Erlotinib Is Being Studied With Or Without An Investigational Drug, PF-02341066, In Patients With Lung Cancer

Phase 1, first cycle DLT includes Grade (Gr) ≥4 hematologic possible drug-related toxicities and Gr ≥3 possible drug-related febrile neutropenia. Gr ≥3 non-hematological possible drug-related toxicities (except asymptomatic lab value elevation). Gr 3/4 nausea, vomiting or diarrhea. Gr 3 hypertension considered DLT if event unmanageable by approved pharmacologic agents or symptomatic sequelae despite medical intervention. Diagnosis of interstitial lung disease. Inability to deliver at least 80 percent (%) of planned dose during cycle 1 due to possible drug-related adverse events (AEs).

Time frame: Baseline up to Day 28

Population: DLT evaluable population: all participants in dose escalation phase receiving at least 1 dose of study medication who did not have a major treatment deviation during the first cycle (for example, less than 80% of planned dose of PF-02341066 or erlotinib in cycle 1 for reasons other than treatment-related toxicities)

Time in weeks from phase 2 study randomization to first documentation of objective disease progression or death due to any cause. Progression-Free Survival was calculated as (first event date minus randomization date plus 1) divided by 7.02. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease \[PD\]), or from AE data (where the outcome was Death; date of death reported in notice of death was used).

Time frame: Baseline, every 42 days up to 20 months, disease progression, or unacceptable toxicity

Population: Not analyzed due to phase 2 study termination

Median duration (50 percent \[%\]) of tumor response. Duration of response (DR) defined as time from start of first documented objective tumor response \[Complete Response (CR) or Partial Response (PR)\] to first documented objective tumor progression or death due to any cause, whichever occurs first. DR calculated as (Weeks) = (the end date for DR minus first subsequent confirmed CR or PR plus 1) divided by 7.02. CR: disappearance of a target lesions. PR: at least 30% decrease in the sum of diameters of target lesions.

Time frame: Baseline, every 42 days until disease progression or unacceptable toxicity

Population: not analyzed due to small number of responses

Median duration (50%) of tumor response. DR defined as time from start of first documented objective tumor response (CR or PR) to first documented objective tumor progression or death due to any cause, whichever occurs first. DR calculated as (Weeks) = (the end date for DR minus first subsequent confirmed CR or PR plus 1) divided by 7.02. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of nontarget disease. No new lesions.

Time frame: Baseline, every 42 days up to 20 months, disease progression, or unacceptable toxicity

Population: Not analyzed due to phase 2 study termination

QLQ-LC13 consisted of 13 questions relating to disease symptoms specific to lung cancer and treatment side effects typical of treatment with chemotherapy and radiotherapy. The 13 questions comprised 1 multi-item scale for dyspnea and 10 single-item symptoms and side effects (coughing, hemoptysis, sore mouth, dysphagia, neuropathy, alopecia, and medicine for pain). Recall period: past week; response range: not at all to very much. Scale score range: 0 to 100. Higher symptom score = greater degree of symptoms.

Time frame: Baseline and every 21 days, up to 20 months

Population: Not analyzed due to phase 2 study termination

Apparent oral Clearance is a measure of combination of the rate at which a drug is removed from the blood (CL) and the bioavailability (F) after oral dose. In this study, it is used to characterize erlotinib CL/F after multiple doses in combination with PF-02341066 (Cycle 1 Day 15).

Time frame: C1D15 i.e., 15 days of giving crizotinib and erlotinib

Population: The pharmacokinetic (PK) parameter analysis population was defined as all participants in the safety analysis set 1 who had at least 1 of the PK parameters of interest.

AUCtau is a measure of the plasma exposure to erlotinib. In this study, it is used to characterize erlotinib exposure after multiple doses of erlotinib were administered alone (Day -1) and in combination of PF-02341066 (Cycle 1 Day 1 and Day 15).

Time frame: C1D-1 i.e., 1 day prior to initiation of continuous dosing of crizotinib; C1D1 i.e., 1 day of giving crizotinib and erlotinib; and C1D15, i.e., 15 days of giving crizotinib and erlotinib

Population: Pharmacokinetic (PK) parameter analysis population included all participants in safety analysis set 1 who had at least 1 of the PK parameters of interest. Number of participants analyzed section in below table includes number of participants in PK analysis population. N=number of participants in treatment group contributing to summary statistics.

Cmax is a measure of the plasma exposure to erlotinib. In this study, it is used to characterize erlotinib exposure after multiple doses of erlotinib were administered alone (Day -1) and in combination of PF-02341066 (Cycle 1 Day 1 and Day 15).

Time frame: C1D-1 i.e., 1 day prior to initiation of continuous dosing of crizotinib; C1D1 i.e., 1 day of giving crizotinib and erlotinib; and C1D15, i.e., 15 days of giving crizotinib and erlotinib

Population: Pharmacokinetic (PK) parameter analysis population included all participants in safety analysis set 1 who had at least 1 of the PK parameters of interest. Number of participants analyzed section in below table includes number of participants in PK analysis population. N=number of participants in treatment group contributing to summary statistics.

