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Non-small Cell Lung CancerPhase 1NCT03711422

Afatinib on CNS Metastases and LMD in EGFR Mutation Positive NSCLC

A Phase 1 study testing Afatinib in people with Non-small Cell Lung Cancer and Leptomeningeal Disease, run by National Cancer Centre, Singapore at 1 site in Singapore.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

Brain metastases occurs in up to 50% of patients with EGFR mutant NSCLC. Leptomeningeal disease is a subset of patients with brain metastases for which there remains an unmet need. Read more about this study

Who is it for?
Ages 21 years and older
What is being tested?
Afatinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
2 participants
Where
1 siteSingapore
Study dates
16 Nov 2018to 20 Dec 2019
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 21 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients progressing locally in the CNS after prior systemic treatment and Whole brain radiotherapy (WBRT)/ Stereotactic radiosurgery (SRS) (or declines radiotherapy), for which no standard therapy options are available
  • Performance status of Eastern Cooperative Oncology Group (ECOG) 0-3
  • Adequate organ function
  • Absolute neutrophil count (ANC) ≥1500 / mm3 . (ANC >1000/mm3 may be considered in special circumstances such as benign cyclical neutropenia as judged by the investigator and in discussion with the sponsor).
  • Platelet count ≥75,000 / mm3 .
  • Estimated creatinine clearance > 45ml/min
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  • Left ventricular function with resting ejection fraction ≥ 50% or above the institutional Lower Limit of Normal (LLN).
  • Total Bilirubin ≤ 1.5 times upper limit of (institutional/central) normal (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) ≤ three times the upper limit of (institutional/central) normal (ULN) (if related to liver metastases ≤ five times ULN).
  • Written informed consent that is consistent with ICH-GCP guidelines

Who cannot join

  • Symptomatic brain metastases requiring high dose steroids. Patients are excluded from Part A if they develop cerebral manifestation under afatinib. (Those progressing on afatinib will proceed to part B with HDI afatinib)
  • Hormonal treatment within 2 weeks prior to start of study treatment (continued use of anti-androgens and/or gonadorelin analogues for treatment of prostate cancer permitted) Radiotherapy within 4 weeks prior to randomization, except as follows:
  • Palliative radiation to target organs other than chest may be allowed up to 2 weeks prior to randomisation, and
  • Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with sponsor prior to enrolling.
  • Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study
  • Known hypersensitivity to afatinib or the excipients of any of the trial drugs
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  • History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of ≥ 3, unstable angina or poorly controlled arrhythmia as determined by the investigator. Myocardial infarction within 6 months prior to randomisation.
  • Women of child-bearing potential (WOCBP) and men who are able to father a child, unwilling to be abstinent or use highly effective methods of birth control that result in a low failure rate of less than 1% per year when used consistently and correctly prior to study entry, for the duration of study participation and for at least <XX weeks; 2 weeks for afatinib, XX weeks for comparator,> after treatment has ended.
  • Women who are pregnant, nursing, or who plan to become pregnant while in the trial
  • 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
  • Previous or concomitant malignancies at other sites, except effectively treated nonmelanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 3 years and is considered to be cured.
  • Requiring treatment with any of the prohibited concomitant medications listed in Section 4.2.2.1 that cannot be stopped for the duration of trial participation
  • 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 diarrhoea, malabsorption)
  • 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.

Trial locations and contacts

1 site in 1 country.

Singapore1 site

  • National Cancer Center Singapore

    Singapore, 169690

Other trials in Singapore

About this study

Official title: A Dose Finding Study of Continuous and Intermittent High-dose (HDI) Afatinib (EGFR TKI) on CNS Metastases and Leptomeningeal Disease (LMD) in Patients With Advanced Refractory EGFR Mutation Positive Non-small Cell Lung Cancer

Brain metastases occurs in up to 50% of patients with EGFR mutant NSCLC. Leptomeningeal disease is a subset of patients with brain metastases for which there remains an unmet need. This trial aims to evaluate the role of two dosing schedules of afatinib in management of leptomeningeal disease in EGFR mutant NSCLC, specifically to determine Central Nervous System (CNS) penetration of afatinib, as well as clinical activity. Patients will start on daily dosing initially followed by pulsed intermittent dosing should we observe no clinical activity. A secondary objective is to identify the resistance spectrum in leptomeningeal disease. It is anticipated that optimal dosing schedule of afatinib e.g. pulsed dosing may improve CNS disease control.

