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

March 30, 2021 updated by: Exelixis

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

330

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Austria
      • Klagenfurt, Austria
      • Wien, Austria
        • Multiple site locations
  • Belgium
      • Brussels, Belgium
        • Cliniques Universitaires St. Luc
      • Leuven, Belgium
        • Universitair Ziekenhuis
  • Brazil
      • Brasilia, Brazil
      • Lajeado, Brazil
      • Porto Alegre, Brazil
      • Sao Paulo, Brazil
        • Multiple site locations
  • Canada
    • Alberta
      • Calgary, Alberta, Canada
    • Ontario
      • Toronto, Ontario, Canada
    • Quebec
      • Montreal, Quebec, Canada
        • CHUM - Hopital Saint-Luc
      • Sherbrooke, Quebec, Canada
  • Chile
      • Santiago, Chile
  • Denmark
      • Odense, Denmark
  • France
      • Angers, France
      • Bordeaux, France
      • Lyon, France
      • Marseille, France
      • Reims, France
      • Villejuif, France
  • Germany
      • Essen, Germany
        • Klinik fuer Nuklearmedizin des Universitaetsklinikums Essen
      • Heidelberg, Germany
        • Gemeinschaftspraxis
      • Leipzig, Germany
        • Universitaetsklinikum Leipzig
      • Mainz, Germany
        • Johannes-Gutenberg Universitaet Mainz
      • Muenchen, Germany
        • Klinikum der Ludwig-Maximilians-Universitaet Muenchen
      • Muenchen, Germany
        • Ludwig-Maximilians-Universitaet Muenchen
      • Tuebingen, Germany
        • Universitaetsklinikum Tuebingen
      • Wuerzburg, Germany
        • Universitaetsklinikum Wuerzburg
  • Greece
      • Athens, Greece
  • India
      • Bangalore, India
        • Kidwai Institute of Oncology
      • Hyderabad, India
        • Indo-American Cancer Institute and Research Center
      • Jaipur, India
        • SEAROC Cancer Institute, S.K. Soni Hospital
      • Kolkata, India
        • Netaji Subhash Chandra Bose Cancer Hospital Research Institute
      • Nagpur, India
        • Central India Cancer Research Institute
      • Nashik, India
        • Shatabdi Superspeciality Hospital
      • New Dehli, India
        • All India Institute of Medical Sciences
      • Pune, India
        • Ruby Hall Clinic
      • Pune, India
        • Deenanath Mangeshkar Hospital & Research Center
  • Israel
      • Haifa, Israel
      • Jerusalem, Israel
      • Petach Tikva, Israel
      • Tel Aviv, Israel
  • Italy
      • Florence, Italy
      • Milan, Italy
      • Naples, Italy
      • Pisa, Italy
      • Rome, Italy
      • Siena, Italy
      • Turin, Italy
  • Korea, Republic of
      • Seoul, Korea, Republic of
        • Multiple site locations
  • Netherlands
      • Amsterdam, Netherlands
      • Groningen, Netherlands
      • Leiden, Netherlands
  • Peru
      • Lima, Peru
        • Multiple site locations
  • Poland
      • Bydgoszcz, Poland
      • Gliwice, Poland
      • Pozan, Poland
      • Szczecin, Poland
      • Warszawa, Poland
  • Portugal
      • Coimbra, Portugal
      • Oporto, Portugal
      • Porto, Portugal
  • Russian Federation
      • Obninsk, Russian Federation
      • Ufa, Russian Federation
      • Voronezh, Russian Federation
      • Yaroslavl, Russian Federation
  • Saudi Arabia
      • Riyadh, Saudi Arabia
  • Spain
      • Barcelona, Spain
        • Multiple site locations
      • Madrid, Spain
      • Murcia, Spain
      • Santiago de Compostela, Spain
      • Sevilla, Spain
      • Valencia, Spain
  • Sweden
      • Gothenburg, Sweden
      • Lund, Sweden
      • Uppsala, Sweden
  • Switzerland
      • Berne, Switzerland
      • Geneve, Switzerland
  • United Kingdom
      • Cardiff, United Kingdom
      • Glasgow, United Kingdom
      • London, United Kingdom
      • Manchester, United Kingdom
      • Newcastle Upon Tyne, United Kingdom
      • Oxford, United Kingdom
      • Sheffield, United Kingdom
  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35294
        • University of Alabama at Birmingham, Comprehensive Cancer Center
    • Arizona
      • Scottsdale, Arizona, United States, 85258
        • TGEN Clinical Research Service at Scottsdale Healthcare
    • Arkansas
      • Little Rock, Arkansas, United States, 72205
        • University of Arkansas for Medical Sciences
    • California
      • Burbank, California, United States, 91505
      • Los Angeles, California, United States, 90095
        • UCLA
      • Stanford, California, United States, 94305
        • Stanford Cancer Center
    • Colorado
      • Aurora, Colorado, United States, 80045
        • University of Colorado Cancer Center
    • Connecticut
      • New Haven, Connecticut, United States, 06520
        • Yale University, School of Medicine
    • District of Columbia
      • Washington, District of Columbia, United States, 20010
        • Washington Cancer Institute
    • Florida
      • Tampa, Florida, United States, 33612
        • H. Lee Moffet Cancer Center and Research Institute
    • Illinois
      • Chicago, Illinois, United States, 60637
        • University of Chicago
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Indiana University Melvin and Bren Simon Cancer Center
    • Iowa
      • Iowa City, Iowa, United States, 52242
        • University of Iowa
    • Kansas
      • Kansas City, Kansas, United States, 66160
        • Kansas University Medical Center
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins University
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital
    • Michigan
      • Detroit, Michigan, United States, 48202
        • Henry Ford Health System
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic
    • Missouri
      • Jefferson City, Missouri, United States, 65109
        • Capitol Comprehensive Cancer Care Clinic and Research Institute
      • Saint Louis, Missouri, United States, 63110
        • Washington University School of Medicine
    • Nebraska
      • Omaha, Nebraska, United States, 68114
        • Nebraska Methodist Hospital
    • Ohio
      • Columbus, Ohio, United States, 43210
        • Ohio State University, James Cancer Hospital
    • Oregon
      • Portland, Oregon, United States, 97239
        • Oregon Health & Science University
    • Pennsylvania
      • Bethlehem, Pennsylvania, United States, 18015
        • St. Luke's Hospital & Health Network
      • Philadelphia, Pennsylvania, United States, 19104
        • Hospital of the University of Pennsylvania
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Hollings Cancer Center
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt University Medical Center
    • Vermont
      • Burlington, Vermont, United States, 05401
        • Vermont Cancer Center at Fletcher Allen Health Care
    • Virginia
      • Newport News, Virginia, United States, 23601
        • Peninsula Cancer Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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
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.
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)
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
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
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.
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) %
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.
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) %
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.
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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Exelixis

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2008

Primary Completion (Actual)

October 1, 2011

Study Completion (Actual)

September 1, 2020

Study Registration Dates

First Submitted

June 23, 2008

First Submitted That Met QC Criteria

June 23, 2008

First Posted (Estimate)

June 25, 2008

Study Record Updates

Last Update Posted (Actual)

April 20, 2021

Last Update Submitted That Met QC Criteria

March 30, 2021

Last Verified

March 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • XL184-301

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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