Metastatic Cancer Pancreas
Conditions
Brief summary
This study consists of a Phase 1b portion aimed to determine the maximum tolerated dose and the safety profile of PF-03084014 in combination with gemcitabine and nab-paclitaxel followed by a Phase 2 portion to evaluate the efficacy of the triple combination in terms of overall survival in patients with metastatic pancreatic ductal adenocarcinoma not previously treated with anticancer therapies.
Interventions
DRUGPF-03084014
Tablets, orally administered twice daily on a continuous dosing schedule in 28 days cycles. Doses: 100 -150 mg BID
DRUGGemcitabine
Intravenously administered on Days 1, 8, 15 in 28 days cycles at the dose of 1000 mg/m2.
DRUGNab-paclitaxel
Intravenously administered on Days 1, 8, 15 in 28 days cycles at the dose of 125 mg/m2.
Sponsors
Academic GI Cancer Consortium (AGICC)
Pfizer
Study design
Allocation
RANDOMIZED
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically diagnosis of metastatic ductal adenocarcinoma of the pancreas. * No prior radiotherapy, surgery chemotherapy or investigational therapy for metastatic disease. Prior adjuvant therapy with 5-FU or gemcitabine (± gemcitabine post radiation) administered as radiosensitizer allowed, provided at least 6 months have elapsed between the last dose and study registration * Tumor tissue available (Archival 6 months old or de novo biopsy) * Measurable disease as per RECIST 1.1 * Performance Status (ECOG) 0 or 1
Exclusion criteria
* Symptomatic brain metastases requiring steroids * Prior therapy with gamma secretase inhibitors or other Notch pathway inhibitor * Major surgery within 4 weeks of registration in the current study * Known hypersensitivity to gemcitabine or nab-paclitaxel or any of the excipients * Current or anticipated need for food or drugs that are strong/moderate CYP3A4 inhibitors or inducers * Diagnosis of any second malignancy within 3 years prior to registration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLTs) in Cycle 1 | Cycle 1 (28 days) | DLT was defined as any of the following events occurring during the first cycle of treatment and considered at least possibly-related to study medication: any Grade 3 or 4 clinically-relevant non-hematologic and/or hematologic toxicity, delay of more than 2 weeks in receiving the next scheduled cycle due to persisting treatment-related toxicities. |
| Overall Survival (OS) in Phase 2 | From start of study treatment, collected every 3 months until death (up to 5 years) | Overall survival was the duration from randomization to death. For participants who are alive, overall survival was censored at the last contact. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Systemic Clearance (CL) of PF-03084014, Nab-P and GEM in Phase 2 | Cycle 1 Day 1 till end of last cycle | — |
| Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment in Phase 1 | Baseline up to 28-35 days post last administration of study drug | Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to study drug was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category. Severity was graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Grade 1=mild, Grade 2=moderate, Grade 3=Severe or medically significant but not immediately life-threatening, Grade 4=life-threatening. |
| Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment in Phase 2 | Baseline up to 28-35 days post last administration of study drug | Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to study drug was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category. Severity was graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Grade 1=mild, Grade 2=moderate, Grade 3=Severe or medically significant but not immediately life-threatening, Grade 4=life-threatening. |
| Maximum Observed Plasma Concentration (Cmax) for PF-03084014, Nab-P and GEM in Phase 1 | PF-03084014: Cycle 1 Days 3, 15, 22; Day 1 of subsequent cycles; and end of treatment. nab-P: Cycle 1 Days 1-3 and 15-17. Gemcitabine: Cycle 1 Days 1 and 15. | — |
