Study For Patients With NSCLC EGFR Mutations (Del 19 or L858R +/- T790M)

Study Overview
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Brief Summary
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This is a Phase 1/2 study of PF-06747775 as a single agent and in combination with other cancer treatments in patients with advanced EGFRm NSCLC. The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M).

Detailed Description
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There remains an unmet medical need to develop EGFR TKI agents that effectively target both the single activating mutations of del 19 and L858R, and the secondary resistance mutation T790M, while sparing WT EGFR. Drugs active against the resistance mutation will enable molecularly targeted therapy with a more favorable toxicity profile than the current standard of cytotoxic chemotherapy platinum based doublets. Furthermore, by having a wide margin of selectivity favoring the EGFR mutants versus WT EGFR, PF 06747775 is likely to be positioned to improve patient outcomes from an efficacy and safety perspective.

Official Title
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PHASE 1/2 OPEN-LABEL STUDY OF PF-06747775 (EPIDERMAL GROWTH FACTOR RECEPTOR T790M INHIBITOR) IN PATIENTS WITH ADVANCED EPIDERMAL GROWTH FACTOR RECEPTOR MUTANT (DEL 19 OR L858R ± T790M) NON-SMALL CELL LUNG CANCER

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: PF-06747775
* Drug: Palbociclib
* Drug: Avelumab


Participation Criteria
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Eligibility Criteria
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Partial Inclusion criteria: Evidence of histologically or cytologically confirmed diagnosis of locally advanced or metastatic EGFRm (del 19 or L858R) NSCLC: As detected by local EGFR mutation test that includes QIAGEN therascreen EGFR RGQ PCR kit, Roche cobas® EGFR Mutation Test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory (with tissue submitted for central laboratory confirmation via FDA approved QIAGEN therascreen RCQ PCR kit). T790M disease as follows: Phase 1 If a repeat biopsy was performed on the tumor following prior EGFR TKI therapy, then T790M positive disease must be present. Patients of unknown T790M status following EGFR TKI progression (ie, no post EGFR TKI progression biopsy was performed) are eligible. In the PK sub-studies involving food/antacid and CYP3A4 effects, patients with EGFRm (del 19 or L858R) with any T790M status are eligible to enroll. Studies at RP2D Cohort 1: Patients may have de novo T790M mutation, but it is not required. Cohort 2 and Cohort 3: Patients must have EGRFm (del 19 AND T790M or L858R AND T790M) NSCLC tumors as detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR RGQ PCR kit, Roche cobas® EGFR Mutation Test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by the central validated Thermo Fisher Scientific Oncomine Next Generation Sequencing (NGS) cancer panel test. Patients will also be enrolled if they solely test positive for EGFR (del 19 AND T790M or L858R AND T790M) NSCLC in plasma detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR Plasma RGQ kit, Roche cobas® EGFR mutation test v2 (US-IVD) or Sysmex Inostic's OncoBEAMTM EGFR test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by a validated cfDNA test as determined by the Sponsor. Prior treatment for EGFRm NSCLC as follows: Phase 1 Has progressed after at least 1 prior line of therapy including and EGFR TKI. Patients may have also received other lines of therapy before or after the EGFR TKI. Studies at RP2D Cohort 1: no prior treatment for locally advanced or metastatic EGFRm NSCLC. Cohorts 2 and 3: must have had disease progression on treatment with an approved 1st or 2nd generation EGFR TKI. Patients who have been treated with a 3rd generation EGFR TKI are ineligible for this study. Patients may have had multiple lines of therapy; however, the last therapy prior to study treatment must have been an approved EGFR TKI and received within 6 weeks prior to study registration. Patients must have at least one measurable lesion as defined by RECIST version 1.1 that has not been previously irradiated. Tumor tissue available. Requesting formalin fixed paraffin embedded (FFPE) block or 15 unstained sections (5 micron). If a lesser amount of tissue is available, contact the sponsor. An archival specimen is acceptable for Phase 1; a de novo specimen is required for Cohorts 2, and 3 if the T790M status was confirmed by tissue biopsy. Partial Exclusion Criteria: For All Phases/Cohorts Previously diagnosed brain metastases, unless the patient has completed the treatment that is clinically indicated, if any, and has recovered from the acute effects of any treatment that was delivered prior to study registration, have discontinued corticosteroid treatment for these metastases prior to registration, and are neurologically stable. Major surgery within 2 weeks prior to registration. Radiation therapy, excluding stereotactic radiosurgery (SRS), within 1 week prior