NICHE: Afatinib in NSCLC With HER2 Mutation

Sponsor
ETOP IBCSG Partners Foundation (Other)
Overall Status
Completed
CT.gov ID
NCT02369484
Collaborator
(none)
13
5
1
24
2.6
0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate the control of disease in pretreated patients with advanced non small cell lung cancer (NSCLC) harbouring HER2 exon 20 mutations as well as the safety and tolerability (how severe the side effects are) of the treatment with afatinib.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Previous clinical studies of NSCLC have shown that patients with tumors harboring specific gene mutations (changes) in the epithelial growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) showed better results after treatment with tyrosine kinase inhibitors (TKI), like afatinib (tradename Giotrif®) , compared with classical treatment with chemotherapy. The treatment with TKI has become a new standard-of-care for patient with advanced lung cancer and EGFR or ALK changes. Several novel mutations, which are candidates as targets for specific medication have been discovered. Human epidermal growth factor 2 (HER2, erbB-2/neu) is a protein of the so called ErbB family (including HER2 [ErbB2], ErbB3 and ErbB4). These proteins are involved in the growth and spread of cancer cells. Mutations in HER2 are found in about 2% of the NSCLC.

Afatinib works by blocking the activity of the ErbB family proteins and can inhibit growth and spread of cancer cells. Afatinib is approved by the European and the Swiss Medicines Agencies for the treatment of adult patients with a specific type of cancer of the lung (non-small cell lung cancer) that is identified by a change (mutation) in the gene for EGFR as first treatment or if prior chemotherapy treatment has been insufficient.

A total of 22 patients from centers around Europe are expected to be enrolled in this study over a period of 24 months.

All patients will be treated in the same way. The study will take approximately 40 months to be completed.

This clinical trial is conducted according to the applicable national laws and international guidelines.

Study Design

Study Type:
Interventional
Actual Enrollment :
13 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Afatinib in Pretreated Patients With Advanced NSCLC Harbouring HER2 Exon 20 Mutations
Actual Study Start Date :
Sep 16, 2015
Actual Primary Completion Date :
Sep 15, 2017
Actual Study Completion Date :
Sep 15, 2017

Arms and Interventions

Arm Intervention/Treatment
Other: Afatinib

Afatinib 40 mg p.o./day until tumour progression or lack of tolerability

Drug: Afatinib
40mg p.o./ day until documented progression or unacceptable toxicity
Other Names:
  • Giotrif
  • BIBW 2992
  • Outcome Measures

    Primary Outcome Measures

    1. Disease Control (Defined as Complete or Partial Response, or Disease Stabilisation Lasting at Least 12 Weeks) [at interim (after the first 9 pts have been followed for 12 weeks) & final analysis (approx. 40 months after inclusion of first pt)]

      Disease control (DC) is defined as complete or partial response, or disease stabilisation lasting at least 12 weeks. Disease control will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions denotes disease progression. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.

    Secondary Outcome Measures

    1. Progression-free Survival [Time assessed from the date of enrolment until documented progression or death (max 36 months)]

      Progression-free survival (PFS) is defined as the time from date of enrollment until documented progression or death, if progression is not documented. Censoring will occur at the last tumor assessment only if patients is lost to follow-up

    2. Objective Response [Assessed across all time-points during the period from enrolment to termination of trial treatment (max. 36 months)]

      Objective response is defined as best overall response (CR or PR) across all assessment time-points during the period from enrollment to termination of trial treatment. Objective response to afatinib treatment will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions denotes disease progression. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.

    3. Overall Survival [Time assessed from the date of enrolment until death (max 36 months)]

      Overall survival (OS) is defined as the time from the date of enrollment until death from any cause. Censoring will occur at the last follow-up.

    4. Toxicities of Treatment [Assessed from the date of informed consent until 90 days after the final dose of afatinib (max 18 months).]

      Adverse events classified according to NCI CTCAE version 4.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Histologically or cytologically confirmed non small cell lung cancer

    • Stage IIIB (non amenable to curative-intent multimodal treatment) or IV NSCLC, according to 7th TNM classification.

    • Contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals);

    • brain MRI or CT within 28 days before the date of enrolment.

    • Non-predominant squamous subtype (<50% squamous cells).

    • Previous treatment with a platinum based chemotherapy for advanced disease; or Disease relapse or progression within <6 months after adjuvant platinum based chemotherapy, or (definitive) platinum-based chemo(radio)therapy for stage I-III NSCLC

    • Measurable or evaluable disease (according to RECIST 1.1 criteria). Not eligible: patients with only one measurable or evaluable tumour lesion which was resected or irradiated prior to enrolment.

    • Locally documented HER2 mutation

    • Age ≥ 18 years

    • Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

    • Life expectancy >3 months.

    • Adequate haematological function:

    • WBC ≥ 2000/μL

    • haemoglobin ≥ 9 g/dL

    • neutrophils count ≥1.5×109/L

    • platelet count ≥ 100 × 109/L

    • Adequate liver function:

    • Total bilirubin ≤ 1.5 × ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)

    • ALT < 2.5 × ULN

    • AST < 2.5 × ULN

    • GGT < 2.5 × ULN.

    • Adequate renal function: Calculated creatinine clearance ≥ 45mL/min (Cockroft-Gault)

    • Patient capable of proper therapeutic compliance, and accessible for correct followup.

    • Women of childbearing potential (< 1 year without menstruation or < 2 years without menstruation following chemotherapy) must have a negative serum or urine pregnancy test within 7 days before beginning trial treatment.

    • Sexually active men and women of childbearing potential must use an effective contraceptive method (two barrier methods or a barrier method plus a hormonal method) during the trial treatment and for a period of at least 28 days following the last administration of trial drug.

    • Recovered from any previous therapy related toxicity to ≤Grade 1 at date of enrolment (except for recovery to ≤Grade 2 of alopecia, fatigue, creatinine increased, lack of appetite as well as stable sensory neuropathy)

    • Written Informed Consent (IC) for trial treatment must be signed and dated by the patient and the investigator prior to any trial-related intervention.

    • Tumour block available for central review of HER2 mutation status.

    Exclusion Criteria:
    • Patient with mixed small-cell and non-small-cell histologic features

    • Uncontrolled lepto-meningeal metastatic disease. Radiotherapy-treated or asymptomatic brain metastases are allowed (no systematic screening). Patients with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids or have been on stable dose of corticosteroids for at least 4 weeks before starting trial treatment. Any symptoms attributed to brain metastases must be stable for at least 4 weeks before date of enrolment.

    • Previous treatment with HER2 targeted antibody or tyrosine kinase inhibitor including afatinib.

    • Major surgery within 4 weeks before starting trial treatment or scheduled for surgery during the projected course of the trial.

    • Patient who has had in the past 3 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ ductal carcinoma of the breast.

    • History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of III or IV (see Table 2 below), unstable angina or poorly controlled arrhythmia as determined by the investigator. Myocardial infarction within 6 months prior to enrolment.

    • Patient with other serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical processes that could affect the patient's capacity to participate in the trial.

    • Known HIV, active Hepatitis B or Hepatitis C infection (screening not required).

    • Known or suspected hypersensitivity to afatinib or any of its excipients.

    • Interstitial lung disease or pulmonary fibrosis.

    • Women who are pregnant or in the period of lactation.

    • Patients with any concurrent systemic anticancer therapy.

    • Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the trial drug (e.g. Crohn's disease, ulcerative colitis, chronic diarrhea, malabsorption.

    • Patient who received treatment with an investigational drug agent during the 3 weeks before enrolment in the trial.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Universitätsklinikum Köln Köln Germany
    2 NKI-AVL Amsterdam Netherlands
    3 Vall d'Hebron University Hospital Barcelona Spain
    4 CHUV Lausanne Switzerland
    5 USZ Zürich Switzerland

    Sponsors and Collaborators

    • ETOP IBCSG Partners Foundation

    Investigators

    • Study Chair: Solange Peters, MD-PhD, Centre Hospitalier Universitaire Vaudois (CHUV); Lausanne, Switzerland
    • Study Chair: Rafal Dziadziuszko, MD, Medical University of Gdansk, Gdansk, Poland

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    Responsible Party:
    ETOP IBCSG Partners Foundation
    ClinicalTrials.gov Identifier:
    NCT02369484
    Other Study ID Numbers:
    • ETOP 7-14
    • 2014-005098-35
    • 1200.230
    • SNCTP000001674
    First Posted:
    Feb 24, 2015
    Last Update Posted:
    Aug 24, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by ETOP IBCSG Partners Foundation
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details ETOP/7-14 NICHE trial was activated in December 2014. The first patient was enrolled on September 2015 while the last one on August 2016, before accrual was suspended in October 2016. Patients were enrolled in 3 centers (Netherlands Cancer Institute of Amsterdam, Vall d' Herbon Univesity Hospital (Spain) and Universitatsklinikum Koln (Germany)).
    Pre-assignment Detail All 13 patients eligible for enrollment received treatment
    Arm/Group Title Afatinib
    Arm/Group Description Afatinib 40 mg p.o./day until tumour progression or lack of tolerability
    Period Title: Overall Study
    STARTED 13
    COMPLETED 13
    NOT COMPLETED 0

    Baseline Characteristics

    Arm/Group Title Afatinib
    Arm/Group Description Afatinib 40 mg p.o./day until tumour progression or lack of tolerability Afatinib: 40mg p.o./ day until documented progression or unacceptable toxicity
    Overall Participants 13
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    59
    Sex: Female, Male (Count of Participants)
    Female
    9
    69.2%
    Male
    4
    30.8%
    Race and Ethnicity Not Collected (Count of Participants)
    Region of Enrollment (participants) [Number]
    Netherlands
    7
    53.8%
    Germany
    3
    23.1%
    Spain
    3
    23.1%
    Smoking history (Count of Participants)
    Current
    1
    7.7%
    Former
    4
    30.8%
    Never
    8
    61.5%
    ECOG Performance status (Count of Participants)
    0
    7
    53.8%
    1
    4
    30.8%
    2
    2
    15.4%
    T parameter (Count of Participants)
    T1b
    1
    7.7%
    T2a
    3
    23.1%
    T3
    3
    23.1%
    T4
    6
    46.2%
    N parameter (Count of Participants)
    N0
    5
    38.5%
    N2
    3
    23.1%
    N3
    5
    38.5%
    M parameter (Count of Participants)
    M0
    1
    7.7%
    M1a
    6
    46.2%
    M1b
    6
    46.2%
    TNM staging (Count of Participants)
    T1b-N3-M1b
    1
    7.7%
    T2a-N0-M1a
    1
    7.7%
    T2a-N2-M1b
    1
    7.7%
    T2a-N3-M1b
    1
    7.7%
    T3-N0-M1b
    1
    7.7%
    T3-N2-M1a
    1
    7.7%
    T3-N3-M1b
    1
    7.7%
    T4-N0-M1a
    3
    23.1%
    T4-N2-M0
    1
    7.7%
    T4-N3-M1a
    1
    7.7%
    T4-N3-M1b
    1
    7.7%
    Type of prior platinum treatment (Count of Participants)
    Adjuvant
    2
    15.4%
    Advanced disease
    11
    84.6%

    Outcome Measures

    1. Primary Outcome
    Title Disease Control (Defined as Complete or Partial Response, or Disease Stabilisation Lasting at Least 12 Weeks)
    Description Disease control (DC) is defined as complete or partial response, or disease stabilisation lasting at least 12 weeks. Disease control will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions denotes disease progression. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.
    Time Frame at interim (after the first 9 pts have been followed for 12 weeks) & final analysis (approx. 40 months after inclusion of first pt)

    Outcome Measure Data

    Analysis Population Description
    The statistical design of the trial, included an interim efficacy analysis to be performed as soon as the 12-week status of the first 9 patients was available. So, the interim analysis was performed but up to then 13 patients have been enrolled.
    Arm/Group Title Afatinib
    Arm/Group Description Afatinib 40 mg p.o./day until tumour progression or lack of tolerability
    Measure Participants 13
    DC at 12 weeks- "Yes"
    7
    53.8%
    DC at 12 weeks- "No"
    6
    46.2%
    DC at 12 weeks- "Yes"
    4
    30.8%
    DC at 12 weeks- "No"
    5
    38.5%
    2. Secondary Outcome
    Title Progression-free Survival
    Description Progression-free survival (PFS) is defined as the time from date of enrollment until documented progression or death, if progression is not documented. Censoring will occur at the last tumor assessment only if patients is lost to follow-up
    Time Frame Time assessed from the date of enrolment until documented progression or death (max 36 months)

    Outcome Measure Data

    Analysis Population Description
    All patients enrolled up to trial termination
    Arm/Group Title Afatinib
    Arm/Group Description Afatinib 40 mg p.o./day until tumour progression or lack of tolerability
    Measure Participants 13
    Median (95% Confidence Interval) [weeks]
    15.9
    3. Secondary Outcome
    Title Objective Response
    Description Objective response is defined as best overall response (CR or PR) across all assessment time-points during the period from enrollment to termination of trial treatment. Objective response to afatinib treatment will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions denotes disease progression. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.
    Time Frame Assessed across all time-points during the period from enrolment to termination of trial treatment (max. 36 months)

    Outcome Measure Data

    Analysis Population Description
    All patients enrolled in the trial up to trial termination. From the total of 13 patients, one patient had only one tumor assessment and was classified as "Non-Evaluable", since she cannot be accounted for the Objective Response rate.
    Arm/Group Title Afatinib
    Arm/Group Description Afatinib 40 mg p.o./day until tumour progression or lack of tolerability
    Measure Participants 13
    Objective response (CR or PR)
    1
    7.7%
    Stable disease
    6
    46.2%
    Progression disease
    5
    38.5%
    Non-evaluable
    1
    7.7%
    4. Secondary Outcome
    Title Overall Survival
    Description Overall survival (OS) is defined as the time from the date of enrollment until death from any cause. Censoring will occur at the last follow-up.
    Time Frame Time assessed from the date of enrolment until death (max 36 months)

    Outcome Measure Data

    Analysis Population Description
    All patients enrolled in the trial up to trial termination
    Arm/Group Title Afatinib
    Arm/Group Description Afatinib 40 mg p.o./day until tumour progression or lack of tolerability
    Measure Participants 13
    Median (95% Confidence Interval) [weeks]
    56.0
    5. Secondary Outcome
    Title Toxicities of Treatment
    Description Adverse events classified according to NCI CTCAE version 4.
    Time Frame Assessed from the date of informed consent until 90 days after the final dose of afatinib (max 18 months).

    Outcome Measure Data

    Analysis Population Description
    All patients enrolled in the trial up to trial termination
    Arm/Group Title Afatinib
    Arm/Group Description Afatinib 40 mg p.o./day until tumour progression or lack of tolerability
    Measure Participants 13
    Experienced AE/SAE
    13
    100%
    No AE/SAE
    0
    0%

    Adverse Events

    Time Frame From the date of informed consent until 90 days after the final dose of afatinib (max 18 months).
    Adverse Event Reporting Description
    Arm/Group Title Afatinib
    Arm/Group Description Afatinib 40 mg p.o./day until tumour progression or lack of tolerability Afatinib: 40mg p.o./ day until documented progression or unacceptable toxicity
    All Cause Mortality
    Afatinib
    Affected / at Risk (%) # Events
    Total 1/13 (7.7%)
    Serious Adverse Events
    Afatinib
    Affected / at Risk (%) # Events
    Total 5/13 (38.5%)
    Blood and lymphatic system disorders
    Febrile neutropenia 1/13 (7.7%)
    Cardiac disorders
    Pericardial effusion 1/13 (7.7%)
    Gastrointestinal disorders
    Diarrhea 1/13 (7.7%)
    Metabolism and nutrition disorders
    Dehydration 1/13 (7.7%)
    Musculoskeletal and connective tissue disorders
    Muscle weakness lower limb 1/13 (7.7%)
    Renal and urinary disorders
    Acute kidney injury 1/13 (7.7%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 1/13 (7.7%)
    Epistaxis 1/13 (7.7%)
    Pleural effusion 1/13 (7.7%)
    Other (Not Including Serious) Adverse Events
    Afatinib
    Affected / at Risk (%) # Events
    Total 13/13 (100%)
    Blood and lymphatic system disorders
    Anemia 2/13 (15.4%)
    Cardiac disorders
    Ventricular arrhythmia 1/13 (7.7%)
    Eye disorders
    Dry eye 2/13 (15.4%)
    Gastrointestinal disorders
    Diarrhea 11/13 (84.6%)
    Mucositis oral 4/13 (30.8%)
    Abdominal pain 3/13 (23.1%)
    Vomiting 3/13 (23.1%)
    Constipation 1/13 (7.7%)
    Dry mouth 1/13 (7.7%)
    Nausea 1/13 (7.7%)
    General disorders
    Fatigue 3/13 (23.1%)
    Flu like symptoms 2/13 (15.4%)
    Non-cardiac chest 2/13 (15.4%)
    Malaise 1/13 (7.7%)
    Infections and infestations
    Paronyclia 5/13 (38.5%)
    Bladder infection 1/13 (7.7%)
    Eye infection 1/13 (7.7%)
    Sinusitis 1/13 (7.7%)
    Tooth infection 1/13 (7.7%)
    Urinary track infection 1/13 (7.7%)
    Nail infection 1/13 (7.7%)
    Papulopustular rash 1/13 (7.7%)
    Other (tonsillitis) 1/13 (7.7%)
    Investigations
    GGT increased 2/13 (15.4%)
    Asparate aminotransferase increased 1/13 (7.7%)
    Creatine increased 1/13 (7.7%)
    Platelet count decreased 1/13 (7.7%)
    Weight loss 1/13 (7.7%)
    Metabolism and nutrition disorders
    Hyperkalemia 1/13 (7.7%)
    Hypermagnesemia 1/13 (7.7%)
    Hypoalbuminemia 1/13 (7.7%)
    Hypomagnesemia 1/13 (7.7%)
    Hyponatremia 1/13 (7.7%)
    Musculoskeletal and connective tissue disorders
    Arthalgia 1/13 (7.7%)
    Back pain 1/13 (7.7%)
    Bone pain 1/13 (7.7%)
    Myalgia 1/13 (7.7%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain 1/13 (7.7%)
    Nervous system disorders
    Headache 2/13 (15.4%)
    Dysgeusia 1/13 (7.7%)
    Peripheral sensory neuropathy 1/13 (7.7%)
    Other (paraplegia from Th4)) 1/13 (7.7%)
    Renal and urinary disorders
    Cystitis noninfective 1/13 (7.7%)
    Urinary incontinence 1/13 (7.7%)
    Urinary track obstruction 1/13 (7.7%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 3/13 (23.1%)
    Cough 2/13 (15.4%)
    Epistaxis 1/13 (7.7%)
    Pleural effusion 1/13 (7.7%)
    Skin and subcutaneous tissue disorders
    Erythema multiforme 4/13 (30.8%)
    Rash acneiform 4/13 (30.8%)
    Dry skin 3/13 (23.1%)
    Other 2/13 (15.4%)
    Alopecia 1/13 (7.7%)
    Vascular disorders
    Hypertension 1/13 (7.7%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Heidi Roschitzki-Voser, Lead Trial Activities
    Organization European Thoracic Oncology Platform (ETOP)
    Phone +41 31 511 94 18
    Email Heidi.Roschitzki@etop-eu.org
    Responsible Party:
    ETOP IBCSG Partners Foundation
    ClinicalTrials.gov Identifier:
    NCT02369484
    Other Study ID Numbers:
    • ETOP 7-14
    • 2014-005098-35
    • 1200.230
    • SNCTP000001674
    First Posted:
    Feb 24, 2015
    Last Update Posted:
    Aug 24, 2022
    Last Verified:
    Aug 1, 2022