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A7471055 Treatment Access Protocol For Dacomitinib A7471055 Protocol, 28 January 2015 CLINICAL PROTOCOL — A7471055 TREATMENT ACCESS PROTOCOL FOR PATIENTS PREVIOUSLY TREATED WITH DACOMITINIB ON A CLINICAL TRIAL IN JAPAN Compound: PF-00299804 Compound Name: Dacomitinib United States (US) Investigational New CCI Drug (IND) Number: European Clinical Trials Database N/A (EudraCT) Number: Protocol Number: A7471055 Phase: Phase 2 Page 1 Dacomitinib A7471055 Protocol, 28 January 2015 Document History Document Version Date Summary of Changes Original Protocol 28 January 2015 Not Applicable (N/A) Page 2 Dacomitinib A7471055 Protocol, 28 January 2015 Abbreviations Abbreviation Term AE adverse event ALT alanine transaminase AST aspartate transaminase ATP adenosine triphosphate BUN blood urea nitrogen CRF case report form CSA clinical study agreement CSR clinical study report CTCAE Common Terminology Criteria for Adverse Events DAI dosage and administration instructions DMC data monitoring committee DVT deep vein thrombosis EC ethics committee ECG Electrocardiogram ECOG Eastern Cooperative Group EDP exposure during pregnancy EGFR epidermal growth factor receptor EDTA edetic acid (ethylenediaminetetraacetic acid) GCP Good Clinical Practice HDPE High Density PolyEthylene HER Human Epidermal Growth Factor receptor IB Investigator’s Brochure ICH International Conference on Harmonisation ID Identification IEC institutional ethics committee IND investigational new drug application INR international normalized ratio IRB institutional review board IUD intrauterine device KRAS Kirsten Rat Sarcoma viral oncogene homolog LFT liver function test LSLV last subject last visit N/A not applicable NCIC-CTG National Cancer Institute of Canada-Clinical Trials Group NSCLC non-small cell lung cancer OS overall survival PCD primary completion date PFS progression-free survival PS performance status PT prothrombin time RTK receptor tyrosine kinase Page 3 Dacomitinib A7471055 Protocol, 28 January 2015 SAE serious adverse event SOP standard operating procedure SRSD single reference safety document ULN upper limit of normal US United States WBC white blood cell Page 4 Dacomitinib A7471055 Protocol, 28 January 2015 PROTOCOL SUMMARY Indication: This treatment extension study will enroll patients with advanced cancer who are receiving single-agent dacomitinib in a prior study in Japan, and have the potential to derive clinical benefit without unacceptable toxicity from continued single-agent dacomitinib treatment. Background and Rationale: Dacomitinib is an orally available, selective adenosine triphosphate (ATP)-competitive irreversible small-molecule inhibitor of Human Epidermal Growth Factor receptor (HER, erbB) family receptor tyrosine kinases (RTKs) including the epidermal growth factor receptor (EGFR, HER-1), HER-2 receptor (erbB2), and HER-4 (erbB4) receptor and their oncogenic variants (ie, EGFR exon 19 deletion, EGFR L858R point mutation, and EGFR T790M mutation). Dacomitinib is being developed globally in locally advanced or metastatic non-small cell lung cancer (NSCLC) after at least one prior chemotherapy regimen. In the course of development, Phase 2 and 3 studies are being conducted in several NSCLC treatment settings. Complete information for this compound may be found in the Single Reference Safety Document (SRSD), which for this study is the Investigator’s Brochure (IB). Indications of activity have been seen in a number of dacomitinib clinical trials. This protocol permits continued access to dacomitinib for patients who participated in other dacomitinib monotherapy treatment protocols and have the potential to derive clinical benefit without unacceptable toxicity from continued dacomitinib treatment. This treatment access protocol is only open to patients in Japan. Patients will follow a schedule of visits and data collection that permits continued safety monitoring. Objectives: Primary Objective: To allow access to dacomitinib for patients who received dacomitinib on a prior study in Japan and who have the potential to derive continued clinical benefit from single-agent dacomitinib treatment without unacceptable toxicity based upon the investigator’s judgment. Secondary Objective: To monitor the specific long-term safety and tolerability of single-agent dacomitinib in patients who have already received dacomitinib on a prior study in Japan. Page 5 Dacomitinib A7471055 Protocol, 28 January 2015 Endpoints: Adverse events as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE.v4.0). Study Design: This is a multi-center, open-label, treatment extension study open in Japan only. Eligible patients include those with advanced cancer who received and tolerated single-agent dacomitinib in a prior clinical