To assess the safety and efficacy of PF-00299804 in patients with advanced lung cancer.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
55
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
Seoul National University Hospital, Department of Internal Medicine
Seoul, South Korea
Severance Hospital, Yonsei University College of Medicine, Yonsei Cancer Center
Seoul, South Korea
Samsung Medical Center, Department of Medicine
Seoul, South Korea
Recommended Phase 2 Dose (RP2D) - Phase 1
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.
Time frame: Baseline up to Day 21
Progression-Free Survival (PFS) at Month 4 (PFS4m) - Phase 2
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.
Time frame: Month 4
Progression-Free Survival (PFS) at Month 6 (PFS6m) - Phase 2
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.
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Time frame: Month 6
Overall Survival (OS) at Month 6 (OS6m) - Phase 2
OS6m was defined as percent chance of being alive at Month 6.
Time frame: Month 6
Percentage of Participants With Objective Response - Phase 1
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.
Time frame: Baseline until disease progression or initiation of new anti-cancer therapy or death, assessed every 2 (odd-numbered) cycles up to 12 months after end of treatment (EOT) (EOT: up to Day 506)
Soluble Protein Biomarkers Level
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.
Time frame: Cycle 1 Day 1 (C1D1, Baseline), Day 1 of each odd-numbered cycle up to Cycle 17 for both Phase 1 and Phase 2
Number of Participants With Epidermal Growth Factor Receptor (EGFR), Kirsten Rat Sarcoma (KRAS), and Human Epidermal Growth Factor Receptor-2 (HER2) Mutation Status
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.
Time frame: Screening
Maximum Observed Plasma Concentration (Cmax) of PF-00299804 30 mg and PF-00299804 45 mg
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.
Time frame: 0 (pre-dose), 2, 4, 6, 8, 24, 72, 144, 216 hours post-dose on C0D-9 for Phase 1, 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on C1D14 for Phase 1 and 2
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-00299804 30 mg and PF-00299804 45 mg
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.
Time frame: 0 (pre-dose), 2, 4, 6, 8, 24, 72, 144, 216 hours post-dose on Cycle 0 Day -9 (C0D-9) for Phase 1, 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on C1D14 for Phase 1 and 2
Plasma Decay Half-Life (t1/2) of PF-00299804 30 mg and PF-00299804 45 mg - Phase 1
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: 0 (pre-dose), 2, 4, 6, 8, 24, 72, 144, 216 hours post-dose on Cycle 0 Day -9 (C0D-9)
Area Under the Curve From Time Zero to 24 Hour Post-Dose (AUC0-24) of PF-00299804 30 mg and PF-00299804 45 mg
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.
Time frame: 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on Cycle 0 Day -9 (C0D-9) for Phase 1, 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on C1D14 for Phase 1 and 2
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-00299804 30 mg and PF-00299804 45 mg- Phase 1
AUClast: Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration.
Time frame: 0 (pre-dose), 2, 4, 6, 8, 24, 72, 144, 216 hours post-dose on C0D-9
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of PF-00299804 30 mg and PF-00299804 45 mg - Phase 1
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 - ∞).
Time frame: 0 (pre-dose), 2, 4, 6, 8, 24, 72, 144, 216 hours post-dose on C0D-9
Accumulation Ratio (Rac) of PF-00299804 30 mg and PF-00299804 45 mg - Phase 1
Rac was calculated by dividing AUC0-24 (C1D14) by AUC0-24 (C0D-9).
Time frame: 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on C0D-9, 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on C1D14
Average Plasma Concentration (Cavg) of PF-00299804 30 mg and PF-00299804 45 mg
Data in "PF-00299804 45 mg" treatment arm represents participants from both Phase 1 and Phase 2.
Time frame: 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on C1D14 for Phase 1 and 2
Linearity Ratio (Rss) of PF-00299804 30 mg and PF-00299804 45 mg - Phase 1
Rss was calculated by dividing AUC0-24 (C1D14) by AUCinf (C0D-9).
Time frame: 0 (pre-dose), 2, 4, 6, 8, 24, 72, 144, 216 hours post-dose on C0D-9, 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on C1D14
Minimum Observed Plasma Trough Concentration (Ctrough) of PF-00299804 30 mg and PF-00299804 45 mg
Data in "PF-00299804 45 mg" treatment arm represents participants from both Phase 1 and Phase 2.
Time frame: 0 hours (pre-dose) on C2D1, C3D1, C4D1
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
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.
Time frame: Baseline up to end of treatment (up to Day 889)
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
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.
Time frame: Baseline up to end of treatment (up to Day 889)
Dermatology Life Quality Index (DLQI) Total Score - Phase 2
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.
Time frame: C1D1 (baseline), D1 of each subsequent cycle up to C44
Best Overall Response (BOR) - Phase 2
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 frame: Baseline until disease progression or initiation of new anti-cancer therapy or death, assessed every 2 (odd-numbered) cycles up to 12 months after EOT (EOT: up to Day 1723)
Duration of Response (DR)
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.
Time frame: Baseline until disease progression or initiation of new anti-cancer therapy or death, assessed every 2 (odd-numbered) cycles up to 12 months after EOT (EOT: up to Day 506 for Phase 1 and up to Day 1723 for Phase 2)