Afatinib in Locally Advanced and Metastatic Chordoma

A Phase 2, Single Arm, European Multi-center Trial Evaluating the Efficacy of Afatinib as First-line or Later-line Treatment in Advanced Chordoma.

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Chordoma
• Intervention / Treatment: Drug: Afatinib

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy
    • Istituto Nazionale dei Tumori: Fondazione IRCCS
• Netherlands
  • Leiden, Netherlands
    • Leiden University Medical Center
• United Kingdom
  • London, United Kingdom
    • University College London Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: Giotrif

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median PFS according to RECIST 1.1 criteria on afatinib treatment (first-line cohort)	The objective is to increase the median PFS ≥ 12 months in first-line treatment cohort.	From date of start treatment until date of first documented of progression or withdrawal (through study completion, an average of 1 year).
Median PFS according to RECIST 1.1 criteria on afatinib treatment (second or later line cohort)	The objective is to increase the median PFS ≥ 9 months in later-line treatment cohort.	From date of start treatment until date of first documented of progression or withdrawal (through study completion, an average of 1 year).
Quality of life assessment by EORTC QLC-30 questionnaire.	Change from baseline in EORTC QLC-30 questionnaire score.	From date of start treatment until date of first documented of progression of withdrawal (through study completion, an average of 1 year).
Quality of life assessment by Brief pain inventory short form	Change from baseline on Brief pain inventory short form score.	From date of start treatment until date of first documented of progression of withdrawal (through study completion, an average of 1 year).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Growth modulation index.	Time to progression during afatinib treatment (TTP2) divided by time to progression before start of this treatment TTP1 (= growth modulation index)	From date of start treatment until date of first documented of progression (through study completion, an average of 1 year).
Toxicity determined by CTCAE v 4.03 criteria	Toxicity determined by CTCAE v 4.03 criteria	From date of start treatment until date of first documented of progression or withdrawal (through study completion, an average of 1 year).
Overall survival.	Overall survival from start of afatinib treatment	Survival follow-up after end of treatment every 3 months for up to 2 years followed by contact at 3 years.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Translational research - EGFR pathway analysis in tumor tissue	EGFR status by FISH / immunohistochemistry	From date of inclusion until date of first documented of progression or withdrawal (through study completion, an average of 1 year)
Translational research - Genome sequence analysis of available tumor samples	Genetic mutations by DNA whole genome sequencing of fresh samples	From date of inclusion until date of first documented of progression or withdrawal (through study completion, an average of 1 year)
Translational research - circulating tumor DNA	Circulating chordoma tumor DNA identification by WGS and PCR	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).
Translational research - circulating exosomes	Circulating exosomes identification by PCR	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.
Pharmacokinetic research	Area under the curve	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.

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Boehringer Ingelheim; Chordoma Foundation
• Investigators: Principal Investigator: AJ Gelderblom, Prof, Leiden University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2018
• Primary Completion (Anticipated): July 1, 2023
• Study Completion (Anticipated): October 1, 2023

Study Registration Dates

• First Submitted: February 10, 2017
• First Submitted That Met QC Criteria: March 13, 2017
• First Posted (Actual): March 20, 2017

Study Record Updates

• Last Update Posted (Actual): April 20, 2022
• Last Update Submitted That Met QC Criteria: April 19, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: EGFR; Afatinib
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Germ Cell and Embryonal; Chordoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Afatinib
• Other Study ID Numbers: 1200.277

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• 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