| Number of Participants With Laboratory Abnormalities in Phase 1 | Screening; Cycle 1 Days 1, 8, 15, 22; up to 28-35 days post last administration of study drug | Following parameters were analyzed for laboratory examination: hematology (hemoglobin, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (urea, creatinine, glucose, calcium, sodium, potassium, chloride, magnesium, phosphate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid); urinalysis (protein, blood, microscopy\[if urine tested positive for blood or protein\]). |
| Number of Participants With Laboratory Abnormalities in Phase 2 | Screening; Days 1, 8, 15 of each cycle; up to 28-35 days post last administration of study drug | Following parameters were analyzed for laboratory examination: hematology (hemoglobin, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (urea, creatinine, glucose, calcium, sodium, potassium, chloride, magnesium, phosphate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid); urinalysis (protein, blood, microscopy\[if urine tested positive for blood or protein\]). |
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs at Phases 1 and 2 | Baseline up to 28-35 days after treatment discontinuation | Following parameters were analyzed for examination of vital signs: systolic and diastolic blood pressure, heart rate, weight and body surface area. |
| Number of Participants With Worsening QTc Results in Phase 1 | Screening, Cycle 1 Days 3 and 22, Cycles 2 and 3 Day 1, end of treatment | Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) were corrected for heart rate (QTc) using Fridericia (QTcF) and Bazett (QTcB) formulas. Any change from baseline in QTc was considered as worsening in ECG and was classified accordingly to the Common Terminology Criteria (CTC) grade. Grading was as follows: prolonged QTc of 450 to 480 milliseconds (msec)=Grade 1, 481 to 500 msec=Grade 2, more than or equal to (\>=) 501 msec on at least 2 seperate ECGs=Grade 3, \>=501 or more than (\>) 60 msec change from baseline and Torsade de pointes or polymorphic ventricular tachycardia or signs of serious arrhythmia=Grade 4. |
| Maximum Observed Plasma Concentration (Cmax) for PF-03084014, Nab-P and GEM in Phase 2 | Cycle 1 Day 1 till end of last cycle | — |
| Number of Participants With Worsening QTc Results in Phase 2 | Screening, Cycle 1 Days 1 and 22, Cycles 2 and 3 Day 1, end of treatment | Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) were corrected for heart rate (QTc) using Fridericia (QTcF) and Bazett (QTcB) formulas. Any change from baseline in QTc was considered as worsening in ECG and was classified accordingly to the Common Terminology Criteria (CTC) grade. Grading was as follows: prolonged QTc of 450 to 480 milliseconds (msec)=Grade 1, 481 to 500 msec=Grade 2, more than or equal to (\>=) 501 msec on at least 2 seperate ECGs=Grade 3, \>=501 or more than (\>) 60 msec change from baseline and Torsade de pointes or polymorphic ventricular tachycardia or signs of serious arrhythmia=Grade 4. |
| Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 1 | PF-03084014: Cycle 1 Days 3, 15, 22; Day 1 of subsequent cycles; and end of treatment. nab-P: Cycle 1 Days 1-3 and 15-17. Gemcitabine: Cycle 1 Days 1 and 15. | AUC included AUC from time 0 extrapolated to infinite time (AUCinf), AUC from time 0 to end of dosing interval (AUCtau, tau=12 hours), and AUC from time 0 to last measured concentration (AUClast). |
| Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 2 | Cycle 1 Day 1 till end of last cycle | AUC included AUC from time 0 extrapolated to infinite time (AUCinf), AUC from time 0 to end of dosing interval (AUCtau), and AUC from time 0 to last measured concentration (AUClast). |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-03084014, Nab-P and GEM in Phase 1 | PF-03084014: Cycle 1 Days 3, 15, 22; Day 1 of subsequent cycles; and end of treatment. nab-P: Cycle 1 Days 1-3 and 15-17. Gemcitabine: Cycle 1 Days 1 and 15. | — |
| Systemic Clearance (CL) of Nab-paclitaxel in Phase 1 | Cycle 1 Days 1-3, and 15-17 | — |
| Volume of Distribution at Steady State (Vss) for Nab-P and GEM in Phase 1 | Cycle 1 (Days 1 and 15 for gemcitabine; Days 1-3 and 15-17 for nab-paclitaxel) | — |
| Volume of Distribution at Steady State (Vss) for PF-03084014, Nab-P and GEM in Phase 2 | Cycle 1 Day 1 till end of last cycle | — |
| Plasma Decay Half-life (t1/2) for Nab-P and GEM in Phase 1 | Cycle 1 (Days 1 and 15 for gemcitabine; Days 1-3 and 15-17 for nab-paclitaxel) | — |
| Plasma Decay Half-life (t1/2) for PF-03084014, Nab-P and GEM in Phase 2 | Cycle 1 Day 1 till end of last cycle | — |
| Number of Participants With Objective Response (OR) in Phase 1 | Screening till 28-35 days post last administration of study drug | Number of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST). 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 less than (\<) 10 mm). No new lesions. PR was defined as more than or equal to (\>=) 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 non-target disease. No new lesions. |
| Number of Participants With Objective Response (OR) in Phase 2 | Screening till 28-35 days post last administration of study drug | Number of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST). 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 less than (\<) 10 mm). No new lesions. PR was defined as more than or equal to (\>=) 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 non-target disease. No new lesions. |
| Duration of Response (DR) for Phases 1 and 2 | Baseline, every 8 weeks until disease progression or unacceptable toxicity (up to 5 years) | Duration of response (DR) defined as the difference in days between the first date criteria for progression occurred or the participant died due to any cause and the first date that criteria for a PR or CR were met. DR calculated as (months) = (progression/death date - first date of OR + 1) divided by 30.4. CR: disappearance of all target lesions. PR: at least 30% decrease in the sum of diameters of target lesions. |
| 1-year and 2-year OS in Phase 2 | From start of study treatment, collected every 3 months until death (up to 5 years) | Overall survival was the duration from randomization to death. For participants who are alive, overall survival was censored at the last contact. |
| Progression-free Survival (PFS) in Phase 2 | From start of study treatment, collected every 3 months until death (up to 5 years) | PFS was defined as the time from the date of first dose to the date of the first documentation of objective tumor progression or death on study due to any cause, whichever occurred first. PFS (in months) was calculated as (first event date - date of randomization +1) divided by 30.4. |
| Brief Pain Inventory-Short Form (BPI-sf) Score - Phase 2 | Day 1 of Cycle 1 and subsequent cycles; end of treatment | BPI-sf is an 11-item self-report questionnaire that is designed to assess the severity and impact of pain on daily functions. BPI-sf are 4 questions that assess pain intensity (worst, least, average, right now) and 7 questions that assess impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). Each question is answered on a scale ranging from 0 to 10; '0=No pain and 10=Pain as bad as you can imagine'. Measure can be scored by item, with lower scores being indicative of less pain or pain interference. |
| Change From Baseline in European Quality of Life Questionnaire (EQ-5D) - Phase 2 | Baseline till end of treatment | EQ-5D: 6-item participant rated questionnaire to assess health-related quality of life in terms of a single utility score. There were 2 components: a Health State Profile and a Visual Analog Scale. Published weights are available that allow for the creation of a single summary score. Overall scores range from 0-1, with low scores representing a higher level of dysfunction. |
| European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire (EORTC QLQ-C30) - Phase 2 | Baseline till end of treatment | 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 to Reach Maximum Observed Plasma Concentration (Tmax) for PF-03084014, Nab-P and GEM in Phase 2 | Cycle 1 Day 1 till end of last cycle | — |
| Systemic Clearance (CL) of Gemcitabine in Phase 1 | Cycle 1 Days 1 and 15 | — |
Countries
United States
Participant flow
Recruitment details
The study planned to include 2 phases: Phase 1 (dose-finding phase) followed by Phase 2 (randomized phase). Due to early termination of the study, only 3 participants were enrolled in Phase 1 and Phase 2 was not conducted.
