Clinical Trials List
Protocol NumberXL184–311
NCT Number(ClinicalTrials.gov Identfier)NCT03690388
2019-06-01 - 2022-12-31
Phase III
Recruiting4
ICD-10C73
Malignant neoplasm of thyroid gland
ICD-10E31.22
Multiple endocrine neoplasia [MEN] type IIA
ICD-10Z51.12
Encounter for antineoplastic immunotherapy
ICD-9193
Malignant neoplasm of thyroid gland
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Cabozantinib (XL184) in Subjects with Radioiodine-Refractory Differentiated Thyroid Cancer Who Have Progressed after Prior VEGFR-Targeted Therapy
-
Trial Applicant
Pharmaceutical Research Associates Taiwan Inc.
-
Sponsor
Exelixis, Inc.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2023/03/10
Investigators and Locations
Co-Principal Investigator
- Liu Yi-Sheng 未分科
- Li-Tzong Chen 未分科
- Shang-Hung Chen 未分科
- 洪崇傑 未分科
The Actual Total Number of Participants Enrolled
0 Recruiting
The Actual Total Number of Participants Enrolled
0 Recruiting
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- 呂金盈 Division of Hematology & Oncology
- JHE-CYUAN GUO Division of Hematology & Oncology
- 徐偉勛 Division of Hematology & Oncology
- 施翔蓉 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Condition/Disease
Differentiated Thyroid Cancer
Objectives
Main objective
The objective of this study is to evaluate the effect of cabozantinib compared with placebo on PFS and ORR in subjects with RAI refractory DTC who have progressed after prior VEGFR targeted therapy.
Test Drug
Cabozantinib (XL184) 20mg and 60mg tablet
Active Ingredient
Cabozantinib
Dosage Form
tablet
tablet
tablet
Dosage
20 mg
60 mg
60 mg
Endpoints
Primary endpoint
• Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by blinded independent radiology committee (BIRC)
• Objective response rate (ORR) per RECIST 1.1 by BIRC
Secondary endpoints
• Overall survival (OS)
• Duration of objective tumor response
• Safety and tolerability
• Pharmacokinetics (PK) of cabozantinib
• Relationship of baseline and postbaseline changes in biomarkers, serum thyroglobulin (Tg), and circulating tumor cells (CTCs) and/or circulating DNA (ctDNA) with treatment and/or clinical outcome assessments may be performed
• Change in mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and global health as assessed by the EuroQol Health questionnaire instrument (EQ-5D-5L)
• Health care resource utilization
• Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by blinded independent radiology committee (BIRC)
• Objective response rate (ORR) per RECIST 1.1 by BIRC
Secondary endpoints
• Overall survival (OS)
• Duration of objective tumor response
• Safety and tolerability
• Pharmacokinetics (PK) of cabozantinib
• Relationship of baseline and postbaseline changes in biomarkers, serum thyroglobulin (Tg), and circulating tumor cells (CTCs) and/or circulating DNA (ctDNA) with treatment and/or clinical outcome assessments may be performed
• Change in mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and global health as assessed by the EuroQol Health questionnaire instrument (EQ-5D-5L)
• Health care resource utilization
Inclution Criteria
1. Histologically or cytologically confirmed diagnosis of DTC, including the following
subtypes (Note: results of a previous biopsy will be accepted):
a. 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
b. FTC including histological variants of FTC such as Hürthle cell, clear cell, insular, and
poorly differentiated
2. Measurable disease according to RECIST 1.1 on CT/MRI performed within 28 days prior to
randomization
3. Must have been previously treated with or deemed ineligible for treatment with Iodine-131
for DTC
4. Must have been previously treated with at least one of the following VEGFR-targeting TKI
agents for DTC: lenvatinib or sorafenib.
(Note: Up to two prior VEGFR-targeting TKI agents are allowed including (but not limited
to) lenvatinib and sorafenib.)
5. Must have experienced documented radiographic progression per RECIST 1.1 per
Investigator during or following treatment with a VEGFR-targeting TKI prior to starting the
next anticancer therapy (which may be treatment in this study)
6. Recovery to baseline or ≤ Grade 1 (Common Terminology Criteria for Adverse Events
Version 5 [CTCAE v5]) from toxicities related to any prior treatments, unless AE(s) are
clinically nonsignificant and/or stable on supportive therapy
7. Age ≥ 16 years old on the day of consent
8. Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1
9. Adequate organ and marrow function, based upon meeting all of the following laboratory
criteria within 10 days before randomization:
a. 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
b. Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without receipt of transfusion within 2 weeks
before screening laboratory sample collection
c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without receipt of transfusion within 2 weeks before
screening laboratory sample collection
d. Alanine aminotransferase (ALT), AST, and alkaline phosphatase (ALP) ≤ 3 × upper
limit of normal (ULN). ALP ≤ 5 × ULN if the subject has documented bone metastases
e. Bilirubin ≤ 1.5 × the ULN. For subjects with known Gilbert’s disease ≤ 3 × ULN
f. Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 30 mL/min
(≥ 0.5 mL/sec) using the Cockcroft-Gault (see Table 5-2 for Cockcroft-Gault formula).
g. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)
10. Must be receiving thyroxine suppression therapy, and TSH must be below the lower cutoff
of the reference range or less than 0.50 mIU/L (< 0.50 μIU/mL), whichever is lower, within
28 days before randomization.
