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Carcinoma, Non-Small-Cell Lung

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Amino Acids

Crizotinib

Erlotinib Hydrochloride

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Erlotinib, 150 mg, QD will be administered orally on a continuous schedule (Phase 2 only)

Erlotinib

For Phase 1 - escalating doses of erlotinib will be administered orally on a continuous schedule. The planned doses to be evaluated are 100 and 150 mg QD. The dose determined in Phase 1 will be used in Phase 2

For Phase 1 - escalating doses of PF-02341066 will be administered orally on a continuous schedule. The planned doses to be evaluated are 200 and 250 mg BID. The dose determined in Phase 1 will be used in Phase 2

PF-02341066

Pfizer CT.gov Call Center

This is a Phase 1/2 study comparing the safety and anti-tumor activity of erlotinib alone versus erlotinib in combination with PF-02341066 in patients with advanced non-small cell lung cancer.

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

Phase 1/2, Open Label, Randomized Study Of The Safety, Efficacy, And Pharmacokinetics Of Erlotinib With Or Without Pf 02341066 In Patients With Advanced Non Small Cell Adenocarcinoma Of The Lung.

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.

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.

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 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).

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.

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

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.

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.

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.

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.

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).

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).

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).

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.

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 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).

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.

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.

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

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.

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.

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 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.

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.

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.

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

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

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.

Pfizer

The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

PF-02341066 200 milligrams (mg) administered orally twice daily (BID) in combination with erlotinib 100 mg administered orally once daily (QD) in a continuous schedule for 28 days (Cycle 1) and then in continuous 21-day cycles. Prior to combination treatment, participants completed a 7 to 14 day lead-in period where they received erlotinib 100 mg administered orally QD.

PF-02341066 (200 mg) and Erlotinib (100 mg)

PF-02341066 150 mg administered orally BID in combination with erlotinib 100 mg administered orally QD in a continuous schedule for 28 days (Cycle 1) and then in continuous 21-day cycles. Prior to combination treatment, participants completed a 7 to 14 day lead-in period where they received erlotinib 100 mg administered orally QD.

PF-02341066 (150 mg) and Erlotinib (100 mg)

Total

18 to 44 years

45 to 64 years

greater than or equal to (≥) 65

Age, Customized

Sex: Female, Male

The sponsor terminated phase 2 of this study; no data was collected during phase 2, leading to phase 2 outcomes not analyzed. The decision was based on strategic considerations regarding the clinical program only; there were no safety concerns.

Pfizer ClinicalTrials.gov Call Center

PF-02341066 200 milligrams (mg) administered orally twice daily (BID) and erlotinib 100 mg administered orally once daily (QD) in a continuous schedule for 28 days (Cycle 1) and then in continuous 21-day cycles. Prior to combination treatment, participants completed a 7 to 14 day lead-in period where they received erlotinib 100 mg administered orally QD.

PF-02341066 150 mg administered orally BID and erlotinib 100 mg administered orally QD in a continuous schedule for 28 days (Cycle 1) and then in continuous 21-day cycles. Prior to combination treatment, participants completed a 7 to 14 day lead-in period where they received erlotinib 100 mg administered orally QD.

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)

Number of Participants With Dose-Limiting Toxicities (DLT) (Phase 1)

PF-02341066 (BID) and erlotinib (QD) administered at the recommended Phase 2 dose (RP2D) in continuous 21-day cycles.

PF-02341066 and Erlotinib

Erlotinib 150 mg was to be administered orally QD in continuous 21-day cycles

Not analyzed due to phase 2 study termination

Progression-Free Survival (Phase 2)

C1D1 Crizotinib (N=7, 19)

C1D15 Crizotinib (N=5, 14)

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.

PF-02341066 (Crizotinib) Area Under the Concentration-Time Curve During Dosing Interval (AUCtau) (Phase 1)

PF-02341066 (Crizotinib) Maximum Observed Plasma Concentration (Cmax) (Phase 1)

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.

PF-02341066 (Crizotinib) Apparent Oral Clearance (CL/F) (Phase 1)

C1D1 PF-06260182 (N=7, 19)

C1D15 PF-06260182 (N=5, 14)

PF-06260182 Area Under the Concentration-Time Curve During Dosing Interval (AUCtau) (Phase 1)

PF-06260182 Maximum Observed Plasma Concentration (Cmax) (Phase 1)

C1D1 (N=7, 19)

C1D15 (N=5, 14)

Molecular Weight Adjusted PF-06260182-to-PF-02341006 Ratio of AUCtau (Phase 1)

C1D-1 Erlotinib Alone (N=7,19)

C1D1 Erlotinib+Crizotinib Single Dose (N=7,19)

C1D15 Erlotinib+Crizotinib Multiple Doses (N=5,14)

Erlotinib Area Under the Concentration-Time Curve During Dosing Interval (AUCtau) (Phase 1)

Erlotinib Maximum Observed Plasma Concentration (Cmax) (Phase 1)

Erlotinib Apparent Oral Clearance (CL/F) (Phase 1)

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 AUCtau (Crizotinib + Erlotinib / Erlotinib Alone) (Phase 1)

Ratio of Adjusted Means of Erlotinib Cmax (Crizotinib + Erlotinib / Erlotinib Alone) (Phase 1)

not analyzed due to small number of study participants

Progression-Free Survival (Phase 1)

not analyzed due to small number of responses

Duration of Response (Phase 1)

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 With Objective Response (Phase 1)

Baseline

C3D1 0 Hour

C3D1 6 Hour

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.

Plasma Level of Soluble Marker: c-Met Ectodomain (Phase 1)

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

Plasma Level of Soluble Marker: Hepatocyte Growth Factor (HGF) Scatter Factor (Phase 1)

Erlotinib 150 mg was to be administered orally QD in continuous 21-day cycles.

Plasma Level of Soluble Marker: c-Met Ectodomain (Phase 2)

Plasma Level of Soluble Marker: HGF Scatter Factor (Phase 2)

Duration of Response (Phase 2)

Percentage of Participants With Confirmed CR, PR or Stable Disease (SD) at Phase 2

Percentage of Participants With Objective Response (Phase 2)

Overall Survival (OS) at Phase 2

European Organization for Research and Treatment of Cancer (EORTC), Quality of Life Questionnaire (QLQ-C30) Score at Phase 2

EORTC Quality of Life Questionnaire -Lung Cancer 13 (QLQ-LC13) Score at Phase 2

Plasma Concentration of PF-02341066 and Erlotinib (Phase 2)

Plasma Concentration of Erlotinib (Phase 2)

PF-02341033 (BID) and erlotinib (QD) administered at the recommended Phase 2 dose (RP2D) in continuous 21-day cycles

Percentage of Participants With Mutations in Tumor Tissue (Phase 2)

PF-02341066 (BID)

Erlotinib (QD)

All participants who received PF-02341066 (200 mg or 150 mg) administered orally BID and erlotinib 100 mg administered orally QD in a continuous schedule for 28 days (Cycle 1) and then in continuous 21-day cycles. Prior to combination treatment, participants completed a 7 to 14 day lead-in period where they received erlotinib 100 mg administered orally QD.

Spots Global Cancer Trial Database for Erlotinib Is Being Studied With Or Without An Investigational Drug, PF-02341066, In Patients With Lung Cancer

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