A Study Of Combined C- MET Inhibitor And PAN-HER Inhibitor (PF-02341066 And PF-00299804) In Patients With Non- Small Cell Lung Cancer

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01121575
• Collaborator: (none)
• Enrollment: 70
• Locations: 10
• Arms: 2
• Duration (Months): 42.1
• Patients Per Site: 7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Lung cancer tumors become resistant to the first generation epidermal growth factor receptor (EGFR) inhibitors erlotinib or gefitinib by changing and increasing the activity of two cell signaling pathways: the cMET pathway and the EGFR pathway. Both resistance mechanisms can occur at the same time, in the same patient and even in the same tumor. This study combines a second generation EGFR inhibitor and a cMET inhibitor to block both these pathways in order to overcome resistance and treat this disease.

Condition or Disease	Intervention/Treatment	Phase
Non Small Cell Lung Cancer	Drug: PF-02341066; Drug: PF-00299804; Drug: PF-02341066; Drug: PF-00299804	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Open-label, Dose Escalation Study To Evaluate Safety, Pharmacokinetics And Pharmacodynamics Of Combined Oral C-met/Alk Inhibitor (Pf-02341066) And Pan-her Inhibitor (Pf-00299804) In Patients With Advanced Non-small Cell Lung Cancer
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: Feb 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 PF-02341066 AND PF-00299804: Patients will be treated with combined cMET inhibitor (PF-02341066) and panHER inhibitor (PF-00299804).	Drug: PF-02341066; Arm 1: The starting dose will be 200 mg by mouth, twice a day of PF 02341066 in tablet form The dose of each drug in the combination [PF-02341066 and PF-00299804] will be escalated or de-escalated until the maximum tolerated combined dose is reached. Patients will then be treated with the maximum tolerated combined dose.; Other Names: cMET inhibitor ; Drug: PF-00299804; Arm 1: The starting dose will be 30 mg by mouth once a day of PF-0029804 in tablet form. The dose of each drug in the combination [PF-02341066 and PF-00299804] will be escalated or de-escalated until the maximum tolerated combined dose is reached. Patients will then be treated with the maximum tolerated combined dose.; Other Names: panHER inhibitor
Experimental: Arm 2 PF-00299804 FOLLOWED BY COMBINED PF-02341066 AND PF-00299804: Patients will be treated with single agent panHER inhibitor (PF-00299804) until disease progression and then with the maximum tolerated combined dose of cMET inhibitor (PF-02341066) and panHER inhibitor (PF-00299804).	Drug: PF-02341066; Arm 2: With progressive disease the maximum tolerated combined dose of PF-02341066 (given by mouth twice a day in tablet form) and PF-00299804 (given by mouth once a day in tablet form).; Other Names: cMET inhibitor ; Drug: PF-00299804; Arm 2: The dose of 45 mg by mouth once a day of PF-00299804 in tablet form until progressive disease and then the maximum tolerated combined dose of PF-02341066 (given by mouth twice a day in tablet form) and PF-00299804 (given by mouth once a day in tablet form).; Other Names: panHER inhibitor

Outcome Measures

Primary Outcome Measures

1. Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase [Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)]

   AE was any untoward medical occurrence with study drug/ device in a trial participant. Serious adverse event (SAE) was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.

2. Overview of Treatment-emergent All Causalities AEs in Expansion Phase [Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)]

   AE was any untoward medical occurrence with study drug/ device in a trial participant. SAE was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using NCI CTCAE v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.

3. Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase [Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)]

   An AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. SAE was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using NCI CTCAE v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.

4. Overview of Treatment-emergent, Treatment-related AEs in Expansion Phase [Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)]

   An AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. SAE was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using NCI CTCAE v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.

5. Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase [Cycle 1 (4 weeks)]

   DLTs were those AEs which occurred in Cycle 1 of treatment in Dose Escalation Phase which may be attributed to study drug [combined Crizotinib (PF-02341066) plus Dacomitinib (PF-00299804)] without a clear alternative explanation and despite the use of adequate/maximal medical intervention as dictated by local institutional clinical practices or the judgment of the investigator. The following events were considered DLTs (using CTCAE version 4.02);1. Grade ≥4 hematologic events. 2. Grade ≥3 non-hematological events (except Grade 3/4 asymptomatic hypophosphatemia and Grade 3/4 hyperuricemia without signs and symptoms of gout). Nausea, vomiting or diarrhea had to have persisted at Grade 3 or 4 despite maximal medical therapy. Grade 3 hypertension will be considered a DLT only if the event is unmanageable by standard approved pharmacologic agents or if the symptomatic sequelae are identified despite appropriate medical intervention.

Secondary Outcome Measures

1. Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase [From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment)]

   If a participant had not achieved an objective response with confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) - 1.1 as determined by the investigators, relative to the response evaluable population, but remained stable for at least 6 weeks after first dose, then the best overall response for such a participant was considered as stable disease.

2. Number of Participants With Stable Disease and Stable Disease Duration in Expansion Phase [From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment)]

   If a participant had not achieved an objective response with confirmed complete response (CR) or partial response (PR) according to RECIST (1.1) as determined by the investigators, relative to the response evaluable population, but remained stable for at least 6 weeks after first dose, then the best overall response for such a participant was considered as stable disease.

3. Number of Participants With Objective Response Rate (ORR) in Escalation Phase [From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment)]

   ORR was defined as the percent of participants with CR or PR according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) determined by study physicians, relative to the response evaluable population. Participants were considered non-responders until proven otherwise. Thus, participants who: 1) Did not have CR or PR while on study, or 2) Did not have a post-baseline tumor evaluation, or 3) Received anti-tumor treatment other than the study medication prior to reaching a CR or PR, or 4) Died, in progress, or drop out for any reason prior to reaching a CR or PR, were counted as non-responders in the assessment of ORR. To be assigned a status of PR or CR, changes in tumor measurements in participants with responding tumors were confirmed by repeated tumor assessment that were performed 4 weeks after the criteria for response were first met.

4. Number of Participants With ORR in Expansion Phase [From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment)]

   ORR was defined as the percent of participants with CR or PR according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) determined by study physicians, relative to the response evaluable population. Participants were considered non-responders until proven otherwise. Thus, participants who: 1) Did not have CR or PR while on study, or 2) Did not have a post-baseline tumor evaluation, or 3) Received anti-tumor treatment other than the study medication prior to reaching a CR or PR, or 4) Died, in progress, or drop out for any reason prior to reaching a CR or PR, were counted as non-responders in the assessment of ORR. To be assigned a status of PR or CR, changes in tumor measurements in participants with responding tumors were confirmed by repeated tumor assessment that were performed 4 weeks after the criteria for response were first met.

5. Duration of Response for the Only Participant Shown Partial Response in Expansion Phase [From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment)]

   This outcome measure presented the duration of response for one participant in expansion cohort 1 who showed partial response.

6. Progression Free Survival (PFS) in Escalation Phase [From randomization to objective tumor progression or death (up to post treatment follow-up as 28-35 days after last dose of study treatment)]

   PFS was defined as the time from the date of the first dose to the date of the first documentation of objective tumor progression according to RECIST 1.1 or death on study due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used.

7. Progression Free Survival (PFS) in Expansion Phase [From randomization to objective tumor progression or death (up to post treatment follow-up as 28-35 days after last dose of study treatment)]

   PFS was defined as the time from the date of the first dose to the date of the first documentation of objective tumor progression according to RECIST 1.1 or death on study due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used.

8. Expression Analysis of Tumor Biomarkers (HGF, EGFR, and c-Met ) at Baseline Using Immunohistochemistry (IHC) Method [Baseline]

   Tumor biomarkers such as HGF, EGFR, and c-Met were analyzed in tumor cells (neoplastic compartment) of tumor specimens from both expansion cohorts 1 and 2 by IHC. The H score was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0, 1+, 2+, 3+, where 3+ indicates the strongest staining, 2+ indicates medium staining, 1+ indicates weak staining, and 0 indicates no staining). Minimum calculated score of 0 to maximum calculated score of 300, where 0 correspond to no expression and maximum score of 300 indicates the strongest expression. However, the biomarker expression level (higher or lower) was not a predictor of outcome.

9. Expression Analysis of Tumor Biomarkers (EGFR, and c-Met) at Baseline Using Fluorescent in Situ Hybridization (FISH) Method [Baseline]

   Expression of tumor biomarkers EGFR and cMet at Baseline (using FISH method) are presented in this outcome measure.

10. Number of Participants With c-Met, HER2, EGFR Amplification and ALK Rearrangement at Baseline Using FISH Method [Baseline]

    Participants showed amplification of c-Met, HER2, and EGFR in the tumor cells and gene rearrangement of ALK are presented in this outcome measure.