study and have the potential to derive continued clinical benefit based on investigator judgment. Patients enrolled in this extension study may continue to receive dacomitinib starting at the current dose level in the prior study. Dose reductions and re-escalations are allowed based on tolerability. Patients may continue to be treated with dacomitinib on this protocol as long as there is evidence of clinical benefit in the judgment of the investigator. Adverse events will be graded according to NCI CTCAE v4.0, and monitored according to the frequency outlined in the Safety Review Plan. Study Treatment: Patients will receive continuous daily dosing of dacomitinib at a dose of 45 mg, 30 mg, or 15 mg. The starting dose of dacomitinib on this treatment extension study will be the patient’s ending dose from the prior study. Patients may continue single-agent dacomitinib treatment on this treatment extension study as long as there is reasonable evidence of clinical benefit without unacceptable toxicity per investigator judgment and with agreement of the Sponsor (see Section 6.1 Patient Withdrawal). Statistical Methods: Due to the nature of this study, the number of patients to be enrolled is not predetermined. No statistical methods will be employed to test a specific hypothesis in this study. Only descriptive summaries of safety will be provided, and no inferential analyses are planned. Page 6 Dacomitinib A7471055 Protocol, 28 January 2015 SCHEDULE OF ACTIVITIES The Schedule of Activities table provides details of the protocol visits and procedures. Refer to the Study Procedures and Assessments sections of the protocol for additional information on certain specific procedures and assessments required for compliance with the protocol. The investigator may schedule visits (unplanned visits), in addition to those listed on the schedule of activities, in order to conduct evaluations or assessments required to protect the well-being of the patient. Page 7 Dacomitinib A7471055 Protocol, 28 January 2015 Table 1. SCHEDULE OF ACTIVITIES Protocol Activity Screening Cycle 1 Cycles 2 and beyond End of Follow-up (28 days Day 1 Treatment Visit9 prior to Every Every study entry) 8 weeks 6 months Informed Consent1 X Patient History X Registration X Laboratory Hematology2 X X X Blood Chemistry3 X X X Urinalysis4 X Pregnancy test5 XX X Safety/Disease Assessments Tumor Assessments6 X AdAdverse Event XX X X X Assessments7 Concomitant Medication8 XX X X X Study Treatment As per dosing regimen in original Dacomitinib protocol 1. Informed Consent: All patients must sign an informed consent document prior to any study-related procedures that are not considered to be standard of care and prior to receiving study drug. 2. Hematology: Be performed according to local standard clinical practice. The interval for laboratory assessments should not be longer than every 8 weeks. 3. Blood Chemistry: Be performed according to local standard clinical practice. The interval for laboratory assessments should not be longer than every 8 weeks. 4. Urinalysis: Be performed according to local standard clinical practice. 5. Pregnancy Test: Pregnancy Test (serum or urine) for women of child-bearing potential shall be done at screening and before investigational product administration at the baseline visit. It should be repeated the end of study treatment, and additionally whenever one menstrual cycle is missed, or when potential pregnancy is otherwise suspected. Additional pregnancy tests may also be undertaken if requested by institutional review boards (IRBs)/ethics committees (ECs), or if required by local regulations. 6. Tumor Assessments: On-study tumor assessments should be performed according to site standard-of-care imaging modality. The interval for monitoring disease status and for progression of disease should not be longer than every 6 months. 7. Adverse Event Assessment: Following the first dose, adverse events (AEs) and serious adverse events (SAEs) should be assessed and documented during the study reporting period. All reported study drug-related adverse events must be followed until the event has resolved, returned to baseline, or has been deemed irreversible, or until death, whichever occurs first. 8. Concomitant Medications: Review medications taken by the patient since the last visit to determine whether or not treatment with dacomitinib is contraindicated. 9. Follow-up Visit: At least 28 days, and no more than 35 days, after discontinuation of treatment, patients will return to undergo review of concomitant medications and assessment for resolution of any treatment-related toxicity. Patients continuing to experience toxicity at this point following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination,
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