Medullary Thyroid Cancer
Conditions
Keywords
thyroid cancer, medullary thyroid cancer
Brief summary
The objective of this study is to evaluate the efficacy and safety of oral cabozantinib at a 60 mg dose compared with a 140 mg dose in subjects with progressive, metastatic MTC. It will test if the lower dose results in similar progression free survival (PFS) and overall response rate (ORR) with fewer adverse events compared to the PFS, ORR and adverse events found in previous clinical trials of 140 mg.
Interventions
DRUGCabozantinib (XL184) 140 mg
DRUGCabozantinib (XL184) 60 mg
DRUGPlacebo tablet
DRUGPlacebo capsule
Sponsors
Exelixis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. The subject has a histologically confirmed diagnosis of MTC. 2. All subjects will need to be tested for RET mutational status. If subjects do not have documentation confirming they have a RET mutation, a sample of their tumor (taken either during screening or from a procedure within 6 months prior to randomization) will need to be tested. 3. The subject has measurable disease per RECIST 1.1 that is metastatic as determined by the investigator based upon computerized tomography (CT), magnetic resonance imaging (MRI), PET scan, bone scan, or X-ray taken within 28 days before randomization. 4. The subject has documented worsening of disease (progressive disease) at screening as compared with a previous CT, PETor MRI scan, bone scan, or X-ray as determined by the investigator per RECIST 1.1 on qualifying screening images taken within 28 days prior to randomization as compared to previous images taken within 14 months before the qualifying screening images. 5. The subject has recovered to baseline or CTCAE v4.0 (Common Terminology Criteria for Adverse Events, version 4.0) ≤ Grade 1 from toxicities related to any prior treatments, unless AE(s) are clinically non-significant and/or stable on supportive therapy. 6. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 at screening. 7. The subject has adequate organ and marrow function 8. The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document. 9. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment.
Exclusion criteria
1. The subject has previously received cabozantinib. 2. Receipt of any type of small molecule kinase inhibitor or hormonal therapy within 28 days or 5 half-lives of the compound or active metabolites, whichever is shorter, before randomization. 3. Receipt of any systemic anti-tumor therapy within 28 days of randomization (42 days for nitrosoureas or/ mitomycin C). 4. Receipt of any other type of investigational agent within 28 days of randomization. 5. Receipt of radiation therapy within 28 days (14 days for radiation for bone metastases) of randomization or radionuclide treatment within 42 days of randomization. Subject is ineligible if there are any clinically relevant ongoing complications from prior radiation therapy. 6. The subject has untreated and/or active (progressing or requiring anticonvulsants or corticosteroids for symptomatic control) central nervous system (CNS) metastasis. Must have completed radiation therapy ≥ 28 days prior to randomization and be stable without corticosteroids or anti-convulsant treatment for ≥ 10 days. 7. Treatment at therapeutic doses with oral anticoagulants or platelet inhibitors (examples are warfarin and clopidogrel). 8. The subject has uncontrolled, significant intercurrent illness including, but not limited to, cardiovascular disorders, gastrointestinal disorders, active infections, non-healing wounds, recent surgery. 9. Corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms within 28 days before randomization. 10. The subject is unable to swallow multiple tablets or capsules. 11. The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation. 12. The subject is pregnant or breastfeeding. 13. The subject has had a diagnosis of another malignancy within 2 years before randomization, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Per Blinded Independent Radiology Committee (BIRC) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Median time of follow-up (from the date of randomization of the first participant through primary data cut off [15 July 2020]) was 30.2 months | PFS per BIRC per RECIST 1.1 was measured from randomization until the date of first documented disease progression or date of death from any cause, whichever came first, and was assessed for up to 31 months. The prespecified primary analysis was triggered by the required number of at least 150 events occurring in the ITT population, The data cutoff date for this event-driven analysis in the ITT population was when a total of 155 events were reported. Median PFS was calculated using the Kaplan-Meier estimates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Per BIRC Per RECIST 1.1 | Median time of follow-up (from the date of randomization of the first participant through primary data cut off [15 July 2020]) was 30.2 months | ORR per BIRC per RECIST 1.1 is the percentage of ITT participants who experienced a best overall response of complete response (CR) or partial response (PR), confirmed ≥ 28 days later, CR defined as disappearance of all non-target lesions. All lymph nodes must have been non-pathological in size (\<10 mm short axis). PR defined as unequivocal progression of non-target lesions. Unequivocal progression was to trump target lesion status. It must have been representative of overall disease status change, not a single lesion increase. |
Countries
Australia, Canada, Croatia, France, Hungary, Israel, Italy, Netherlands, Poland, Romania, Russia, South Korea, Spain, Sweden
Participant flow
Pre-assignment details
Cabozantinib-matched placebo capsules and tablets were administered along with the corresponding tablets and capsules to maintain the blinding of the study treatment. Per prespecified analysis, all participants who died during the study met the study requirements of study completion. Therefore, none of the deaths that occurred during the study were recorded as leading to study discontinuation.
Participants by arm
| Arm | Count |
|---|---|
| Cabozantinib (XL184) 60 mg Cabozantinib (XL184) 60 mg tablets were administered with cabozantinib-matched placebo capsules orally once a day. | 123 |
| Cabozantinib (XL184) 140 mg Cabozantinib (XL184) 140 mg capsules were administered with cabozantinib-matched placebo tablets administered orally once a day. | 124 |
| Total | 247 |
Baseline characteristics
| Characteristic | Cabozantinib (XL184) 60 mg | Total | Cabozantinib (XL184) 140 mg |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 38 Participants | 84 Participants | 46 Participants |
| Age, Categorical Between 18 and 65 years | 85 Participants | 163 Participants | 78 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 8 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 103 Participants | 205 Participants | 102 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants | 34 Participants | 16 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 19 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 18 Participants | 31 Participants | 13 Participants |
| Race (NIH/OMB) White | 92 Participants | 194 Participants | 102 Participants |
| Region of Enrollment Australia | 19 participants | 39 participants | 20 participants |
| Region of Enrollment Canada | 2 participants | 3 participants | 1 participants |
| Region of Enrollment Croatia | 4 participants | 9 participants | 5 participants |
| Region of Enrollment France | 21 participants | 34 participants | 13 participants |
| Region of Enrollment Hungary | 4 participants | 5 participants | 1 participants |
| Region of Enrollment Israel | 3 participants | 8 participants | 5 participants |
| Region of Enrollment Italy | 9 participants | 22 participants | 13 participants |
| Region of Enrollment Netherlands | 4 participants | 8 participants | 4 participants |
| Region of Enrollment Poland | 13 participants | 30 participants | 17 participants |
| Region of Enrollment Romania | 9 participants | 18 participants | 9 participants |
| Region of Enrollment Russia | 14 participants | 30 participants | 16 participants |
| Region of Enrollment South Korea | 10 participants | 17 participants | 7 participants |
| Region of Enrollment Spain | 6 participants | 18 participants | 12 participants |
| Region of Enrollment Sweden | 5 participants | 6 participants | 1 participants |
| Sex: Female, Male Female | 33 Participants | 83 Participants | 50 Participants |
| Sex: Female, Male Male | 90 Participants | 164 Participants | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 59 / 123 | 51 / 124 |
| other Total, other adverse events | 122 / 123 | 123 / 124 |
| serious Total, serious adverse events | 55 / 123 | 62 / 124 |
Outcome results
Primary
Progression Free Survival (PFS) Per Blinded Independent Radiology Committee (BIRC) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
PFS per BIRC per RECIST 1.1 was measured from randomization until the date of first documented disease progression or date of death from any cause, whichever came first, and was assessed for up to 31 months. The prespecified primary analysis was triggered by the required number of at least 150 events occurring in the ITT population, The data cutoff date for this event-driven analysis in the ITT population was when a total of 155 events were reported. Median PFS was calculated using the Kaplan-Meier estimates.
Time frame: Median time of follow-up (from the date of randomization of the first participant through primary data cut off [15 July 2020]) was 30.2 months
Population: Measured in the Intent-to-Treat (ITT) Population, which included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabozantinib (XL184) 60 mg | Progression Free Survival (PFS) Per Blinded Independent Radiology Committee (BIRC) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 11 months |
| Cabozantinib (XL184) 140 mg | Progression Free Survival (PFS) Per Blinded Independent Radiology Committee (BIRC) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 13.9 months |
p-value: 0.191695% CI: [0.9, 1.7]Log Rank
Secondary
Objective Response Rate (ORR) Per BIRC Per RECIST 1.1
ORR per BIRC per RECIST 1.1 is the percentage of ITT participants who experienced a best overall response of complete response (CR) or partial response (PR), confirmed ≥ 28 days later, CR defined as disappearance of all non-target lesions. All lymph nodes must have been non-pathological in size (\<10 mm short axis). PR defined as unequivocal progression of non-target lesions. Unequivocal progression was to trump target lesion status. It must have been representative of overall disease status change, not a single lesion increase.
Time frame: Median time of follow-up (from the date of randomization of the first participant through primary data cut off [15 July 2020]) was 30.2 months
Population: Measured in the ITT Population, which included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib (XL184) 60 mg | Objective Response Rate (ORR) Per BIRC Per RECIST 1.1 | 33 percentage of participants |
| Cabozantinib (XL184) 140 mg | Objective Response Rate (ORR) Per BIRC Per RECIST 1.1 | 33 percentage of participants |
p-value: 0.943795% CI: [0.6, 1.7]Cochran-Mantel-Haenszel