Participants by arm
| Arm | Count |
|---|---|
| PF-03084014+Nab-Paclitaxel+Gemcitabine PF-03084014 was administered twice daily (BID) orally via tablets at a starting dose of 100 milligrams (mg). Nab-paclitaxel (nab-P) and gemcitabine (GEM) were administered intravenously at a starting dose of 125 mg/square meter (m\^2) and 1000 mg/m\^2, respectively. Decisions to escalate, de-escalate or stay at the same dose were made based on the number of dose-limiting toxicities (DLTs) observed. In any case, PF-03084014 dose was not to exceed 150 mg BID and nab-P and GEM were not to exceed 125 mg/m\^2 and 1000 mg/m\^2, respectively. | 3 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Symptomatic deterioration | 2 |
Baseline characteristics
| Characteristic | PF-03084014+Nab-Paclitaxel+Gemcitabine |
|---|---|
| Age, Continuous | 64.3 years STANDARD_DEVIATION 4.7 |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 2 / 3 |
Outcome results
Primary
Number of Participants With Dose-limiting Toxicities (DLTs) in Cycle 1
DLT was defined as any of the following events occurring during the first cycle of treatment and considered at least possibly-related to study medication: any Grade 3 or 4 clinically-relevant non-hematologic and/or hematologic toxicity, delay of more than 2 weeks in receiving the next scheduled cycle due to persisting treatment-related toxicities.
Time frame: Cycle 1 (28 days)
Population: All enrolled participants who received study treatment and who either experienced DLT during the first cycle, or completed the 1-cycle observation period, were considered evaluable for DLT. Only 2 of the 3 participants were evaluable for DLTs.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Number of Participants With Dose-limiting Toxicities (DLTs) in Cycle 1 | 2 participants |
Primary
Overall Survival (OS) in Phase 2
Overall survival was the duration from randomization to death. For participants who are alive, overall survival was censored at the last contact.
Time frame: From start of study treatment, collected every 3 months until death (up to 5 years)
Population: All randomized participants in Phase 2 were to be analyzed for OS. However, since Phase 2 was not carried out due to early termination, no subjects were analyzed for OS.
Secondary
1-year and 2-year OS in Phase 2
Overall survival was the duration from randomization to death. For participants who are alive, overall survival was censored at the last contact.
Time frame: From start of study treatment, collected every 3 months until death (up to 5 years)
Population: All randomized participants in Phase 2 were to be analyzed for OS. However, since Phase 2 was not carried out due to early termination, no subjects were analyzed for OS.
Secondary
Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 1
AUC included AUC from time 0 extrapolated to infinite time (AUCinf), AUC from time 0 to end of dosing interval (AUCtau, tau=12 hours), and AUC from time 0 to last measured concentration (AUClast).
Time frame: PF-03084014: Cycle 1 Days 3, 15, 22; Day 1 of subsequent cycles; and end of treatment. nab-P: Cycle 1 Days 1-3 and 15-17. Gemcitabine: Cycle 1 Days 1 and 15.
Population: All treated participants who had at least 1 of the pharmacokinetic (PK) parameters of interest of any of the study drugs. n=number of evaluable participants for that parameter at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 1 | AUClast for nab-paclitaxel on Day 15 (n=1) | 4600 nanogram*hour/milliliter (ng*hr/mL) | — |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 1 | AUCinf for gemcitabine on Day 1 (n=3) | 5316 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 172 |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 1 | AUClast for gemcitabine on Day 1 (n=3) | 5262 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 176 |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 1 | AUCinf for gemcitabine on Day 15 (n=1) | 2510 nanogram*hour/milliliter (ng*hr/mL) | — |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 1 | AUClast for PF-03084014 on Day 3 (n=3) | 1122 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 913 |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 1 | AUClast for PF-03084014 on Day 15 (n=1) | 1770 nanogram*hour/milliliter (ng*hr/mL) | — |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 1 | AUCinf for nab-paclitaxel on Day 1 (n=3) | 5774 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 11 |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 1 | AUClast for nab-paclitaxel on Day 1 (n=3) | 5185 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 9 |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 1 | AUCinf for nab-paclitaxel on Day 15 (n=1) | 5050 nanogram*hour/milliliter (ng*hr/mL) | — |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 1 | AUClast for gemcitabine on Day 15 (n=1) | 2500 nanogram*hour/milliliter (ng*hr/mL) | — |
Secondary
Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 2
AUC included AUC from time 0 extrapolated to infinite time (AUCinf), AUC from time 0 to end of dosing interval (AUCtau), and AUC from time 0 to last measured concentration (AUClast).
Time frame: Cycle 1 Day 1 till end of last cycle
Population: As Phase 2 was not performed, no participants were analyzed for this outcome measure.
Secondary
Brief Pain Inventory-Short Form (BPI-sf) Score - Phase 2
BPI-sf is an 11-item self-report questionnaire that is designed to assess the severity and impact of pain on daily functions. BPI-sf are 4 questions that assess pain intensity (worst, least, average, right now) and 7 questions that assess impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). Each question is answered on a scale ranging from 0 to 10; '0=No pain and 10=Pain as bad as you can imagine'. Measure can be scored by item, with lower scores being indicative of less pain or pain interference.
Time frame: Day 1 of Cycle 1 and subsequent cycles; end of treatment
Population: As Phase 2 was not performed due to early termination, there were no participants to analyse for this outcome measure.
Secondary
Change From Baseline in European Quality of Life Questionnaire (EQ-5D) - Phase 2
EQ-5D: 6-item participant rated questionnaire to assess health-related quality of life in terms of a single utility score. There were 2 components: a Health State Profile and a Visual Analog Scale. Published weights are available that allow for the creation of a single summary score. Overall scores range from 0-1, with low scores representing a higher level of dysfunction.
Time frame: Baseline till end of treatment
Population: As Phase 2 was not performed due to early termination, there were no participants to analyse for this outcome measure.
Secondary
Duration of Response (DR) for Phases 1 and 2
Duration of response (DR) defined as the difference in days between the first date criteria for progression occurred or the participant died due to any cause and the first date that criteria for a PR or CR were met. DR calculated as (months) = (progression/death date - first date of OR + 1) divided by 30.4. CR: disappearance of all target lesions. PR: at least 30% decrease in the sum of diameters of target lesions.
Time frame: Baseline, every 8 weeks until disease progression or unacceptable toxicity (up to 5 years)
Population: No participants were analyzed for this outcome measure as there were no participants with OR in Phase 1 and Phase 2 was not done.
Secondary
European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire (EORTC QLQ-C30) - 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 till end of treatment
Population: As Phase 2 was not performed due to early termination, there were no participants to analyse for this outcome measure.
Secondary
Maximum Observed Plasma Concentration (Cmax) for PF-03084014, Nab-P and GEM in Phase 1
Time frame: PF-03084014: Cycle 1 Days 3, 15, 22; Day 1 of subsequent cycles; and end of treatment. nab-P: Cycle 1 Days 1-3 and 15-17. Gemcitabine: Cycle 1 Days 1 and 15.
Population: All treated participants who had at least 1 of the PK parameters of interest of any of the study drugs. n=number of evaluable participants for that parameter at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Maximum Observed Plasma Concentration (Cmax) for PF-03084014, Nab-P and GEM in Phase 1 | Cmax for PF-03084014 on Day 3 (n=3) | 527.3 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 710 |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Maximum Observed Plasma Concentration (Cmax) for PF-03084014, Nab-P and GEM in Phase 1 | Cmax for PF-03084014 on Day 15 (n=1) | 943.0 nanogram/milliliter (ng/mL) | — |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Maximum Observed Plasma Concentration (Cmax) for PF-03084014, Nab-P and GEM in Phase 1 | Cmax for nab-paclitaxel on Day 1 (n=3) | 6023 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 6 |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Maximum Observed Plasma Concentration (Cmax) for PF-03084014, Nab-P and GEM in Phase 1 | Cmax for nab-paclitaxel on Day 15 (n=1) | 5140 nanogram/milliliter (ng/mL) | — |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Maximum Observed Plasma Concentration (Cmax) for PF-03084014, Nab-P and GEM in Phase 1 | Cmax for gemcitabine on Day 1 (n=3) | 10760 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 212 |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Maximum Observed Plasma Concentration (Cmax) for PF-03084014, Nab-P and GEM in Phase 1 | Cmax for gemcitabine on Day 15 (n=1) | 3620 nanogram/milliliter (ng/mL) | — |
Secondary
Maximum Observed Plasma Concentration (Cmax) for PF-03084014, Nab-P and GEM in Phase 2
Time frame: Cycle 1 Day 1 till end of last cycle
Population: As Phase 2 was not performed, no participants were analyzed for this outcome measure.