to registration. Systemic anti cancer therapy within 2 weeks or 5 half-lives (whichever is longer) of registration excluding EGFR TKIs. Patients on EGFR TKIs must discontinue the agent for a minimum of: 2 days prior to registration for erlotinib or afatinib, or 3 days for gefitinib if they will be part of the lead-in single dose PF-06747775 PK study (Phase 1 Dose Escalation Single and Multiple dose PK and ECG Assessments; Phase 1 Sildenafil at MTD; and Phase 1b/2 First-Line Single Agent). Please contact the Sponsor for direction for any other EGFR TKI. 5 half-lives or 5 days (whichever is longer) prior to registration if they will be starting on continuous PF-06747775 dosing directly (Phase 1 PK sub-studies at RP2D; Phase 1b/2 Combination with Palbociclib; Phase 1b Combination with Avelumab). Partial Exclusions for Cohort 2A and 2B (Palbociclib combo): Prior treatment with a CDK 4/6 inhibitor. Partial Exclusions for Cohort 3 (Avelumab combo): Prior therapy with an anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti cytotoxic T lymphocyte associated antigen 4 (CTLA 4) antibody (including ipilimumab, tremelimumab or any other antibody or drug specifically targeting T cell co stimulation or immune checkpoint pathways). Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible Use of immunosuppressive medication at time of randomization

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Cohort 1 will be initiated (current dose 200 mg) | Drug: PF-06747775<br> <br> |
| Experimental: Cohort 2A<br>Cohort 2A will evaluate PF-06747775 200 mg by mouth (PO) daily (QD) in combination with palbociclib continuous PO QD dosing in 21-day cycles. The starting dose (DL1) for palbociclib will be 100 mg PO daily. Dose finding will follow mTPI method with adjustments using DLT rate. | Drug: PF-06747775<br> <br> Drug: Palbociclib<br> <br> |
| Experimental: Cohort 2B<br>Cohort 2B will be initiated once the RP2D of the PF-06747775 and palbociclib combination is determined. | Drug: PF-06747775<br> <br> Drug: Palbociclib<br> <br> |
| Experimental: Cohort 3<br>Cohort 3 combination is PF-06747775 200 mg PO QD and avelumab 10 mg/kg IV Q2W in 28-day (4-week) cycles. Dose finding will follow the mTPI design. Once RP2D of PF-06747775 in combination with avelumab is determined, the Dose Expansion Phase will be opened. | Drug: PF-06747775<br> <br> Drug: Avelumab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) During the First Cycle in Phase 1 Dose-escalation Cohorts, Japan LIC and Phase 1b Cohort 3, and First 2 Cycles in Phase 1b Cohort 2A | DLT was defined as any of the following adverse events (AEs) occurring during the first cycle for Phase 1 dose-escalation cohorts, Japan LIC and Phase 1b Cohort 3, or the first 2 cycles for Phase 1b Cohort 2A of treatment, and considered attributable to study intervention: Grade 4 neutropenia >7 days; febrile neutropenia; Grade >=3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia; Grade >=3 non-hematologic toxicities; Grade 4 rash, mucositis, or diarrhea; failure to receive at least 70% of planned doses; Grade 3 QTcF prolongation in asymptomatic participants; treatment-related AEs attributable to PF-06747775, palbociclib or both that caused palbociclib treatment delay >= 10 days or omission of at least 12 doses of the combination. Grade of AE was defined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. | 21 days for Phase 1 dose-escalation cohorts and Japan LIC; 42 days for Phase 1b Cohort 2A; 28 days for Phase 1b Cohort 3 | 
| Number of Participants With Confirmed Objective Response (OR) in PF-06747775 200 mg QD Group | Number of participants with confirmed OR according to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1. Complete response (CR) was defined as complete disappearance of all target lesions with the exception of nodal disease. Partial response (PR) was defined as Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. | Baseline up to end of treatment (maximum of 165 weeks) | 
| Progression-free Survival (PFS) in Phase 2 Cohort 2B | PFS was based on Kaplan-Meier estimates. PFS was defined as the time from Cycle 1 Day 1 to the date of the first documentation of objective progression (PD) or death due to any cause. PD was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm. | Cycle 1 Day 1 up to the end of study (maximum of 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent AEs (TEAEs) in All Cohorts All Phases (All-causality) | AE = any untoward medical occurrence in participant who received study treatment without regard to possibility of causal relationship. Grade 3 (Severe) events = unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death. Grade 5 (Death) events = death related to an AE. Treatment-emergent events = between first dose of study treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. | Baseline up to 28 days after last dose of study treatment (maximum of 199 weeks) | 
