| 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 |
| PF-0299804 is for the potential treatment of patients with locally advanced or metastatic non-small cell lung cancer after failing of at least one prior chemotherapy regimen |
|
| 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 | 17.1 |
| 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 erlotinib treatment with respect to Progression Free Survival (PFS) in either of the co primary populations |
|
| E.2.2 | Secondary objectives of the trial |
• To compare secondary measures of Overall Survival (OS), Objective Response and Duration of Response between arms in the co primary populations;
• To evaluate the safety and tolerability in each arm;
• To compare the Patient Reported Outcomes (PRO) of health related quality of life, and disease/treatment related symptoms between arms in the co primary populations respectively;
• To compare Patient Reported Outcomes (PRO) of health status between arms in the co primary populations respectively;
• To determine KRAS genotype, and explore HER family genotype, in tumor tissue;
• To determine PF 00299804 and PF 05199265, (O desmethyl metabolite of PF 00299804, a major circulating metabolite in human plasma) trough concentrations (Ctrough) for the evaluation of steady state pharmacokinetics;
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study (additional details can be found in the protocol, Section 4.1):
1. Provision of a voluntarily given, personally signed, and dated written informed consent document;
2. Age ≥18 years, male or female;
3. Evidence of pathologically confirmed, advanced NSCLC for which there is no curative standard therapy in the judgment of the investigator;
a. For randomization/ stratification, the histologic subtype of NSCLC must be documented;
b. Diagnosis of NSCLC NOS (not otherwise specified) will not be sufficient for enrollment and randomization/stratification.
4. Specimen from archival or recently obtained tumor tissue is required, and will be sent to the Sponsor-designated central laboratory for molecular testing of tumor tissue, including KRAS mutation status, and HER family testing (as available tissue allows);
5. ECOG 0-2 performance status;
6. Prior treatment with at least one and no more than two regimens of systemic therapy which include at least one standard chemotherapy for advanced NSCLC;
7. Any prior treatment (chemotherapy, radiation or surgery) must have been completed at least 2 weeks prior to randomization. Any acute toxicity related to prior therapy must have been recovered to Grade 1 (per NCI CTCAE v4) or baseline;
8. Radiologically measurable disease by RECIST v1.1 criteria:
a. At least one target lesion, that has not previously been radiated, and measurable as per RECIST (Appendix 5 of the protocol);
b. Acceptable radiologic procedures for disease assessment include contrast enhanced conventional or spiral CT, or MRI; contrast enhanced scans are required in the absence of contrast-allergy and patient intolerance of MRI. The following are not allowed as sole documentation of target lesions: CT component of a Positron Emission Tomography/CT, ultrasound alone, nuclear scans (including bone or PET scans), plain CXR or bone radiographs, and tumor markers.
9. Brain metastases treated with radiation or surgery are allowed if radiologically and neurologically stable and the subject is off corticosteroids for at least 2 weeks prior to randomization;
10. Adequate Renal Function, including:
a. Estimated creatinine clearance ≥15 mL/min (as determined by site’s standard formula);
b. No known history of renal papillary necrosis or pyelonephritis.
11. Adequate Liver Function, including:
• Bilirubin ≤ 1.5 x upper limit of normal (ULN);
• AST (SGOT) or ALT (SGPT) ≤ 2.5 x ULN (≤ 5.0 x ULN if hepatic metastases);
12. Female patients or their partners must be surgically sterile or be postmenopausal (defined as 12 months of amenorrhea following last menses), or must agree to use effective contraception while receiving trial treatment and for at least 3 months thereafter. (The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate. Where advised by investigator, double barrier contraception is defined as condom plus spermicide in combination with a female condom, diaphragm, cervical cap or intrauterine device).
13. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) within 72 hours prior to starting treatment.
14. Male patients or their partners must be surgically sterile or must agree to use effective contraception while receiving trial treatment and for at least 3 months thereafter. The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate.
15. Patients who are willing and able to comply with study scheduled visits, treatment plans, laboratory tests, and other study procedures including patient reported measures. |
|
| E.4 | Principal exclusion criteria |
1. Any evidence of mixed histology that includes elements of small cell or carcinoid lung cancer.
2. Patients with known leptomeningeal metastases, or symptomatic brain metastases. Patients with previously diagnosed brain metastases for which treatment (radiation or surgery) is recommended in the judgment of investigator are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 2 weeks, and are neurologically stable.
3. Chemotherapy, radiotherapy (other than palliative radiotherapy to lesions that will not be followed for tumor assessment on this study, ie, non target lesions), biological or investigational agents within 2 weeks of baseline disease assessments.
4. Prior therapy with an agent that is known or proposed to be active by action on: EGFR tyrosine kinase or other HER family proteins including but not limited to erlotinib (Tarceva®), gefitinib (Iressa®), lapatinib (Tykerb®), cetuximab (Erbitux®), panitumumab (Vectibix®), trastuzumab (Herceptin®), ZD6474 (Zactima®), cantertinib (CI 1033), neratinib (HKI 272), Tovok (BIBW 2992), XL 647, AEE788, matuzumab, and pertuzumab.
