Differentiated Thyroid Cancer
Conditions
Keywords
Thyroid cancer, papillary, Papillary thyroid carcinoma, Nonmedullary thyroid carcinoma, Cancer of the thyroid, Thyroid cancer, Follicular thyroid cancer, Thyroid cancer, follicular, Hürthle cell cancer
Brief summary
The objective of this study is to evaluate the effect of cabozantinib compared with placebo on progression free survival (PFS) and objective response rate (ORR) in subjects with Radioiodine-Refractory Differentiated Thyroid Cancer (DTC) who have progressed after prior vascular endothelial growth factor receptor (VEGFR)-Targeted therapy.
Interventions
DRUGCabozantinib
Tablets containing 60-mg or 20-mg cabozantinib once daily orally.
DRUGPlacebo
Tablets containing placebo equivalent of 60-mg or 20-mg cabozantinib once daily orally.
Sponsors
Ipsen
Exelixis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Study treatment assignment will be unknown to the subjects, investigators, study centers, Sponsor, and any Contract Research Organization affiliated with the study other than those authorized to access treatment assignment for regulatory safety reporting and submission processes, interactive response technology (IRT) system administration, and drug supply management. Cabozantinib-matched placebo will be packaged and color-, size-, and shape-matched to be indistinguishable from cabozantinib. Individual study treatment assignment will be unblinded and information provided to the Investigators upon request for subjects with radiographic progressive disease (PD) per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 confirmed by the blinded independent radiology committee (BIRC).
Intervention model description
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study of cabozantinib in subjects with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) after prior vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy. Cabozantinib-matched placebo will be given in the control arm to blind (mask) study treatment. Approximately 300 eligible subjects will be randomized in a 2:1 ratio to receive either cabozantinib or placebo. After the primary efficacy endpoints have been analyzed and sufficient data have been collected to adequately evaluate all study endpoints to establish, for regulatory purposes, the safety and efficacy profile of the experimental drug within this study, the study will transition to an open label Maintenance Phase.
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytologically confirmed diagnosis of Differentiated Thyroid Cancer (DTC) 2. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 3. Previously treated with or deemed ineligible for treatment with Iodine- 131 for differentiated thyroid cancer (DTC) 4. Previously treated with at least one of the following vascular endothelial growth factor receptor (VEGFR)-targeting tyrosine kinase inhibitor (TKI) agents for DTC: lenvatinib or sorafenib. Note: Up to two prior VEGFR-targeting TKI agents are allowed 5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
Exclusion criteria
1. Prior treatment with any of the following: Cabozantinib; Selective small-molecule v-raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase inhibitor; More than 2 VEGFR-targeting TKI agents; More than 1 immune checkpoint inhibitor therapy; 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. 5. Known brain metastases or cranial epidural disease unless adequately treated
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Up to approximately twenty months after the first subject is randomized. Time from randomization to the earlier of the following events: radiographic PD as determined by the blinded independent central review (BIRC) or death due to any cause. | Time to the earlier of either radiographic progressive disease (PD) or death from any cause. |
| Objective Response Rate (ORR) | Six months after 100 subjects are randomized. Time from randomization to best overall response of confirmed complete response (CR) or confirmed partial response (PR) per BIRC per RECIST 1.1. | Proportion of subjects with the best overall response of complete response (CR) or partial response (PR). |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Croatia, Czechia, France, Germany, Hong Kong, Hungary, Israel, Italy, Mexico, Netherlands, Poland, Romania, Russia, South Korea, Spain, Taiwan, Thailand, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cabozantinib cabozantinib (60 mg) once daily orally (qd)
Cabozantinib: Tablets containing 60-mg or 20-mg cabozantinib once daily orally. | 125 |
| Placebo placebo once daily orally (qd)
Placebo: Tablets containing placebo equivalent of 60-mg or 20-mg cabozantinib once daily orally. | 62 |
| Total | 187 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 1 |
| Overall Study | Clinical deterioration | 10 | 6 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Radiographic Progression | 14 | 29 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Cabozantinib |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 33 Participants | 96 Participants | 63 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 91 Participants | 62 Participants |
| Age, Continuous | 66 years | 66 years | 65 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 27 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 53 Participants | 148 Participants | 95 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 12 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 14 Participants | 34 Participants | 20 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 16 Participants | 11 Participants |
| Race (NIH/OMB) White | 41 Participants | 131 Participants | 90 Participants |
| Receipt of prior lenvatinib | 39 Participants | 118 Participants | 79 Participants |
| Region of Enrollment Argentina | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Australia | 1 participants | 6 participants | 5 participants |
| Region of Enrollment Austria | 0 participants | 4 participants | 4 participants |
| Region of Enrollment Belgium | 2 participants | 5 participants | 3 participants |
| Region of Enrollment Brazil | 4 participants | 15 participants | 11 participants |
| Region of Enrollment Canada | 0 participants | 3 participants | 3 participants |
| Region of Enrollment Croatia | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Czechia | 0 participants | 1 participants | 1 participants |
| Region of Enrollment France | 3 participants | 11 participants | 8 participants |
| Region of Enrollment Germany | 1 participants | 3 participants | 2 participants |
| Region of Enrollment Hong Kong | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Hungary | 3 participants | 8 participants | 5 participants |
| Region of Enrollment Israel | 0 participants | 3 participants | 3 participants |
| Region of Enrollment Italy | 5 participants | 19 participants | 14 participants |
| Region of Enrollment Mexico | 0 participants | 3 participants | 3 participants |
| Region of Enrollment Netherlands | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Poland | 4 participants | 13 participants | 9 participants |
| Region of Enrollment Romania | 1 participants | 4 participants | 3 participants |
| Region of Enrollment Russia | 3 participants | 11 participants | 8 participants |
| Region of Enrollment South Korea | 8 participants | 16 participants | 8 participants |
| Region of Enrollment Spain | 9 participants | 19 participants | 10 participants |
| Region of Enrollment Taiwan | 3 participants | 9 participants | 6 participants |
| Region of Enrollment Thailand | 1 participants | 3 participants | 2 participants |
| Region of Enrollment United Kingdom | 3 participants | 7 participants | 4 participants |
| Region of Enrollment United States | 9 participants | 19 participants | 10 participants |
| Sex: Female, Male Female | 34 Participants | 102 Participants | 68 Participants |
| Sex: Female, Male Male | 28 Participants | 85 Participants | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 17 / 125 | 14 / 62 |
| other Total, other adverse events | 112 / 125 | 32 / 62 |
| serious Total, serious adverse events | 43 / 125 | 18 / 62 |
Outcome results
Primary
Objective Response Rate (ORR)
Proportion of subjects with the best overall response of complete response (CR) or partial response (PR).
Time frame: Six months after 100 subjects are randomized. Time from randomization to best overall response of confirmed complete response (CR) or confirmed partial response (PR) per BIRC per RECIST 1.1.
Population: The first 100 subjects randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib | Objective Response Rate (ORR) | 15 percentage of participants |
| Placebo | Objective Response Rate (ORR) | 0 percentage of participants |
Primary
Progression Free Survival (PFS)
Time to the earlier of either radiographic progressive disease (PD) or death from any cause.
Time frame: Up to approximately twenty months after the first subject is randomized. Time from randomization to the earlier of the following events: radiographic PD as determined by the blinded independent central review (BIRC) or death due to any cause.
Population: All subjects randomized at the time of the analysis (N=187).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabozantinib | Progression Free Survival (PFS) | NA months |
| Placebo | Progression Free Survival (PFS) | 1.9 months |
p-value: <0.000196% CI: [0.13, 0.36]Log Rank