| Number of Participants With TEAEs in All Cohorts All Phases (Treatment-related) | Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Grade 3 (Severe) events = unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death. Grade 5 (Death) events = death related to an AE. Treatment-emergent events = between first dose of study treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Treatment-related AEs were determined by the investigator. | Baseline up to 28 days after last dose of study treatment (maximum of 199 weeks) | 
| Number of Participants With Serious Adverse Events (SAEs) in All Cohorts All Phases | An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-related SAEs were determined by the investigator. | Baseline up to 28 days after last dose of study treatment (maximum of 199 weeks) | 
| Number of Participants With Shifts of Laboratory Results From Grade <=2 at Baseline to Grade 3 or 4 Post-baseline in All Cohorts All Phases | Laboratory values included hemoglobin, platelets, white blood cell count (WBC), absolute (abs) neutrophils, abs lymphocytes, abs monocytes, abs eosinophils, abs basophils, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (Alk Phos), sodium, potassium, magnesium, chloride, total calcium, total bilirubin, blood urea nitrogen (BUN) or urea, creatinine, uric acid, glucose, albumin, phosphorous or phosphate, prothrombin time (PT) or international normalized ratio (INR), partial thromboplastin time (PTT), urinalysis and pregnancy test. Grades of laboratory results were defined by NCI CTCAE version 4.03. Grade 3 (Severe) events = unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death. | Baseline up to the end of treatment (maximum of 195 weeks) | 
| Number of Participants Meeting Categorical Criteria of QTcF Values When PF-06747775 Was Given as a Single Agent, and in Combination With Palbociclib and Avelumab. | Number of participants meeting categorical criteria of QTcF values when PF-06747775 was given as a single agent in Phase 1 dose-escalation cohorts, PF-06747775 200 mg QD group (only participants in Phase 2 Cohort 1 and Japan LIC were eligible for QTcF within this combined group), and in combination with palbociclib and avelumab in Phase 1b/2 Cohorts 2A, 2B and 3. Criteria for categorization of QTcF were defined as: maximum values 450 - <480 msec, 480 - <500 msec and >=500 msec. | Baseline up to Cycle 4 Day 1 (maximum of 10 weeks) | 
| Number of Participants Meeting Categorical Criteria of QTcB Values When PF-06747775 Was Given as a Single Agent, and in Combination With Palbociclib and Avelumab. | Number of participants meeting categorical criteria of QTcB values when PF-06747775 was given as a single agent in Phase 1 dose-escalation cohorts, PF-06747775 200 mg QD group (only participants in Phase 2 Cohort 1 and Japan LIC were eligible for QTcB within this combined group), and in combination with palbociclib and avelumab in Phase 1b/2 Cohorts 2A, 2B and 3. Criteria for categorization of QTcB were defined as: maximum values 450 - <480 msec, 480 - <500 msec and >=500 msec. | Baseline up to Cycle 4 Day 1 (maximum of 10 weeks) | 
| Number of Participants With Confirmed and Unconfirmed OR in Phase 1 Cohorts | Number of participants in Phase 1 cohorts with confirmed and unconfirmed OR according to RECIST v1.1. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. PR was defined as Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. Stable was defined as not qualifying for CR, PR or PD. PD was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm. Indeterminate was defined as progression not documented. | Baseline up to end of treatment (maximum of 195 weeks) | 
| Objective Response Rate (ORR) in Phase 1b/2 Cohorts 2A, 2B and 3 | ORR was defined as percentage of participants with OR based assessment of CR or PR according to RECIST v1.1 that must have been confirmed ≥4 weeks later. Participants who did not have an on treatment radiographic tumor assessment due to early progression, who received anti tumor treatment other than the study medication prior to reaching a CR or PR, or who died, progressed, or dropped out for any reason prior to reaching a CR or PR were counted as non responders in the assessment of ORR. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. PR was defined as Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. | Baseline up to end of treatment (maximum of 108 weeks) | 
| PFS in PF-06747775 200 mg QD Group, Phase 1b Cohorts 2A and 3 | PFS was based on Kaplan-Meier estimates. PFS was defined as the time from Cycle 1 Day 1 to the date of the first documentation of PD or death due to any cause. PD was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm. | Cycle 1 Day 1 up to the end of study (maximum of 5 years) | 
| Duration of Objective Response (DOR) in Phase 1b/2 Cohorts | DOR was the time from the date of first documentation of confirmed CR or PR to the date of first documentation of PD or death due to any cause. If tumor progression data included more than 1 date, the first date was used. DOR (months) = [progression/death date - first date of OR + 1]/30.4. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. PR was defined as Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. Stable was defined as not qualifying for CR, PR or PD. PD was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm. | Baseline up to the end of study (maximum of 5 years) | 
