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

• ClinicalTrials.gov Identifier: NCT01121575
• Recruitment Status: Completed
• First Posted: May 12, 2010
• Results First Posted: March 30, 2015
• Last Update Posted: October 28, 2015
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

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

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

Study Design

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

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase [ Time Frame: Up to Maximum of treatment duration + 28 days for each participant (could be 295 days) ]
   AE was any untoward medical occurrence with study drug/ device in a trial participant. Serious adverse event (SAE) was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
2. Overview of Treatment-emergent All Causalities AEs in Expansion Phase [ Time Frame: Up to Maximum of treatment duration + 28 days for each participant (could be 295 days) ]
   AE was any untoward medical occurrence with study drug/ device in a trial participant. SAE was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using NCI CTCAE v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
3. Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase [ Time Frame: Up to Maximum of treatment duration + 28 days for each participant (could be 295 days) ]
   An AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. SAE was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using NCI CTCAE v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
4. Overview of Treatment-emergent, Treatment-related AEs in Expansion Phase [ Time Frame: Up to Maximum of treatment duration + 28 days for each participant (could be 295 days) ]
   An AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. SAE was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using NCI CTCAE v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
5. Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase [ Time Frame: Cycle 1 (4 weeks) ]
   DLTs were those AEs which occurred in Cycle 1 of treatment in Dose Escalation Phase which may be attributed to study drug [combined Crizotinib (PF-02341066) plus Dacomitinib (PF-00299804)] without a clear alternative explanation and despite the use of adequate/maximal medical intervention as dictated by local institutional clinical practices or the judgment of the investigator. The following events were considered DLTs (using CTCAE version 4.02);1. Grade ≥4 hematologic events. 2. Grade ≥3 non-hematological events (except Grade 3/4 asymptomatic hypophosphatemia and Grade 3/4 hyperuricemia without signs and symptoms of gout). Nausea, vomiting or diarrhea had to have persisted at Grade 3 or 4 despite maximal medical therapy. Grade 3 hypertension will be considered a DLT only if the event is unmanageable by standard approved pharmacologic agents or if the symptomatic sequelae are identified despite appropriate medical intervention.

Secondary Outcome Measures :

1. Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase [ 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) ]
   If a participant had not achieved an objective response with confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) - 1.1 as determined by the investigators, relative to the response evaluable population, but remained stable for at least 6 weeks after first dose, then the best overall response for such a participant was considered as stable disease.
2. Number of Participants With Stable Disease and Stable Disease Duration in Expansion Phase [ 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) ]
   If a participant had not achieved an objective response with confirmed complete response (CR) or partial response (PR) according to RECIST (1.1) as determined by the investigators, relative to the response evaluable population, but remained stable for at least 6 weeks after first dose, then the best overall response for such a participant was considered as stable disease.
3. Number of Participants With Objective Response Rate (ORR) in Escalation Phase [ 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) ]
   ORR was defined as the percent of participants with CR or PR according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) determined by study physicians, relative to the response evaluable population. Participants were considered non-responders until proven otherwise. Thus, participants who: 1) Did not have CR or PR while on study, or 2) Did not have a post-baseline tumor evaluation, or 3) Received anti-tumor treatment other than the study medication prior to reaching a CR or PR, or 4) Died, in progress, or drop out for any reason prior to reaching a CR or PR, were counted as non-responders in the assessment of ORR. To be assigned a status of PR or CR, changes in tumor measurements in participants with responding tumors were confirmed by repeated tumor assessment that were performed 4 weeks after the criteria for response were first met.
4. Number of Participants With ORR in Expansion Phase [ 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) ]
   ORR was defined as the percent of participants with CR or PR according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) determined by study physicians, relative to the response evaluable population. Participants were considered non-responders until proven otherwise. Thus, participants who: 1) Did not have CR or PR while on study, or 2) Did not have a post-baseline tumor evaluation, or 3) Received anti-tumor treatment other than the study medication prior to reaching a CR or PR, or 4) Died, in progress, or drop out for any reason prior to reaching a CR or PR, were counted as non-responders in the assessment of ORR. To be assigned a status of PR or CR, changes in tumor measurements in participants with responding tumors were confirmed by repeated tumor assessment that were performed 4 weeks after the criteria for response were first met.
5. Duration of Response for the Only Participant Shown Partial Response in Expansion Phase [ 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) ]
   This outcome measure presented the duration of response for one participant in expansion cohort 1 who showed partial response.
6. Progression Free Survival (PFS) in Escalation Phase [ 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) ]
   PFS was defined as the time from the date of the first dose to the date of the first documentation of objective tumor progression according to RECIST 1.1 or death on study due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used.
7. Progression Free Survival (PFS) in Expansion Phase [ 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) ]
   PFS was defined as the time from the date of the first dose to the date of the first documentation of objective tumor progression according to RECIST 1.1 or death on study due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used.
8. Expression Analysis of Tumor Biomarkers (HGF, EGFR, and c-Met ) at Baseline Using Immunohistochemistry (IHC) Method [ Time Frame: Baseline ]
   Tumor biomarkers such as HGF, EGFR, and c-Met were analyzed in tumor cells (neoplastic compartment) of tumor specimens from both expansion cohorts 1 and 2 by IHC. The H score was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0, 1+, 2+, 3+, where 3+ indicates the strongest staining, 2+ indicates medium staining, 1+ indicates weak staining, and 0 indicates no staining). Minimum calculated score of 0 to maximum calculated score of 300, where 0 correspond to no expression and maximum score of 300 indicates the strongest expression. However, the biomarker expression level (higher or lower) was not a predictor of outcome.
9. Expression Analysis of Tumor Biomarkers (EGFR, and c-Met) at Baseline Using Fluorescent in Situ Hybridization (FISH) Method [ Time Frame: Baseline ]
   Expression of tumor biomarkers EGFR and cMet at Baseline (using FISH method) are presented in this outcome measure.
10. Number of Participants With c-Met, HER2, EGFR Amplification and ALK Rearrangement at Baseline Using FISH Method [ Time Frame: Baseline ]
    Participants showed amplification of c-Met, HER2, and EGFR in the tumor cells and gene rearrangement of ALK are presented in this outcome measure.
11. Plasma Concentration of sMet by Study Visits [ Time Frame: At screening and Cycle 1 Day 1 (C1D1) (6 hours post dose), and C1D15, C2D1, C2D15 (all predose). ]
    This outcome measure presented the plasma concentration of sMet at different study visits. s-Met was analyzed using an enzyme-linked immunosorbent assay (ELISA).
12. Number of Participants With EGFR Mutation at Baseline [ Time Frame: Baseline ]
    Sample analyses were performed in accordance to Good Laboratory Practice (GLP) guidance and included mutation detection for EGFR gene.
13. Number of Participants With KRAS Mutation (GLY12CYS) at Baseline [ Time Frame: Baseline ]
    Sample analyses were performed in accordance to GLP guidance and included mutation detection for KRAS gene.
14. Number of Participants With PIK3CA Mutation at Baseline [ Time Frame: Baseline ]
    Sample analyses were performed in accordance to GLP guidance and included mutation detection for PIK3CA gene.
15. Number of Participants With ROS1 Gene Translocation at Baseline [ Time Frame: Baseline ]
    Sample analyses were performed in accordance to GLP guidance and included translocation detection (RNA based) for ROS1 gene.
16. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Profile From Time Zero to the Last Quantifiable Concentration (AUClast) [ Time Frame: Cycle 1 (C1)/Day 1 (D1), C1D15 ]
    At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included AUClast for crizotinib and PF-06260182. AUClast was calculated using Linear/Log trapezoidal method.
17. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) [ Time Frame: C1D1, C1D15 ]
    At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). AUC10 was calculated using Linear/Log trapezoidal method. The below analysis table included geometric Mean and Geometric Coefficient of Variation of AUC10 for crizotinib and PF-06260182. Arithmetic mean was presented if the n=2.
18. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) [ Time Frame: C1D1, C1D15 ]
    At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Cmax for crizotinib and PF-06260182. Cmax was observed directly from data.
19. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) [ Time Frame: C1D1, C1D15 ]
    At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tlast for crizotinib and PF-06260182. Tlast was observed directly from data.
20. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) [ Time Frame: C1D1, C1D15 ]
    At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tmax for crizotinib and PF-06260182. Tmax was observed directly from data as time of first occurrence.
21. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast [ Time Frame: C1D1, C1D15 ]
    At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included AUClast for dacomitinib and PF-05199265. AUClast was calculated using Linear/Log trapezoidal method.
22. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 [ Time Frame: C1D1, C1D15 ]
    At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included AUC24 for dacomitinib and PF-05199265. AUC24 was calculated using Linear/Log trapezoidal method.
23. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax [ Time Frame: C1D1, C1D15 ]
    At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Cmax for dacomitinib and PF-05199265. Cmax was observed directly from data.
24. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast [ Time Frame: C1D1, C1D15 ]
    At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tlast for dacomitinib and PF-05199265. Tlast was observed directly from data.
25. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax [ Time Frame: C1D1, C1D15 ]
    At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tmax for dacomitinib and PF-05199265. Tmax was observed directly from data as time of first occurrence.
26. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUClast [ Time Frame: Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib) ]
    Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for AUClast. AUClast was calculated using Linear/Log trapezoidal method.
27. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUC10 [ Time Frame: Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib) ]
    Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for AUC10. AUC10 was calculated using Linear/Log trapezoidal method.
28. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmin [ Time Frame: Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib) ]
    Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Cmin. Cmin was observed directly from data.
29. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmax [ Time Frame: Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib) ]
    Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Cmax. Cmax was observed directly from data.
30. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tlast [ Time Frame: Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib) ]
    Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Tlast. Tlast was observed directly from data.
31. Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tmax [ Time Frame: Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib) ]
    Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Tmax. Tmax was observed directly from data as time of first occurrence.
32. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUClast [ Time Frame: Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib) ]
    PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (AUClast) following dacomitinib alone and in combination with crizotinib are summarized in the below table. AUClast was calculated using Linear/Log trapezoidal method.
33. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUC24 [ Time Frame: Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib) ]
    PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (AUC24) following dacomitinib alone and in combination with crizotinib are summarized in the below table. AUC24 was calculated using Linear/Log trapezoidal method.
34. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmin [ Time Frame: Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib) ]
    PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Cmin) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Cmin was observed directly from data.
35. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmax [ Time Frame: Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib) ]
    PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Cmax) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Cmax was observed directly from data.
36. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tlast [ Time Frame: Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib) ]
    PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Tlast) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Tlast was observed directly from data.
37. Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tmax [ Time Frame: Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib) ]
    PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Tmax) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Tmax was observed directly from data as time of first occurrence.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• advanced non small cell lung cancer (dose escalation phase)
• acquired resistance to erlotinib or gefitinib (expansion phase)
• mandatory entrance biopsy (expansion phase)

