Moderate to severe hepatic impairment (Child-Pugh B or C). v. Requirement for
hemodialysis or peritoneal dialysis. vi. Uncontrolled diabetes mellitus. vii. History
of solid organ transplantation.
8. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks
before the first dose of study treatment. Complete wound healing from major surgery
must have occurred 4 weeks before the first dose of study treatment and from minor
surgery (eg, simple excision, tooth extraction) at least 10 days before the first dose
of study treatment. Patients with clinically relevant ongoing complications from prior
surgery are not eligible.
9. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28
days before the first dose of study treatment.
Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional
ECGs at intervals of approximately 3 min must be performed within 30 min after the
initial ECG, and the average of these 3 consecutive results for QTcF will be used to
determine eligibility.
10. Patients who are not able to swallow tablets.
11. Previously identified allergy or hypersensitivity to components of the study treatment
formulations.
12. Diagnosis of another malignancy within 3 years before the first dose of study
treatment, except for superficial skin cancers, or localized, low grade tumors deemed
cured and not treated with systemic therapy.
13. Women pregnant or breastfeeding. Fertile and sexually active patients who are not
willing to use the appropriate highly effective contraceptive methods.
14. Any underlying medical or psychiatric disorder, which, in the opinion of the
investigator, makes the administration of cabozantinib unsafe or interferes with the
informed consent process or trial procedures.
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