| Overall Survival (OS) Probability at 12 Months in Phase 1b/2 Cohorts | OS probability was based on Kaplan-Meier method. OS was defined as the time from the start date to date of death due to any cause. In the absence of confirmation of death, survival time was censored at the last date the participant was known to be alive. | Baseline up to the end of study (maximum of 5 years) | 
| Plasma Area Under the Curve From Zero to Infinite Time (AUCinf) of PF-06747775 as a Single Agent After Single Dose on Day -8 lead-in Period in Phase 1 Dose-escalation Cohorts and on Day -4 lead-in Period in Phase 2 Cohort 1 | Plasma area under the curve from zero to infinite time (AUCinf) of PF-06747775 as a single agent after single dose on Day -8 lead-in period in Phase 1 dose-escalation cohorts and on Day -4 lead-in period in Phase 2 Cohort 1. AUCinf was area under the plasma concentration versus time curve (AUC) from zero to extrapolated infinite time. | 1, 2, 4, 6, 8, 24, 48 and 72 hours post-dose on Day -8 (+/- 3 days) in lead-in period for Phase 1 dose-escalation cohorts and on Day -4 in lead-in period for Phase 2 Cohort 1 | 
| Maximum Concentration Observed After Dose Administration (Cmax) of PF-06747775 as a Single Agent After Single Dose on Day -8 lead-in Period in Phase 1 Dose-escalation Cohorts and on Day -4 lead-in Period in Phase 2 Cohort 1 | Cmax of PF-06747775 as a single agent after single dose on Day -8 lead-in period in Phase 1 dose-escalation cohorts and on Day -4 lead-in period in Phase 2 Cohort 1. Cmax was the maximum concentration after dose administration observed directly from the data. | 1, 2, 4, 6, 8, 24, 48 and 72 hours post-dose on Day -8 (+/- 3 days) in lead-in period for Phase 1 dose-escalation cohorts and on Day -4 in lead-in period for Phase 2 Cohort 1 | 
| Half-life (t1/2) of PF-06747775 as a Single Agent After Single Dose on Day -8 lead-in Period in Phase 1 Dose-escalation Cohorts and on Day -4 lead-in Period in Phase 2 Cohort 1 | Half-life (t1/2) of PF-06747775 as a single agent after single dose on Day -8 lead-in period in Phase 1 dose-escalation cohorts and on Day -4 lead-in period in Phase 2 Cohort 1. t1/2 was defined as the time measured for the plasma concentration to decrease by one half. | 1, 2, 4, 6, 8, 24, 48 and 72 hours post-dose on Day -8 (+/- 3 days) in lead-in period for Phase 1 dose-escalation cohorts and on Day -4 in lead-in period for Phase 2 Cohort 1 | 
| Apparent Clearance (CL/F) of PF-06747775 as a Single Agent After Single Dose on Day -8 lead-in Period in Phase 1 Dose-escalation Cohorts and on Day -4 lead-in Period in Phase 2 Cohort 1 | Apparent clearance (CL/F) of PF-06747775 as a single agent after single dose on Day -8 lead-in period in Phase 1 dose-escalation cohorts and on Day -4 lead-in period in Phase 2 Cohort 1. CL/F was calculated as: CL/F = dose / AUCinf. AUCinf was area under the plasma concentration versus time curve (AUC) from zero to extrapolated infinite time. | 1, 2, 4, 6, 8, 24, 48 and 72 hours post-dose on Day -8 (+/- 3 days) in lead-in period for Phase 1 dose-escalation cohorts and on Day -4 in lead-in period for Phase 2 Cohort 1 | 
| Volume of Distribution (Vz/F) of PF-06747775 as a Single Agent After Single Dose on Day -8 lead-in Period in Phase 1 Dose-escalation Cohorts and on Day -4 lead-in Period in Phase 2 Cohort 1 | Vz/F was defined as apparent volume of distribution. Vz/F was calculated as: Vz/F = dose / (AUCinf * kel). kel was defined as terminal phase rate constant and calculated by a linear regression of the log-linear concentration-time curve. AUCinf was area under the plasma concentration versus time curve (AUC) from zero to extrapolated infinite time. | 1, 2, 4, 6, 8, 24, 48 and 72 hours post-dose on Day -8 (+/- 3 days) in lead-in period for Phase 1 dose-escalation cohorts and on Day -4 in lead-in period for Phase 2 Cohort 1 | 
| Pre-dose Concentration at Steady State (Ctrough) of PF-06747775 as a Single Agent After Multiple Doses on Cycle 1 Day 11 in Phase 1 Dose-escalation Cohorts and Phase 2 Cohorts 1 and 2B | Pre-dose concentration at steady state (Ctrough) of PF-06747775 as a single agent after multiple doses on Cycle 1 Day 11 in Phase 1 dose-escalation cohorts, Phase 2 Cohorts 1 and 2B. Ctrough was defined as pre-dose concentration during multiple dosing and observed directly from data. | Pre-dose on Cycle 1 Day 11 | 
| Area Under the Curve at Steady State (AUCtau) of PF-06747775 as a Single Agent After Multiple Doses on Cycle 1 Day 11 in Phase 1 Dose-escalation Cohorts and Phase 2 Cohorts 1 and 2B | AUCtau was defined as area under the plasma concentration-time profile from time zero to tau, the dosing interval, where tau = 24 hours. AUCtau was calculated using Linear/Log trapezoidal method. | 0 (pre-dose), 1, 2, 4, 6, 8, 24 hours post-dose on Cycle 1 Day 11 for Phase 1 dose-escalation cohorts; 0 (pre-dose), 1, 2, 4, 6, 24 hours post-dose on Cycle 1 Day 11 for Phase 2 Cohorts 1 and 2B | 