Secondary
Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment in Phase 1
Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to study drug was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category. Severity was graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Grade 1=mild, Grade 2=moderate, Grade 3=Severe or medically significant but not immediately life-threatening, Grade 4=life-threatening.
Time frame: Baseline up to 28-35 days post last administration of study drug
Population: All enrolled participants in Phase 1 who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment in Phase 1 | Grade 3 or 4 TEAEs | 3 participants |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment in Phase 1 | All-causality TEAEs | 3 participants |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment in Phase 1 | Treatment-related TEAEs | 3 participants |
Secondary
Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment in Phase 2
Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to study drug was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category. Severity was graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Grade 1=mild, Grade 2=moderate, Grade 3=Severe or medically significant but not immediately life-threatening, Grade 4=life-threatening.
Time frame: Baseline up to 28-35 days post last administration of study drug
Population: No participants were analyzed since Phase 2 was not performed.
Secondary
Number of Participants With Clinically Significant Change From Baseline in Vital Signs at Phases 1 and 2
Following parameters were analyzed for examination of vital signs: systolic and diastolic blood pressure, heart rate, weight and body surface area.
Time frame: Baseline up to 28-35 days after treatment discontinuation
Population: All enrolled participants in Phase 1, or all randomized participants in Phase 2, who received at least 1 dose of study medication. Due to early termination of the study, vital sign evaluations were not performed.
Secondary
Number of Participants With Laboratory Abnormalities in Phase 1
Following parameters were analyzed for laboratory examination: hematology (hemoglobin, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (urea, creatinine, glucose, calcium, sodium, potassium, chloride, magnesium, phosphate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid); urinalysis (protein, blood, microscopy\[if urine tested positive for blood or protein\]).
Time frame: Screening; Cycle 1 Days 1, 8, 15, 22; up to 28-35 days post last administration of study drug
Population: All participants who received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Number of Participants With Laboratory Abnormalities in Phase 1 | 3 participants |
Secondary
Number of Participants With Laboratory Abnormalities in Phase 2
Following parameters were analyzed for laboratory examination: hematology (hemoglobin, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (urea, creatinine, glucose, calcium, sodium, potassium, chloride, magnesium, phosphate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid); urinalysis (protein, blood, microscopy\[if urine tested positive for blood or protein\]).
Time frame: Screening; Days 1, 8, 15 of each cycle; up to 28-35 days post last administration of study drug
Population: Due to early termination, Phase 2 was not performed and thus no participants were included in this analysis.
Secondary
Number of Participants With Objective Response (OR) in Phase 1
Number of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST). 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 less than (\<) 10 mm). No new lesions. PR was defined as more than or equal to (\>=) 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 non-target disease. No new lesions.
Time frame: Screening till 28-35 days post last administration of study drug
Population: All enrolled participants in Phase 1 who were eligible for enrollment, received study treatment, had measurable disease and adequate baseline assessments, and had at least 1 on-study tumor assessment, were considered evaluable for response. Only 1 participant was evaluable for OR in Phase 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Number of Participants With Objective Response (OR) in Phase 1 | 0 participants |
Secondary
Number of Participants With Objective Response (OR) in Phase 2
Number of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST). 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 less than (\<) 10 mm). No new lesions. PR was defined as more than or equal to (\>=) 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 non-target disease. No new lesions.
Time frame: Screening till 28-35 days post last administration of study drug
Population: No participants were analyzed for this outcome measure as Phase 2 was not done.