Phase 2 EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.

Time frame: Baseline and every 21 days, up to 20 months

Population: Not analyzed due to phase 2 study termination

Molecular weight adjusted PF-06260182-to-PF-02341006 ratio of AUCtau is a measure of how much PF-02341066 (parent drug) was converted to the metabolite PF-06260182 after PF-02341066 dosing. In this study, it is used to characterize the metabolite-to-parent ratio exposure after a single dose (Cycle 1 Day 1) and multiple doses (Cycle 1 Day 15) of PF-02341066 were administered in combination of Erlotinib.

Time frame: C1D1 i.e., 1 day of giving crizotinib and erlotinib; and C1D15, i.e., 15 days of giving crizotinib and erlotinib

Population: Pharmacokinetic (PK) parameter analysis population included all participants in safety analysis set 1 who had at least 1 of the PK parameters of interest. Number of participants analyzed section in below table includes number of participants in PK analysis population. N=number of participants in treatment group contributing to summary statistics.

Time in months from randomization to date of death due to any cause. OS was calculated as (the death date minus the date of randomization plus 1) divided by 30.4.

Time frame: Baseline until death, up to 20 months

Population: Not analyzed due to phase 2 study termination

Percentage of participants during phase 2 with confirmed CR, confirmed PR or SD according to RECIST 1.1. Also known as Disease Control Rate (DCR). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of nontarget disease. No new lesions. SD: neither sufficient shrinkage or increase to qualify for PR or PD.

Time frame: Week 6 and Week 12

Population: Not analyzed due to phase 2 study termination

Tumor tissue samples collected for molecular profiling were to be analyzed to assess Kirsten rat sarcoma (KRAS) mutations, mutations, amplification and expression of Epidermal Growth Factor Receptor (EGFR) and c-Met, and echinoderm microtubule-associated protein-like 4-anaplastic large cell receptor kinase (EML4-ALK) fusion in tumors.

Time frame: Screening

Population: Not analyzed due to phase 2 study termination

Percentage of participants during phase 1 with objective response based assessment of confirmed CR or confirmed PR according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Confirmed responses: persist on repeat imaging study at least 4 weeks after initial documentation of response. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of nontarget disease. No new lesions.

Time frame: Baseline, every 42 days until disease progression or unacceptable toxicity

Population: Response Evaluable Population: all participants enrolled into the Phase 1 portion of the study who receive at least one dose of study medication (either PF-02341066 or erlotinib) and have an adequate baseline tumor assessment.

Percentage of participants during phase 2 with objective response based assessment of confirmed CR or confirmed PR according to RECIST (1.1). Confirmed responses: persist on repeat imaging study at least 4 weeks after initial documentation of response. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of nontarget disease. No new lesions.

Time frame: Baseline, every 42 days up to 20 months, disease progression, or unacceptable toxicity

Population: Not analyzed due to phase 2 study termination

Apparent oral Clearance is a measure of combination of the rate at which a drug is removed from the blood (CL) and the bioavailability (F) after oral dose. In this study, It is used to characterize PF-02341066 CL/F after multiple doses (Cycle 1 Day 15) of PF-02341066 were administered in combination of Erlotinib.

Time frame: C1D15 i.e., 15 days of giving crizotinib and erlotinib

Population: The pharmacokinetic (PK) parameter analysis population was defined as all participants in the safety analysis set 1 who had at least 1 of the PK parameters of interest.

AUCtau is a measure of the plasma exposure to PF-02341066. In this study, it is used to characterize PF-02341066 exposure after a single dose (Cycle 1 Day 1) and multiple doses (Cycle1 Day 15) of PF-02341066 were administered in combination of Erlotinib.

Time frame: Cycle 1 (C1) Day 1 (D1) i.e., 1 day of giving crizotinib and erlotinib; and C1D15, i.e., 15 days of giving crizotinib and erlotinib

Population: Pharmacokinetic (PK) parameter analysis population included all participants in safety analysis set 1 who had at least 1 of the PK parameters of interest. Number of participants analyzed section in below table includes number of participants in PK analysis population. N=number of participants in treatment group contributing to summary statistics.

Cmax is a measure of the plasma exposure to PF-02341066. In this study, it is used to characterize PF-02341066 exposure after a single dose (Cycle 1 Day 1) and multiple doses (Cycle 1 Day 15) of PF-02341066 were administered in combination of Erlotinib

Time frame: C1D1 i.e., 1 day of giving crizotinib and erlotinib; and C1D15, i.e., 15 days of giving crizotinib and erlotinib

Population: Pharmacokinetic (PK) parameter analysis population included all participants in safety analysis set 1 who had at least 1 of the PK parameters of interest. Number of participants analyzed section in below table includes number of participants in PK analysis population. N=number of participants in treatment group contributing to summary statistics.

AUCtau is a measure of the plasma exposure to PF-06260182, a PF-02341066 metabolite. In this study, it is used to characterize the metabolite exposure after a single dose (Cycle 1 Day 1) and multiple doses (Cycle 1 Day 15) of PF-02341066 were administered in combination of Erlotinib.

Time frame: C1D1 i.e., 1 day of giving crizotinib and erlotinib; and C1D15, i.e., 15 days of giving crizotinib and erlotinib

Population: Pharmacokinetic (PK) parameter analysis population included all participants in safety analysis set 1 who had at least 1 of the PK parameters of interest. Number of participants analyzed section in below table includes number of participants in PK analysis population. N=number of participants in treatment group contributing to summary statistics.

Cmax is a measure of the plasma exposure to PF-06260182, a PF-02341066 metabolite. In this study, it is used to characterize the metabolite exposure after a single dose (Cycle 1 Day 1) and multiple doses (Cycle 1 Day 15) of PF-02341066 were administered in combination of Erlotinib.

Time frame: C1D1 i.e., 1 day of giving crizotinib and erlotinib; and C1D15, i.e., 15 days of giving crizotinib and erlotinib

Population: Pharmacokinetic (PK) parameter analysis population included all participants in safety analysis set 1 who had at least 1 of the PK parameters of interest. Number of participants analyzed section in below table includes number of participants in PK analysis population. N=number of participants in treatment group contributing to summary statistics.

Plasma concentration of erlotinib when administered as a single agent during phase 2

Time frame: Day 1 of cycles 1, 3, and 5 (i.e., up to 15 weeks) at 0 hours (pre-dose)

Population: Not analyzed due to phase 2 study termination

Plasma concentration of PF-02341066 and erlotinib when administered in combination during phase 2

Time frame: Day 1 of cycles 1, 3, and 5 (i.e., up to 15 weeks) at 0 (pre-dose) and 2 to 6 hours post dose

Population: Not analyzed due to phase 2 study termination

Levels of soluble protein biomarker c-MET was analyzed at Baseline and at Day 50.

Time frame: Baseline and Day 50 (Cycle 3, Day 1)

Population: The soluble biomarker evaluable population was defined as participants from the safety analysis set of phase 1 who had a soluble protein blood sample taken prior to dosing on Cycle 3 Day 1 and 1 soluble biomarker evaluation after dosing on Cycle 3 Day 1.

Time frame: Baseline and Day 50 (Cycle 3, Day 1)

Population: Not analyzed due to phase 2 study termination

Time frame: Baseline and Day 50 (Cycle 3, Day 1)

Population: Plasma level of soluble marker HGF scatter factor not analyzed due to prior experience with high levels of intra participant variability

Time frame: Baseline and Day 50 (Cycle 3, Day 1)

Population: Not analyzed due to phase 2 study termination

Time in weeks from phase 1 randomization to first documentation of objective disease progression or death due to any cause. Progression-Free Survival was calculated as (first event date minus randomization date plus 1) divided by 7.02. Tumor progression was determined from oncologic assessment data (where data meet the criteria for PD), or from AE data (where the outcome was Death; date of death reported in notice of death was used).

Time frame: Baseline, every 42 days until disease progression or unacceptable toxicity

Population: not analyzed due to small number of study participants

Ratio of adjusted means of Erlotinib AUCtau (Crizotinib + Erlotinib / Erlotinib Alone) is a measure of the plasma exposure to erlotinib after erlotinib dosing with crizotinib compared with that after erlotinib dosing alone. In this study, it is used to characterize the effect magnitude of crizotinib on the erlotinib exposure after combinational use of crizotinib and erlotinib.

Time frame: C1D-1 (i.e., 1 day prior to initiation of continuous dosing of crizotinib) to C1D15 (i.e., 15 days of giving crizotinib and erlotinib)

Population: The PK parameter analysis population was defined as all participants in the safety analysis set 1 who had at least 1 of the PK parameters of interest.

Ratio of adjusted means of Erlotinib Cmax (Crizotinib + Erlotinib / Erlotinib Alone) is a measure of the plasma exposure to erlotinib after erlotinib dosing with crizotinib compared with that after erlotinib dosing alone. In this study, it is used to characterize the effect magnitude of crizotinib on the erlotinib exposure after combinational use of crizotinib and erlotinib.

Time frame: C1D-1 (i.e., 1 day prior to initiation of continuous dosing of crizotinib) to C1D15 (i.e., 15 days of giving crizotinib and erlotinib)

Population: The pharmacokinetic (PK) parameter analysis population was defined as all participants in the safety analysis set 1 who had at least 1 of the PK parameters of interest.

MTD: the combination dose level of PF-02341066 and erlotinib in which 0/6 or 1/6 participants experienced DLT after 28 days of treatment (Cycle 1) with the next higher dose level having at least 2/3 or 2/6 participants with DLT during Cycle 1 of treatment.

Time frame: Baseline up to 28 days (Cycle 1)

Population: DLT evaluable population

If no more than 1/6 participants presented with a DLT during Cycle 1 at the MTD, then this dose level was considered the RP2D. If \>1/6 participants experienced a DLT, then the previous lower level was considered the MTD and RP2D.

Time frame: Baseline up to 28 days (Cycle 1)

Population: DLT evaluable population