Exclusion Criteria:

• interstitial lung disease
• unstable brain metastases
• leptomeningeal disease

Contacts and Locations

Locations

United States, Colorado

Clinical Trials Office University of Colorado Hospital (CTO)

Aurora, Colorado, United States, 80045

DRUG SHIPMENT: University of Colorado Cancer Center

Aurora, Colorado, United States, 80045

Rocky Mountain Lions Eye Institute

Aurora, Colorado, United States, 80045

University of Colorado Hospital

Aurora, Colorado, United States, 80045

United States, Maryland

CCR, National Cancer Institute

Bethesda, Maryland, United States, 20892

United States, Massachusetts

Drug Shipment Only

Boston, Massachusetts, United States, 02114

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Brigham & Women's Hospital

Boston, Massachusetts, United States, 02115

Drug Shipment Only

Boston, Massachusetts, United States, 02215

Australia, Victoria

Peter MacCallum Cancer Centre, Division of Haematology and Medical Oncology

East Melbourne, Victoria, Australia, 3002

Sponsors and Collaborators

Pfizer

Investigators

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

More Information

Additional Information:

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

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01121575
• Other Study ID Numbers: A8081006
• First Posted: May 12, 2010
• Results First Posted: March 30, 2015
• Last Update Posted: October 28, 2015
• Last Verified: October 2015

Keywords provided by Pfizer:

Phase 1 acquired resistance to erlotinib or gefitinib cMET inhibitor EGFR inhibitor panHER inhibitor combination trial Crizotinib

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Crizotinib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action