Secondary
Number of Participants With Worsening QTc Results in Phase 1
Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) were corrected for heart rate (QTc) using Fridericia (QTcF) and Bazett (QTcB) formulas. Any change from baseline in QTc was considered as worsening in ECG and was classified accordingly to the Common Terminology Criteria (CTC) grade. Grading was as follows: prolonged QTc of 450 to 480 milliseconds (msec)=Grade 1, 481 to 500 msec=Grade 2, more than or equal to (\>=) 501 msec on at least 2 seperate ECGs=Grade 3, \>=501 or more than (\>) 60 msec change from baseline and Torsade de pointes or polymorphic ventricular tachycardia or signs of serious arrhythmia=Grade 4.
Time frame: Screening, Cycle 1 Days 3 and 22, Cycles 2 and 3 Day 1, end of treatment
Population: All enrolled participants in Phase 1 who had at least 1 ECG assessment after receiving PF-03084014.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Number of Participants With Worsening QTc Results in Phase 1 | NA participants |
Secondary
Number of Participants With Worsening QTc Results in Phase 2
Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) were corrected for heart rate (QTc) using Fridericia (QTcF) and Bazett (QTcB) formulas. Any change from baseline in QTc was considered as worsening in ECG and was classified accordingly to the Common Terminology Criteria (CTC) grade. Grading was as follows: prolonged QTc of 450 to 480 milliseconds (msec)=Grade 1, 481 to 500 msec=Grade 2, more than or equal to (\>=) 501 msec on at least 2 seperate ECGs=Grade 3, \>=501 or more than (\>) 60 msec change from baseline and Torsade de pointes or polymorphic ventricular tachycardia or signs of serious arrhythmia=Grade 4.
Time frame: Screening, Cycle 1 Days 1 and 22, Cycles 2 and 3 Day 1, end of treatment
Population: Due to early termination, Phase 2 was not performed and thus no participants were analyzed for this outcome measure.
Secondary
Plasma Decay Half-life (t1/2) for Nab-P and GEM in Phase 1
Time frame: Cycle 1 (Days 1 and 15 for gemcitabine; Days 1-3 and 15-17 for nab-paclitaxel)
Population: All treated participants who had at least 1 of the PK parameters of interest of any of the study drugs. n=number of evaluable participants for that parameter at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Plasma Decay Half-life (t1/2) for Nab-P and GEM in Phase 1 | t1/2 of gemcitabine on Day 1 (n=3) | 0.2813 hours | Standard Deviation 0.14838 |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Plasma Decay Half-life (t1/2) for Nab-P and GEM in Phase 1 | t1/2 of nab-paclitaxel on Day 1 (n=3) | 2.500 hours | Standard Deviation 0.26851 |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Plasma Decay Half-life (t1/2) for Nab-P and GEM in Phase 1 | t1/2 of nab-paclitaxel on Day 15 (n=1) | 2.030 hours | — |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Plasma Decay Half-life (t1/2) for Nab-P and GEM in Phase 1 | t1/2 of gemcitabine on Day 15 (n=1) | 0.2230 hours | — |
Secondary
Plasma Decay Half-life (t1/2) for PF-03084014, Nab-P and GEM in Phase 2
Time frame: Cycle 1 Day 1 till end of last cycle
Population: As Phase 2 was not performed, no participants were analyzed for this outcome measure.
Secondary
Progression-free Survival (PFS) in Phase 2
PFS was defined as the time from the date of first dose to the date of the first documentation of objective tumor progression or death on study due to any cause, whichever occurred first. PFS (in months) was calculated as (first event date - date of randomization +1) divided by 30.4.
Time frame: From start of study treatment, collected every 3 months until death (up to 5 years)
Population: All randomized participants in Phase 2 were to be analyzed for PFS. However, since Phase 2 was not carried out due to early termination, no subjects were analyzed for PFS.