(Note: If hormone replacement therapy is tolerated a TSH level of ≤ 0.1 mIU/L should be
targeted.)
11. Capable of understanding and complying with the protocol requirements and signed
informed consent (or informed assent and parental/guardian consent for subjects < 18 years
of age)
12. Sexually active fertile subjects and their partners must agree to use highly effective methods
of contraception that alone or in combination result in a failure rate of less than 1% per year
when used consistently and correctly during the course of the study and for 4 months after
the last dose of study treatment. For females, such methods include combined hormonal
contraception (oral, intravaginal, dermal), progestogen-only hormonal contraception
associated with inhibition of ovulation (oral, injectable hormonal contraception, implantable
hormonal contraception), placement of an intrauterine device, or placement of an
intrauterine hormone-releasing system. Males must agree to use a barrier method (eg,
condom) unless they have had a vasectomy.
13. Female subjects of childbearing potential must not be pregnant at screening. Female subjects
are considered to be of childbearing potential unless one of the following criteria is met:
permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy)
or documented postmenopausal status (defined as 12 months of amenorrhea in a woman
over 45 years-of-age in the absence of other biological or physiological causes. In addition,
females under 55 years-of-age must have a serum follicle stimulating hormone (FSH)
level > 40 mIU/mL to confirm menopause). Note: Documentation may include review of
medical records, medical examination, or medical history interview by study site staff.
subtypes (Note: results of a previous biopsy will be accepted):
a. 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
b. FTC including histological variants of FTC such as Hürthle cell, clear cell, insular, and
poorly differentiated
2. Measurable disease according to RECIST 1.1 on CT/MRI performed within 28 days prior to
randomization
3. Must have been previously treated with or deemed ineligible for treatment with Iodine-131
for DTC
4. Must have been previously treated with at least one of the following VEGFR-targeting TKI
agents for DTC: lenvatinib or sorafenib.
(Note: Up to two prior VEGFR-targeting TKI agents are allowed including (but not limited
to) lenvatinib and sorafenib.)
5. Must have experienced documented radiographic progression per RECIST 1.1 per
Investigator during or following treatment with a VEGFR-targeting TKI prior to starting the
next anticancer therapy (which may be treatment in this study)
6. Recovery to baseline or ≤ Grade 1 (Common Terminology Criteria for Adverse Events
Version 5 [CTCAE v5]) from toxicities related to any prior treatments, unless AE(s) are
clinically nonsignificant and/or stable on supportive therapy
7. Age ≥ 16 years old on the day of consent
8. Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1
9. Adequate organ and marrow function, based upon meeting all of the following laboratory
criteria within 10 days before randomization:
a. 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
b. Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without receipt of transfusion within 2 weeks
before screening laboratory sample collection
c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without receipt of transfusion within 2 weeks before
screening laboratory sample collection
d. Alanine aminotransferase (ALT), AST, and alkaline phosphatase (ALP) ≤ 3 × upper
limit of normal (ULN). ALP ≤ 5 × ULN if the subject has documented bone metastases
e. Bilirubin ≤ 1.5 × the ULN. For subjects with known Gilbert’s disease ≤ 3 × ULN
f. Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 30 mL/min
(≥ 0.5 mL/sec) using the Cockcroft-Gault (see Table 5-2 for Cockcroft-Gault formula).
g. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)
10. Must be receiving thyroxine suppression therapy, and TSH must be below the lower cutoff
of the reference range or less than 0.50 mIU/L (< 0.50 μIU/mL), whichever is lower, within
28 days before randomization.
(Note: If hormone replacement therapy is tolerated a TSH level of ≤ 0.1 mIU/L should be
targeted.)
11. Capable of understanding and complying with the protocol requirements and signed
informed consent (or informed assent and parental/guardian consent for subjects < 18 years
of age)
12. Sexually active fertile subjects and their partners must agree to use highly effective methods
of contraception that alone or in combination result in a failure rate of less than 1% per year
when used consistently and correctly during the course of the study and for 4 months after
the last dose of study treatment. For females, such methods include combined hormonal
contraception (oral, intravaginal, dermal), progestogen-only hormonal contraception
associated with inhibition of ovulation (oral, injectable hormonal contraception, implantable
hormonal contraception), placement of an intrauterine device, or placement of an
intrauterine hormone-releasing system. Males must agree to use a barrier method (eg,
condom) unless they have had a vasectomy.
13. Female subjects of childbearing potential must not be pregnant at screening. Female subjects
are considered to be of childbearing potential unless one of the following criteria is met:
permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy)
or documented postmenopausal status (defined as 12 months of amenorrhea in a woman
over 45 years-of-age in the absence of other biological or physiological causes. In addition,
females under 55 years-of-age must have a serum follicle stimulating hormone (FSH)
level > 40 mIU/mL to confirm menopause). Note: Documentation may include review of
medical records, medical examination, or medical history interview by study site staff.