5. Investigational therapy as only treatment for advanced NSCLC, without administration of an approved chemotherapy for advanced NSCLC.
6. Any surgery (not including minor procedures such as lymph node biopsy) within 2 weeks of baseline disease assessments; or not fully recovered from any side effects of previous procedures.
7. Any clinically significant gastrointestinal abnormalities, which may impair intake, transit or absorption of the study drug, such as the inability to take oral medication.
8. Current enrollment in another therapeutic clinical trial.
9. 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.
10. Patients with known diffuse interstitial lung disease.
11. uncontrolled or significant cardiovascular disease, including:
a. Myocardial infarction within 12 months;
b. Uncontrolled angina within 6 months;
c. Congestive heart failure within 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 pre entry electrocardiogram. QTc must be less than CTC Grade 2 (≤480 msec) using Fredricia’s correction formula with manual read by 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 (may be eligible if currently have a pacemaker);
h. Heart rate <50/minute on baseline electrocardiogram;
i. Uncontrolled hypertension.
12. Prior malignancy: Patients will not be eligible if they have evidence of other malignancy (other than non melanoma skin cancer or in situ cervical cancer, or localized and presumed cured prostate cancer with Prostate Specific Antigen (PSA) < ULN) within the last 3 years.
13. Other severe acute or chronic medical condition that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
14. Medications are prohibited at baseline and prior to randomization if
they affect the pharmacokinetics of erlotinib. For CYP2D6 substrates,
drug substitution is recommended, if possible. The administration of
CYP2D6 substrates requires
consideration of the therapeutic index and the degree of CYP2D6
metabolism of the dependent CYP2D6 drug. Guidelines about
administration of CYP2D6 substrates provided in the protocol.
15.Patients who are investigational site staff members or patients who
are Pfizer employees directly involved in the conduct of the trial |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Progression Free Survival (PFS) per Independent Radiologic Review in the co primary populations. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Progression Free Survival (PFS) as per the Independent Radiological Imaging Vendor – final analysis will be done approximately 10 months after anticipated LSLV. There will be periodic evaluations during the course of the study as individual patients progress (come off study treatment). |
|
| E.5.2 | Secondary end point(s) |
• Overall Survival (OS);
• Progression Free Survival (PFS) per investigator assessment;
• Best Overall Response (BOR);
• Duration of Response (DR).
Overall safety profile as characterized by type, frequency, severity of adverse events as graded by NCI Common Toxicity Criteria for Adverse Events version 4 (NCI CTCAE.v4, Publish Date: 2010, http://ctep.cancer.gov/reporting/ctc.html), timing and relationship to treatment on each arm, laboratory abnormalities observed, and left ventricular imaging observed.
Patient Reported Outcomes of health related quality of life, and disease/treatment related symptoms for patients in each arm as measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30), Appendix 5, and its Lung Cancer module (QLQ LC13) Appendix 6 of the protocol.
Patient Reported Outcomes of health status for patients in each arm as measured by the EuroQol 5 Dimension (EQ 5D) Appendix 7 of the protocol.
KRAS and HER family genotypes in tumor tissue (fresh or archived);
Trough concentrations (Ctrough) of PF-00299804 and PF-05199265, as determined from trough plasma samples;
Pre- and post-treatment levels in serum of protein which interact with or are part of HER signaling pathways or escape pathways (including, but possibly not limited to TGFalpha, EGF, amphiregulin, HGF), or proteins/peptides potentially predicting response or resistance to dacomitinib or erlotinib;
Optional Research Components:
Subject to IRB/IEC approval/favorable opinion, this study will include an additional research component involving collection of biological samples (whole blood and plasma) at baseline for de identified exploratory molecular profiling (“ ‘omics”) analysis. The Molecular Profiling Supplement to this protocol provides a description of this additional research. Patients may participate in the study even if they choose not to participate in this sample banking component.
Subject to IRB/IEC approval/favorable opinion, this study will include an additional optional research component involving the collection of tissue samples at progression for exploratory biomarker studies (eg, biopsy, or thoracentesis or paracentesis for preparation of a cell block). Tumor tissue would be obtained from patients agreeing to undergo sampling procedure and who in judgment of investigator have accessible tissue and are clinically stable within 4 weeks of progression. Patients, Investigators and/or Institutions may elect not to participate in this portion of the study. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Overall Survival. Patients will be followed up until death (unless the patient is lost to follow-up). |
|
| 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 | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 74 |
| 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 |
| Austria |
| Belgium |
| China |
| Denmark |
| Finland |
| France |
| Germany |
| Greece |
| Hong Kong |
| Hungary |
| India |
| Ireland |
| Japan |
| Korea, Republic of |
| Mexico |
| Peru |
| Poland |
| Russian Federation |
| Slovakia |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| Turkey |
| United Kingdom |
| United States |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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