Secondary
Systemic Clearance (CL) of Gemcitabine in Phase 1
Time frame: Cycle 1 Days 1 and 15
Population: All treated participants who had at least 1 of the PK parameters of interest of any of the study drugs. n=number of evaluable participants for that parameter at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Systemic Clearance (CL) of Gemcitabine in Phase 1 | Day 15 (n=1) | 8.160 liter (L)/minute (min) | — |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Systemic Clearance (CL) of Gemcitabine in Phase 1 | Day 1 (n=3) | 5.434 liter (L)/minute (min) | Geometric Coefficient of Variation 165 |
Secondary
Systemic Clearance (CL) of Nab-paclitaxel in Phase 1
Time frame: Cycle 1 Days 1-3, and 15-17
Population: All treated participants who had at least 1 of the PK parameters of interest of any of the study drugs. n=number of evaluable participants for that parameter at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Systemic Clearance (CL) of Nab-paclitaxel in Phase 1 | Day 1 (n=3) | 37.88 liter (L)/hour (hr) | Geometric Coefficient of Variation 25 |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Systemic Clearance (CL) of Nab-paclitaxel in Phase 1 | Day 15 (n=1) | 38.60 liter (L)/hour (hr) | — |
Secondary
Systemic Clearance (CL) of PF-03084014, Nab-P and GEM in Phase 2
Time frame: Cycle 1 Day 1 till end of last cycle
Population: As Phase 2 was not performed, no participants were analyzed for this outcome measure.
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-03084014, Nab-P and GEM in Phase 1
Time frame: PF-03084014: Cycle 1 Days 3, 15, 22; Day 1 of subsequent cycles; and end of treatment. nab-P: Cycle 1 Days 1-3 and 15-17. Gemcitabine: Cycle 1 Days 1 and 15.
Population: All treated participants who had at least 1 of the PK parameters of interest of any of the study drugs. n=number of evaluable participants for that parameter at the specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-03084014, Nab-P and GEM in Phase 1 | Tmax of PF-03084014 on Day 3 (n=3) | 1.23 hours |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-03084014, Nab-P and GEM in Phase 1 | Tmax of PF-03084014 on Day 15 (n=1) | 0.900 hours |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-03084014, Nab-P and GEM in Phase 1 | Tmax of nab-paclitaxel on Day 1 (n=3) | 0.550 hours |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-03084014, Nab-P and GEM in Phase 1 | Tmax of nab-paclitaxel on Day 15 (n=1) | 0.217 hours |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-03084014, Nab-P and GEM in Phase 1 | Tmax of gemcitabine on Day 1 (n=3) | 0.517 hours |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-03084014, Nab-P and GEM in Phase 1 | Tmax of gemcitabine on Day 15 (n=1) | 0.350 hours |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-03084014, Nab-P and GEM in Phase 2
Time frame: Cycle 1 Day 1 till end of last cycle
Population: As Phase 2 was not performed, no participants were analyzed for this outcome measure.
Secondary
Volume of Distribution at Steady State (Vss) for Nab-P and GEM in Phase 1
Time frame: Cycle 1 (Days 1 and 15 for gemcitabine; Days 1-3 and 15-17 for nab-paclitaxel)
Population: All treated participants who had at least 1 of the PK parameters of interest of any of the study drugs. n=number of evaluable participants for that parameter at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Volume of Distribution at Steady State (Vss) for Nab-P and GEM in Phase 1 | Vss of nab-paclitaxel on Day 1 (n=3) | 64.46 liters | Geometric Coefficient of Variation 6 |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Volume of Distribution at Steady State (Vss) for Nab-P and GEM in Phase 1 | Vss of nab-paclitaxel on Day 15 (n=1) | 60.80 liters | — |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Volume of Distribution at Steady State (Vss) for Nab-P and GEM in Phase 1 | Vss of gemcitabine on Day 1 (n=3) | 61.76 liters | Geometric Coefficient of Variation 186 |
| PF-03084014 + Nab-Paclitaxel + Gemcitabine | Volume of Distribution at Steady State (Vss) for Nab-P and GEM in Phase 1 | Vss of gemcitabine on Day 15 (n=1) | 201.0 liters | — |
Secondary
Volume of Distribution at Steady State (Vss) for PF-03084014, Nab-P and GEM in Phase 2
Time frame: Cycle 1 Day 1 till end of last cycle
Population: As Phase 2 was not performed, no participants were analyzed for this outcome measure.