| CL/F of PF-06747775 as a Single Agent After Multiple Doses on Cycle 1 Day 11 in Phase 1 Dose-escalation Cohorts and Phase 2 Cohorts 1 and 2B | CL/F of PF-06747775 as a single agent after multiple doses on Cycle 1 Day 11 in Phase 1 dose-escalation cohorts, Phase 2 Cohorts 1 and 2B. CL/F was calculated as: CL/F = dose / AUCtau. AUCtau was defined as area under the plasma concentration-time profile from time zero to tau, the dosing interval, where tau = 24 hours. AUCtau was calculated using Linear/Log trapezoidal method. | 0 (pre-dose), 1, 2, 4, 6, 8, 24 hours post-dose on Cycle 1 Day 11 for Phase 1 dose-escalation cohorts; 0 (pre-dose), 1, 2, 4, 6, 24 hours post-dose for Phase 2 Cohorts 1 and 2B | 
| Observed Accumulation Ratio (Rac) of PF-06747775 as a Single Agent After Multiple Doses on Cycle 1 Day 11 in Phase 1 Dose-escalation Cohorts and Phase 2 Cohorts 1 and 2B | Rac was calculated as: Rac = (steady state AUCtau) / (single dose AUC24). AUCtau was defined as area under the plasma concentration-time profile from time zero to tau, the dosing interval, where tau = 24 hours. AUCtau was calculated using Linear/Log trapezoidal method. AUC24 was defined as area under the plasma concentration-time curve from time 0 to 24 hours. | 1, 2, 4, 6, 8 and 24 hours post dose on Lead-in Day -8 (dose-escalation cohorts) or -4 (Cohort 1); 0 (pre-dose), 1, 2, 4, 6, 8 (except for Cohort 1) and 24 hours post dose on Cycle 1 Day 11 for dose-escalation cohorts, Cohorts 1 and 2B | 
| Steady State Accumulation Ratio (Rss) of PF-06747775 as a Single Agent After Multiple Doses on Cycle 1 Day 11 in Phase 1 Dose-escalation Cohorts and Phase 2 Cohorts 1 and 2B | Steady state accumulation ratio (Rss) of PF-06747775 as a single agent after multiple doses on Cycle 1 Day 11 in Phase 1 dose-escalation cohorts, Phase 2 Cohorts 1 and 2B. Rss was calculated as: Rss = (steady state AUCtau) / (single dose AUCinf). AUCtau was defined as area under the plasma concentration-time profile from time zero to tau, the dosing interval, where tau = 24 hours. AUCtau was calculated using Linear/Log trapezoidal method. AUCinf was area under the plasma concentration versus time curve (AUC) from zero to extrapolated infinite time. | 1, 2, 4, 6, 8, 24, 48 and 72 hours post dose on Lead-in Day -8 (dose-escalation cohorts) or Day -4 (Cohort 1); 0 (pre-dose), 1, 2, 4, 6, 8 (except for Cohort 1) and 24 hours post dose on Cycle 1 Day 11 | 
| AUCinf of Sildenafil Dosed Alone on Day -8 lead-in Period in Phase 1 Sildenafil Sub-study | AUCinf of sildenafil dosed alone and in combination with PF-06747775 200 mg or 300 mg on Day -8 lead-in period in Phase 1 Sildenafil sub-study. AUCinf was defined as area under the plasma concentration versus time curve from zero to extrapolated infinite time. | 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose on Day -8 (+/- 3 days) in lead-in period | 
| Cmax of Sildenafil Dosed Alone on Day -8 lead-in Period in Phase 1 Sildenafil Sub-study | Cmax values for sildenafil were analyzed using a mixed effects model with treatment as fixed effect and participant as random effect to estimate the effect of steady state PF-06747775 on sildenafil exposure. Cmax was the maximum concentration after dose administration observed directly from the data. | 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post dose on Day -8 (+/- 3 days) in lead-in period | 
| CL/F of Sildenafil Dosed Alone on Day -8 lead-in Period in Phase 1 Sildenafil Sub-study | CL/F of sildenafil dosed alone on Day -8 lead-in period in Phase 1 Sildenafil sub-study. CL/F was calculated as: CL/F = dose / AUCinf. AUCinf was area under the plasma concentration versus time curve (AUC) from zero to extrapolated infinite time. | 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post dose on Day -8 (+/- 3 days) in lead-in period | 
| AUCinf of Sildenafil Dosed in Combination With PF-06747775 200 mg or 300 mg on Cycle 1 Day 11 in Phase 1 Sildenafil Sub-study | AUCinf of sildenafil dosed alone and in combination with PF-06747775 200 mg or 300 mg on Day -8 lead-in period in Phase 1 Sildenafil sub-study. AUCinf was defined as area under the plasma concentration versus time curve from zero to extrapolated infinite time. | 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 11 (+/- 4 days) | 
| Cmax of Sildenafil Dosed in Combination With PF-06747775 200 mg or 300 mg on Cycle 1 Day 11 in Phase 1 Sildenafil Sub-study | Cmax values for sildenafil were analyzed using a mixed effects model with treatment as fixed effect and participant as random effect to estimate the effect of steady state PF-06747775 on sildenafil exposure. | 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 11 (+/- 4 days) | 
| CL/F of Sildenafil Dosed in Combination With PF-06747775 200 mg or 300 mg on Cycle 1 Day 11 in Phase 1 Sildenafil Sub-study | CL/F of sildenafil dosed alone and in combination with PF-06747775 200 mg or 300 mg on Day -8 lead-in period and Cycle 1 Day 11 in Phase 1 Sildenafil sub-study. CL/F was calculated as: CL/F = dose / AUCinf. AUCinf was area under the plasma concentration versus time curve (AUC) from zero to extrapolated infinite time. | 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 11 (+/- 4 days) | 
| AUCtau of PF-06747775 at RP2D Under Fed and Overnight Fasted Conditions in Phase 1 Food Effect and Rifampin DDI Sub-study | AUCtau of PF-06747775 at the RP2D under fed and overnight fasted conditions in Phase 1 Food Effect and Rifampin DDI sub-study. AUCtau was defined as area under the plasma concentration-time profile from time zero to tau, the dosing interval, where tau = 24 hours. AUCtau was calculated using Linear/Log trapezoidal method. | Pre-dose, 1, 2, 4, 6, 8 and 24 hours post dose of PF-06747775 on Cycle 1 Days 8 and 9 | 
| Cmax of PF-06747775 at RP2D Under Fed and Overnight Fasted Conditions in Phase 1 Food Effect and Rifampin DDI Sub-study | Cmax of PF-06747775 at the RP2D under fed and overnight fasted conditions in Phase 1 Food Effect and Rifampin DDI sub-study. Cmax was the maximum concentration after dose administration observed directly from the data. | Pre-dose, 1, 2, 4, 6, 8 and 24 hours post dose of PF-06747775 on Cycle 1 Days 8 and 9 | 
| AUCtau of PF-06747775 at RP2D When Dosed Alone and After Esomeprazole/Itraconazole Treatment in Phase 1 Esomeprazole-Itraconazole DDI Sub-study | AUCtau of PF-06747775 at the RP2D when dosed alone and after esomeprazole/itraconazole treatment in Phase 1 Esomeprazole-Itraconazole DDI sub-study. AUCtau was defined as area under the plasma concentration-time profile from time zero to tau, the dosing interval, where tau = 24 hours. AUCtau was calculated using Linear/Log trapezoidal method. | 0 (pre-dose), 1, 2, 4, 6, 8 and 24 hours post dose of PF-06747775 on Cycle 1 Days 8, 13 and 21 | 
| Cmax of PF-06747775 at RP2D When Dosed Alone and After Esomeprazole/Itraconazole Treatment in Phase 1 Esomeprazole-Itraconazole DDI Sub-study | Cmax of PF-06747775 at RP2D when dosed alone and after esomeprazole/itraconazole treatment in Phase 1 Esomeprazole-Itraconazole DDI sub-study. Cmax was the maximum concentration after dose administration observed directly from the data. | 0 (pre-dose), 1, 2, 4, 6, 8 and 24 hours post dose of PF-06747775 on Cycle 1 Days 8, 13 and 21 | 
| AUCtau of PF-06747775 at RP2D Dosed Alone and After Rifampin Treatment in Phase 1 Food Effect and Rifampin DDI Sub-study | AUCtau of PF-06747775 at RP2D dosed alone and after rifampin treatment in Phase 1 Food Effect and Rifampin DDI sub-study. AUCtau was defined as area under the plasma concentration-time profile from time zero to tau, the dosing interval, where tau = 24 hours. AUCtau was calculated using Linear/Log trapezoidal method. | Pre-dose, 1, 2, 4, 6, 8 and 24 hours post dose of PF-06747775 on Cycle 1 Day 21 | 
| Cmax of PF-06747775 at RP2D Dosed Alone and After Rifampin Treatment in Phase 1 Food Effect and Rifampin DDI Sub-study | Cmax of PF-06747775 at RP2D dosed alone and after rifampin treatment in Phase 1 Food Effect and Rifampin DDI sub-study. Cmax was the maximum concentration after dose administration observed directly from the data. | Pre-dose, 1, 2, 4, 6, 8 and 24 hours post dose of PF-06747775 on Cycle 1 Day 21 | 
| AUCtau of PF-06747775 Following Multiple Doses When Given in Combination With Palbociclib on Cycle 1 Day 15 in Phase 1b Cohort 2A and Phase 2 Cohort 2B | AUCtau of PF-06747775 following multiple doses when given in combination with palbociclib on Cycle 1 Day 15 in Phase 1b Cohort 2A and Phase 2 Cohort 2B. AUCtau was defined as area under the plasma concentration-time profile from time zero to tau, the dosing interval, where tau = 24 hours. AUCtau was calculated using Linear/Log trapezoidal method. | 0 (pre-dose), 1, 2, 4, 6 and 24 hours post dose on Cycle 1 Day 15 | 
| Cmax of PF-06747775 Following Multiple Doses When Given in Combination With Palbociclib on Cycle 1 Day 15 in Phase 1b Cohort 2A and Phase 2 Cohort 2B | Cmax of PF-06747775 following multiple doses when given in combination with palbociclib on Cycle 1 Day 15 in Phase 1b Cohort 2A and Phase 2 Cohort 2B. Cmax was the maximum concentration after dose administration observed directly from the data. | 0 (pre-dose), 1, 2, 4, 6 and 24 hours post dose on Cycle 1 Day 15 | 
| CL/F of PF-06747775 Following Multiple Doses When Given in Combination With Palbociclib on Cycle 1 Day 15 in Phase 1b Cohort 2A and Phase 2 Cohort 2B | CL/F of PF-06747775 following multiple doses when given in combination with palbociclib on Cycle 1 Day 15 in Phase 1b Cohort 2A and Phase 2 Cohort 2B. CL/F was calculated as: CL/F = dose / AUCtau. AUCtau was defined as area under the plasma concentration-time profile from time zero to tau, the dosing interval, where tau = 24 hours. AUCtau was calculated using Linear/Log trapezoidal method. | 0 (pre-dose), 1, 2, 4, 6 and 24 hours post dose on Cycle 1 Day 15 | 
| Ctrough of PF-06747775 Following Multiple Doses When Given in Combination With Palbociclib on Day 15 of Cycles 1-2 and Day 1 of Cycles 2-4 in Phase 1b Cohort 2A and Phase 2 Cohort 2B | Ctrough of PF-06747775 following multiple doses when given in combination with palbociclib on Day 15 of Cycles 1-2 and Day 1 of Cycles 2-4 in Phase 1b Cohort 2A and Phase 2 Cohort 2B. Ctrough was defined as pre-dose concentration during multiple dosing and observed directly from data. | Pre-dose on Day 15 of Cycles 1-2 and Day 1 of Cycles 2-4 | 
| Ctrough of PF-06747775 Following Multiple Doses When Given in Combination With Avelumab on Cycle 1 Day 15 in Phase 1b Cohort 3 | Ctrough of PF-06747775 following multiple doses when given in combination with avelumab on Cycle 1 Day 15 in Phase 1b Cohort 3. Ctrough was defined as pre-dose concentration during multiple dosing and observed directly from data. | Pre-dose on Cycle 1 Day 15 | 
| AUCtau of Palbociclib Following Multiple Doses When Given in Combination With PF-06747775 on Cycle 1 Day 15 in Phase 1b Cohort 2A and Phase 2 Cohort 2B | AUCtau of palbociclib following multiple doses when given in combination with PF-06747775 on Cycle 1 Day 15 in Phase 1b Cohort 2A and Phase 2 Cohort 2B. AUCtau was defined as area under the plasma concentration-time profile from time zero to tau, the dosing interval, where tau = 24 hours. AUCtau was calculated using Linear/Log trapezoidal method. | 0 (pre-dose), 1, 2, 4, 6 and 24 hours post dose on Cycle 1 Day 15 | 
| Cmax of Palbociclib Following Multiple Doses When Given in Combination With PF-06747775 on Cycle 1 Day 15 in Phase 1b Cohort 2A and Phase 2 Cohort 2B | Cmax of palbociclib following multiple doses when given in combination with PF-06747775 on Cycle 1 Day 15 in Phase 1b Cohort 2A and Phase 2 Cohort 2B. Cmax was the maximum concentration after dose administration observed directly from the data. | 0 (pre-dose), 1, 2, 4, 6 and 24 hours post dose on Cycle 1 Day 15 | 
| Ctrough of Palbociclib Following Multiple Doses When Given in Combination With PF-06747775 on Day 15 of Cycles 1-2 and Day 1 of Cycles 2-4 in Phase 1b Cohort 2A and Phase 2 Cohort 2B | Ctrough of palbociclib following multiple doses when given in combination with PF-06747775 on Day 15 of Cycles 1-2 and Day 1 of Cycles 2-4 in Phase 1b/2 Cohorts 2A and 2B. Ctrough was defined as pre-dose concentration during multiple dosing and observed directly from data. | Pre-dose on Day 15 of Cycles 1-2 and Day 1 of Cycles 2-4 | 
| Ctrough of Avelumab When Given in Combination With PF-06747775 on Day 1 of Cycles 1-3 and Cycle 1 Day 15 in Phase 1b Cohort 3 | Ctrough of avelumab when given in combination with PF-06747775 on Day 1 of Cycles 1-3 and Cycle 1 Day 15 in Phase 1b Cohort 3. Ctrough was defined as pre-dose concentration during multiple dosing and observed directly from data. | Pre-dose on Day 1 of Cycles 1-3 and Cycle 1 Day 15 | 
| Cmax of Avelumab When Given in Combination With PF-06747775 on Day 1 of Cycles 1-3 and Cycle 1 Day 15 in Phase 1b Cohort 3 | Cmax of avelumab when given in combination with PF-06747775 on Day 1 of Cycles 1-3 and Cycle 1 Day 15 in Phase 1b Cohort 3. Cmax was the end of infusion peak concentration observed directly from data. | End of infusion of avelumab on Day 1 of Cycles 1-3 and Cycle 1 Day 15 | 
| Number of Participants With Epidermal Growth Factor Receptor (EGFR) Mutations in Tumor Tissue in All Cohorts All Phases | Number of participants with EGFR mutations in tumor tissue in all cohorts all phases. EGFR mutation assessments in tumor tissue included the mutations statuses of exon 19 deletion (del 19), exon 21 (L858R), G719X, L861Q, S768I, exon 20 insertions and T790M. | Baseline | 
| Number of Participants With EGFR Mutations in Plasma in All Cohorts All Phases | Number of participants with EGFR mutations in plasma in all cohorts all phases. EGFR mutation assessments in plasma included the mutations statuses of exon 19 deletion (del 19), exon 21 (L858R) and T790M. | Baseline | 
| Number of Participants With Positive Serum Anti-drug Antibody (ADA) of Avelumab in Phase 1b Cohort 3 | Number of participants with positive serum ADA of avelumab at pre-dose on Day 1 of Cycles 1-3 and Cycle 1 Day 15 in Phase 1b Cohort 3. | Pre-dose on Day 1 of Cycles 1-3 and Cycle 1 Day 15 | 
| AUCinf of PF-06747775 Following Single Dose on Lead-in Day -4 in Japan LIC RP2D Cohort, Lead-in Day -7 and Cycle 1 Day 1 in Japan LIC PK Cohort | AUCinf of PF-06747775 following a 200 mg single dose on Lead-in Day -4 in Japan LIC RP2D cohort and Cycle 1 Day 1 in Japan LIC PK cohort, and following a 100 mg single dose on Lead-in Day -7 in Japan LIC PK cohort. AUCinf was defined as area under the plasma concentration versus time curve from zero to extrapolated infinite time. | 0 (pre-dose), 1, 2, 4, 6, 8 and 24 hours post dose on Lead-in Day -4 for Japan LIC RP2D cohort, Lead-in Day -7 and Cycle 1 Day 1 for Japan LIC PK cohort | 
| Cmax of PF-06747775 Following Single Dose on Lead-in Day -4 in Japan LIC RP2D Cohort, Lead-in Day -7 and Cycle 1 Day 1 in Japan LIC PK Cohort | Cmax of PF-06747775 following a 200 mg single dose on Lead-in Day -4 in Japan LIC RP2D cohort and Cycle 1 Day 1 in Japan LIC PK cohort, and following a 100 mg single dose on Lead-in Day -7 in Japan LIC PK cohort. Cmax was the maximum concentration observed from data. | 0 (pre-dose), 1, 2, 4, 6, 8 and 24 hours post dose on Lead-in Day -4 for Japan LIC RP2D cohort, Lead-in Day -7 and Cycle 1 Day 1 for Japan LIC PK cohort | 
| Vz/F of PF-06747775 Following Single Dose on Lead-in Day -4 in Japan LIC RP2D Cohort, Lead-in Day -7 and Cycle 1 Day 1 in Japan LIC PK Cohort | Vz/F of PF-06747775 following a 200 mg single dose on Lead-in Day -4 in Japan LIC RP2D cohort and Cycle 1 Day 1 in Japan LIC PK cohort, and following a 100 mg single dose on Lead-in Day -7 in Japan LIC PK cohort. Vz/F was defined as apparent volume of distribution. Vz/F was calculated as: Vz/F = dose / (AUCinf * kel). kel was defined as terminal phase rate constant and calculated by a linear regression of the log-linear concentration-time curve. AUCinf was area under the plasma concentration versus time curve (AUC) from zero to extrapolated infinite time. | 0 (pre-dose), 1, 2, 4, 6, 8 and 24 hours post dose on Lead-in Day -4 for Japan LIC RP2D cohort, Lead-in Day -7 and Cycle 1 Day 1 for Japan LIC PK cohort | 
| t1/2 of PF-06747775 Following Single Dose on Lead-in Day -4 in Japan LIC RP2D Cohort, Lead-in Day -7 and Cycle 1 Day 1 in Japan LIC PK Cohort | t1/2 of PF-06747775 following a 200 mg single dose on Lead-in Day -4 in Japan LIC RP2D cohort and Cycle 1 Day 1 in Japan LIC PK cohort, and following a 100 mg single dose on Lead-in Day -7 in Japan LIC PK cohort. t1/2 was defined as the time measured for the plasma concentration to decrease by one half. | 0 (pre-dose), 1, 2, 4, 6, 8 and 24 hours post dose on Lead-in Day -4 for Japan LIC RP2D cohort, Lead-in Day -7 and Cycle 1 Day 1 for Japan LIC PK cohort | 
| AUCtau of PF-06747775 Following Multiple Doses in Japan LIC RP2D and PK Cohorts | AUCtau of PF-06747775 following multiple doses on Cycle 1 Day 11 in Japan LIC RP2D cohort and Cycle 1 Day 15 in Japan LIC PK cohort. AUCtau was defined as area under the plasma concentration-time profile from time zero to tau, the dosing interval, where tau = 24 hours. AUCtau was calculated using Linear/Log trapezoidal method. | 0 (pre-dose), 1, 2, 4, 6, 8 and 24 hours post dose on Cycle 1 Day 11 (Japan LIC RP2D cohort) and Day 15 (Japan LIC PK cohort) | 
| Ctrough of PF-06747775 Following Multiple Doses in Japan LIC RP2D and PK Cohorts | Ctrough of PF-06747775 following multiple doses on Cycle 1 Day 11 in Japan LIC RP2D cohort and Cycle 1 Day 15 in Japan LIC PK cohort. Ctrough was defined as pre-dose concentration during multiple dosing and observed directly from data. | Pre-dose on Cycle 1 Day 11 (Japan LIC RP2D cohort) and Day 15 (Japan LIC PK cohort) | 
| Rac of PF-06747775 Following Multiple Doses in Japan LIC RP2D and PK Cohorts | Rac of PF-06747775 following multiple doses on Cycle 1 Day 11 in Japan LIC RP2D cohort and Cycle 1 Day 15 in Japan LIC PK cohort. Rac was calculated as: Rac = (steady state AUCtau) / (single dose AUC24). AUC24 was defined as area under the plasma concentration-time curve from time 0 to 24 hours following single dose. AUCtau was defined as area under the plasma concentration-time profile from time zero to tau, the dosing interval, where tau = 24 hours. | 0 (pre-dose), 1, 2, 4, 6, 8 and 24 hours post dose on Lead-in Day -4, Cycle 1 Day 11 for Japan LIC RP2D cohort, Cycle 1 Days 1 and 15 for Japan LIC PK cohort | 
| Rss of PF-06747775 Following Multiple Doses in Japan LIC RP2D and PK Cohorts | Rss of PF-06747775 following multiple doses on Cycle 1 Day 11 in Japan RP2D cohort and Cycle 1 Day 15 in Japan PK cohort. Rss was calculated as: Rss = (steady state AUCtau) / (single dose AUCinf). AUCtau was defined as area under the plasma concentration-time profile from time zero to tau, the dosing interval, where tau = 24 hours. AUCinf was area under the plasma concentration versus time curve (AUC) from zero to extrapolated infinite time. | 0 (pre-dose), 1, 2, 4, 6, 8 and 24 hours post dose on Lead-in Day -4, Cycle 1 Day 11 for Japan LIC RP2D cohort, Cycle 1 Days 1 and 15 for Japan LIC PK cohort | 
| CL/F of PF-06747775 Following Single and Multiple Doses in Japan LIC RP2D and PK Cohorts | CL/F of PF-06747775 following single dose on Lead-in Day -4 in Japan LIC RP2D cohort, Lead-in Day -7 and Cycle 1 Day 1 in Japan LIC PK cohort, and following multiple doses on Cycle 1 Day 11 in Japan LIC RP2D cohort and on Cycle 1 Day 15 in Japan LIC PK cohort. CL/F was calculated as: CL/F = dose/AUCinf for single dose or dose/AUCtau for multiple doses. AUCtau was defined as area under the plasma concentration-time profile from time zero to tau, the dosing interval, where tau = 24 hours. AUCinf was area under the plasma concentration versus time curve (AUC) from zero to extrapolated infinite time. | 0 (pre-dose), 1, 2, 4, 6, 8 and 24 hours post dose on Lead-in Day -4, Cycle 1 Day 11 for Japan LIC RP2D cohort, Lead-in Day-7, Days 1 and 15 for Japan LIC PK cohort | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EGFRm - Epidermal Growth Factor Receptor Mutation, Advanced EGFRm (del19 or L858R +/- T790M NSCLC