| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| locally advanced or metastatic squamous cell carcinoma of the lung |
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| E.1.1.1 | Medical condition in easily understood language |
| locally advanced or metastatic squamous cell carcinoma of the lung |
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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 | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The main objective is to assess the efficacy of afatinib in combination with pembrolizumab, as measured by objective response (OR) in patients with locally advanced or metastatic squamous NSCLC who progressed during or after first line platinum-based treatment. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives are to confirm the RP2D, assess the safety profile, and the secondary measures of clinical efficacy including disease control (DC), duration of objective response (DoR), progression-free survival (PFS), overall survival (OS), and tumour shrinkage. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Pathologically confirmed diagnosis of NSCLC considered to be of squamous histology, including mixed histology, in the opinion of the investigator.
- Locally advanced (stage IIIb) or metastatic (stage IV) NSCLC not considered eligible for curative therapy.
- Documented disease progression or relapse (based on investigator’s assessment) during or after completion of at least 2 cycles of platinum-based chemotherapy as first line treatment of Stage IIIB/IV SCC of the lung. This includes patients relapsing within 6 months of completing (neo)adjuvant/curative-intent chemotherapy or definitive chemoradiotherapy. Patients should be eligible to receive 2nd line therapy in the opinion of the investigator.
- At least one target lesion (outside the brain) that can be accurately measured per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. In patients who only have one target lesion and a biopsy of the lesion is required; the baseline imaging must be performed at least two weeks after the biopsy.
- Availability and willingness to provide a fresh tumour tissue sample obtained after relapse or progression on or after prior therapy. In case a fresh biopsy cannot be obtained (e.g. inaccessible lesions or patient safety concern), an archived specimen may be submitted.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Recovery from major surgery or any previous anti-cancer or radiation therapy-related toxicity to ≤ CTCAE Grade 1 at C1_V1 (except for alopecia; stable sensory neuropathy must be ≤ CTCAE Grade 2).
- At least 18 years of age or over the legal age of consent in countries where that is greater than 18 years at screening.
- Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial.
- Male or female patients. Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly, starting with the screening visit and through 120 days after the last dose of pembrolizumab treatment and 2 weeks after last afatinib treatment, respectively, as listed in the protocol. A list of contraception methods meeting these criteria is provided in the patient information.
-- Note: Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to taking study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the patient to be eligible.
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| E.4 | Principal exclusion criteria |
- Prior therapy with any immune checkpoint inhibitor; however, prior (neo) adjuvant checkpoint inhibitor therapy is allowed if completed at least 12 months before relapse.
- Prior therapy with EGFR inhibiting drugs; however, prior EGFR-targeted (neo) adjuvant therapy is allowed if completed at least 12 months before relapse.
- Treatment with prior chemotherapy, non-EGFR targeted therapy, or anti-cancer hormonal treatment within 2 weeks prior to the first dose of trial treatment.
- Current or previous treatment with experimental therapy or use of an investigational device within 30 days prior to the first dose of trial treatment.
- Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the first dose of trial treatment.
- Received a live vaccine within 30 days prior to the first dose of trial treatment. Seasonal flu vaccines that do not contain live virus are permitted.
- Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids is allowed.
- Any history of or concomitant condition that, in the opinion of the investigator, would compromise the patient’s ability to comply with the trial or interfere with the evaluation of the efficacy and safety of the test drugs.
- Radiotherapy within 4 weeks prior to start of treatment except as follows:
-- Palliative radiotherapy to regions other than the chest is allowed up to 2 weeks prior to start of treatment;
-- Single dose palliative radiotherapy for symptomatic metastasis within 2 weeks prior to start of treatment may be allowed but must be agreed with the Sponsor.
- Major surgery (according to the investigator’s assessment) performed within 4 weeks prior to start of treatment or planned during the projected course of the study.
- Requirement or wish to continue the intake of restricted medications (see Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial.
- Known history of hypersensitivity to afatinib or any of its excipients.
- Known history of hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
-- Note: Patients with previously treated brain metastases may participate provided they are stable without evidence of progression by imaging (using the identical imaging modality for each assessment, either MRI or CT scan) for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
- Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, systemic corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
- History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids or current ILD/pneumonitis.
- Any history or presence of uncontrolled gastrointestinal disorders that could affect the intake and/or absorption of the study drug (e.g. nausea, vomiting, Crohn’s disease, ulcerative colitis, chronic diarrhoea, malabsorption) in the opinion of the investigator.
- Active infectious disease requiring intravenous systemic therapy or which puts the patient at increased risk in the opinion of the investigator.
- Previous or concomitant malignancies at other sites than the lung, except:
-- Effectively treated non-melanoma skin cancers;
-- Effectively treated carcinoma in situ of the cervix;
-- Effectively treated ductal carcinoma in situ;
-- Other effectively treated malignancy that has been in remission for more than 3 years and is considered to be cured.
- Known human immunodeficiency virus (HIV) (HIV 1/2 antibodies), active hepatitis B (e.g. HBsAg reactive) or hepatitis C (e.g. HCV RNA [qualitative] is detected).
- History of active TB (Bacillus Tuberculosis).
- History or presence of cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of ≥3, unstable angina or poorly controlled arrhythmia which are considered as clinically relevant by the investigator. Myocardial infarction within 6 months prior to start of treatment.
- Psychiatric, substance abuse disorders, or chronic alcohol abuse or any condition that in the investigator’s opinion would interfere with cooperation with the requirements of the trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1) Objective Response (OR), defined as best overall response of complete response (CR) or partial response (PR) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) Disease control (DC), defined as best overall response of CR, PR, or stable disease (SD)
2) Duration of objective response (DoR), defined as the time from first documented CR or PR until the earliest of disease progression or death among patients with OR.
3) Progression-free survival (PFS), defined as the time from first drug intake until disease progression or death from any cause, whichever occurs earlier.
4) Overall survival (OS), defined as time from first drug intake until death from any cause.
5) Tumour shrinkage (in millimeters), defined as the difference between the minimum post-baseline sum of diameters of target lesions (longest for non-nodal lesions, short axis for nodal lesions) and the baseline sum of diameters of the same set of target lesions. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) up to two years after the last patient entered
2) up to two years after the last patient entered
3) up to two years after the last patient entered
4) up to two years after the last patient entered
5) up to two years after the last patient entered
|
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Korea, Republic of |
| Spain |
| Turkey |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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