Exclusion Criteria
1. Prior treatment with any of the following:
a. Cabozantinib
b. Selective small-molecule BRAF kinase inhibitor (eg, vemurafenib, dabrafenib)
c. More than 2 VEGFR-targeting TKI agents (eg, lenvatinib, sorafenib, sunitinib,
pazopanib, axitinib, vandetanib)
d. More than 1 immune checkpoint inhibitor therapy (eg, PD-1 or PD-L1 targeting agent)
e. More than 1 systemic chemotherapy regimen (given as 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
randomization
3. Receipt of any type of anticancer antibody (including investigational antibody) or systemic
chemotherapy within 4 weeks before randomization
4. Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation
therapy within 4 weeks before randomization. Subjects 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
randomization. Eligible subjects must be neurologically asymptomatic and without
corticosteroid treatment at the time of randomization.
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:
• Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose
low molecular weight heparins (LMWH)
• 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
randomization 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 blood pressure (BP) > 150 mm Hg
systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment
iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or
other ischemic event, or thromboembolic event (eg, deep venous thrombosis [DVT],
pulmonary embolism) within 6 months before randomization. Subjects with a more
recent diagnosis of DVT are allowed if stable, asymptomatic, and treated with
LMWH for at least 6 weeks before randomization.
b. Gastrointestinal disorders (GI; 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 randomization
Note: Complete healing of an intra-abdominal abscess must be confirmed prior to
randomization
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 randomization
d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation
e. Lesions invading major pulmonary blood vessels
f. Other clinically significant disorders such as:
• Active infection requiring systemic treatment, infection with human
immunodeficiency virus or acquired immunodeficiency syndrome-related illness, or
chronic hepatitis B or C infection
• Serious non-healing wound/ulcer/bone fracture
• Malabsorption syndrome
• Moderate to severe hepatic impairment (Child-Pugh B or C)
• Requirement for hemodialysis or peritoneal dialysis
• Uncontrolled diabetes mellitus
• History of solid organ transplantation
8. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before
randomization. Complete wound healing from major surgery must have occurred 4 weeks
before randomization and from minor surgery (eg, simple excision, tooth extraction) at least
10 days before randomization. Subjects 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 randomization
Note: If a single electrocardiogram (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. Pregnant or lactating females
11. Inability to swallow tablets
12. Previously identified allergy or hypersensitivity to components of the study treatment
formulations
13. Diagnosis of another malignancy within 3 years before randomization, except for superficial
skin cancers, or localized, low grade tumors deemed cured and not treated with systemic
therapy
a. Cabozantinib
b. Selective small-molecule BRAF kinase inhibitor (eg, vemurafenib, dabrafenib)
c. More than 2 VEGFR-targeting TKI agents (eg, lenvatinib, sorafenib, sunitinib,
pazopanib, axitinib, vandetanib)
d. More than 1 immune checkpoint inhibitor therapy (eg, PD-1 or PD-L1 targeting agent)
e. More than 1 systemic chemotherapy regimen (given as 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
randomization
3. Receipt of any type of anticancer antibody (including investigational antibody) or systemic
chemotherapy within 4 weeks before randomization
4. Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation
therapy within 4 weeks before randomization. Subjects 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
randomization. Eligible subjects must be neurologically asymptomatic and without
corticosteroid treatment at the time of randomization.
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:
• Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose
low molecular weight heparins (LMWH)
• 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
randomization 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 blood pressure (BP) > 150 mm Hg
systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment
iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or
other ischemic event, or thromboembolic event (eg, deep venous thrombosis [DVT],
pulmonary embolism) within 6 months before randomization. Subjects with a more
recent diagnosis of DVT are allowed if stable, asymptomatic, and treated with
LMWH for at least 6 weeks before randomization.
b. Gastrointestinal disorders (GI; 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 randomization
Note: Complete healing of an intra-abdominal abscess must be confirmed prior to
randomization
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 randomization
d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation
e. Lesions invading major pulmonary blood vessels
f. Other clinically significant disorders such as:
• Active infection requiring systemic treatment, infection with human
immunodeficiency virus or acquired immunodeficiency syndrome-related illness, or
chronic hepatitis B or C infection
• Serious non-healing wound/ulcer/bone fracture
• Malabsorption syndrome
• Moderate to severe hepatic impairment (Child-Pugh B or C)
• Requirement for hemodialysis or peritoneal dialysis
• Uncontrolled diabetes mellitus
• History of solid organ transplantation
8. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before
randomization. Complete wound healing from major surgery must have occurred 4 weeks
before randomization and from minor surgery (eg, simple excision, tooth extraction) at least
10 days before randomization. Subjects 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 randomization
Note: If a single electrocardiogram (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. Pregnant or lactating females
11. Inability to swallow tablets
12. Previously identified allergy or hypersensitivity to components of the study treatment
formulations
13. Diagnosis of another malignancy within 3 years before randomization, except for superficial
skin cancers, or localized, low grade tumors deemed cured and not treated with systemic
therapy
The Estimated Number of Participants
-
Taiwan
12 participants
-
Global
400 participants