Being tested
Afatinib
Medical subject headings
Carcinoma, Non-Small-Cell Lung, Meningeal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AfatinibDrug

    Also called Gilotrif

    40mg daily

  • AfatinibDrug

    Also called Gilotrif

    160mg for 3 days every 3 weeks

Study groups in NCT03711422
Study groupRoleWhat they receive
Part AExperimentalStandard dose oral afatinib. If patients in Part A do not benefit from the regimen, they can be enrolled into Part B
Receives: Drug: Afatinib
Part BExperimentalIntermittent high dose oral afatinib
Receives: Drug: Afatinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Afatinib concentration in plasma using standard dosing and high intermittent dosing

    To assess the difference in drug ratio from two difference dosing of afatinib

    Measured: Day 1 to Day 29 of drug treatment

  2. Afatinib concentration in Cerebral Spinal Fluid (CSF) using standard dosing and high intermittent dosing

    To assess the difference in drug ratio from two difference dosing of afatinib

    Measured: Part A: Day 15; Part B: Day 17 and 31

  3. Neurological Progression Free Survival

    Measured: From time of first study drug administration until first occurrence of disease progression, or death from any cause, up to 2 years

  4. Neurological Response Rate

    Measured: From time of first study drug administration until first occurrence of disease progression, up to 2 years

  5. Overall Survival

    Measured: From time of first study drug administration to death from any cause, up to 2 years

Secondary outcomes (4)

  1. Cell-free DNA sequencing of Cerebrospinal Fluid

    To detect EGFR T790M and activating mutation status

    Measured: From time of first study drug administration to end of study treatment, up to 2 years

  2. European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30

    To assess the physical, physiological and social functions. The scale ranges from 1="not all all" to 4-"very much"

    Measured: From time of first study drug administration through to end of study treatment or disease progression, up to 2 years

  3. EORTC Quality of Life Questionnaire Brain Cancer Module

    To assess future uncertainty, visual disorder, motor dysfunction, and communication deficit. The scale ranges from 1="not all all" to 4-"very much"

    Measured: From time of first study drug administration through to end of study treatment or disease progression, up to 2 years

  4. Incidences of treatment-emergent adverse events (AE)

    AEs will be graded according to CTCAE, Version 4.0

    Measured: From time of first study drug administration to 28 days after last treatment administration

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Oct 2018
  2. Study start16 Nov 2018
  3. Primary completion20 Dec 2019
  4. Study completion20 Dec 2019

Why it stopped: Decision to close the trial made due to low recruitment.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
2 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03711422
Sponsor's protocol ID
1200.275
Status last verified
Apr 2021
First submitted
10 Oct 2018
Last updated
14 Jun 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Hoffknecht P, Tufman A, Wehler T, Pelzer T, Wiewrodt R, Schutz M, Serke M, Stohlmacher-Williams J, Marten A, Maria Huber R, Dickgreber NJ; Afatinib Compassionate Use Consortium (ACUC). Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol. 2015 Jan;10(1):156-63. doi: 10.1097/JTO.0000000000000380.

    PubMed 25247337

  • Awada AH, Dumez H, Hendlisz A, Wolter P, Besse-Hammer T, Uttenreuther-Fischer M, Stopfer P, Fleischer F, Piccart M, Schoffski P. Phase I study of pulsatile 3-day administration of afatinib (BIBW 2992) in combination with docetaxel in advanced solid tumors. Invest New Drugs. 2013 Jun;31(3):734-41. doi: 10.1007/s10637-012-9880-0. Epub 2012 Nov 17.

    PubMed 23161334

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Afatinib in people with Non-small Cell Lung Cancer and Leptomeningeal Disease, run by National Cancer Centre, Singapore at 1 site in Singapore.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 14 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Decision to close the trial made due to low recruitment.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Afatinib concentration in plasma using standard dosing and high intermittent dosing (time frame: Day 1 to Day 29 of drug treatment). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03711422, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jun 2022.

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