11. Plasma Concentration of sMet by Study Visits [At screening and Cycle 1 Day 1 (C1D1) (6 hours post dose), and C1D15, C2D1, C2D15 (all predose).]

    This outcome measure presented the plasma concentration of sMet at different study visits. s-Met was analyzed using an enzyme-linked immunosorbent assay (ELISA).

12. Number of Participants With EGFR Mutation at Baseline [Baseline]

    Sample analyses were performed in accordance to Good Laboratory Practice (GLP) guidance and included mutation detection for EGFR gene.

13. Number of Participants With KRAS Mutation (GLY12CYS) at Baseline [Baseline]

    Sample analyses were performed in accordance to GLP guidance and included mutation detection for KRAS gene.

14. Number of Participants With PIK3CA Mutation at Baseline [Baseline]

    Sample analyses were performed in accordance to GLP guidance and included mutation detection for PIK3CA gene.

15. Number of Participants With ROS1 Gene Translocation at Baseline [Baseline]

    Sample analyses were performed in accordance to GLP guidance and included translocation detection (RNA based) for ROS1 gene.

16. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Profile From Time Zero to the Last Quantifiable Concentration (AUClast) [Cycle 1 (C1)/Day 1 (D1), C1D15]

    At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included AUClast for crizotinib and PF-06260182. AUClast was calculated using Linear/Log trapezoidal method.

17. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) [C1D1, C1D15]

    At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). AUC10 was calculated using Linear/Log trapezoidal method. The below analysis table included geometric Mean and Geometric Coefficient of Variation of AUC10 for crizotinib and PF-06260182. Arithmetic mean was presented if the n=2.

18. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) [C1D1, C1D15]

    At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Cmax for crizotinib and PF-06260182. Cmax was observed directly from data.

19. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) [C1D1, C1D15]

    At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tlast for crizotinib and PF-06260182. Tlast was observed directly from data.

20. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) [C1D1, C1D15]

    At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tmax for crizotinib and PF-06260182. Tmax was observed directly from data as time of first occurrence.

21. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast [C1D1, C1D15]

    At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included AUClast for dacomitinib and PF-05199265. AUClast was calculated using Linear/Log trapezoidal method.

22. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 [C1D1, C1D15]

    At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included AUC24 for dacomitinib and PF-05199265. AUC24 was calculated using Linear/Log trapezoidal method.

23. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax [C1D1, C1D15]

    At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Cmax for dacomitinib and PF-05199265. Cmax was observed directly from data.

24. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast [C1D1, C1D15]

    At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tlast for dacomitinib and PF-05199265. Tlast was observed directly from data.

25. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax [C1D1, C1D15]

    At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tmax for dacomitinib and PF-05199265. Tmax was observed directly from data as time of first occurrence.

26. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUClast [Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)]

    Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for AUClast. AUClast was calculated using Linear/Log trapezoidal method.

27. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUC10 [Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)]

    Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for AUC10. AUC10 was calculated using Linear/Log trapezoidal method.

28. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmin [Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)]

    Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Cmin. Cmin was observed directly from data.

29. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmax [Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)]

    Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Cmax. Cmax was observed directly from data.

30. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tlast [Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)]

    Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Tlast. Tlast was observed directly from data.

31. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tmax [Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)]

    Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Tmax. Tmax was observed directly from data as time of first occurrence.

32. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUClast [Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)]

    PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (AUClast) following dacomitinib alone and in combination with crizotinib are summarized in the below table. AUClast was calculated using Linear/Log trapezoidal method.

33. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUC24 [Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)]

    PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (AUC24) following dacomitinib alone and in combination with crizotinib are summarized in the below table. AUC24 was calculated using Linear/Log trapezoidal method.

34. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmin [Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)]

    PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Cmin) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Cmin was observed directly from data.

35. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmax [Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)]

    PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Cmax) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Cmax was observed directly from data.

36. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tlast [Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)]

    PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Tlast) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Tlast was observed directly from data.

37. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tmax [Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)]

    PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Tmax) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Tmax was observed directly from data as time of first occurrence.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• advanced non small cell lung cancer (dose escalation phase)

• acquired resistance to erlotinib or gefitinib (expansion phase)

• mandatory entrance biopsy (expansion phase)

Exclusion Criteria:

• interstitial lung disease

• unstable brain metastases

• leptomeningeal disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Trials Office University of Colorado Hospital (CTO)	Aurora	Colorado	United States	80045
2	DRUG SHIPMENT: University of Colorado Cancer Center	Aurora	Colorado	United States	80045
3	Rocky Mountain Lions Eye Institute	Aurora	Colorado	United States	80045
4	University of Colorado Hospital	Aurora	Colorado	United States	80045
5	CCR, National Cancer Institute	Bethesda	Maryland	United States	20892
6	Drug Shipment Only	Boston	Massachusetts	United States	02114
7	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
8	Brigham & Women's Hospital	Boston	Massachusetts	United States	02115
9	Drug Shipment Only	Boston	Massachusetts	United States	02215
10	Peter MacCallum Cancer Centre, Division of Haematology and Medical Oncology	East Melbourne	Victoria	Australia	3002

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01121575
• Other Study ID Numbers: A8081006
• First Posted: May 12, 2010
• Last Update Posted: Oct 28, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by Pfizer: Phase 1 acquired resistance to erlotinib or gefitinib cMET inhibitor EGFR inhibitor panHER inhibitor combination trial Crizotinib
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib

Study Results

Participant Flow

Recruitment Details	This was a Phase 1, multicenter, open-label, non-randomized study of combined oral crizotinib and oral dacomitinib in participants with advanced non-small cell lung cancer (NSCLC). The study consisted of a dose Escalation Phase and an Expansion Phase. The Expansion Phase consisted of Expansion Cohort 1 and 2 which ran concurrently.
Pre-assignment Detail	A total of 70 participants were enrolled and received study treatment in the United States (3 centers) and Australia (1 center). 33 participants in Escalation Phase and 37 participants in Expansion Phase (25 participants in Cohort 1 and 12 participants in Cohort 2) received treatment. The last participant completed the study on 11 Feb 2014.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD	Expansion Cohort 1	Expansion Cohort 2
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg twice a day (BID) and oral dacomitinib 30 mg once daily (QD). The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
Period Title: Overall Study
STARTED	14	6	7	6	25	12
Treated	14	6	7	6	25	12
COMPLETED	0	0	0	0	0	0
NOT COMPLETED	14	6	7	6	25	12

Baseline Characteristics

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD	Expansion Cohort 1	Expansion Cohort 2	Total
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.	Total of all reporting groups
Overall Participants	14	6	7	6	25	12	70
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	53.6 (9.87)	61.7 (7.53)	54.7 (11.34)	62.2 (13.61)	61.8 (10.83)	59.6 (11.74)	59.1 (11.05)
Sex: Female, Male (Count of Participants)
Female	5 35.7%	5 83.3%	6 85.7%	2 33.3%	16 64%	9 75%	43 61.4%
Male	9 64.3%	1 16.7%	1 14.3%	4 66.7%	9 36%	3 25%	27 38.6%

Outcome Measures

1. Primary Outcome

Title	Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase
Description	AE was any untoward medical occurrence with study drug/ device in a trial participant. Serious adverse event (SAE) was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
Time Frame	Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)

Outcome Measure Data

Analysis Population Description

The safety analysis population included all enrolled participants who had received at least 1 dose of study medication.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	14	6	7	6
Participants with AEs	14 100%	6 100%	7 100%	6 100%
Participants with Grade 3 or 4 AEs	9 64.3%	4 66.7%	5 71.4%	5 83.3%
Participants with Grade 5 AEs	3 21.4%	0 0%	0 0%	1 16.7%
Participants with SAEs	6 42.9%	2 33.3%	1 14.3%	4 66.7%

2. Primary Outcome

Title	Overview of Treatment-emergent All Causalities AEs in Expansion Phase
Description	AE was any untoward medical occurrence with study drug/ device in a trial participant. SAE was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using NCI CTCAE v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
Time Frame	Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)

Outcome Measure Data

Analysis Population Description

The safety analysis population included all enrolled participants who had received at least 1 dose of study medication.

Arm/Group Title	Expansion Cohort 1	Expansion Cohort 2
Arm/Group Description	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
Measure Participants	25	12
Participants with AEs	22 157.1%	11 183.3%
Participants with Grade 3 or 4 AEs	12 85.7%	8 133.3%
Participants with Grade 5 AEs	3 21.4%	2 33.3%
Participants with SAEs	8 57.1%	8 133.3%

3. Primary Outcome

Title	Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase
Description	An AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. SAE was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using NCI CTCAE v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
Time Frame	Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)

Outcome Measure Data

Analysis Population Description

The safety analysis population included all enrolled participants who had received at least 1 dose of study medication.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	14	6	7	6
Participants with treatment-related AEs	14 100%	6 100%	7 100%	6 100%
Participants with treatment-related Grade 3/ 4 AEs	8 57.1%	3 50%	3 42.9%	3 50%
Participants with treatment-related Grade 5 AEs	0 0%	0 0%	0 0%	0 0%
Participants with treatment-related SAEs	1 7.1%	2 33.3%	0 0%	1 16.7%

4. Primary Outcome

Title	Overview of Treatment-emergent, Treatment-related AEs in Expansion Phase
Description	An AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. SAE was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using NCI CTCAE v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
Time Frame	Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)

Outcome Measure Data

Analysis Population Description

The safety analysis population included all enrolled participants who had received at least 1 dose of study medication.

Arm/Group Title	Expansion Cohort 1	Expansion Cohort 2
Arm/Group Description	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
Measure Participants	25	12
Participants with treatment-related AEs	22 157.1%	11 183.3%
Participants with treatment-related Grade 3/ 4 AEs	7 50%	6 100%
Participants with treatment-related Grade 5 AEs	0 0%	0 0%
Participants with treatment-related SAEs	3 21.4%	3 50%

5. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase
Description	DLTs were those AEs which occurred in Cycle 1 of treatment in Dose Escalation Phase which may be attributed to study drug [combined Crizotinib (PF-02341066) plus Dacomitinib (PF-00299804)] without a clear alternative explanation and despite the use of adequate/maximal medical intervention as dictated by local institutional clinical practices or the judgment of the investigator. The following events were considered DLTs (using CTCAE version 4.02);1. Grade ≥4 hematologic events. 2. Grade ≥3 non-hematological events (except Grade 3/4 asymptomatic hypophosphatemia and Grade 3/4 hyperuricemia without signs and symptoms of gout). Nausea, vomiting or diarrhea had to have persisted at Grade 3 or 4 despite maximal medical therapy. Grade 3 hypertension will be considered a DLT only if the event is unmanageable by standard approved pharmacologic agents or if the symptomatic sequelae are identified despite appropriate medical intervention.
Time Frame	Cycle 1 (4 weeks)

Outcome Measure Data

Analysis Population Description

The DLT evaluable population was defined as safety analysis (SA) participants in the Dose Escalation phase who did not have a major treatment deviation during the first cycle.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	14	6	7	6
Grade 3 Alanine aminotransferase increased	0 0%	1 16.7%	0 0%	0 0%
Grade 3 Diarrhoea	0 0%	1 16.7%	0 0%	0 0%
Grade 3 Mucosal inflammation	0 0%	0 0%	1 14.3%	0 0%

6. Secondary Outcome

Title	Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase
Description	If a participant had not achieved an objective response with confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) - 1.1 as determined by the investigators, relative to the response evaluable population, but remained stable for at least 6 weeks after first dose, then the best overall response for such a participant was considered as stable disease.
Time Frame	From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment)

Outcome Measure Data

Analysis Population Description

The response evaluable population included participants in safety analysis population who had an adequate Baseline tumor assessment.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	14	6	7	6
Stable Disease	10 71.4%	3 50%	2 28.6%	5 83.3%
0- < 3 months	3 21.4%	2 33.3%	1 14.3%	0 0%
3- < 6 months	6 42.9%	1 16.7%	1 14.3%	3 50%
6- < 9 months	1 7.1%	0 0%	0 0%	2 33.3%

7. Secondary Outcome

Title	Number of Participants With Stable Disease and Stable Disease Duration in Expansion Phase
Description	If a participant had not achieved an objective response with confirmed complete response (CR) or partial response (PR) according to RECIST (1.1) as determined by the investigators, relative to the response evaluable population, but remained stable for at least 6 weeks after first dose, then the best overall response for such a participant was considered as stable disease.
Time Frame	From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment)

Outcome Measure Data

Analysis Population Description

The response evaluable population included participants in safety analysis population who had an adequate Baseline tumor assessment.

Arm/Group Title	Expansion Cohort 1	Expansion Cohort 2
Arm/Group Description	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
Measure Participants	22	12
Stable Disease	6 42.9%	5 83.3%
0- < 3 months	1 7.1%	0 0%
3- < 6 months	4 28.6%	4 66.7%
6- < 9 months	1 7.1%	1 16.7%

8. Secondary Outcome

Title	Number of Participants With Objective Response Rate (ORR) in Escalation Phase
Description	ORR was defined as the percent of participants with CR or PR according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) determined by study physicians, relative to the response evaluable population. Participants were considered non-responders until proven otherwise. Thus, participants who: 1) Did not have CR or PR while on study, or 2) Did not have a post-baseline tumor evaluation, or 3) Received anti-tumor treatment other than the study medication prior to reaching a CR or PR, or 4) Died, in progress, or drop out for any reason prior to reaching a CR or PR, were counted as non-responders in the assessment of ORR. To be assigned a status of PR or CR, changes in tumor measurements in participants with responding tumors were confirmed by repeated tumor assessment that were performed 4 weeks after the criteria for response were first met.
Time Frame	From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment)

Outcome Measure Data

Analysis Population Description

The response evaluable population included participants in safety analysis population who had an adequate Baseline tumor assessment.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	14	6	7	6
Number (95% Confidence Interval) [Participants]	0 0%	0 0%	0 0%	0 0%

9. Secondary Outcome

Title	Number of Participants With ORR in Expansion Phase
Description	ORR was defined as the percent of participants with CR or PR according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) determined by study physicians, relative to the response evaluable population. Participants were considered non-responders until proven otherwise. Thus, participants who: 1) Did not have CR or PR while on study, or 2) Did not have a post-baseline tumor evaluation, or 3) Received anti-tumor treatment other than the study medication prior to reaching a CR or PR, or 4) Died, in progress, or drop out for any reason prior to reaching a CR or PR, were counted as non-responders in the assessment of ORR. To be assigned a status of PR or CR, changes in tumor measurements in participants with responding tumors were confirmed by repeated tumor assessment that were performed 4 weeks after the criteria for response were first met.
Time Frame	From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment)

Outcome Measure Data

Analysis Population Description

The response evaluable population included participants in safety analysis population who had an adequate Baseline tumor assessment.

Arm/Group Title	Expansion Cohort 1	Expansion Cohort 2
Arm/Group Description	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
Measure Participants	22	12
Number (95% Confidence Interval) [Participants]	1 7.1%	0 0%

10. Secondary Outcome

Title	Duration of Response for the Only Participant Shown Partial Response in Expansion Phase
Description	This outcome measure presented the duration of response for one participant in expansion cohort 1 who showed partial response.
Time Frame	From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment)

Outcome Measure Data

Analysis Population Description

This Outcome Measure was only assessed for participants with response.

Arm/Group Title	Expansion Cohort 1	Expansion Cohort 2
Arm/Group Description	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
Measure Participants	1	0
Number [Weeks]	6.29

11. Secondary Outcome

Title	Progression Free Survival (PFS) in Escalation Phase
Description	PFS was defined as the time from the date of the first dose to the date of the first documentation of objective tumor progression according to RECIST 1.1 or death on study due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used.
Time Frame	From randomization to objective tumor progression or death (up to post treatment follow-up as 28-35 days after last dose of study treatment)

Outcome Measure Data

Analysis Population Description

The safety analysis population included all enrolled participants who had received at least 1 dose of study medication.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	14	6	7	6
Median (95% Confidence Interval) [Months]	3.1	3.0	1.7	4.4

12. Secondary Outcome

Title	Progression Free Survival (PFS) in Expansion Phase
Description	PFS was defined as the time from the date of the first dose to the date of the first documentation of objective tumor progression according to RECIST 1.1 or death on study due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used.
Time Frame	From randomization to objective tumor progression or death (up to post treatment follow-up as 28-35 days after last dose of study treatment)

Outcome Measure Data

Analysis Population Description

The safety analysis population included all enrolled participants who had received at least 1 dose of study medication. In Expansion Cohort 1, two participants had censored reasons of "no adequate baseline", of which one participant had a censored reason "no tumor assessment data available.

Arm/Group Title	Expansion Cohort 1	Expansion Cohort 2
Arm/Group Description	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
Measure Participants	23	12
Median (95% Confidence Interval) [Months]	2.1	2.1

13. Secondary Outcome

Title	Expression Analysis of Tumor Biomarkers (HGF, EGFR, and c-Met ) at Baseline Using Immunohistochemistry (IHC) Method
Description	Tumor biomarkers such as HGF, EGFR, and c-Met were analyzed in tumor cells (neoplastic compartment) of tumor specimens from both expansion cohorts 1 and 2 by IHC. The H score was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0, 1+, 2+, 3+, where 3+ indicates the strongest staining, 2+ indicates medium staining, 1+ indicates weak staining, and 0 indicates no staining). Minimum calculated score of 0 to maximum calculated score of 300, where 0 correspond to no expression and maximum score of 300 indicates the strongest expression. However, the biomarker expression level (higher or lower) was not a predictor of outcome.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

The tumor analysis population included participants in safety analysis population who had a screening and on-treatment tumor biopsy for assessment of tumor biomarkers.

Arm/Group Title	Expansion Cohort 1	Expansion Cohort 2
Arm/Group Description	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
Measure Participants	23	12
HGF (N= 19, 11)	40.0	67.0
EGFR (N= 14, 8)	193.2	170.0
cMet (N= 19, 11)	125.0	165.0

14. Secondary Outcome

Title	Expression Analysis of Tumor Biomarkers (EGFR, and c-Met) at Baseline Using Fluorescent in Situ Hybridization (FISH) Method
Description	Expression of tumor biomarkers EGFR and cMet at Baseline (using FISH method) are presented in this outcome measure.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

The tumor analysis population included participants in safety analysis population who had a screening and on-treatment tumor biopsy for assessment of tumor biomarkers.

Arm/Group Title	Expansion Cohort 1	Expansion Cohort 2
Arm/Group Description	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
Measure Participants	23	12
Ratio of Red to Green of EGFR (N= 11, 11)	1.580	1.180
Ratio of Green to Orange for cMET (N = 19, 11)	1.040	1.000

15. Secondary Outcome

Title	Number of Participants With c-Met, HER2, EGFR Amplification and ALK Rearrangement at Baseline Using FISH Method
Description	Participants showed amplification of c-Met, HER2, and EGFR in the tumor cells and gene rearrangement of ALK are presented in this outcome measure.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

The tumor analysis population included participants in safety analysis population who had a screening and on-treatment tumor biopsy for assessment of tumor biomarkers.

Arm/Group Title	Expansion Cohort 1	Expansion Cohort 2
Arm/Group Description	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
Measure Participants	23	12
c-Met amplification (N= 19, 11)	1 7.1%	0 0%
HER2 amplification (N= 19, 7)	0 0%	0 0%
EGFR amplification (N= 11,11)	2 14.3%	3 50%
ALK rearrangement (N= 19, 11)	0 0%	0 0%

16. Secondary Outcome

Title	Plasma Concentration of sMet by Study Visits
Description	This outcome measure presented the plasma concentration of sMet at different study visits. s-Met was analyzed using an enzyme-linked immunosorbent assay (ELISA).
Time Frame	At screening and Cycle 1 Day 1 (C1D1) (6 hours post dose), and C1D15, C2D1, C2D15 (all predose).

Outcome Measure Data

Analysis Population Description

The soluble protein analysis population included participants in safety analysis who had a screening or C1D1 soluble protein assessment, and at least one on-treatment soluble protein assessment (C1D14 C2D1 or C2D14).

Arm/Group Title	Expansion Cohort 1	Expansion Cohort 2
Arm/Group Description	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
Measure Participants	21	7
Baseline at Screening	1353411.8 (349746.88)	1557000.0 (514352.02)
C1D1	1519047.6 (230995.77)	1450500.0 (553557.13)
C1D15	1483157.9 (243904.64)	1676666.7 (540246.86)
C2D1	1525666.7 (394836.61)	1540000.0 (315515.45)
C2D15	1564666.7 (224367.90)	1602500.0 (126589.89)

17. Secondary Outcome

Title	Number of Participants With EGFR Mutation at Baseline
Description	Sample analyses were performed in accordance to Good Laboratory Practice (GLP) guidance and included mutation detection for EGFR gene.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

The tumor analysis population included participants in safety analysis population who had a screening and on-treatment tumor biopsy for assessment of tumor biomarkers.

Arm/Group Title	Expansion Cohort 1	Expansion Cohort 2
Arm/Group Description	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
Measure Participants	23	12
Exon 18 (G719X)	1 7.1%	1 16.7%
Exon 19 (Deletion)	6 42.9%	3 50%
Exon 20 (T790M)	6 42.9%	3 50%
Exon 20 (T790M/S768I)	1 7.1%	0 0%
Exon 20 (S768I)	0 0%	1 16.7%
Exon 21 (L858R)	6 42.9%	1 16.7%

18. Secondary Outcome

Title	Number of Participants With KRAS Mutation (GLY12CYS) at Baseline
Description	Sample analyses were performed in accordance to GLP guidance and included mutation detection for KRAS gene.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

The tumor analysis population included participants in safety analysis population who had a screening and on-treatment tumor biopsy for assessment of tumor biomarkers.

Arm/Group Title	Expansion Cohort 1	Expansion Cohort 2
Arm/Group Description	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
Measure Participants	23	12
Number [Participants]	1 7.1%	0 0%

19. Secondary Outcome

Title	Number of Participants With PIK3CA Mutation at Baseline
Description	Sample analyses were performed in accordance to GLP guidance and included mutation detection for PIK3CA gene.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

The tumor analysis population included participants in safety analysis population who had a screening and on-treatment tumor biopsy for assessment of tumor biomarkers.

Arm/Group Title	Expansion Cohort 1	Expansion Cohort 2
Arm/Group Description	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
Measure Participants	23	12
Exon 20 (M1004I) (N= 14, 6)	1 7.1%	0 0%
Exon 20 (Q1061K) (N= 14, 6)	1 7.1%	0 0%
Exon 20 (H1047R) (N= 14, 6)	2 14.3%	0 0%
Exon 9 (E545K) (N= 14, 6)	1 7.1%	0 0%

20. Secondary Outcome

Title	Number of Participants With ROS1 Gene Translocation at Baseline
Description	Sample analyses were performed in accordance to GLP guidance and included translocation detection (RNA based) for ROS1 gene.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

The tumor analysis population included participants in safety analysis population who had a screening and on-treatment tumor biopsy for assessment of tumor biomarkers. However, number of participants analyzed in the below table included the participants evaluated for ROS1 gene translocation.

Arm/Group Title	Expansion Cohort 1	Expansion Cohort 2
Arm/Group Description	Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.	Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
Measure Participants	6	3
Number [Participants]	0 0%	0 0%

21. Secondary Outcome

Title	Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Profile From Time Zero to the Last Quantifiable Concentration (AUClast)
Description	At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included AUClast for crizotinib and PF-06260182. AUClast was calculated using Linear/Log trapezoidal method.
Time Frame	Cycle 1 (C1)/Day 1 (D1), C1D15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	11	6	7	6
Crizotinib C1D1 - single dose (n= 11, 6, 7, 6)	509.7 (62)	420.8 (53)	506.6 (29)	656.6 (65)
Crizotinib C1D15 multiple dose (n=8, 3, 6, 5)	1759 (39)	2464 (14)	1732 (35)	1672 (44)
PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6)	121.3 (76)	103.2 (74)	121.6 (29)	220.7 (55)
PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5)	382.3 (52)	593.5 (53)	440.5 (37)	532.0 (68)

22. Secondary Outcome

Title	Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10)
Description	At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). AUC10 was calculated using Linear/Log trapezoidal method. The below analysis table included geometric Mean and Geometric Coefficient of Variation of AUC10 for crizotinib and PF-06260182. Arithmetic mean was presented if the n=2.
Time Frame	C1D1, C1D15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	11	6	7	6
Crizotinib C1D1 - single dose (n= 8, 3, 4, 6)	624.9 (57)	500.8 (9)	559.6 (26)	655.8 (65)
Crizotinib C1D15 multiple dose (n= 5, 2, 6, 5)	2000 (43)	2620 (NA)	1732 (35)	1644 (44)
PF-06260182 C1D1 - single dose (n= 8, 3, 4, 6)	162.1 (57)	127.6 (32)	141.5 (25)	228.0 (57)
PF-06260182 C1D15 - multiple dose (n= 5, 2, 6, 5)	452.5 (48)	798.0 (NA)	473.3 (39)	525.5 (68)

23. Secondary Outcome

Title	Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax)
Description	At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Cmax for crizotinib and PF-06260182. Cmax was observed directly from data.
Time Frame	C1D1, C1D15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	11	6	7	6
Crizotinib C1D1 - single dose (n= 11, 6, 7, 6)	84.24 (58)	94.13 (22)	90.86 (29)	114.0 (61)
Crizotinib C1D15 multiple dose (n=8, 3, 6, 5)	231.5 (41)	329.7 (12)	218.1 (33)	268.9 (77)
PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6)	18.50 (72)	22.37 (26)	20.97 (29)	34.33 (61)
PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5)	49.73 (50)	78.45 (44)	57.56 (34)	83.23 (91)

24. Secondary Outcome

Title	Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast)
Description	At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tlast for crizotinib and PF-06260182. Tlast was observed directly from data.
Time Frame	C1D1, C1D15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	11	6	7	6
Crizotinib C1D1 - single dose (n= 11, 6, 7, 6)	9.92 (58)	9.33 (22)	9.05 (29)	9.75 (61)
Crizotinib C1D15 multiple dose (n=8, 3, 6, 5)	9.29 (41)	9.42 (25)	9.05 (47)	10.2 (35)
PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6)	9.92 (72)	9.33 (26)	9.05 (29)	9.75 (61)
PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5)	9.29 (50)	9.42 (44)	9.05 (34)	10.2 (91)

25. Secondary Outcome

Title	Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax)
Description	At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tmax for crizotinib and PF-06260182. Tmax was observed directly from data as time of first occurrence.
Time Frame	C1D1, C1D15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	11	6	7	6
Crizotinib C1D1 - single dose (n= 11, 6, 7, 6)	3.00 (58)	3.53 (22)	3.92 (29)	3.06 (61)
Crizotinib C1D15 multiple dose (n=8, 3, 6, 5)	1.68 (41)	6.17 (25)	2.00 (47)	6.00 (35)
PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6)	4.07 (72)	4.00 (26)	3.98 (29)	4.99 (61)
PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5)	4.03 (50)	6.17 (44)	4.09 (34)	6.00 (91)

26. Secondary Outcome

Title	Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast
Description	At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included AUClast for dacomitinib and PF-05199265. AUClast was calculated using Linear/Log trapezoidal method.
Time Frame	C1D1, C1D15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	11	6	7	6
Dacomitinib C1D1 - single dose (n= 10, 6, 7, 5)	208.3 (72)	132.3 (153)	146.3 (86)	307.7 (56)
Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4)	1339 (47)	2343 (70)	1212 (15)	1775 (31)
PF-5199265 C1D1 - single dose (n= 8, 6, 6, 6)	27.68 (80)	7.438 (115)	10.19 (190)	55.00 (75)
PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4)	51.48 (108)	52.24 (78)	44.97 (90)	161.0 (33)

27. Secondary Outcome

Title	Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24
Description	At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included AUC24 for dacomitinib and PF-05199265. AUC24 was calculated using Linear/Log trapezoidal method.
Time Frame	C1D1, C1D15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	11	6	7	6
Dacomitinib C1D1 - single dose (n= 8, 3, 5, 5)	252.7 (61)	347.9 (26)	223.4 (23)	306.6 (57)
Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4)	1336 (48)	2334 (69)	1203 (15)	1745 (30)
PF-5199265 C1D1 - single dose (n= 9, 3, 5, 6)	28.57 (87)	14.80 (51)	16.08 (169)	54.72 (76)
PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4)	51.37 (108)	51.97 (78)	44.72 (90)	158.1 (31)

28. Secondary Outcome

Title	Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax
Description	At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Cmax for dacomitinib and PF-05199265. Cmax was observed directly from data.
Time Frame	C1D1, C1D15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	11	6	7	6
Dacomitinib C1D1 - single dose (n= 10, 6, 7, 5)	15.56 (58)	17.49 (23)	12.40 (21)	18.22 (64)
Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4)	65.00 (52)	122.4 (75)	57.04 (13)	86.81 (38)
PF-5199265 C1D1 - single dose (n= 10, 6, 6, 7)	1.894 (89)	0.9888 (79)	0.8833 (130)	3.193 (74)
PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4)	2.367 (115)	2.649 (75)	2.073 (95)	7.560 (34)

29. Secondary Outcome

Title	Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast
Description	At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tlast for dacomitinib and PF-05199265. Tlast was observed directly from data.
Time Frame	C1D1, C1D15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	11	6	7	6
Dacomitinib C1D1 - single dose (n= 11, 6, 7, 5)	24.0 (8.00)	15.9 (15.9)	23.6 (24.0)	24.0
Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4)	24.00	23.9	23.9	24.4
PF-5199265 C1D1 - single dose (n= 8, 6, 6, 6)	24.0	15.9	23.5	24.1
PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4)	24.0	23.9	23.9	24.4

30. Secondary Outcome

Title	Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax
Description	At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tmax for dacomitinib and PF-05199265. Tmax was observed directly from data as time of first occurrence.
Time Frame	C1D1, C1D15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD	Crizotinib 200 mg BID/ Dacomitinib 45 mg QD	Crizotinib 250 mg BID/ Dacomitinib 30 mg QD	Crizotinib 250 mg QD/ Dacomitinib 45 mg QD
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.	Participants received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg QD. The first cycle was for 28 days thereafter, each cycle was 21 days.
Measure Participants	11	6	7	6
Dacomitinib C1D1 - single dose (n= 11, 6, 7, 5)	5.99 (8.00)	8.03 (15.9)	6.00 (24.0)	6.17
Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4)	6.00	5.09	6.09	5.00
PF-5199265 C1D1 - single dose (n= 8, 6, 6, 6)	6.95	4.04	6.78	6.08
PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4)	6.98	3.95	5.92	2.00

31. Secondary Outcome

Title	Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUClast
Description	Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for AUClast. AUClast was calculated using Linear/Log trapezoidal method.
Time Frame	Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib Alone (Expansion Cohort 1)	Crizotinib + Dacomitinib (Expansion Cohort 1)
Arm/Group Description	Participants received crizotinib alone continuous 200 mg BID dosing for approximately 12 days (±2 days).	Participants received combined oral crizotinib (200 mg BID) and oral dacomitinib (30 mg QD) on a continuous daily schedule.
Measure Participants	19	19
Crizotinib (n = 16, 13)	2223 (53)	1365 (47)
PF-06260182 (n = 16, 13)	616.3 (77)	356.6 (61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD, Crizotinib 200 mg BID/ Dacomitinib 45 mg QD
	Comments	Statistical analysis was performed for crizotinib AUClast for participants who had both Day -1 and C2D1 data. Result for the analysis of AUClast was based on data from 11 participants. No statistical analysis was performed for PF-06260182.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjust geometric mean
	Estimated Value	69.25
	Confidence Interval	(2-Sided) 90%; 54.22 to 88.44
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of crizotinib + dacomitinib / crizotinib alone adjust geometric mean was analyzed using the mixed effect model and displayed as percentage.

32. Secondary Outcome

Title	Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUC10
Description	Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for AUC10. AUC10 was calculated using Linear/Log trapezoidal method.
Time Frame	Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib Alone (Expansion Cohort 1)	Crizotinib + Dacomitinib (Expansion Cohort 1)
Arm/Group Description	Participants received crizotinib alone continuous 200 mg BID dosing for approximately 12 days (±2 days).	Participants received combined oral crizotinib (200 mg BID) and oral dacomitinib (30 mg QD) on a continuous daily schedule. Each cycle was 21 days.
Measure Participants	19	19
Crizotinib (n = 11, 9)	2167 (56)	1489 (44)
PF-06260182 (n = 11, 9)	634.3 (82)	422.3 (55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD, Crizotinib 200 mg BID/ Dacomitinib 45 mg QD
	Comments	Statistical analysis was performed for crizotinib AUC10 for participants who had both Day -1 and C2D1 data. Result for the analysis of AUC10 was based on data from 6 participants. No statistical analysis was performed for PF-06260182.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjust geometric mean
	Estimated Value	78.84
	Confidence Interval	(2-Sided) 90%; 58.90 to 105.54
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of crizotinib + dacomitinib / crizotinib alone adjust geometric mean was analyzed using the mixed effect model and displayed as percentage.

33. Secondary Outcome

Title	Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmin
Description	Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Cmin. Cmin was observed directly from data.
Time Frame	Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib Alone (Expansion Cohort 1)	Crizotinib + Dacomitinib (Expansion Cohort 1)
Arm/Group Description	Participants received crizotinib alone continuous 200 mg BID dosing for approximately 12 days (±2 days).	Participants received combined oral crizotinib (200 mg BID) and oral dacomitinib (30 mg QD) on a continuous daily schedule. Each cycle was 21 days.
Measure Participants	19	19
Crizotinib (n = 16, 13)	181.8 (64)	102.8 (51)
PF-06260182 (n = 16, 13)	47.22 (99)	25.53 (60)

34. Secondary Outcome

Title	Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmax
Description	Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Cmax. Cmax was observed directly from data.
Time Frame	Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib Alone (Expansion Cohort 1)	Crizotinib + Dacomitinib (Expansion Cohort 1)
Arm/Group Description	Participants received crizotinib alone continuous 200 mg BID dosing for approximately 12 days (±2 days).	Participants received combined oral crizotinib (200 mg BID) and oral dacomitinib (30 mg QD) on a continuous daily schedule. Each cycle was 21 days.
Measure Participants	19	19
Crizotinib (n = 16, 13)	306.0 (57)	191.5 (43)
PF-06260182 (n = 16, 13)	82.92 (79)	51.15 (56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD, Crizotinib 200 mg BID/ Dacomitinib 45 mg QD
	Comments	Statistical analysis was performed for crizotinib Cmax for participants who had both Day -1 and C2D1 data. Result for the analysis of Cmax was based on data from 11 participants. No statistical analysis was performed for PF-06260182.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ration of adjust geometric mean
	Estimated Value	70.60
	Confidence Interval	(2-Sided) 90%; 54.71 to 91.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of crizotinib + dacomitinib / crizotinib alone adjust geometric mean was analyzed using the mixed effect model and displayed as percentage.

35. Secondary Outcome

Title	Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tlast
Description	Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Tlast. Tlast was observed directly from data.
Time Frame	Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib Alone (Expansion Cohort 1)	Crizotinib + Dacomitinib (Expansion Cohort 1)
Arm/Group Description	Participants received crizotinib alone continuous 200 mg BID dosing for approximately 12 days (±2 days).	Participants received combined oral crizotinib (200 mg BID) and oral dacomitinib (30 mg QD) on a continuous daily schedule. Each cycle was 21 days.
Measure Participants	19	19
Crizotinib (n = 16, 13)	9.650 (57)	9.000 (43)
PF-06260182 (n = 16, 13)	9.650 (79)	9.000 (56)

36. Secondary Outcome

Title	Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tmax
Description	Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Tmax. Tmax was observed directly from data as time of first occurrence.
Time Frame	Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Crizotinib Alone (Expansion Cohort 1)	Crizotinib + Dacomitinib (Expansion Cohort 1)
Arm/Group Description	Participants received crizotinib alone continuous 200 mg BID dosing for approximately 12 days (±2 days).	Participants received combined oral crizotinib (200 mg BID) and oral dacomitinib (30 mg QD) on a continuous daily schedule. Each cycle was 21 days.
Measure Participants	19	19
Crizotinib (n = 16, 13)	2.04 (57)	3.20 (43)
PF-06260182 (n = 16, 13)	3.96 (79)	3.95 (56)

37. Secondary Outcome

Title	Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUClast
Description	PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (AUClast) following dacomitinib alone and in combination with crizotinib are summarized in the below table. AUClast was calculated using Linear/Log trapezoidal method.
Time Frame	Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Dacomitinib Alone (Expansion Cohort 2)	Crizotinib + Dacomitinib (Expansion Cohort 2)
Arm/Group Description	Participants received dacomitinib (30 mg, QD) alone in 21-day cycles until disease progression.	Participants who progressed on dacomitinib were changed from single agent dacomitinib at the prevailing dose to combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles) as soon as feasible, and no later than 28 days after documentation of disease progression. The participants in this group received 30 mg QD doses of dacomitinib in combination with 200 mg BID doses of crizotinib.
Measure Participants	10	10
Dacomitinib (n = 6, 5)	1016 (45)	1148 (44)
PF-05199265 (n = 7, 6)	80.94 (598)	78.22 (42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD, Crizotinib 200 mg BID/ Dacomitinib 45 mg QD
	Comments	Statistical analysis was performed for dacomitinib AUClast for participants who had both Day -1 and C2D1 data. Result for the analysis of AUClast was based on data from 3 participants. No statistical analysis was performed for PF-05199265.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjust geometric mean
	Estimated Value	117.81
	Confidence Interval	(2-Sided) 90%; 64.97 to 213.61
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of crizotinib + dacomitinib / dacomitinib alone adjust geometric mean was analyzed using the mixed effect model and displayed as percentage.

38. Secondary Outcome

Title	Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUC24
Description	PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (AUC24) following dacomitinib alone and in combination with crizotinib are summarized in the below table. AUC24 was calculated using Linear/Log trapezoidal method.
Time Frame	Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Dacomitinib Alone (Expansion Cohort 2)	Crizotinib + Dacomitinib (Expansion Cohort 2)
Arm/Group Description	Participants received dacomitinib (30 mg, QD) alone in 21-day cycles until disease progression.	Participants who progressed on dacomitinib were changed from single agent dacomitinib at the prevailing dose to combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles) as soon as feasible, and no later than 28 days after documentation of disease progression. The participants in this group received 30 mg QD doses of dacomitinib in combination with 200 mg BID doses of crizotinib.
Measure Participants	10	10
Dacomitinib (n = 6, 5)	995.7 (45)	1148 (44)
PF-05199265 (n = 7, 6)	78.57 (587)	78.36 (42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD, Crizotinib 200 mg BID/ Dacomitinib 45 mg QD
	Comments	Statistical analysis was performed for dacomitinib AUC24 for participants who had both Day -1 and C2D1 data. Result for the analysis of AUC24 was based on data from 3 participants. No statistical analysis was performed for PF-05199265.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjust geometric mean
	Estimated Value	121.90
	Confidence Interval	(2-Sided) 90%; 70.20 to 211.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of crizotinib + dacomitinib / dacomitinib alone adjust geometric mean was analyzed using the mixed effect model and displayed as percentage.

39. Secondary Outcome

Title	Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmin
Description	PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Cmin) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Cmin was observed directly from data.
Time Frame	Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Dacomitinib Alone (Expansion Cohort 2)	Crizotinib + Dacomitinib (Expansion Cohort 2)
Arm/Group Description	Participants received dacomitinib (30 mg, QD) alone in 21-day cycles until disease progression.	Participants who progressed on dacomitinib were changed from single agent dacomitinib at the prevailing dose to combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles) as soon as feasible, and no later than 28 days after documentation of disease progression. The participants in this group received 30 mg QD doses of dacomitinib in combination with 200 mg BID doses of crizotinib.
Measure Participants	10	10
Dacomitinib (n = 6, 5)	33.11 (58)	39.92 (47)
PF-05199265 (n = 7, 6)	5.440 (83)	2.901 (47)

40. Secondary Outcome

Title	Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmax
Description	PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Cmax) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Cmax was observed directly from data.
Time Frame	Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Dacomitinib Alone (Expansion Cohort 2)	Crizotinib + Dacomitinib (Expansion Cohort 2)
Arm/Group Description	Participants received dacomitinib (30 mg, QD) alone in 21-day cycles until disease progression.	Participants who progressed on dacomitinib were changed from single agent dacomitinib at the prevailing dose to combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles) as soon as feasible, and no later than 28 days after documentation of disease progression. The participants in this group received 30 mg QD doses of dacomitinib in combination with 200 mg BID doses of crizotinib.
Measure Participants	10	10
Dacomitinib (n = 6, 5)	47.15 (44)	59.58 (49)
PF-05199265 (n = 7, 6)	4.222 (375)	4.070 (37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crizotinib 200 mg BID/ Dacomitinib 30 mg QD, Crizotinib 200 mg BID/ Dacomitinib 45 mg QD
	Comments	Statistical analysis was performed for dacomitinib Cmax for participants who had both Day -1 and C2D1 data. Result for the analysis of Cmax was based on data from 3 participants. No statistical analysis was performed for PF-05199265.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjust geometric mean
	Estimated Value	130.57
	Confidence Interval	(2-Sided) 90%; 82.46 to 206.73
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of crizotinib + dacomitinib / dacomitinib alone adjust geometric mean was analyzed using the mixed effect model and displayed as percentage.

41. Secondary Outcome

Title	Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tlast
Description	PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Tlast) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Tlast was observed directly from data.
Time Frame	Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Dacomitinib Alone (Expansion Cohort 2)	Crizotinib + Dacomitinib (Expansion Cohort 2)
Arm/Group Description	Participants received dacomitinib (30 mg, QD) alone in 21-day cycles until disease progression.	Participants who progressed on dacomitinib were changed from single agent dacomitinib at the prevailing dose to combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles) as soon as feasible, and no later than 28 days after documentation of disease progression. The participants in this group received 30 mg QD doses of dacomitinib in combination with 200 mg BID doses of crizotinib.
Measure Participants	10	10
Dacomitinib (n = 6, 5)	24.40 (44)	23.80 (49)
PF-05199265 (n = 7, 6)	24.50 (375)	23.80 (37)

42. Secondary Outcome

Title	Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tmax
Description	PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Tmax) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Tmax was observed directly from data as time of first occurrence.
Time Frame	Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population was defined as all participants in the safety analysis population who had at least 1 of the PK parameters of interest. N= Number of participants in the treatment group in the indicated population. n= Number of participants contributing to the summary statistics.

Arm/Group Title	Dacomitinib Alone (Expansion Cohort 2)	Crizotinib + Dacomitinib (Expansion Cohort 2)
Arm/Group Description	Participants received dacomitinib (30 mg, QD) alone in 21-day cycles until disease progression.	Participants who progressed on dacomitinib were changed from single agent dacomitinib at the prevailing dose to combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles) as soon as feasible, and no later than 28 days after documentation of disease progression. The participants in this group received 30 mg QD doses of dacomitinib in combination with 200 mg BID doses of crizotinib.
Measure Participants	10	10
Dacomitinib (n = 6, 5)	16.0 (44)	5.92 (49)
PF-05199265 (n = 7, 6)	5.90 (375)	4.35 (37)

Adverse Events

Time Frame	Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)
Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. The below tables included all causality SAEs (frequency threshold 0%) and AEs ( frequency threshold 5%).
Arm/Group Title	PF-02341066, 200 mg BID/ PF-00299804, 30 mg QD		PF-02341066, 200 mg BID/ PF-00299804, 45 mg QD		PF-02341066, 250 mg BID/ PF-00299804, 30 mg QD		PF-02341066, 250 mg QD/ PF-00299804, 45 mg QD		Expansion Cohort 1		Expansion Cohort 2
Arm/Group Description	Participants enrolled in dose escalation phase received combined oral crizotinib 200 mg BID and oral dacomitinib 30 mg. The first cycle was for 28 days thereafter, each cycle was 21 days.		Participants enrolled in dose escalation received combined oral crizotinib 200 mg BID and oral dacomitinib 45 mg. The first cycle was for 28 days thereafter, each cycle was 21 days.		Participants enrolled in dose escalation received combined oral crizotinib 250 mg BID and oral dacomitinib 30 mg. The first cycle was for 28 days thereafter, each cycle was 21 days.		Participants enrolled in dose escalation received combined oral crizotinib 250 mg BID and oral dacomitinib 45 mg. The first cycle was for 28 days thereafter, each cycle was 21 days.		Participants enrolled in expansion cohort 1 received combined oral crizotinib and oral dacomitinib on a continuous daily schedule of crizotinib 200 mg BID + dacomitinib 30 mg QD. Each cycle was 21 days. If there was unacceptable toxicity or tolerability the dose could be adjusted to a lower combined dose. Expansion Cohort 1 was designed to examine the safety of crizotinib and dacomitinib administered concomitantly in NSCLC participants with acquired resistance to erlotinib or gefitinib.		Participants were treated first with single agent dacomitinib at a dose determined by agreement between the investigator and the sponsor, and then, at progression, with combined maximum tolerated dose of crizotinib and dacomitinib (given orally on a continuous schedule in 21-day cycles of crizotinib 200 mg BID + dacomitinib 30 mg QD) as soon as feasible, and no later than 28 days after documentation of progressive disease. Expansion Cohort 2 used the same participant population as Expansion Cohort 1 and was designed to assess the clinical value of adding crizotinib to dacomitinib treatment after disease progression on dacomitinib alone.
All Cause Mortality
	PF-02341066, 200 mg BID/ PF-00299804, 30 mg QD		PF-02341066, 200 mg BID/ PF-00299804, 45 mg QD		PF-02341066, 250 mg BID/ PF-00299804, 30 mg QD		PF-02341066, 250 mg QD/ PF-00299804, 45 mg QD		Expansion Cohort 1		Expansion Cohort 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	PF-02341066, 200 mg BID/ PF-00299804, 30 mg QD		PF-02341066, 200 mg BID/ PF-00299804, 45 mg QD		PF-02341066, 250 mg BID/ PF-00299804, 30 mg QD		PF-02341066, 250 mg QD/ PF-00299804, 45 mg QD		Expansion Cohort 1		Expansion Cohort 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/14 (42.9%)		2/6 (33.3%)		1/7 (14.3%)		4/6 (66.7%)		9/25 (36%)		9/12 (75%)
Blood and lymphatic system disorders
Anaemia	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Febrile neutropenia	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Cardiac disorders
Myocardial infarction	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Syncope	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Gastrointestinal disorders
Diarrhoea	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		2/12 (16.7%)
Nausea	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		1/12 (8.3%)
General disorders
Chest pain	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Disease progression	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		2/12 (16.7%)
Fatigue	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Hepatobiliary disorders
Bile duct obstruction	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Immune system disorders
Hypersensitivity	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Infections and infestations
Lung infection	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Pneumonia	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Sepsis	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Injury, poisoning and procedural complications
Fall	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Hip fracture	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Investigations
Alanine aminotransferase increased	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Blood creatinine increased	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Metabolism and nutrition disorders
Dehydration	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		1/25 (4%)		0/12 (0%)
Hypercalcaemia	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Hyperuricaemia	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Hyponatraemia	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm malignant	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Tumour pain	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Acute respiratory failure	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Chronic respiratory failure	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Dyspnoea	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Hypoxia	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		2/25 (8%)		0/12 (0%)
Pleural effusion	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Pulmonary embolism	0/14 (0%)		1/6 (16.7%)		1/7 (14.3%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Vascular disorders
Embolism	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Hypotension	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	PF-02341066, 200 mg BID/ PF-00299804, 30 mg QD		PF-02341066, 200 mg BID/ PF-00299804, 45 mg QD		PF-02341066, 250 mg BID/ PF-00299804, 30 mg QD		PF-02341066, 250 mg QD/ PF-00299804, 45 mg QD		Expansion Cohort 1		Expansion Cohort 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/14 (100%)		6/6 (100%)		7/7 (100%)		6/6 (100%)		25/25 (100%)		12/12 (100%)
Blood and lymphatic system disorders
Anaemia	4/14 (28.6%)		1/6 (16.7%)		1/7 (14.3%)		0/6 (0%)		2/25 (8%)		1/12 (8.3%)
Neutropenia	1/14 (7.1%)		0/6 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Thrombocytopenia	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Cardiac disorders
Bradycardia	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		3/25 (12%)		0/12 (0%)
Endocrine disorders
Hypogonadism	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Eye disorders
Dry eye	1/14 (7.1%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		2/12 (16.7%)
Erythema of eyelid	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Eye inflammation	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Eye irritation	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Eye pruritus	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Lacrimation increased	0/14 (0%)		2/6 (33.3%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Periorbital oedema	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Photopsia	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		4/25 (16%)		0/12 (0%)
Punctate keratitis	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Pupils unequal	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Trichiasis	1/14 (7.1%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Vision blurred	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Visual acuity reduced	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Visual impairment	4/14 (28.6%)		2/6 (33.3%)		3/7 (42.9%)		0/6 (0%)		5/25 (20%)		2/12 (16.7%)
Gastrointestinal disorders
Abdominal distension	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		3/25 (12%)		1/12 (8.3%)
Abdominal pain	2/14 (14.3%)		1/6 (16.7%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		1/12 (8.3%)
Abdominal pain upper	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		1/12 (8.3%)
Ascites	0/14 (0%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Chapped lips	4/14 (28.6%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Cheilitis	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		1/12 (8.3%)
Constipation	3/14 (21.4%)		1/6 (16.7%)		0/7 (0%)		2/6 (33.3%)		7/25 (28%)		4/12 (33.3%)
Diarrhoea	12/14 (85.7%)		6/6 (100%)		6/7 (85.7%)		6/6 (100%)		19/25 (76%)		10/12 (83.3%)
Dry mouth	1/14 (7.1%)		1/6 (16.7%)		1/7 (14.3%)		0/6 (0%)		2/25 (8%)		1/12 (8.3%)
Dyspepsia	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		9/25 (36%)		1/12 (8.3%)
Dysphagia	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		0/12 (0%)
Flatulence	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		0/12 (0%)
Gastrointestinal pain	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		0/12 (0%)
Gastrooesophageal reflux disease	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Glossodynia	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Haemorrhoidal haemorrhage	1/14 (7.1%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Haemorrhoids	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		1/25 (4%)		0/12 (0%)
Lip disorder	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Lip dry	0/14 (0%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Mouth ulceration	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Nausea	10/14 (71.4%)		4/6 (66.7%)		5/7 (71.4%)		6/6 (100%)		19/25 (76%)		10/12 (83.3%)
Oesophageal pain	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		0/12 (0%)
Oral pain	0/14 (0%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Rectal lesion	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Retching	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Stomatitis	2/14 (14.3%)		1/6 (16.7%)		1/7 (14.3%)		1/6 (16.7%)		4/25 (16%)		2/12 (16.7%)
Vomiting	9/14 (64.3%)		2/6 (33.3%)		1/7 (14.3%)		5/6 (83.3%)		11/25 (44%)		6/12 (50%)
General disorders
Asthenia	1/14 (7.1%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Axillary pain	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Chest discomfort	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Chest pain	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Chills	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Disease progression	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		0/12 (0%)
Face oedema	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Fatigue	7/14 (50%)		3/6 (50%)		3/7 (42.9%)		3/6 (50%)		13/25 (52%)		7/12 (58.3%)
Gait disturbance	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Influenza like illness	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		2/25 (8%)		0/12 (0%)
Local swelling	1/14 (7.1%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Mucosal inflammation	1/14 (7.1%)		1/6 (16.7%)		3/7 (42.9%)		2/6 (33.3%)		6/25 (24%)		2/12 (16.7%)
Oedema	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		3/25 (12%)		0/12 (0%)
Oedema peripheral	7/14 (50%)		2/6 (33.3%)		3/7 (42.9%)		1/6 (16.7%)		7/25 (28%)		4/12 (33.3%)
Pain	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Pyrexia	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Immune system disorders
Seasonal allergy	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Infections and infestations
Bronchitis viral	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Candida infection	0/14 (0%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Conjunctivitis	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Dermatitis infected	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Enterocolitis infectious	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Folliculitis	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Gastrointestinal viral infection	0/14 (0%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Herpes zoster	0/14 (0%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Intertrigo candida	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Omphalitis	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Oral candidiasis	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Paronychia	6/14 (42.9%)		2/6 (33.3%)		1/7 (14.3%)		3/6 (50%)		8/25 (32%)		7/12 (58.3%)
Upper respiratory tract infection	1/14 (7.1%)		1/6 (16.7%)		1/7 (14.3%)		0/6 (0%)		2/25 (8%)		1/12 (8.3%)
Rash pustular	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Rhinitis	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Skin infection	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		1/12 (8.3%)
Urinary tract infection	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		0/12 (0%)
Viral infection	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Viral upper respiratory tract infection	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Vulvovaginal mycotic infection	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Injury, poisoning and procedural complications
Bone contusion	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Chemical eye injury	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Fall	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Investigations
Activated partial thromboplastin time prolonged	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Alanine aminotransferase increased	2/14 (14.3%)		2/6 (33.3%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		2/12 (16.7%)
Aspartate aminotransferase increased	0/14 (0%)		2/6 (33.3%)		1/7 (14.3%)		1/6 (16.7%)		2/25 (8%)		3/12 (25%)
Blood alkaline phosphatase increased	1/14 (7.1%)		1/6 (16.7%)		1/7 (14.3%)		1/6 (16.7%)		2/25 (8%)		2/12 (16.7%)
Blood creatinine increased	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		1/6 (16.7%)		1/25 (4%)		1/12 (8.3%)
Blood glucose increased	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Blood phosphorus decreased	0/14 (0%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Blood testosterone decreased	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Blood uric acid increased	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Electrocardiogram QT prolonged	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		0/12 (0%)
Haemoglobin decreased	0/14 (0%)		0/6 (0%)		0/7 (0%)		2/6 (33.3%)		0/25 (0%)		1/12 (8.3%)
International normalised ratio increased	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Neutrophil count decreased	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Weight decreased	3/14 (21.4%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		2/12 (16.7%)
White blood cell count decreased	0/14 (0%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Metabolism and nutrition disorders
Decreased appetite	7/14 (50%)		4/6 (66.7%)		3/7 (42.9%)		3/6 (50%)		10/25 (40%)		5/12 (41.7%)
Dehydration	1/14 (7.1%)		2/6 (33.3%)		2/7 (28.6%)		1/6 (16.7%)		3/25 (12%)		0/12 (0%)
Hyperglycaemia	0/14 (0%)		0/6 (0%)		1/7 (14.3%)		2/6 (33.3%)		0/25 (0%)		0/12 (0%)
Hyperkalaemia	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Hyperuricaemia	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Hypoalbuminaemia	2/14 (14.3%)		1/6 (16.7%)		1/7 (14.3%)		2/6 (33.3%)		4/25 (16%)		2/12 (16.7%)
Hypocalcaemia	2/14 (14.3%)		0/6 (0%)		1/7 (14.3%)		2/6 (33.3%)		1/25 (4%)		1/12 (8.3%)
Hypokalaemia	1/14 (7.1%)		1/6 (16.7%)		2/7 (28.6%)		1/6 (16.7%)		3/25 (12%)		2/12 (16.7%)
Hyponatraemia	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		2/12 (16.7%)
Hypophosphataemia	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		3/25 (12%)		1/12 (8.3%)
Hypomagnesaemia	2/14 (14.3%)		0/6 (0%)		2/7 (28.6%)		1/6 (16.7%)		3/25 (12%)		0/12 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/14 (7.1%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Back pain	1/14 (7.1%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		2/12 (16.7%)
Flank pain	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Joint swelling	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Muscle spasms	5/14 (35.7%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		1/25 (4%)		2/12 (16.7%)
Musculoskeletal chest pain	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		2/12 (16.7%)
Musculoskeletal discomfort	1/14 (7.1%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Musculoskeletal pain	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Musculoskeletal stiffness	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Myalgia	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		1/12 (8.3%)
Synovial cyst	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pyogenic granuloma	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Tumour pain	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Nervous system disorders
Dementia	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Dizziness	1/14 (7.1%)		1/6 (16.7%)		0/7 (0%)		1/6 (16.7%)		3/25 (12%)		1/12 (8.3%)
Dizziness postural	0/14 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		0/12 (0%)
Dysgeusia	2/14 (14.3%)		2/6 (33.3%)		0/7 (0%)		2/6 (33.3%)		3/25 (12%)		1/12 (8.3%)
Headache	1/14 (7.1%)		1/6 (16.7%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		1/12 (8.3%)
Hyperaesthesia	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Migraine	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Myoclonus	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Peripheral sensory neuropathy	1/14 (7.1%)		2/6 (33.3%)		0/7 (0%)		1/6 (16.7%)		2/25 (8%)		0/12 (0%)
Psychiatric disorders
Anxiety	1/14 (7.1%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Depression	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Insomnia	3/14 (21.4%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Personality change	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Renal and urinary disorders
Dysuria	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Urinary hesitation	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Reproductive system and breast disorders
Genital rash	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Vulvovaginal dryness	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic respiratory failure	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Cough	2/14 (14.3%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		3/25 (12%)		2/12 (16.7%)
Dry throat	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Dysphonia	2/14 (14.3%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Dyspnoea	2/14 (14.3%)		0/6 (0%)		0/7 (0%)		2/6 (33.3%)		4/25 (16%)		2/12 (16.7%)
Dyspnoea exertional	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		2/6 (33.3%)		0/25 (0%)		1/12 (8.3%)
Epistaxis	3/14 (21.4%)		3/6 (50%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		0/12 (0%)
Nasal discomfort	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		1/12 (8.3%)
Nasal disorder	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Nasal dryness	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Oropharyngeal pain	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Pleural effusion	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		0/12 (0%)
Pneumonitis	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		2/12 (16.7%)
Productive cough	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Pulmonary embolism	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		3/12 (25%)
Rhinorrhoea	1/14 (7.1%)		1/6 (16.7%)		0/7 (0%)		1/6 (16.7%)		0/25 (0%)		1/12 (8.3%)
Upper-airway cough syndrome	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Wheezing	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Skin and subcutaneous tissue disorders
Alopecia	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		1/12 (8.3%)
Dermatitis acneiform	4/14 (28.6%)		1/6 (16.7%)		1/7 (14.3%)		3/6 (50%)		10/25 (40%)		2/12 (16.7%)
Dry skin	7/14 (50%)		2/6 (33.3%)		1/7 (14.3%)		3/6 (50%)		6/25 (24%)		5/12 (41.7%)
Erythema	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Facial wasting	0/14 (0%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Onychoclasis	2/14 (14.3%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		1/25 (4%)		0/12 (0%)
Pruritus	2/14 (14.3%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		4/25 (16%)		0/12 (0%)
Rash	9/14 (64.3%)		3/6 (50%)		3/7 (42.9%)		3/6 (50%)		5/25 (20%)		7/12 (58.3%)
Rash maculo-papular	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		0/12 (0%)
Scab	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Skin fissures	1/14 (7.1%)		1/6 (16.7%)		1/7 (14.3%)		1/6 (16.7%)		3/25 (12%)		1/12 (8.3%)
Skin lesion	1/14 (7.1%)		1/6 (16.7%)		1/7 (14.3%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Skin toxicity	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Skin ulcer	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		1/12 (8.3%)
Vascular disorders
Deep vein thrombosis	1/14 (7.1%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Embolism	0/14 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/25 (8%)		0/12 (0%)
Hypotension	2/14 (14.3%)		0/6 (0%)		1/7 (14.3%)		1/6 (16.7%)		2/25 (8%)		0/12 (0%)
Intra-abdominal haematoma	0/14 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Lymphoedema	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Poor venous access	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/25 (0%)		0/12 (0%)
Thrombophlebitis superficial	1/14 (7.1%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/25 (4%)		0/12 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.