Clinical trial NCT03083678: Afatinib in Locally Advanced and Metastatic Chordoma
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chordoma
Keywords: EGFR
Afatinib
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Chordoma Foundation
name: Boehringer Ingelheim
First posted: 2017-03-20
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Median PFS according to RECIST 1.1 criteria on afatinib treatment (first-line cohort)
timeFrame: From date of start treatment until date of first documented of progression or withdrawal (through study completion, an average of 1 year).
measure: Median PFS according to RECIST 1.1 criteria on afatinib treatment (second or later line cohort)
timeFrame: From date of start treatment until date of first documented of progression or withdrawal (through study completion, an average of 1 year).
measure: Quality of life assessment by EORTC QLC-30 questionnaire.
timeFrame: From date of start treatment until date of first documented of progression of withdrawal (through study completion, an average of 1 year).
measure: Quality of life assessment by Brief pain inventory short form
timeFrame: From date of start treatment until date of first documented of progression of withdrawal (through study completion, an average of 1 year).
Secondary outcomes:
measure: Growth modulation index.
timeFrame: From date of start treatment until date of first documented of progression (through study completion, an average of 1 year).
measure: Toxicity determined by CTCAE v 4.03 criteria
timeFrame: From date of start treatment until date of first documented of progression or withdrawal (through study completion, an average of 1 year).
measure: Overall survival.
timeFrame: Survival follow-up after end of treatment every 3 months for up to 2 years followed by contact at 3 years.
Other outcomes:
measure: Translational research - EGFR pathway analysis in tumor tissue
timeFrame: From date of inclusion until date of first documented of progression or withdrawal (through study completion, an average of 1 year)
measure: Translational research - Genome sequence analysis of available tumor samples
timeFrame: From date of inclusion until date of first documented of progression or withdrawal (through study completion, an average of 1 year)
measure: Translational research - circulating tumor DNA
timeFrame: 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).
measure: Translational research - circulating exosomes
timeFrame: 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.
measure: Pharmacokinetic research
timeFrame: 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.
Locations:
city: Milan
country: Italy
facility: Istituto Nazionale dei Tumori: Fondazione IRCCS
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: London
country: United Kingdom
facility: University College London Hospital
Study officials:
affiliation: Leiden University Medical Center
name: AJ Gelderblom, Prof
role: PRINCIPAL_INVESTIGATOR
References: