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Afatinib in Locally Advanced and Metastatic Chordoma

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ClinicalTrials.gov Identifier: NCT03083678
Recruitment Status : Recruiting
First Posted : March 20, 2017
Last Update Posted : July 10, 2018
Sponsor:
Collaborators:
Chordoma Foundation
Boehringer Ingelheim
Information provided by (Responsible Party):
HansGelderblom, Leiden University Medical Center

Brief Summary:
In this phase 2, single arm trial patients with locally advanced or metastatic, pathologically proven, EGFR expressing chordoma will be treated with afatinib. Two cohorts of patients will be included: 20 first line patients and 20 second or further line patients. The treatment will be given in 4 week cycles until disease progression. Median PFS according to RECIST 1.1 will be evaluated. The objective is to increase the median PFS ≥ 12 months in first-line treatment cohort and ≥ 9 months in later-line treatment cohort. Additional exploratory research will be performed, consisting of a pharmacokinetic study and translational studies on EGFR pathway activation and signalling on blood and tumor samples.

Condition or disease Intervention/treatment Phase
Chordoma Drug: Afatinib Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2, Single Arm, European Multi-center Trial Evaluating the Efficacy of Afatinib as First-line or Later-line Treatment in Advanced Chordoma.
Actual Study Start Date : June 21, 2018
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Afatinib
Afatinib active treatment.
Drug: Afatinib
Afatinib will be given daily in a dose of 40 mg orally in a 4 week cycle until disease progression or patient withdrawal.
Other Name: Giotrif




Primary Outcome Measures :
  1. Median PFS according to RECIST 1.1 criteria on afatinib treatment (first-line cohort) [ Time Frame: From date of start treatment until date of first documented of progression or withdrawal (through study completion, an average of 1 year). ]
    The objective is to increase the median PFS ≥ 12 months in first-line treatment cohort.

  2. Median PFS according to RECIST 1.1 criteria on afatinib treatment (second or later line cohort) [ Time Frame: From date of start treatment until date of first documented of progression or withdrawal (through study completion, an average of 1 year). ]
    The objective is to increase the median PFS ≥ 9 months in later-line treatment cohort.

  3. Quality of life assessment by EORTC QLC-30 questionnaire. [ Time Frame: From date of start treatment until date of first documented of progression of withdrawal (through study completion, an average of 1 year). ]
    Change from baseline in EORTC QLC-30 questionnaire score.

  4. Quality of life assessment by Brief pain inventory short form [ Time Frame: From date of start treatment until date of first documented of progression of withdrawal (through study completion, an average of 1 year). ]
    Change from baseline on Brief pain inventory short form score.


Secondary Outcome Measures :
  1. Growth modulation index. [ Time Frame: From date of start treatment until date of first documented of progression (through study completion, an average of 1 year). ]
    Time to progression during afatinib treatment (TTP2) divided by time to progression before start of this treatment TTP1 (= growth modulation index)

  2. Toxicity determined by CTCAE v 4.03 criteria [ Time Frame: From date of start treatment until date of first documented of progression or withdrawal (through study completion, an average of 1 year). ]
    Toxicity determined by CTCAE v 4.03 criteria

  3. Overall survival. [ Time Frame: Survival follow-up after end of treatment every 3 months for up to 2 years followed by contact at 3 years. ]
    Overall survival from start of afatinib treatment


Other Outcome Measures:
  1. Translational research - EGFR pathway analysis in tumor tissue [ Time Frame: From date of inclusion until date of first documented of progression or withdrawal (through study completion, an average of 1 year) ]
    EGFR status by FISH / immunohistochemistry

  2. Translational research - Genome sequence analysis of available tumor samples [ Time Frame: From date of inclusion until date of first documented of progression or withdrawal (through study completion, an average of 1 year) ]
    Genetic mutations by DNA whole genome sequencing of fresh samples

  3. Translational research - circulating tumor DNA [ Time Frame: Analysis on blood samples to be taken at baseline, cycle 4 day 1, cycle 7 day 1 and at end of treatment (within 30 days after last dose of study drug). ]
    Circulating chordoma tumor DNA identification by WGS and PCR

