E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Chordoma - a rare type of cancer that occurs in the bones of the skull base and spine. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10008747 |
E.1.2 | Term | Chordoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to evaluate the effect of afatinib treatment on the progression of disease (progression free survival) and quality of life in patients with chordoma. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are: - to assess the safety and tolerability of afatinib in chordoma, - to determine the overall survival after start of treatment, - to assess the efficacy of the treatment with an indicator of clinical benefit in phase II studies called GMI (Growth Modulation Index).
The exploratory objectives are: - to assess the role of the EGFR pathway in patients with chordoma treated with afatinib, - to find out if any genes, proteins or other biomarkers can help to diagnose chordoma or predict response to treatment, - to assess what the body does to the drug (pharmacokinetics) and how what's the effect of the drug on the body (pharmacodynamics). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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
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E.4 | Principal 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
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E.5 End points |
E.5.1 | Primary end point(s) |
For cohort 1: Progression-free survival at 12 months For cohort 2: Progression-free survival at 9 months |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Tumour imaging will be performed every 3 cycles (every 84 days) |
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E.5.2 | Secondary end point(s) |
- Time to progression during afatinib treatment (TTP2) divided by time to progression before start of this treatment TTP1 (= growth modulation index) - Toxicity determined by CTCAE v 4.03 criteria - Overall survival from start of afatinib treatment |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Tumour imaging will be performed every 3 cycles (every 84 days) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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30 days post-last dose visit of the last subject in the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 2 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |