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Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00704730
Recruitment Status : Active, not recruiting
First Posted : June 25, 2008
Results First Posted : September 9, 2014
Last Update Posted : December 19, 2018
Sponsor:
Information provided by (Responsible Party):
Exelixis

Tracking Information
First Submitted Date  ICMJE June 23, 2008
First Posted Date  ICMJE June 25, 2008
Results First Submitted Date  ICMJE April 8, 2014
Results First Posted Date  ICMJE September 9, 2014
Last Update Posted Date December 19, 2018
Study Start Date  ICMJE June 2008
Actual Primary Completion Date October 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 29, 2014)
Progression-Free Survival (PFS) [ 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. ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 23, 2008)
To evaluate progression-free survival (PFS) with XL184 treatment as compared with placebo in subjects with unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC) [ Time Frame: Assessed at periodic visits ]
Change History Complete list of historical versions of study NCT00704730 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 29, 2014)
  • Overall Survival (OS) With XL184 Compared With Placebo [ 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. ]
    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) [ 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. ]
    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 [ 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. ]
    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) % [ 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. ]
    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) % [ 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. ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2008)
  • To evaluate overall survival (OS) with XL184 treatment as compared with placebo [ Time Frame: Assessed as applicable ]
  • To evaluate the objective response rate (ORR) and duration of response in subjects with measurable disease with XL184 treatment as compared with placebo [ Time Frame: Assessed at periodic visits ]
  • To evaluate the safety and tolerability of XL184 treatment [ Time Frame: Assessed at periodic visits ]
  • To assess the pharmacokinetics and pharmacodynamic effects of XL184 treatment [ Time Frame: Assessed at periodic visits ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer
Official Title  ICMJE An International, Randomized, Double-Blinded, Phase 3 Efficacy Study of XL184 Versus Placebo in Subjects With Unresectable, Locally Advanced, or Metastatic Medullary Thyroid Cancer
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Thyroid Cancer
Intervention  ICMJE
  • Drug: XL184
    Gelatin capsules supplied in 25-mg and 100-mg strengths administered orally daily
  • Drug: Placebo
    Gelatin capsules color and size-matched to XL184 capsules administered orally daily
Study Arms  ICMJE
  • Experimental: 1
    Intervention: Drug: XL184
  • Placebo Comparator: 2
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: August 29, 2014)
330
Original Estimated Enrollment  ICMJE
 (submitted: June 23, 2008)
315
Estimated Study Completion Date  ICMJE June 2019
Actual Primary Completion Date October 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Belgium,   Brazil,   Canada,   Chile,   Denmark,   France,   Germany,   Greece,   India,   Israel,   Italy,   Korea, Republic of,   Netherlands,   Peru,   Poland,   Portugal,   Russian Federation,   Saudi Arabia,   Spain,   Sweden,   Switzerland,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00704730
Other Study ID Numbers  ICMJE XL184-301
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Exelixis
Study Sponsor  ICMJE Exelixis
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Exelixis
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP