| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029514 |
| E.1.2 | Term | Non-small cell lung cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| To demonstrate that dacomitinib treatment is superior to gefitinib treatment with respect to Progression-Free Survival (PFS) as determined by blinded independent radiologic central (IRC) review, in the study population. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare secondary measures of efficacy: Overall Survival (OS), PFS, Objective Response Rate (ORR) and Duration of Response (DR)
• To evaluate the safety and tolerability between the two treatment arms;
• To compare the Patient Reported Outcomes (PRO) of health-related quality of life (HRQOL), and disease/treatment-related symptoms between the two arms;
• To compare the PRO of health status between the two arms;
• To characterize the multiple-dose PK of dacomitinib and its major circulating metabolite PF-05199265 in Chinese subjects currently residing in mainland China, who were born in China, and whose parents are both Chinese descent (Arm A only);
• To determine dacomitinib and its major circulating metabolite PF-05199265 trough concentrations (Ctrough) for the evaluation of steady-state PK (Arm A only, at selected sites). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of a voluntarily given, personally signed and dated, written informed consent document;
2. Age ≥20 years in Japan and Korea, and ≥18 years in other countries, male or female;
3. The presence of an EGFR activating mutation (exon 19 deletion or the L858R mutation in exon 21) in tumor tissue determined by the local laboratory based on the Qiagen - Therascreen® EGFR Mutation Detection Kit RGQ (Scorpions ARMS) in ex-China, or similar test methods approved by the sponsor. It is acceptable for subjects with the presence of the exon 20 T790M mutation together with either EGFR activating mutation (exon 19 deletion or the L858R mutation in exon 21) to be included in this study;
4. Evidence of stage IIIB/IV (based on Union for International Cancer Control (UICC) staging system version 77) NSCLC of adenocarcinoma histology or its pathologically accepted variants using tumor tissue (assessed by a local laboratory in ex-China, by a central laboratory in China). For this purpose the World Health Organization/International Association of Study of Lung Cancer Histologic Classification of Lung Cancer Criteria will be used and the diagnosis of NSCLC NOS (not otherwise specified), squamous or mixed adeno-squamous lung carcinomas will not be allowed;
5. Tumor tissue must be available for central laboratory confirmation of adenocarcinoma histology and presence of activating mutation. In the situation of reccurent NSCLC after treated neoadjuvant/adjuvant chemotherapy, tumor specimenr needs to be obtained at the time of recurrence after competion of neo/adj therapy. Tumor obtained by smear preparation is not allowed. Ten (10) unstained, 4-6 micron thick sections from a formalin fixed paraffin embedded (FFPE) block or a FFPE block is requested. If the site is unable to provide 10 sections as requested, 4-6 unstained, 4-6 micron thick sections from a FFPE block are required;
6. Have an ECOG PS of 0 or 1;
7. No prior treatment with systemic therapy for NSCLC;
8. Radiologically measurable disease by RECIST v1.1 criteria:
a. At least one target lesion that has not previously been radiated, and is measurable according to RECIST v1.1;
b. Acceptable radiologic procedures for disease assessment include contrast enhanced conventional or spiral computed tomography (CT), or contrast enhanced magnetic resonance imaging (MRI); Non contrast CT scan is acceptable only for subjects who are both allergic to intravenous contrast and unable to cooperate with MRI, or MRI is not available. The following are not allowed as sole documentation of target lesions: CT component of a positron emission tomography (PET)/CT, ultrasound alone, nuclear scans (including bone or PET scans), chest X-ray or bone radiographs, and tumor markers;
9. Adequate organ function, including:
a. Estimated creatinine clearance ≥30 mL/min (as determined by Cockcroft-Gault formula or the study site’s standard formula);
b. Urinary protein <3+ by urine dipstick. If urine protein by dipstick is ≥3+, then a urine protein/creatinine ratio (UPC) should be obtained. The subject may enter only if UPC is <2.0;
c. Absolute neutrophil count (ANC) ≥1500 cells/mm3;
d. Platelets ≥100,000 cells/mm3;
e. Hemoglobin ≥10.0 g/dL;
f. Bilirubin ≤ 1.5 x ULN;
g. AST (also known as SGOT) and ALT (also known as SGPT) ≤2.5 x ULN (≤5.0 x ULN if hepatic metastases).
10. Female subjects must be postmenopausal (defined as 12 months of amenorrhea following last menses), or they or their partners must be surgically sterile, or must agree to use effective contraception while receiving study treatment and for at least 3 months thereafter. The definition of effective contraception will be based on the judgment of the investigator;
11. All female subjects with reproductive potential must have a negative pregnancy test (serum or urine) within 72 hours prior to starting study treatment;
12. Male subjects or their female partners must be surgically sterile or must agree to use effective contraception while receiving study treatment and for at least 3 months thereafter. The definition of effective contraception will be based on the judgment of the investigator. Or female partners must be postmenopausal (defined as 12 months of amenorrhea following last menses);
13. Willing and able to comply with study scheduled visits, treatment plans, laboratory tests, and other study procedures. |
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| E.4 | Principal exclusion criteria |
1. Any evidence of mixed histology that includes elements of small cell or carcinoid lung cancer. Variations of adenocarcinoma are allowed, however no squamous element can be present;
2. Any other mutation other than exon 19 deletion or L858R in exon 21, with or without the presence of the exon 20 T790M mutation. Both mutations (exon 19 deletion and L858R mutation in exon 21) within a tumor sample;
3. Any history of brain metastases or leptomeningeal metastases, even if treated with radiation or surgery in the past and now stable;
4. Any previous anti-cancer systemic treatment of early, locally advanced, or metastatic NSCLC including but not limited to chemotherapy, targeted therapies, small molecules, EGFR-TKIs and other tyrosine-kinase-inhibitors, monoclonal antibodies, anti-cancer vaccines, radiotherapy (other than palliative radiotherapy to lesions that will not be followed for tumor assessment on this study, i.e., non target lesions);
5. Any surgery (not including minor procedures such as lymph node biopsy), palliative radiotherapy or pleurodesis within 2 weeks of baseline assessments;
6. Any clinically significant gastrointestinal abnormalities that may impair intake, transit or absorption of the study drug, such as the inability to take oral medication;
7. Current enrollment in another therapeutic clinical study;
8. Any psychiatric or cognitive disorder that would limit the understanding or rendering of informed consent and/or compromise compliance with the requirements of this study; or known drug abuse/alcohol abuse;
9. History of, or currently suspected, diffuse non-infectious pneumonitis or interstitial lung disease including:
a. Past medical history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which required steroid treatment or any evidence of clinically active interstitial lung disease;
b. Pre-existing idiopathic pulmonary fibrosis evidenced by CT scan at baseline;
c. Insufficient lung function as determined by either clinical examination or an arterial oxygen tension of <70 Torr.
10. Any history of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
11. Uncontrolled or significant cardiovascular disease, including:
a. Myocardial infarction within the last 12 months;
b. Uncontrolled angina within the last 6 months;
c. Congestive heart failure within the last 6 months;
d. Diagnosed or suspected congenital long QT syndrome;
e. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes);
f. Prolonged QTc interval on ECG; QTc must be less than CTCAE v4.0 Grade 2 (≤480 msec) using Fridericia’s or Bazett’s correction formula with a manual reading by the investigator if required. The ECG may be repeated for evaluation of eligibility after management of correctable causes for observed QTc prolongation;
g. Any history of second or third degree heart block;
h. Heart rate <50 beats per minute on ECG in the presence of clinical symptoms (e.g., hypotension, evidence of hypoperfusion);
i. Uncontrolled hypertension.
12. Severely impaired (defined as Child-Pugh Class C) hepatic dysfunction;
13. Prior malignancy: Subjects will not be eligible if they have history of, or evidence of another concurrent malignancy. Exception would be effectively treated past history of non-melanoma skin cancer or in-situ cervical cancer with no evidence of active disease;
14. Other severe acute or chronic medical condition that may increase the risk associated with study participation or investigational drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study;
15. Use of narrow therapeutic index drugs that are CYP2D6 substrates (procainamide, pimozide, and thioridazine etc.) from screening to randomization. Use of a product with known effects on pharmacokinetics of gefitinib in reference to package insert from screening to randomization. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as determined by blinded IRC review. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Evaluated at the end of Cycle 1 and Cycle 2, then every other cycle (within 7 days of the start of subsequent cycle including Day 1 of subsequent cycle), |
|
| E.5.2 | Secondary end point(s) |
• Overall Survival (OS) and OS at 30 months (OS30m);
• PFS as determined by investigator assessment (INV);
• Best Overall Response (BOR) as determined by both IRC and INV assessments;
• Duration of Response (DR) as determined by both IRC and INV assessments;
• Overall safety profile: adverse events (AEs) and laboratory abnormalities by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.0, and left ventricular ejection fraction (LVEF);
• Patient Reported Outcomes (PRO) of health related quality of life (HRQOL), and disease/treatment-related symptoms between the two arms as measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30), its Lung Cancer module (QLQ-LC13);
• Patient Reported Outcomes (PRO) of health status between the two arms as measured by the EuroQol 5 Dimension (EQ-5D);
• Multiple dose PK parameter estimates of dacomitinib and its major circulating metabolite PF-05199265 in Chinese subjects currently residing in mainland China, who were born in China, and whose parents are both Chinese descent (Arm A only);
• Trough concentrations (Ctrough) of dacomitinib and its major circulating metabolite PF-05199265, as determined from pre-dose plasma samples (Arm A only, at selected sites).
Optional Research Components:
Based on availability of tumor samples not consumed by confirmatory
central testing (see inclusion criteria 5), subjects may choose (optional)
to consent to donate left over tumor sample for scientific and medical
research to increase knowledge and understanding of disease biology. If
subjects choose not to donate their left over tumor sample material,
unused tumor samples will be destroyed.
For subjects who agree to have additional blood samples collected, blood
will be collected at baseline, during treatment (every 3rd cycle) and end
of treatment and processed to plasma (as described in the Study
Manual) for use in a retrospective analysis for the presence of circulating
EGFR mutations, including exon 19 deletion, L858R mutation in exon 21
and exon 20 T790M, to test if these markers can be of diagnostic and/or
prognostic value. As sample availability allows, additional markers
(including, but possibly not limited to, phoshoinositide 3-Kinase (PI3K),
Phosphatase and Tensin Homolog (PTEN), AXL tyrosine kinase) may be
included as pre clinical studies or literature reports further elucidate the
mechanism of action of dacomitinib or the relevant signaling pathways—
including potential resistance pathways─or as new technology becomes
available.
For subjects in Arm A who agree to have additional blood samples
collected, blood will be collected at baseline for use in a retrospective
analysis for CYP2D6 genotyping. CYP2D6 can show phenotypical
variability for its metabolic function. By analyzing the specific genotype
for CYP2D6 by genotyping the individual subject's capacity for normal,
reduced, or non-existent CYP2D6 function will be known. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Evaluated throughout the treatment phase |
|
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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 |
| China |
| Hong Kong |
| Italy |
| Japan |
| Korea, Democratic People's Republic of |
| Taiwan |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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