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Single arm (no comparator) study, oral once daily dosing, dose escalation (it is a phase 1/2 study) until disease progression, unacceptable toxicity or withdrawal of consent

PF-00299804

Pfizer CT.gov Call Center

To assess the safety and efficacy of PF-00299804 in patients with advanced lung cancer.

Trial Of PF-00299804 In Patients With Advanced Refractory Lung Cancer

A PHASE 1/2, OPEN-LABEL, SINGLE ARM TRIAL TO DETERMINE THE RECOMMENDED PHASE 2 DOSE AND EVALUATE THE EFFICACY OF PF-00299804 IN PATIENTS IN KOREA WITH KRAS WILD TYPE ADVANCED NSCLC, WHICH IS REFRACTORY TO CHEMOTHERAPY AND ERLOTINIB OR GEFITINIB

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

The highest dose at which less than (\<) 33 percent (%) of participants experienced dose-limiting toxicities (DLT) was to be designated as the maximum tolerated dose (MTD) as well as the RP2D. DLT was defined as any of the following events: Grade 3/4 (severe or life-threatening/ disabling adverse event \[AE\]) nausea, vomiting, or diarrhea (despite the use of adequate/maximal medical intervention and/or prophylaxis); Grade greater than or equal to (\>=) 3 (severe or life-threatening/disabling AE or death related to AE) non-hematological toxicity; delayed (which delayed scheduled treatment for \>14 days) recovery from toxicity related to treatment with PF-00299804; Grade 4 neutropenia (absolute neutrophil count \[ANC\] \<500 cells per cubic millimeter \[cells/mm\^3\] for 5 or more consecutive days or febrile neutropenia \[fever \>=38.5 degrees Celsius with ANC \<1000 cells/mm\^3\]); and Grade 4 thrombocytopenia (\<25,000 cells/mm\^3) or bleeding which required platelet transfusion.

PFS4m was defined as percent chance of being event free (event defined as progressive disease \[PD\] or death due to any cause, whichever occurred first) at 4 months. Progression was defined using Response Evaluation Criteria in Solid Tumors (RECIST), as at least 20 percent (%) increase in the sum of longest dimensions (LD) of target lesions, taking as reference the smallest sum of LD recorded since the treatment started and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.

PFS6m was defined as percent chance of being event free (event defined as PD or death due to any cause, whichever occurred first) at 6 months. Progression was defined using RECIST, as at least 20% increase in the sum of longest dimensions (LD) of target lesions, taking as reference the smallest sum of LD recorded since the treatment started and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.

OS6m was defined as percent chance of being alive at Month 6.

Percentage of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST. CR: disappearance of all target and non-target lesions. PR: at least 30 % decrease in sum of the longest dimensions (LDs) of target lesion, taking as reference the baseline sum LD, associated to non-progressive disease response for non-target lesions. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response.

Blood specimens were analyzed at a sponsor-designated laboratory for analysis of shed proteins/receptors related to Human Epidermal Growth Factor Receptor (HER) signaling (epidermal growth factor receptor \[EGFR\], HER2). These measurements were determined by enzyme-linked immunosorbent assay (ELISA). The data for all Phase 1 participants was combined for this outcome.

Tumor tissue was analyzed at a sponsor-designated laboratory to investigate EGFR, KRAS and HER2 status (wild type or mutated). Participants who did not provide samples for central laboratory analysis confirmation were classified as "unknown". The data for all Phase 1 participants was combined for this outcome.

Data in "PF-00299804 45 mg" treatment arm at Cycle 0 Day -9 (C0D-9) represents participants from Phase 1 only and at C1D14 represents participants from both Phase 1 and Phase 2.

Data in "PF-00299804 45 mg" treatment arm at C0D-9 represents participants from Phase 1 only and at C1D14 represents participants from both Phase 1 and Phase 2.

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

AUC0-24: Area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post dose. Data in "PF- 00299804 45 mg" treatment arm at C0D-9 represents participants from Phase 1 only and at C1D14 represents participants from both Phase 1 and Phase 2.

AUClast: Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration.

AUCinf: Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).

Rac was calculated by dividing AUC0-24 (C1D14) by AUC0-24 (C0D-9).

Data in "PF-00299804 45 mg" treatment arm represents participants from both Phase 1 and Phase 2.

Rss was calculated by dividing AUC0-24 (C1D14) by AUCinf (C0D-9).

EORTC QLQ-C30: included global health status/quality of life (QoL), functional (Fn) scales (physical, role, cognitive, emotional, and social), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial difficulties). Scores were averaged, transformed to 0-100 scale; higher score for Global Qol/Fn scales=better level of QoL/functioning or higher score for symptom scales/items=greater degree of symptoms. Overall scale change is categorized as Improved (if average scales change from baseline: for Global QoL/Fn scales \>=10; for symptom scale/item \<=-10), Worsened (if average scales change from baseline: for Global QoL/Fn scales \<=-10; for symptom scale/item \>=10), and Stable (if average scales change from baseline \>-10 but \<10 for Global QoL/Fn scales and symptom scale/item) and participants in each category are reported.

