Thyroid Cancer
Conditions
Keywords
Medullary Thyroid Cancer, MTC
Brief summary
The purpose of this research study is to evaluate the progression-free survival (PFS) with XL184 as compared with placebo (an inactive substance) in subjects with unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC). Subjects will be randomized to receive XL184 or placebo in a 2:1 ratio. XL184 is an investigational drug that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration. The Clinical Steering Committee for this study, comprised of study doctors who specialize in medullary thyroid cancer, has provided guidance regarding the design of the study. The committee includes: Douglas Ball, MD, Barry Nelkin, PhD, Martin Schlumberger, MD and Steven Sherman, MD.
Interventions
DRUGXL184
Gelatin capsules supplied in 25-mg and 100-mg strengths administered orally daily
DRUGPlacebo
Gelatin capsules color and size-matched to XL184 capsules administered orally daily
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
* The subject has a histologically confirmed diagnosis of MTC that cannot be removed by surgery, is locally advanced, or has spread in the body. * The subject is at least 18 years old. * The subject has an ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2. * The subject has documented worsening of disease (progressive disease) at screening compared with a previous CT scan or MRI image done within 14 months of screening. * The subject has recovered from clinically significant adverse events (side effects) due to any other medications that were administered prior to randomization. * The subject has adequate organ and bone marrow function. * Subjects who are sexually active (male and female) must agree to use medically accepted methods of contraception during the course of the study and for 3 months following discontinuation of study treatments. * The subject has no other diagnosis of cancer (unless non-melanoma skin cancer, an early form of cervical cancer, or another cancer diagnosed ≥ 2 years previously) and currently has no evidence of malignancy (unless non-melanoma skin cancer or an early form of cervical cancer). * Female subjects of childbearing potential must have a negative pregnancy test at screening.
Exclusion criteria
* The subject has received prior treatment for their cancer within 4 weeks of randomization (6 weeks for nitrosoureas or mitomycin C). * The subject has received radiation to ≥ 25 % of bone marrow. * The subject has received treatment with other investigational agents (unapproved therapies) within 4 weeks of randomization. * The subject has received treatment with XL184. * The subject has brain metastases or spinal cord compression, unless completed radiation therapy ≥ 4 weeks prior to randomization and stable without steroid and without anti-convulsant treatment for ≥ 10 days. * The subject has a history of clinically significant episodes of vomiting blood or a recent history of vomiting \> 2.5 mL (about 1/2 teaspoon) of red blood. * The subject has serious illness other than cancer. * The subject is pregnant or breastfeeding. * The subject has an active infection requiring ongoing treatment. * The subject is incapable of understanding and complying with the protocol or unable to provide informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Treatment period consisted of 4-week cycles with radiologic tumor assessment every 12 weeks from date of randomization until date of first documented PD or date of death from any cause, whichever came first, assessed up to 34 months. | The duration of Progression-Free Survival (PFS) using progression events as determined by Independent Review Committee (IRC) per mRECIST, or death due to any cause. The analysis was conducted after at least 315 subjects were randomized and at least 138 events were observed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) With XL184 Compared With Placebo | The pre-specified interim analysis of Overall Survival (OS) was assessed at 44% of required events. Includes data up to 15June2011. As of this date, the number of deaths required to conduct the primary analysis had not been reached. | Duration of Overall Survival (OS) from the time of randomization to death due to any cause. A Kaplan-Meier analysis was performed to estimate the median. |