  4. Translational research - circulating exosomes [ Time Frame: Analysis on blood samples to be taken at different time points on cycle 1 day 1, cycle 1 day 15, cycle 3 day 1 and cycle 5 day 1. ]
    Circulating exosomes identification by PCR

  5. Pharmacokinetic research [ Time Frame: Analysis on blood samples to be taken at different time points on cycle 1 day 1, cycle 1 day 15, cycle 3 day 1 and cycle 5 day 1. ]
    Area under the curve



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Locally advanced or metastatic, pathologically proven, EGFR expressing chordoma, not amenable for local therapies
  • Patients of 18 years and up
  • Documented radiographic progression of disease according to RECIST 1.1 criteria in last 6 months
  • ECOG Performance status ≤ 2
  • Adequate bone marrow function (Hb ≥ 6.0 mmol/L, absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥ 75 x 109/L)
  • An adequate renal function with GFR ≥ 45 ml/min calculated by Cockroft-Gault formula
  • Total Bilirubin ≤ 1.5 times upper limit of normal (ULN) (Patients with Gilbert's syndrome total bilirubin must be ≤4 times institutional upper limit of normal).
  • Aspartate amino transferase (AST) or alanine amino transferase (ALT) ≤ 3 times ULN (if related to liver metastases ≤ 5 times ULN)
  • Ability to swallow medication
  • Recovered from any previous therapy related toxicity to ≤ grade 1 at study entry (except for stable sensory neuropathy ≤ grade 2 and alopecia)
  • Availability of archival tumor material for central review (if not please obtain a new tumor biopsy)
  • Written signed informed consent
  • Ability to adhere to the study visits and all protocol requirements

Exclusion Criteria:

  • Life expectancy of less than 3 months
  • No measurable lesions according to RECIST 1.1
  • Known hypersensitivity to afatinib
  • Major surgery less than 4 weeks prior to start of treatment
  • Previous treatment with any other investigational agents within 14 days of first day of study drug dosing
  • History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of ≥ 3, unstable angina or poorly controlled arrhythmia as determined by the investigator. Myocardial infarction within 6 months prior to inclusion.
  • Known pre-existing interstitial lung disease
  • Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug (e.g. Crohn's disease, ulcerative colitis, chronic diarrhea, malabsorption)
  • Known active hepatitis B infection (defined as presence of HepB sAg and/ or Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV carrier.
  • Systemic anti-cancer therapy within 28 days prior to the first dose of study drug , or radiotherapy to an index (or target)lesion within 21 days prior to the first dose of study drug
  • Requiring treatment with any of the prohibited concomitant medications listed in Section 6.3.9 that cannot be stopped for the duration of trial participation
  • Pregnant or lactating women
  • Other invasive malignancies diagnosed within the last 5 years, except non-melanoma skin cancer and localized cured prostate and cervical cancer
  • Any history of or concomitant condition that, in the opinion of the Investigator, would compromise the patient's ability to comply with the study or interfere with the evaluation of the efficacy and safety of the test drug

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03083678


Contacts
Contact: H Gelderblom, Prof 0031715269111 a.j.gelderblom@lumc.nl

Locations
Italy
Istituto Nazionale dei Tumori: Fondazione IRCCS Not yet recruiting
Milan, Italy
Contact: S Stacchiotti, MD         
Netherlands
Leiden University Medical Center Recruiting
Leiden, Netherlands
Contact: H Gelderblom, MD Prof         
United Kingdom
University College London Hospital Not yet recruiting
London, United Kingdom
Contact: S Strauss, MD         
Sponsors and Collaborators
Leiden University Medical Center
Chordoma Foundation
Boehringer Ingelheim
Investigators
Principal Investigator: AJ Gelderblom, Prof Leiden University Medical Center

Responsible Party: HansGelderblom, Prof. Dr., Leiden University Medical Center
ClinicalTrials.gov Identifier: NCT03083678     History of Changes
Other Study ID Numbers: 1200.277
First Posted: March 20, 2017    Key Record Dates
Last Update Posted: July 10, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by HansGelderblom, Leiden University Medical Center:
EGFR
Afatinib

Additional relevant MeSH terms:
Chordoma
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms