Non Small Cell Lung Cancer
Conditions
Keywords
Phase 1 acquired resistance to erlotinib or gefitinib cMET inhibitor EGFR inhibitor panHER inhibitor combination trial Crizotinib
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.
Interventions
DRUGPF-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.
DRUGPF-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.
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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). |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Australia, United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD 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. | 14 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD 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. | 6 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD 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. | 7 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD 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. | 6 |
| Expansion Cohort 1 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. | 25 |
| Expansion Cohort 2 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. | 12 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Death | 6 | 0 | 0 | 1 | 7 | 1 |
| Overall Study | Participant Refused Further Follow-Up | 0 | 0 | 0 | 0 | 5 | 1 |
| Overall Study | Unspecified Reasons | 8 | 6 | 7 | 5 | 13 | 10 |
Baseline characteristics
| Characteristic | 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 |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 53.6 Years STANDARD_DEVIATION 9.87 | 61.7 Years STANDARD_DEVIATION 7.53 | 54.7 Years STANDARD_DEVIATION 11.34 | 62.2 Years STANDARD_DEVIATION 13.61 | 61.8 Years STANDARD_DEVIATION 10.83 | 59.6 Years STANDARD_DEVIATION 11.74 | 59.1 Years STANDARD_DEVIATION 11.05 |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 6 Participants | 2 Participants | 16 Participants | 9 Participants | 43 Participants |
| Sex: Female, Male Male | 9 Participants | 1 Participants | 1 Participants | 4 Participants | 9 Participants | 3 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 14 | 6 / 6 | 7 / 7 | 6 / 6 | 25 / 25 | 12 / 12 |
| serious Total, serious adverse events | 6 / 14 | 2 / 6 | 1 / 7 | 4 / 6 | 9 / 25 | 9 / 12 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase
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)
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase | Grade 3 Alanine aminotransferase increased | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase | Grade 3 Mucosal inflammation | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase | Grade 3 Diarrhoea | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase | Grade 3 Alanine aminotransferase increased | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase | Grade 3 Mucosal inflammation | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase | Grade 3 Diarrhoea | 1 Participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase | Grade 3 Diarrhoea | 0 Participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase | Grade 3 Alanine aminotransferase increased | 0 Participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase | Grade 3 Mucosal inflammation | 1 Participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase | Grade 3 Alanine aminotransferase increased | 0 Participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase | Grade 3 Mucosal inflammation | 0 Participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase | Grade 3 Diarrhoea | 0 Participants |
Primary
Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase
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)
Population: The safety analysis population included all enrolled participants who had received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with AEs | 14 participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with Grade 3 or 4 AEs | 9 participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with Grade 5 AEs | 3 participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with SAEs | 6 participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with Grade 3 or 4 AEs | 4 participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with Grade 5 AEs | 0 participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with SAEs | 2 participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with AEs | 6 participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with Grade 5 AEs | 0 participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with Grade 3 or 4 AEs | 5 participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with SAEs | 1 participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with AEs | 7 participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with SAEs | 4 participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with Grade 3 or 4 AEs | 5 participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with AEs | 6 participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase | Participants with Grade 5 AEs | 1 participants |
Primary
Overview of Treatment-emergent All Causalities AEs in Expansion Phase
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)
Population: The safety analysis population included all enrolled participants who had received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent All Causalities AEs in Expansion Phase | Participants with Grade 5 AEs | 3 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent All Causalities AEs in Expansion Phase | Participants with Grade 3 or 4 AEs | 12 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent All Causalities AEs in Expansion Phase | Participants with SAEs | 8 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent All Causalities AEs in Expansion Phase | Participants with AEs | 22 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent All Causalities AEs in Expansion Phase | Participants with SAEs | 8 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent All Causalities AEs in Expansion Phase | Participants with Grade 3 or 4 AEs | 8 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent All Causalities AEs in Expansion Phase | Participants with Grade 5 AEs | 2 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent All Causalities AEs in Expansion Phase | Participants with AEs | 11 Participants |
Primary
Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase
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)
Population: The safety analysis population included all enrolled participants who had received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related Grade 3/ 4 AEs | 8 participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related SAEs | 1 participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related AEs | 14 participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related Grade 5 AEs | 0 participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related AEs | 6 participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related SAEs | 2 participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related Grade 3/ 4 AEs | 3 participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related Grade 5 AEs | 0 participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related AEs | 7 participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related SAEs | 0 participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related Grade 5 AEs | 0 participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related Grade 3/ 4 AEs | 3 participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related SAEs | 1 participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related Grade 3/ 4 AEs | 3 participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related Grade 5 AEs | 0 participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase | Participants with treatment-related AEs | 6 participants |
Primary
Overview of Treatment-emergent, Treatment-related AEs in Expansion Phase
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)
Population: The safety analysis population included all enrolled participants who had received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Expansion Phase | Participants with treatment-related AEs | 22 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Expansion Phase | Participants with treatment-related Grade 3/ 4 AEs | 7 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Expansion Phase | Participants with treatment-related Grade 5 AEs | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Expansion Phase | Participants with treatment-related SAEs | 3 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Expansion Phase | Participants with treatment-related SAEs | 3 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Expansion Phase | Participants with treatment-related AEs | 11 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Expansion Phase | Participants with treatment-related Grade 5 AEs | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Overview of Treatment-emergent, Treatment-related AEs in Expansion Phase | Participants with treatment-related Grade 3/ 4 AEs | 6 Participants |
Secondary
Duration of Response for the Only Participant Shown Partial Response in Expansion Phase
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)
Population: This Outcome Measure was only assessed for participants with response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Duration of Response for the Only Participant Shown Partial Response in Expansion Phase | 6.29 Weeks |
Secondary
Expression Analysis of Tumor Biomarkers (EGFR, and c-Met) at Baseline Using Fluorescent in Situ Hybridization (FISH) Method
Expression of tumor biomarkers EGFR and cMet at Baseline (using FISH method) are presented in this outcome measure.
Time frame: Baseline
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Expression Analysis of Tumor Biomarkers (EGFR, and c-Met) at Baseline Using Fluorescent in Situ Hybridization (FISH) Method | Ratio of Red to Green of EGFR (N= 11, 11) | 1.580 Ratio |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Expression Analysis of Tumor Biomarkers (EGFR, and c-Met) at Baseline Using Fluorescent in Situ Hybridization (FISH) Method | Ratio of Green to Orange for cMET (N = 19, 11) | 1.040 Ratio |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Expression Analysis of Tumor Biomarkers (EGFR, and c-Met) at Baseline Using Fluorescent in Situ Hybridization (FISH) Method | Ratio of Red to Green of EGFR (N= 11, 11) | 1.180 Ratio |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Expression Analysis of Tumor Biomarkers (EGFR, and c-Met) at Baseline Using Fluorescent in Situ Hybridization (FISH) Method | Ratio of Green to Orange for cMET (N = 19, 11) | 1.000 Ratio |
Secondary
Expression Analysis of Tumor Biomarkers (HGF, EGFR, and c-Met ) at Baseline Using Immunohistochemistry (IHC) Method
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Expression Analysis of Tumor Biomarkers (HGF, EGFR, and c-Met ) at Baseline Using Immunohistochemistry (IHC) Method | HGF (N= 19, 11) | 40.0 H-Score |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Expression Analysis of Tumor Biomarkers (HGF, EGFR, and c-Met ) at Baseline Using Immunohistochemistry (IHC) Method | EGFR (N= 14, 8) | 193.2 H-Score |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Expression Analysis of Tumor Biomarkers (HGF, EGFR, and c-Met ) at Baseline Using Immunohistochemistry (IHC) Method | cMet (N= 19, 11) | 125.0 H-Score |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Expression Analysis of Tumor Biomarkers (HGF, EGFR, and c-Met ) at Baseline Using Immunohistochemistry (IHC) Method | HGF (N= 19, 11) | 67.0 H-Score |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Expression Analysis of Tumor Biomarkers (HGF, EGFR, and c-Met ) at Baseline Using Immunohistochemistry (IHC) Method | EGFR (N= 14, 8) | 170.0 H-Score |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Expression Analysis of Tumor Biomarkers (HGF, EGFR, and c-Met ) at Baseline Using Immunohistochemistry (IHC) Method | cMet (N= 19, 11) | 165.0 H-Score |
Secondary
Number of Participants With c-Met, HER2, EGFR Amplification and ALK Rearrangement at Baseline Using FISH Method
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With c-Met, HER2, EGFR Amplification and ALK Rearrangement at Baseline Using FISH Method | c-Met amplification (N= 19, 11) | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With c-Met, HER2, EGFR Amplification and ALK Rearrangement at Baseline Using FISH Method | HER2 amplification (N= 19, 7) | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With c-Met, HER2, EGFR Amplification and ALK Rearrangement at Baseline Using FISH Method | EGFR amplification (N= 11,11) | 2 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With c-Met, HER2, EGFR Amplification and ALK Rearrangement at Baseline Using FISH Method | ALK rearrangement (N= 19, 11) | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With c-Met, HER2, EGFR Amplification and ALK Rearrangement at Baseline Using FISH Method | ALK rearrangement (N= 19, 11) | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With c-Met, HER2, EGFR Amplification and ALK Rearrangement at Baseline Using FISH Method | c-Met amplification (N= 19, 11) | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With c-Met, HER2, EGFR Amplification and ALK Rearrangement at Baseline Using FISH Method | EGFR amplification (N= 11,11) | 3 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With c-Met, HER2, EGFR Amplification and ALK Rearrangement at Baseline Using FISH Method | HER2 amplification (N= 19, 7) | 0 Participants |
Secondary
Number of Participants With EGFR Mutation at Baseline
Sample analyses were performed in accordance to Good Laboratory Practice (GLP) guidance and included mutation detection for EGFR gene.
Time frame: Baseline
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With EGFR Mutation at Baseline | Exon 18 (G719X) | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With EGFR Mutation at Baseline | Exon 19 (Deletion) | 6 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With EGFR Mutation at Baseline | Exon 20 (T790M) | 6 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With EGFR Mutation at Baseline | Exon 20 (T790M/S768I) | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With EGFR Mutation at Baseline | Exon 20 (S768I) | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With EGFR Mutation at Baseline | Exon 21 (L858R) | 6 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With EGFR Mutation at Baseline | Exon 20 (S768I) | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With EGFR Mutation at Baseline | Exon 18 (G719X) | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With EGFR Mutation at Baseline | Exon 20 (T790M/S768I) | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With EGFR Mutation at Baseline | Exon 19 (Deletion) | 3 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With EGFR Mutation at Baseline | Exon 21 (L858R) | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With EGFR Mutation at Baseline | Exon 20 (T790M) | 3 Participants |
Secondary
Number of Participants With KRAS Mutation (GLY12CYS) at Baseline
Sample analyses were performed in accordance to GLP guidance and included mutation detection for KRAS gene.
Time frame: Baseline
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With KRAS Mutation (GLY12CYS) at Baseline | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With KRAS Mutation (GLY12CYS) at Baseline | 0 Participants |
Secondary
Number of Participants With Objective Response Rate (ORR) in Escalation Phase
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)
Population: The response evaluable population included participants in safety analysis population who had an adequate Baseline tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Objective Response Rate (ORR) in Escalation Phase | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With Objective Response Rate (ORR) in Escalation Phase | 0 Participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Objective Response Rate (ORR) in Escalation Phase | 0 Participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Number of Participants With Objective Response Rate (ORR) in Escalation Phase | 0 Participants |
Secondary
Number of Participants With ORR in Expansion Phase
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)
Population: The response evaluable population included participants in safety analysis population who had an adequate Baseline tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With ORR in Expansion Phase | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With ORR in Expansion Phase | 0 Participants |
Secondary
Number of Participants With PIK3CA Mutation at Baseline
Sample analyses were performed in accordance to GLP guidance and included mutation detection for PIK3CA gene.
Time frame: Baseline
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With PIK3CA Mutation at Baseline | Exon 20 (M1004I) (N= 14, 6) | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With PIK3CA Mutation at Baseline | Exon 20 (Q1061K) (N= 14, 6) | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With PIK3CA Mutation at Baseline | Exon 20 (H1047R) (N= 14, 6) | 2 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With PIK3CA Mutation at Baseline | Exon 9 (E545K) (N= 14, 6) | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With PIK3CA Mutation at Baseline | Exon 9 (E545K) (N= 14, 6) | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With PIK3CA Mutation at Baseline | Exon 20 (M1004I) (N= 14, 6) | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With PIK3CA Mutation at Baseline | Exon 20 (H1047R) (N= 14, 6) | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With PIK3CA Mutation at Baseline | Exon 20 (Q1061K) (N= 14, 6) | 0 Participants |
Secondary
Number of Participants With ROS1 Gene Translocation at Baseline
Sample analyses were performed in accordance to GLP guidance and included translocation detection (RNA based) for ROS1 gene.
Time frame: Baseline
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With ROS1 Gene Translocation at Baseline | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With ROS1 Gene Translocation at Baseline | 0 Participants |
Secondary
Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase
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)
Population: The response evaluable population included participants in safety analysis population who had an adequate Baseline tumor assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | 0- < 3 months | 3 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | 3- < 6 months | 6 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | Stable Disease | 10 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | 6- < 9 months | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | Stable Disease | 3 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | 0- < 3 months | 2 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | 6- < 9 months | 0 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | 3- < 6 months | 1 Participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | Stable Disease | 2 Participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | 6- < 9 months | 0 Participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | 3- < 6 months | 1 Participants |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | 0- < 3 months | 1 Participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | 3- < 6 months | 3 Participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | 0- < 3 months | 0 Participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | 6- < 9 months | 2 Participants |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase | Stable Disease | 5 Participants |
Secondary
Number of Participants With Stable Disease and Stable Disease Duration in Expansion Phase
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)
Population: The response evaluable population included participants in safety analysis population who had an adequate Baseline tumor assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Expansion Phase | Stable Disease | 6 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Expansion Phase | 0- < 3 months | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Expansion Phase | 3- < 6 months | 4 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Expansion Phase | 6- < 9 months | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Expansion Phase | 6- < 9 months | 1 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Expansion Phase | Stable Disease | 5 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Expansion Phase | 3- < 6 months | 4 Participants |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Number of Participants With Stable Disease and Stable Disease Duration in Expansion Phase | 0- < 3 months | 0 Participants |
Secondary
Plasma Concentration of sMet by Study Visits
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).
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Concentration of sMet by Study Visits | C1D1 | 1519047.6 pg/mL | Standard Deviation 230995.77 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Concentration of sMet by Study Visits | C2D1 | 1525666.7 pg/mL | Standard Deviation 394836.61 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Concentration of sMet by Study Visits | C1D15 | 1483157.9 pg/mL | Standard Deviation 243904.64 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Concentration of sMet by Study Visits | C2D15 | 1564666.7 pg/mL | Standard Deviation 224367.9 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Concentration of sMet by Study Visits | Baseline at Screening | 1353411.8 pg/mL | Standard Deviation 349746.88 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Concentration of sMet by Study Visits | C2D15 | 1602500.0 pg/mL | Standard Deviation 126589.89 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Concentration of sMet by Study Visits | Baseline at Screening | 1557000.0 pg/mL | Standard Deviation 514352.02 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Concentration of sMet by Study Visits | C1D1 | 1450500.0 pg/mL | Standard Deviation 553557.13 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Concentration of sMet by Study Visits | C1D15 | 1676666.7 pg/mL | Standard Deviation 540246.86 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Concentration of sMet by Study Visits | C2D1 | 1540000.0 pg/mL | Standard Deviation 315515.45 |
Secondary
Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10)
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | Crizotinib C1D1 - single dose (n= 8, 3, 4, 6) | 624.9 ng•hr/mL | Geometric Coefficient of Variation 57 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | Crizotinib C1D15 multiple dose (n= 5, 2, 6, 5) | 2000 ng•hr/mL | Geometric Coefficient of Variation 43 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | PF-06260182 C1D1 - single dose (n= 8, 3, 4, 6) | 162.1 ng•hr/mL | Geometric Coefficient of Variation 57 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | PF-06260182 C1D15 - multiple dose (n= 5, 2, 6, 5) | 452.5 ng•hr/mL | Geometric Coefficient of Variation 48 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | Crizotinib C1D15 multiple dose (n= 5, 2, 6, 5) | 2620 ng•hr/mL | — |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | PF-06260182 C1D1 - single dose (n= 8, 3, 4, 6) | 127.6 ng•hr/mL | Geometric Coefficient of Variation 32 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | PF-06260182 C1D15 - multiple dose (n= 5, 2, 6, 5) | 798.0 ng•hr/mL | — |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | Crizotinib C1D1 - single dose (n= 8, 3, 4, 6) | 500.8 ng•hr/mL | Geometric Coefficient of Variation 9 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | PF-06260182 C1D1 - single dose (n= 8, 3, 4, 6) | 141.5 ng•hr/mL | Geometric Coefficient of Variation 25 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | Crizotinib C1D15 multiple dose (n= 5, 2, 6, 5) | 1732 ng•hr/mL | Geometric Coefficient of Variation 35 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | PF-06260182 C1D15 - multiple dose (n= 5, 2, 6, 5) | 473.3 ng•hr/mL | Geometric Coefficient of Variation 39 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | Crizotinib C1D1 - single dose (n= 8, 3, 4, 6) | 559.6 ng•hr/mL | Geometric Coefficient of Variation 26 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | PF-06260182 C1D15 - multiple dose (n= 5, 2, 6, 5) | 525.5 ng•hr/mL | Geometric Coefficient of Variation 68 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | Crizotinib C1D15 multiple dose (n= 5, 2, 6, 5) | 1644 ng•hr/mL | Geometric Coefficient of Variation 44 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | Crizotinib C1D1 - single dose (n= 8, 3, 4, 6) | 655.8 ng•hr/mL | Geometric Coefficient of Variation 65 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) | PF-06260182 C1D1 - single dose (n= 8, 3, 4, 6) | 228.0 ng•hr/mL | Geometric Coefficient of Variation 57 |
Secondary
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)
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | 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) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 509.7 ng•hr/mL | Geometric Coefficient of Variation 62 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | 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) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 1759 ng•hr/mL | Geometric Coefficient of Variation 39 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | 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) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 121.3 ng•hr/mL | Geometric Coefficient of Variation 76 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | 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) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 382.3 ng•hr/mL | Geometric Coefficient of Variation 52 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | 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) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 2464 ng•hr/mL | Geometric Coefficient of Variation 14 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | 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) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 103.2 ng•hr/mL | Geometric Coefficient of Variation 74 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | 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) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 593.5 ng•hr/mL | Geometric Coefficient of Variation 53 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | 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) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 420.8 ng•hr/mL | Geometric Coefficient of Variation 53 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | 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) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 121.6 ng•hr/mL | Geometric Coefficient of Variation 29 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | 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) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 1732 ng•hr/mL | Geometric Coefficient of Variation 35 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | 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) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 440.5 ng•hr/mL | Geometric Coefficient of Variation 37 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | 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) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 506.6 ng•hr/mL | Geometric Coefficient of Variation 29 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | 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) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 532.0 ng•hr/mL | Geometric Coefficient of Variation 68 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | 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) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 1672 ng•hr/mL | Geometric Coefficient of Variation 44 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | 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) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 656.6 ng•hr/mL | Geometric Coefficient of Variation 65 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | 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) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 220.7 ng•hr/mL | Geometric Coefficient of Variation 55 |
Secondary
Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax)
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 84.24 ng/mL | Geometric Coefficient of Variation 58 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 231.5 ng/mL | Geometric Coefficient of Variation 41 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 18.50 ng/mL | Geometric Coefficient of Variation 72 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 49.73 ng/mL | Geometric Coefficient of Variation 50 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 329.7 ng/mL | Geometric Coefficient of Variation 12 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 22.37 ng/mL | Geometric Coefficient of Variation 26 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 78.45 ng/mL | Geometric Coefficient of Variation 44 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 94.13 ng/mL | Geometric Coefficient of Variation 22 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 20.97 ng/mL | Geometric Coefficient of Variation 29 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 218.1 ng/mL | Geometric Coefficient of Variation 33 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 57.56 ng/mL | Geometric Coefficient of Variation 34 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 90.86 ng/mL | Geometric Coefficient of Variation 29 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 83.23 ng/mL | Geometric Coefficient of Variation 91 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 268.9 ng/mL | Geometric Coefficient of Variation 77 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 114.0 ng/mL | Geometric Coefficient of Variation 61 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 34.33 ng/mL | Geometric Coefficient of Variation 61 |
Secondary
Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast)
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
Population: 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 | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 9.92 Hour | Full Range 58 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 9.29 Hour | Full Range 41 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 9.92 Hour | Full Range 72 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 9.29 Hour | Full Range 50 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 9.42 Hour | Full Range 25 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 9.33 Hour | Full Range 26 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 9.42 Hour | Full Range 44 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 9.33 Hour | Full Range 22 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 9.05 Hour | Full Range 29 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 9.05 Hour | Full Range 47 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 9.05 Hour | Full Range 34 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 9.05 Hour | Full Range 29 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 10.2 Hour | Full Range 91 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 10.2 Hour | Full Range 35 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 9.75 Hour | Full Range 61 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 9.75 Hour | Full Range 61 |
Secondary
Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax)
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
Population: 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 | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 3.00 Hour | Full Range 58 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 1.68 Hour | Full Range 41 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 4.07 Hour | Full Range 72 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 4.03 Hour | Full Range 50 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 6.17 Hour | Full Range 25 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 4.00 Hour | Full Range 26 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 6.17 Hour | Full Range 44 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 3.53 Hour | Full Range 22 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 3.98 Hour | Full Range 29 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 2.00 Hour | Full Range 47 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 4.09 Hour | Full Range 34 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 3.92 Hour | Full Range 29 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | PF-06260182 C1D15 - multiple dose (n=8, 3, 6, 5) | 6.00 Hour | Full Range 91 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | Crizotinib C1D15 multiple dose (n=8, 3, 6, 5) | 6.00 Hour | Full Range 35 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | Crizotinib C1D1 - single dose (n= 11, 6, 7, 6) | 3.06 Hour | Full Range 61 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) | PF-06260182 C1D1 - single dose (n= 11, 6, 7, 6) | 4.99 Hour | Full Range 61 |
Secondary
Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUC10
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)
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUC10 | Crizotinib (n = 11, 9) | 2167 ng•hr/mL | Geometric Coefficient of Variation 56 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUC10 | PF-06260182 (n = 11, 9) | 634.3 ng•hr/mL | Geometric Coefficient of Variation 82 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUC10 | Crizotinib (n = 11, 9) | 1489 ng•hr/mL | Geometric Coefficient of Variation 44 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUC10 | PF-06260182 (n = 11, 9) | 422.3 ng•hr/mL | Geometric Coefficient of Variation 55 |
Comparison: 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-06260182.90% CI: [58.9, 105.54]
Secondary
Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUClast
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)
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUClast | Crizotinib (n = 16, 13) | 2223 ng•hr/mL | Geometric Coefficient of Variation 53 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUClast | PF-06260182 (n = 16, 13) | 616.3 ng•hr/mL | Geometric Coefficient of Variation 77 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUClast | Crizotinib (n = 16, 13) | 1365 ng•hr/mL | Geometric Coefficient of Variation 47 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUClast | PF-06260182 (n = 16, 13) | 356.6 ng•hr/mL | Geometric Coefficient of Variation 61 |
Comparison: 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-06260182.90% CI: [54.22, 88.44]
Secondary
Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmax
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)
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmax | Crizotinib (n = 16, 13) | 306.0 ng/mL | Geometric Coefficient of Variation 57 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmax | PF-06260182 (n = 16, 13) | 82.92 ng/mL | Geometric Coefficient of Variation 79 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmax | Crizotinib (n = 16, 13) | 191.5 ng/mL | Geometric Coefficient of Variation 43 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmax | PF-06260182 (n = 16, 13) | 51.15 ng/mL | Geometric Coefficient of Variation 56 |
Comparison: 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-06260182.90% CI: [54.71, 91.12]
Secondary
Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmin
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)
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmin | Crizotinib (n = 16, 13) | 181.8 ng/mL | Geometric Coefficient of Variation 64 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmin | PF-06260182 (n = 16, 13) | 47.22 ng/mL | Geometric Coefficient of Variation 99 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmin | Crizotinib (n = 16, 13) | 102.8 ng/mL | Geometric Coefficient of Variation 51 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmin | PF-06260182 (n = 16, 13) | 25.53 ng/mL | Geometric Coefficient of Variation 60 |
Secondary
Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tlast
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)
Population: 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 | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tlast | Crizotinib (n = 16, 13) | 9.650 Hour | Full Range 57 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tlast | PF-06260182 (n = 16, 13) | 9.650 Hour | Full Range 79 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tlast | Crizotinib (n = 16, 13) | 9.000 Hour | Full Range 43 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tlast | PF-06260182 (n = 16, 13) | 9.000 Hour | Full Range 56 |
Secondary
Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tmax
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)
Population: 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 | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tmax | Crizotinib (n = 16, 13) | 2.04 Hour | Full Range 57 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tmax | PF-06260182 (n = 16, 13) | 3.96 Hour | Full Range 79 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tmax | Crizotinib (n = 16, 13) | 3.20 Hour | Full Range 43 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tmax | PF-06260182 (n = 16, 13) | 3.95 Hour | Full Range 56 |
Secondary
Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | Dacomitinib C1D1 - single dose (n= 8, 3, 5, 5) | 252.7 ng•hr/mL | Geometric Coefficient of Variation 61 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 1336 ng•hr/mL | Geometric Coefficient of Variation 48 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | PF-5199265 C1D1 - single dose (n= 9, 3, 5, 6) | 28.57 ng•hr/mL | Geometric Coefficient of Variation 87 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 51.37 ng•hr/mL | Geometric Coefficient of Variation 108 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 2334 ng•hr/mL | Geometric Coefficient of Variation 69 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | PF-5199265 C1D1 - single dose (n= 9, 3, 5, 6) | 14.80 ng•hr/mL | Geometric Coefficient of Variation 51 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 51.97 ng•hr/mL | Geometric Coefficient of Variation 78 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | Dacomitinib C1D1 - single dose (n= 8, 3, 5, 5) | 347.9 ng•hr/mL | Geometric Coefficient of Variation 26 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | PF-5199265 C1D1 - single dose (n= 9, 3, 5, 6) | 16.08 ng•hr/mL | Geometric Coefficient of Variation 169 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 1203 ng•hr/mL | Geometric Coefficient of Variation 15 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 44.72 ng•hr/mL | Geometric Coefficient of Variation 90 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | Dacomitinib C1D1 - single dose (n= 8, 3, 5, 5) | 223.4 ng•hr/mL | Geometric Coefficient of Variation 23 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 158.1 ng•hr/mL | Geometric Coefficient of Variation 31 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 1745 ng•hr/mL | Geometric Coefficient of Variation 30 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | Dacomitinib C1D1 - single dose (n= 8, 3, 5, 5) | 306.6 ng•hr/mL | Geometric Coefficient of Variation 57 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 | PF-5199265 C1D1 - single dose (n= 9, 3, 5, 6) | 54.72 ng•hr/mL | Geometric Coefficient of Variation 76 |
Secondary
Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | Dacomitinib C1D1 - single dose (n= 10, 6, 7, 5) | 208.3 ng•hr/mL | Geometric Coefficient of Variation 72 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 1339 ng•hr/mL | Geometric Coefficient of Variation 47 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | PF-5199265 C1D1 - single dose (n= 8, 6, 6, 6) | 27.68 ng•hr/mL | Geometric Coefficient of Variation 80 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 51.48 ng•hr/mL | Geometric Coefficient of Variation 108 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 2343 ng•hr/mL | Geometric Coefficient of Variation 70 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | PF-5199265 C1D1 - single dose (n= 8, 6, 6, 6) | 7.438 ng•hr/mL | Geometric Coefficient of Variation 115 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 52.24 ng•hr/mL | Geometric Coefficient of Variation 78 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | Dacomitinib C1D1 - single dose (n= 10, 6, 7, 5) | 132.3 ng•hr/mL | Geometric Coefficient of Variation 153 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | PF-5199265 C1D1 - single dose (n= 8, 6, 6, 6) | 10.19 ng•hr/mL | Geometric Coefficient of Variation 190 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 1212 ng•hr/mL | Geometric Coefficient of Variation 15 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 44.97 ng•hr/mL | Geometric Coefficient of Variation 90 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | Dacomitinib C1D1 - single dose (n= 10, 6, 7, 5) | 146.3 ng•hr/mL | Geometric Coefficient of Variation 86 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 161.0 ng•hr/mL | Geometric Coefficient of Variation 33 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 1775 ng•hr/mL | Geometric Coefficient of Variation 31 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | Dacomitinib C1D1 - single dose (n= 10, 6, 7, 5) | 307.7 ng•hr/mL | Geometric Coefficient of Variation 56 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast | PF-5199265 C1D1 - single dose (n= 8, 6, 6, 6) | 55.00 ng•hr/mL | Geometric Coefficient of Variation 75 |
Secondary
Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | Dacomitinib C1D1 - single dose (n= 10, 6, 7, 5) | 15.56 ng/mL | Geometric Coefficient of Variation 58 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 65.00 ng/mL | Geometric Coefficient of Variation 52 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | PF-5199265 C1D1 - single dose (n= 10, 6, 6, 7) | 1.894 ng/mL | Geometric Coefficient of Variation 89 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 2.367 ng/mL | Geometric Coefficient of Variation 115 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 122.4 ng/mL | Geometric Coefficient of Variation 75 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | PF-5199265 C1D1 - single dose (n= 10, 6, 6, 7) | 0.9888 ng/mL | Geometric Coefficient of Variation 79 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 2.649 ng/mL | Geometric Coefficient of Variation 75 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | Dacomitinib C1D1 - single dose (n= 10, 6, 7, 5) | 17.49 ng/mL | Geometric Coefficient of Variation 23 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | PF-5199265 C1D1 - single dose (n= 10, 6, 6, 7) | 0.8833 ng/mL | Geometric Coefficient of Variation 130 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 57.04 ng/mL | Geometric Coefficient of Variation 13 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 2.073 ng/mL | Geometric Coefficient of Variation 95 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | Dacomitinib C1D1 - single dose (n= 10, 6, 7, 5) | 12.40 ng/mL | Geometric Coefficient of Variation 21 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 7.560 ng/mL | Geometric Coefficient of Variation 34 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 86.81 ng/mL | Geometric Coefficient of Variation 38 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | Dacomitinib C1D1 - single dose (n= 10, 6, 7, 5) | 18.22 ng/mL | Geometric Coefficient of Variation 64 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax | PF-5199265 C1D1 - single dose (n= 10, 6, 6, 7) | 3.193 ng/mL | Geometric Coefficient of Variation 74 |
Secondary
Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast
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
Population: 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 | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | Dacomitinib C1D1 - single dose (n= 11, 6, 7, 5) | 24.0 Hour | Full Range 8 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 24.00 Hour | — |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | PF-5199265 C1D1 - single dose (n= 8, 6, 6, 6) | 24.0 Hour | — |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 24.0 Hour | — |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 23.9 Hour | — |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | PF-5199265 C1D1 - single dose (n= 8, 6, 6, 6) | 15.9 Hour | — |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 23.9 Hour | — |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | Dacomitinib C1D1 - single dose (n= 11, 6, 7, 5) | 15.9 Hour | Full Range 15.9 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | PF-5199265 C1D1 - single dose (n= 8, 6, 6, 6) | 23.5 Hour | — |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 23.9 Hour | — |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 23.9 Hour | — |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | Dacomitinib C1D1 - single dose (n= 11, 6, 7, 5) | 23.6 Hour | Full Range 24 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 24.4 Hour | — |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 24.4 Hour | — |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | Dacomitinib C1D1 - single dose (n= 11, 6, 7, 5) | 24.0 Hour | — |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast | PF-5199265 C1D1 - single dose (n= 8, 6, 6, 6) | 24.1 Hour | — |
Secondary
Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax
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
Population: 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 | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | Dacomitinib C1D1 - single dose (n= 11, 6, 7, 5) | 5.99 Hour | Full Range 8 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 6.00 Hour | — |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | PF-5199265 C1D1 - single dose (n= 8, 6, 6, 6) | 6.95 Hour | — |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 6.98 Hour | — |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 3.95 Hour | — |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | PF-5199265 C1D1 - single dose (n= 8, 6, 6, 6) | 4.04 Hour | — |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 5.09 Hour | — |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | Dacomitinib C1D1 - single dose (n= 11, 6, 7, 5) | 8.03 Hour | Full Range 15.9 |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | PF-5199265 C1D1 - single dose (n= 8, 6, 6, 6) | 6.78 Hour | — |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 5.92 Hour | — |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 6.09 Hour | — |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | Dacomitinib C1D1 - single dose (n= 11, 6, 7, 5) | 6.00 Hour | Full Range 24 |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | PF-06260182 C1D15 - multiple dose (n= 8, 4, 6, 4) | 2.00 Hour | — |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | Dacomitinib C1D1 - single dose (n= 11, 6, 7, 5) | 6.17 Hour | — |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | Dacomitinib C1D15 multiple dose (n= 8, 4, 6, 4) | 5.00 Hour | — |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax | PF-5199265 C1D1 - single dose (n= 8, 6, 6, 6) | 6.08 Hour | — |
Secondary
Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUC24
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)
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUC24 | Dacomitinib (n = 6, 5) | 995.7 ng•hr/mL | Geometric Coefficient of Variation 45 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUC24 | PF-05199265 (n = 7, 6) | 78.57 ng•hr/mL | Geometric Coefficient of Variation 587 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUC24 | Dacomitinib (n = 6, 5) | 1148 ng•hr/mL | Geometric Coefficient of Variation 44 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUC24 | PF-05199265 (n = 7, 6) | 78.36 ng•hr/mL | Geometric Coefficient of Variation 42 |
Comparison: 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-05199265.90% CI: [70.2, 211.66]
Secondary
Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUClast
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)
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUClast | Dacomitinib (n = 6, 5) | 1016 ng•hr/mL | Geometric Coefficient of Variation 45 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUClast | PF-05199265 (n = 7, 6) | 80.94 ng•hr/mL | Geometric Coefficient of Variation 598 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUClast | Dacomitinib (n = 6, 5) | 1148 ng•hr/mL | Geometric Coefficient of Variation 44 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUClast | PF-05199265 (n = 7, 6) | 78.22 ng•hr/mL | Geometric Coefficient of Variation 42 |
Comparison: 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-05199265.90% CI: [64.97, 213.61]
Secondary
Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmax
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)
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmax | Dacomitinib (n = 6, 5) | 47.15 ng/mL | Geometric Coefficient of Variation 44 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmax | PF-05199265 (n = 7, 6) | 4.222 ng/mL | Geometric Coefficient of Variation 375 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmax | Dacomitinib (n = 6, 5) | 59.58 ng/mL | Geometric Coefficient of Variation 49 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmax | PF-05199265 (n = 7, 6) | 4.070 ng/mL | Geometric Coefficient of Variation 37 |
Comparison: 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-05199265.90% CI: [82.46, 206.73]
Secondary
Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmin
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)
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmin | Dacomitinib (n = 6, 5) | 33.11 ng/mL | Geometric Coefficient of Variation 58 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmin | PF-05199265 (n = 7, 6) | 5.440 ng/mL | Geometric Coefficient of Variation 83 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmin | Dacomitinib (n = 6, 5) | 39.92 ng/mL | Geometric Coefficient of Variation 47 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmin | PF-05199265 (n = 7, 6) | 2.901 ng/mL | Geometric Coefficient of Variation 47 |
Secondary
Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tlast
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)
Population: 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 | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tlast | Dacomitinib (n = 6, 5) | 24.40 Hour | Full Range 44 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tlast | PF-05199265 (n = 7, 6) | 24.50 Hour | Full Range 375 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tlast | Dacomitinib (n = 6, 5) | 23.80 Hour | Full Range 49 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tlast | PF-05199265 (n = 7, 6) | 23.80 Hour | Full Range 37 |
Secondary
Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tmax
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)
Population: 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 | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tmax | Dacomitinib (n = 6, 5) | 16.0 Hour | Full Range 44 |
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tmax | PF-05199265 (n = 7, 6) | 5.90 Hour | Full Range 375 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tmax | Dacomitinib (n = 6, 5) | 5.92 Hour | Full Range 49 |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tmax | PF-05199265 (n = 7, 6) | 4.35 Hour | Full Range 37 |
Secondary
Progression Free Survival (PFS) in Escalation Phase
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)
Population: The safety analysis population included all enrolled participants who had received at least 1 dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Progression Free Survival (PFS) in Escalation Phase | 3.1 Months |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Progression Free Survival (PFS) in Escalation Phase | 3.0 Months |
| Crizotinib 250 mg BID/ Dacomitinib 30 mg QD | Progression Free Survival (PFS) in Escalation Phase | 1.7 Months |
| Crizotinib 250 mg QD/ Dacomitinib 45 mg QD | Progression Free Survival (PFS) in Escalation Phase | 4.4 Months |
Secondary
Progression Free Survival (PFS) in Expansion Phase
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)
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Crizotinib 200 mg BID/ Dacomitinib 30 mg QD | Progression Free Survival (PFS) in Expansion Phase | 2.1 Months |
| Crizotinib 200 mg BID/ Dacomitinib 45 mg QD | Progression Free Survival (PFS) in Expansion Phase | 2.1 Months |