Thyroid CancerPhase 3EXAMNCT00704730
Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer
A Phase 3 study testing XL184 in people with Thyroid Cancer, run by Exelixis at 113 sites in 24 countries.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Thyroid Cancer
- What is being tested?
- XL184
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 330 participants
- Where
- 113 sitesin 24 countries
- Study dates
- Jun 2008to Sep 2020
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
113 sites in 24 countries.
113 sites in 24 countries
United States29 sites
University of Colorado Cancer Center
Aurora, Colorado, 80045
Johns Hopkins University
Baltimore, Maryland, 21287
St. Luke's Hospital & Health Network
Bethlehem, Pennsylvania, 18015
University of Alabama at Birmingham, Comprehensive Cancer Center
Birmingham, Alabama, 35294
Massachusetts General Hospital
Boston, Massachusetts, 02114
Study site
Burbank, California, 91505
Vermont Cancer Center at Fletcher Allen Health Care
Burlington, Vermont, 05401
Hollings Cancer Center
Charleston, South Carolina, 29425
University of Chicago
Chicago, Illinois, 60637
Ohio State University, James Cancer Hospital
Columbus, Ohio, 43210
Henry Ford Health System
Detroit, Michigan, 48202
Indiana University Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, 46202
University of Iowa
Iowa City, Iowa, 52242
Capitol Comprehensive Cancer Care Clinic and Research Institute
Jefferson City, Missouri, 65109
Kansas University Medical Center
Kansas City, Kansas, 66160
University of Arkansas for Medical Sciences
Little Rock, Arkansas, 72205
UCLA
Los Angeles, California, 90095
Vanderbilt University Medical Center
Nashville, Tennessee, 37232
Yale University, School of Medicine
New Haven, Connecticut, 06520
Peninsula Cancer Institute
Newport News, Virginia, 23601
Nebraska Methodist Hospital
Omaha, Nebraska, 68114
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Oregon Health & Science University
Portland, Oregon, 97239
Mayo Clinic
Rochester, Minnesota, 55905
TGEN Clinical Research Service at Scottsdale Healthcare
Scottsdale, Arizona, 85258
Washington University School of Medicine
St Louis, Missouri, 63110
Stanford Cancer Center
Stanford, California, 94305
H. Lee Moffet Cancer Center and Research Institute
Tampa, Florida, 33612
Washington Cancer Institute
Washington D.C., District of Columbia, 20010
India9 sites
Kidwai Institute of Oncology
Bangalore
Indo-American Cancer Institute and Research Center
Hyderabad
SEAROC Cancer Institute, S.K. Soni Hospital
Jaipur
Netaji Subhash Chandra Bose Cancer Hospital Research Institute
Kolkata
Central India Cancer Research Institute
Nagpur
Shatabdi Superspeciality Hospital
Nashik
All India Institute of Medical Sciences
New Dehli
Deenanath Mangeshkar Hospital & Research Center
Pune
Ruby Hall Clinic
Pune
Germany8 sites
Klinik fuer Nuklearmedizin des Universitaetsklinikums Essen
Essen
Gemeinschaftspraxis
Heidelberg
Universitaetsklinikum Leipzig
Leipzig
Johannes-Gutenberg Universitaet Mainz
Mainz
Klinikum der Ludwig-Maximilians-Universitaet Muenchen
München
Ludwig-Maximilians-Universitaet Muenchen
München
Universitaetsklinikum Tuebingen
Tübingen
Universitaetsklinikum Wuerzburg
Würzburg
Italy7 sites
Study site
Florence
Study site
Milan
Study site
Naples
Study site
Pisa
Study site
Rome
Study site
Siena
Study site
Turin
United Kingdom7 sites
Study site
Cardiff
Study site
Glasgow
Study site
London
Study site
Manchester
Study site
Newcastle upon Tyne
Study site
Oxford
Study site
Sheffield
France6 sites
Study site
Angers
Study site
Bordeaux
Study site
Lyon
Study site
Marseille
Study site
Reims
Study site
Villejuif
Spain6 sites
Multiple site locations
Barcelona
Study site
Madrid
Study site
Murcia
Study site
Santiago de Compostela
Study site
Seville
Study site
Valencia
Poland5 sites
Study site
Bydgoszcz
Study site
Gliwice
Study site
Pozan
Study site
Szczecin
Study site
Warsaw
Brazil4 sites
Study site
Brasília
Study site
Lajeado
Study site
Porto Alegre
Multiple site locations
São Paulo
Canada4 sites
Study site
Calgary, Alberta
CHUM - Hopital Saint-Luc
Montreal, Quebec
Study site
Sherbrooke, Quebec
Study site
Toronto, Ontario
Israel4 sites
Study site
Haifa
Study site
Jerusalem
Study site
Petah Tikva
Study site
Tel Aviv
Russia4 sites
Study site
Obninsk
Study site
Ufa
Study site
Voronezh
Study site
Yaroslavl
Netherlands3 sites
Study site
Amsterdam
Study site
Groningen
Study site
Leiden
Belgium2 sites
Cliniques Universitaires St. Luc
Brussels
Universitair Ziekenhuis
Leuven
About this study
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
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.
- Conditions
- Thyroid Cancer
- Being tested
- XL184, Placebo
- Keywords
- Medullary Thyroid Cancer, MTC
- Medical subject headings
- Thyroid Neoplasms, Carcinoma, Medullary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
XL184Drug
Gelatin capsules supplied in 25-mg and 100-mg strengths administered orally daily
PlaceboDrug
Gelatin capsules color and size-matched to XL184 capsules administered orally daily
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | Not described Receives: Drug: XL184 |
| 2 | Placebo comparator | Not described Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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 outcomes (5)
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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Jun 2008 (estimated)
- Study startJun 2008
- Primary completionOct 2011
- Study completionSep 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Thyroid CancerStudies of the same condition, open and under way.
- More trials run by ExelixisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 330 participants (actual)
Sponsor and investigators
- Lead sponsor
- Exelixis
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00704730
- Sponsor's protocol ID
- XL184-301
- Acronym
- EXAM
- Status last verified
- Mar 2021
- First submitted
- 23 Jun 2008
- Last updated
- 20 Apr 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Schlumberger M, Elisei R, Muller S, Schoffski P, Brose M, Shah M, Licitra L, Krajewska J, Kreissl MC, Niederle B, Cohen EEW, Wirth L, Ali H, Clary DO, Yaron Y, Mangeshkar M, Ball D, Nelkin B, Sherman S. Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Ann Oncol. 2017 Nov 1;28(11):2813-2819. doi: 10.1093/annonc/mdx479.
PubMed 29045520Elisei R, Schlumberger MJ, Muller SP, Schoffski P, Brose MS, Shah MH, Licitra L, Jarzab B, Medvedev V, Kreissl MC, Niederle B, Cohen EE, Wirth LJ, Ali H, Hessel C, Yaron Y, Ball D, Nelkin B, Sherman SI. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013 Oct 10;31(29):3639-46. doi: 10.1200/JCO.2012.48.4659. Epub 2013 Sep 3.
PubMed 24002501