| Objective Response Rate (ORR) | Assessed at the same time as primary analysis of Progression Free Survival (PFS) data. Assessed at baseline and every 12 weeks until Progressive Disease (PD) up to 34 months. | The proportion of subjects with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) as determined by the Independent Review Committee (IRC.) Per Response Evaluation Criteria in Solid Tumor Criteria (mRECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR) disappearance of all target lesions; Partial Response (PR) ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) ≥ 20% increase in the sum of the longest diameter of target lesions. Overall Response Rate: ORR=CR +PR |
| Duration of Objective Response (OR): Independent Radiology Committee (IRC) Determined | From time of first documentation of Objective Response (OR), confirmed at a later visit ≥28 days later as Progressive Disease (PD) as defined by mRECIST or death due to any cause, assessed up to 34 months. | For those subjects with Independent Radiology Committee (IRC) determined Objective Response Rate (ORR), the amount of time from documentation of Objective Response (OR) until Progressive Disease (PD) by mRECIST or death due to any cause. |
| Biochemical Response Calcitonin (CTN) % | Serum tumor markers CTN evaluated from blood samples collected at screening and every 12 weeks (±5 days from randomization) until date of first documented progression or date of death from any cause, whichever came first, assessed for up to 34 months. | For each on-treatment tumor marker assessment from each subject, the biochemical response of CTN was determined based on percent increase or decrease from baseline. Best biochemical response over course of treatment was determined from evaluation of subject's time point response data. Biochemical response criteria: Complete Response (CR) - decrease in tumor marker into normal range from baseline value; Partial Response (PR) - decrease of \>50% from baseline value when baseline value is above normal range; Stable Disease (SD) - no more than a 50% increase and no more than a 50% decrease from baseline value above normal range; Progressive Disease (PD) - increase of \>50% from baseline value when baseline value is above normal range / or increase from low or normal range at baseline to above normal range; Not Evaluable (NE) - missing baseline value / or baseline value is not elevated and response is not PD / or response can not be determined due to change in assay format. |
| Biochemical Response Carcinoembryonic Antigen (CEA) % | Serum tumor markers CEA evaluated from blood samples collected at screening and every 12 weeks (± 5 days from randomization) until date of first documented progression or date of death from any cause, whichever came first, assessed for up to 34 months. | For each on-treatment tumor marker assessment from each subject, the biochemical response of CEA was determined based on percent increase or decrease from baseline. Best biochemical response over the course of treatment was determined from evaluation of each subject's time point response data. Biochemical response: Complete Response (CR)- Decrease in tumor marker into normal range from baseline value; Partial Response (PR)- Decrease of \>50% from baseline value when baseline value is above normal range; Stable Disease (SD)- No more than a 50% increase and no more than a 50% decrease from baseline value above normal range; Progressive Disease (PD)- Increase of \>50% from baseline value when baseline value is above normal range / or increase from low or normal range at baseline to above normal range; Not Evaluable (NE)- Missing baseline value / or baseline value is not elevated and response is not Progressive Disease (PD) / or response can not be determined due to change in assay format. |
Countries
Austria, Belgium, Brazil, Canada, Chile, Denmark, France, Germany, Greece, India, Israel, Italy, Netherlands, Peru, Poland, Portugal, Russia, Saudi Arabia, South Korea, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
First patient enrolled 10 September 2008, last patient enrolled 27 February 2011. Data cut off date 15 June 2011.
Participants by arm
| Arm | Count |
|---|---|
| XL184 (Cabozantinib) XL184 175 mg L-malate salt weight; 138 mg freebase equivalent weight, oral capsules once daily | 219 |
| Placebo oral capsules once daily | 111 |
| Total | 330 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 35 | 9 |
| Overall Study | data unavailable | 1 | 0 |
| Overall Study | Death | 11 | 5 |
| Overall Study | Did not receive drug | 5 | 2 |
| Overall Study | Disease progression per PI | 58 | 67 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Withdrawal by Subject | 9 | 13 |
Baseline characteristics
| Characteristic | XL184 (Cabozantinib) | Total | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 47 Participants | 72 Participants | 25 Participants |
| Age, Categorical Between 18 and 65 years | 172 Participants | 258 Participants | 86 Participants |
| Age, Continuous | 54.4 years STANDARD_DEVIATION 13.33 | 54.2 years STANDARD_DEVIATION 13.33 | 53.8 years STANDARD_DEVIATION 13.39 |
| Region of Enrollment Austria | 8 participants | 9 participants | 1 participants |
| Region of Enrollment Belgium | 7 participants | 12 participants | 5 participants |
| Region of Enrollment Brazil | 4 participants | 7 participants | 3 participants |
| Region of Enrollment Canada | 6 participants | 8 participants | 2 participants |
| Region of Enrollment Chile | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Denmark | 1 participants | 1 participants | 0 participants |
| Region of Enrollment France | 25 participants | 30 participants | 5 participants |
| Region of Enrollment Germany | 15 participants | 25 participants | 10 participants |
| Region of Enrollment Greece | 1 participants | 3 participants | 2 participants |
| Region of Enrollment India | 5 participants | 6 participants | 1 participants |
| Region of Enrollment Israel | 5 participants | 9 participants | 4 participants |
| Region of Enrollment Italy | 28 participants | 42 participants | 14 participants |
| Region of Enrollment Korea, Republic of | 3 participants | 7 participants | 4 participants |
| Region of Enrollment Netherlands | 5 participants | 8 participants | 3 participants |
| Region of Enrollment Peru | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Poland | 12 participants | 15 participants | 3 participants |
| Region of Enrollment Portugal | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Russian Federation | 8 participants | 13 participants | 5 participants |
| Region of Enrollment Spain | 5 participants | 8 participants | 3 participants |
| Region of Enrollment Sweden | 6 participants | 10 participants | 4 participants |
| Region of Enrollment Switzerland | 1 participants | 1 participants | 0 participants |
| Region of Enrollment United Kingdom | 10 participants | 19 participants | 9 participants |
| Region of Enrollment United States | 63 participants | 94 participants | 31 participants |
| Sex: Female, Male Female | 68 Participants | 109 Participants | 41 Participants |
| Sex: Female, Male Male | 151 Participants | 221 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 213 / 214 | 102 / 109 |
| serious Total, serious adverse events | 90 / 214 | 25 / 109 |
Outcome results
Primary
Progression-Free Survival (PFS)
The duration of Progression-Free Survival (PFS) using progression events as determined by Independent Review Committee (IRC) per mRECIST, or death due to any cause. The analysis was conducted after at least 315 subjects were randomized and at least 138 events were observed.
Time frame: Treatment period consisted of 4-week cycles with radiologic tumor assessment every 12 weeks from date of randomization until date of first documented PD or date of death from any cause, whichever came first, assessed up to 34 months.
Population: Intent to Treat (ITT) 330 subjects were randomized and were included in the analysis. A Kaplan-Meyer analysis was performed to estimate the median.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| XL184 (Cabozantinib) | Progression-Free Survival (PFS) | 11.2 months |
| Placebo | Progression-Free Survival (PFS) | 4.0 months |
Secondary
Biochemical Response Calcitonin (CTN) %
For each on-treatment tumor marker assessment from each subject, the biochemical response of CTN was determined based on percent increase or decrease from baseline. Best biochemical response over course of treatment was determined from evaluation of subject's time point response data. Biochemical response criteria: Complete Response (CR) - decrease in tumor marker into normal range from baseline value; Partial Response (PR) - decrease of \>50% from baseline value when baseline value is above normal range; Stable Disease (SD) - no more than a 50% increase and no more than a 50% decrease from baseline value above normal range; Progressive Disease (PD) - increase of \>50% from baseline value when baseline value is above normal range / or increase from low or normal range at baseline to above normal range; Not Evaluable (NE) - missing baseline value / or baseline value is not elevated and response is not PD / or response can not be determined due to change in assay format.
Time frame: Serum tumor markers CTN evaluated from blood samples collected at screening and every 12 weeks (±5 days from randomization) until date of first documented progression or date of death from any cause, whichever came first, assessed for up to 34 months.