EORTC 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, peripheral neuropathy, alopecia, chest pain, arm pain, other pain, and medicine for pain). Scores averaged, transformed to 0-100 scale; higher symptom score = greater degree of symptoms. Overall scale change is categorized as Improved (if average scales change from baseline \<=-10), Worsened (if average scales change from baseline \>=10), and Stable (if average scales change from baseline \>-10 but \<10) and participants in each category are reported.

DLQI: 10-item questionnaire to measure how much the participant's skin problem has impacted their life over the previous week. All questions were answered on a 4-point Likert scale ranging from 0 (not at all/not relevant) to 3 (very much/prevented work or studying). The DLQI was calculated by summing the score of each question and ranged from 0 to 30, where higher scores indicate more quality of life impairment.

Number of participants with BOR according to RECIST: CR= disappearance of all target and non-target lesions. PR= at least 30% decrease in sum of LDs of target lesion, taking as reference baseline sum LD, associated to non-progressive disease response for non-target lesions. Stable/no response= neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Objective progression= at least a 20% increase in sum of LDs of target lesions, taking as reference the smallest sum of LD recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.

Time in weeks from first documentation of objective tumor response to objective tumor progression or death due to any cause, whichever occurred first. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or death due to any cause minus the date of the first CR or PR \[which ever occurred first\] that was subsequently confirmed plus 1) divided by 7. DR was calculated for the subgroup of participants with a confirmed objective tumor response.

Pfizer

The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.

A single dose of PF-00299804 30 milligram (mg) tablet orally on or before Day -9 followed by PF-00299804 30 mg tablet orally once daily continuously in 21-day cycles starting from Day 1 until unacceptable toxicity, disease progression, withdrawal from the trial, or death.

PF-00299804 30 mg - Phase 1

A single dose of PF-00299804 45 mg tablet orally on or before Day -9 followed by PF-00299804 45 mg tablet orally once daily continuously in 21-day cycles starting from Day 1 until unacceptable toxicity, disease progression, withdrawal from the trial, or death.

PF-00299804 45 mg - Phase 1

PF-00299804 45 mg tablet orally once daily continuously in 21-day cycles starting from Day 1 until unacceptable toxicity, disease progression, withdrawal from the trial, or death.

PF-00299804 45 mg - Phase 2

A single dose of PF-00299804 30 mg or 45 mg tablet orally on or before Day -9 followed by PF-00299804 30 mg or 45 mg tablet orally once daily continuously in 21-day cycles starting from Day 1 until unacceptable toxicity, disease progression, withdrawal from the trial, or death.

PF-00299804 - Phase 1 All Participants

Total

Age, Continuous

Sex: Female, Male

Data for baseline characteristics was pre-specified in statistical analysis plan to be analyzed and summarized per phase.

Pfizer ClinicalTrials.gov Call Center

As-treated population included all enrolled participants who received at least 1 dose of study medication.

Recommended Phase 2 Dose (RP2D) - Phase 1

Full analysis set (FAS) included all enrolled participants.

Progression-Free Survival (PFS) at Month 4 (PFS4m) - Phase 2

Progression-Free Survival (PFS) at Month 6 (PFS6m) - Phase 2

Overall Survival (OS) at Month 6 (OS6m) - Phase 2

Response-evaluable population included all enrolled participants who received at least 1 dose of study medication, had an adequate baseline tumor assessment, and had at least 1 on-study tumor assessment after first dosing.

Percentage of Participants With Objective Response - Phase 1

EGFR: C1D1

EGFR: C3D1

EGFR: C5D1

EGFR: C7D1

EGFR: C9D1

EGFR: C11D1

EGFR: C13D1

EGFR: C15D1

EGFR: C17D1

HER2: C1D1

HER2: C3D1

HER2: C5D1

HER2: C7D1

HER2: C9D1

HER2: C11D1

HER2: C13D1

HER2: C15D1

HER2: C17D1

Biomarker analysis set: all enrolled participants who had baseline samples submitted as per Institutional Review Board/Independent Ethics Committee approval and participant consent. Data was pre-specified in statistical analysis plan to be analyzed and summarized per phase. Number analyzed = participants evaluable at specified time-point.

Soluble Protein Biomarkers Level

EGFR Status: Wild Type

EGFR Status: Mutant

EGFR Status: Unknown

KRAS Status: Wild Type

KRAS Status: Mutant

KRAS Status: Unknown

HER2 Status: Wild Type

HER2 Status: Mutant

HER2 Status: Unknown

Biomarker analysis set: all enrolled participants who had baseline samples submitted as per Institutional Review Board/Independent Ethics Committee approval and participant consent. Data was pre-specified in statistical analysis plan to be analyzed and summarized per phase.

Number of Participants With Epidermal Growth Factor Receptor (EGFR), Kirsten Rat Sarcoma (KRAS), and Human Epidermal Growth Factor Receptor-2 (HER2) Mutation Status

C0D-9

C1D14

A single dose of PF-00299804 45 mg tablet orally on or before Day -9 followed by PF-00299804 45 mg tablet orally once daily continuously in 21-day cycles starting from Day 1 during Phase 1 or PF-00299804 45 mg tablet orally once daily continuously in 21-day cycles during Phase 2, until unacceptable toxicity, disease progression, withdrawal from the trial, or death.

PF-00299804 45 mg

Pharmacokinetic (PK): all participants who received at least 1 dose of study drug and had at least 1 measured plasma concentration. "number analyzed"=participants evaluable for specified time-point. PK analysis was done by dose level instead of by phase. Participants started from the same dose level were combined together for PK analysis.

Maximum Observed Plasma Concentration (Cmax) of PF-00299804 30 mg and PF-00299804 45 mg

PK analysis set included all participants who received at least 1 dose of study drug and had at least 1 measured plasma concentration. "number analyzed"=participants evaluable for specified time-point. PK analysis was done by dose level instead of by phase. Participants started from the same dose level were combined together for PK analysis.

Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-00299804 30 mg and PF-00299804 45 mg

PK analysis set for Phase 1 included all participants who received at least 1 dose of study medication and had at least 1 measured plasma concentration.

Plasma Decay Half-Life (t1/2) of PF-00299804 30 mg and PF-00299804 45 mg - Phase 1

Area Under the Curve From Time Zero to 24 Hour Post-Dose (AUC0-24) of PF-00299804 30 mg and PF-00299804 45 mg

Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-00299804 30 mg and PF-00299804 45 mg- Phase 1

Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of PF-00299804 30 mg and PF-00299804 45 mg - Phase 1

Accumulation Ratio (Rac) of PF-00299804 30 mg and PF-00299804 45 mg - Phase 1

PK analysis set included all participants who received at least 1 dose of study drug and had at least 1 measured plasma concentration. PK analysis was done by dose level instead of by phase. Participants started from the same dose level were combined together for PK analysis.

Average Plasma Concentration (Cavg) of PF-00299804 30 mg and PF-00299804 45 mg

Linearity Ratio (Rss) of PF-00299804 30 mg and PF-00299804 45 mg - Phase 1

C2D1

C3D1

C4D1

PK analysis set included all participants who received at least 1 dose of study drug and had at least 1 measured plasma concentration. PK analysis was done by dose level instead of by phase. Participants started from the same dose level were combined together for PK analysis."number analyzed" = participants evaluable for specified time-point.

Minimum Observed Plasma Trough Concentration (Ctrough) of PF-00299804 30 mg and PF-00299804 45 mg

Global QoL: Improved

Global QoL: Worsened

Global QoL: Stable

Physical Functioning: Improved

Physical Functioning: Worsened

Physical Functioning: Stable

Role Functioning: Improved

Role Functioning: Worsened

Role Functioning: Stable

Cognitive Functioning: Improved

Cognitive Functioning: Worsened

Cognitive Functioning: Stable

Emotional Functioning: Improved

Emotional Functioning: Worsened

Emotional Functioning: Stable

Social Functioning: Improved

Social Functioning: Worsened

Social Functioning: Stable

Fatigue: Improved

Fatigue: Worsened

Fatigue: Stable

Pain: Improved

Pain: Worsened

Pain: Stable

Nausea and Vomiting: Improved

Nausea and Vomiting: Worsened

Nausea and Vomiting: Stable

Dyspnea: Improved

Dyspnea: Worsened

Dyspnea: Stable

Loss of Appetite: Improved

Loss of Appetite: Worsened

Loss of Appetite: Stable

Insomnia: Improved

Insomnia: Worsened

Insomnia: Stable

Constipation: Improved

Constipation: Worsened

Constipation: Stable

Diarrhea: Improved

Diarrhea: Worsened

Diarrhea: Stable

Financial Difficulties: Improved

Financial Difficulties: Worsened

Financial Difficulties: Stable

FAS included all enrolled participants. Here "N" (number of participants analyzed) signifies participants who were evaluable for this measure.

Number of Participants With Change in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Phase 2

Dyspnoea: Improved

Dyspnoea: Worsened

Dyspnoea: Stable

Coughing: Improved

Coughing: Worsened

Coughing: Stable

Haemoptysis: Improved

Haemoptysis: Worsened

Haemoptysis: Stable

Sore mouth: Improved

Sore mouth: Worsened

Sore mouth: Stable

Dysphagia: Improved

Dysphagia: Worsened

Dysphagia: Stable

Peripheral: Improved

Peripheral: Worsened

Peripheral: Stable

Alopecia: Improved

Alopecia: Worsened

Alopecia: Stable

Pain in chest: Improved

Pain in chest: Worsened

Pain in chest: Stable

Pain in arm or Shoulder: Improved

Pain in arm or Shoulder: Worsened

Pain in arm or Shoulder: Stable

Pain in other parts: Improved

FAS included all enrolled participants. Here "N" (number of participants analyzed) signifies participants who were evaluable for this measure. Medicine for pain was not summarized because a more comprehensive and reliable summary of concomitant medications was reported separately.

Number of Participants With Change in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module (EORTC QLQ-LC13) - Phase 2

Spots Global Cancer Trial Database for Trial Of PF-00299804 In Patients With Advanced Refractory Lung Cancer

Trial Identification

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Interventions

Study Description

Keywords

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