Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer

Thyroid Cancer Clinical Trial

— EXAM  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00704730
• Other study ID #: XL184-301
• Status: Completed
• Phase: Phase 3
• Start date: June 2008
• Est. completion date: September 2020

Study information

• Verified date: March 2021
• Source: Exelixis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 330
• Est. completion date: September 2020
• Est. primary completion date: October 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Thyroid Cancer
• Thyroid Diseases
• Thyroid Neoplasms

Intervention

Drug:
• XL184
Gelatin capsules supplied in 25-mg and 100-mg strengths administered orally daily
• Placebo
Gelatin capsules color and size-matched to XL184 capsules administered orally daily

Locations

Country	Name	City	State
Austria	Multiple site locations	Wien
Belgium	Cliniques Universitaires St. Luc	Brussels
Belgium	Universitair Ziekenhuis	Leuven
Brazil	Multiple site locations	Sao Paulo
Canada	CHUM - Hopital Saint-Luc	Montreal	Quebec
Germany	Klinik fuer Nuklearmedizin des Universitaetsklinikums Essen	Essen
Germany	Gemeinschaftspraxis	Heidelberg
Germany	Universitaetsklinikum Leipzig	Leipzig
Germany	Johannes-Gutenberg Universitaet Mainz	Mainz
Germany	Klinikum der Ludwig-Maximilians-Universitaet Muenchen	Muenchen
Germany	Ludwig-Maximilians-Universitaet Muenchen	Muenchen
Germany	Universitaetsklinikum Tuebingen	Tuebingen
Germany	Universitaetsklinikum Wuerzburg	Wuerzburg
India	Kidwai Institute of Oncology	Bangalore
India	Indo-American Cancer Institute and Research Center	Hyderabad
India	SEAROC Cancer Institute, S.K. Soni Hospital	Jaipur
India	Netaji Subhash Chandra Bose Cancer Hospital Research Institute	Kolkata
India	Central India Cancer Research Institute	Nagpur
India	Shatabdi Superspeciality Hospital	Nashik
India	All India Institute of Medical Sciences	New Dehli
India	Deenanath Mangeshkar Hospital & Research Center	Pune
India	Ruby Hall Clinic	Pune
Korea, Republic of	Multiple site locations	Seoul
Peru	Multiple site locations	Lima
Spain	Multiple site locations	Barcelona
United States	University of Colorado Cancer Center	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	St. Luke's Hospital & Health Network	Bethlehem	Pennsylvania
United States	University of Alabama at Birmingham, Comprehensive Cancer Center	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Vermont Cancer Center at Fletcher Allen Health Care	Burlington	Vermont
United States	Hollings Cancer Center	Charleston	South Carolina
United States	University of Chicago	Chicago	Illinois
United States	Ohio State University, James Cancer Hospital	Columbus	Ohio
United States	Henry Ford Health System	Detroit	Michigan
United States	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	Capitol Comprehensive Cancer Care Clinic and Research Institute	Jefferson City	Missouri
United States	Kansas University Medical Center	Kansas City	Kansas
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	UCLA	Los Angeles	California
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale University, School of Medicine	New Haven	Connecticut
United States	Peninsula Cancer Institute	Newport News	Virginia
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	TGEN Clinical Research Service at Scottsdale Healthcare	Scottsdale	Arizona
United States	Stanford Cancer Center	Stanford	California
United States	H. Lee Moffet Cancer Center and Research Institute	Tampa	Florida
United States	Washington Cancer Institute	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Exelixis

Countries where clinical trial is conducted

United States,  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, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	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	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.
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	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.
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.	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.
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.	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.
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.	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.