Population: Population was intent to treat (ITT), randomized to either XL184 or placebo. For the CTN measure the analysis population differs from the ITT population of 219 XL184 and 111 Placebo. Three subjects did not provide samples for CTN. The biomarker analysis was based on available samples, not on ITT.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| XL184 (Cabozantinib) | Biochemical Response Calcitonin (CTN) % | 22.6 % participants | 60.71 |
| Placebo | Biochemical Response Calcitonin (CTN) % | 0.9 % participants | 115.4 |
Secondary
Biochemical Response Carcinoembryonic Antigen (CEA) %
For each on-treatment tumor marker assessment from each subject, the biochemical response of CEA was determined based on percent increase or decrease from baseline. Best biochemical response over the course of treatment was determined from evaluation of each subject's time point response data. Biochemical response: Complete Response (CR)- Decrease in tumor marker into normal range from baseline value; Partial Response (PR)- Decrease of \>50% from baseline value when baseline value is above normal range; Stable Disease (SD)- No more than a 50% increase and no more than a 50% decrease from baseline value above normal range; Progressive Disease (PD)- Increase of \>50% from baseline value when baseline value is above normal range / or increase from low or normal range at baseline to above normal range; Not Evaluable (NE)- Missing baseline value / or baseline value is not elevated and response is not Progressive Disease (PD) / or response can not be determined due to change in assay format.
Time frame: Serum tumor markers CEA evaluated from blood samples collected at screening and every 12 weeks (± 5 days from randomization) until date of first documented progression or date of death from any cause, whichever came first, assessed for up to 34 months.
Population: For the CEA measure the analysis population differs from the Intent To Treat (ITT) population of 219 XL184 and 111 Placebo. One subject did not provide samples for CEA. The biomarker analysis was based on available samples, not on ITT.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| XL184 (Cabozantinib) | Biochemical Response Carcinoembryonic Antigen (CEA) % | 21.6 % of participants | 58.21 |
| Placebo | Biochemical Response Carcinoembryonic Antigen (CEA) % | 0.9 % of participants | 182.6 |
Secondary
Duration of Objective Response (OR): Independent Radiology Committee (IRC) Determined
For those subjects with Independent Radiology Committee (IRC) determined Objective Response Rate (ORR), the amount of time from documentation of Objective Response (OR) until Progressive Disease (PD) by mRECIST or death due to any cause.
Time frame: From time of first documentation of Objective Response (OR), confirmed at a later visit ≥28 days later as Progressive Disease (PD) as defined by mRECIST or death due to any cause, assessed up to 34 months.
Population: The primary analysis of Objective Response Rate (ORR) was performed among the subset of Intent To Treat (ITT) subjects with measurable disease at baseline and was based upon response as determined by the Independent Review Committee (IRC.) Subjects who did not have post-baseline adequate tumor assessments were counted as nonresponders.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| XL184 (Cabozantinib) | Duration of Objective Response (OR): Independent Radiology Committee (IRC) Determined | 14.6 months |
Secondary
Objective Response Rate (ORR)
The proportion of subjects with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) as determined by the Independent Review Committee (IRC.) Per Response Evaluation Criteria in Solid Tumor Criteria (mRECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR) disappearance of all target lesions; Partial Response (PR) ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) ≥ 20% increase in the sum of the longest diameter of target lesions. Overall Response Rate: ORR=CR +PR
Time frame: Assessed at the same time as primary analysis of Progression Free Survival (PFS) data. Assessed at baseline and every 12 weeks until Progressive Disease (PD) up to 34 months.
Population: The primary analysis Objective Response Rate (ORR) was performed among subset of Intent To Treat (ITT) subjects with measurable disease at baseline (N = 208 cabozantinib, N = 104 placebo) based upon response determined by Independent Radiology Committee (IRC.) Subjects without post-baseline adequate tumor assessments - counted as nonresponders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| XL184 (Cabozantinib) | Objective Response Rate (ORR) | 28 % of participants |
| Placebo | Objective Response Rate (ORR) | 0 % of participants |
Secondary
Overall Survival (OS) With XL184 Compared With Placebo
Duration of Overall Survival (OS) from the time of randomization to death due to any cause. A Kaplan-Meier analysis was performed to estimate the median.
Time frame: The pre-specified interim analysis of Overall Survival (OS) was assessed at 44% of required events. Includes data up to 15June2011. As of this date, the number of deaths required to conduct the primary analysis had not been reached.
Population: Intent to treat (ITT) randomized to either XL184 or placebo
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| XL184 (Cabozantinib) | Overall Survival (OS) With XL184 Compared With Placebo | 21.1 months |
| Placebo | Overall Survival (OS) With XL184 Compared With Placebo | NA months |