Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer

Study Overview
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Brief Summary
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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.

Official Title
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An International, Randomized, Double-Blinded, Phase 3 Efficacy Study of XL184 Versus Placebo in Subjects With Unresectable, Locally Advanced, or Metastatic Medullary Thyroid Cancer

Conditions
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Thyroid Cancer

Intervention / Treatment
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* Drug: XL184
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: XL184<br>* Gelatin capsules supplied in 25-mg and 100-mg strengths administered orally daily<br>|
| Placebo Comparator: 2<br> | Drug: Placebo<br>* Gelatin capsules color and size-matched to XL184 capsules administered orally daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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 | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Medullary Thyroid Cancer, MTC