Trial Outcomes & Findings for Study Of PF-03084014 In Combination With Gemcitabine And Nab-Paclitaxel In Patients With Metastatic Pancreatic Adenocarcinoma Not Previously Treated With Anticancer Therapies (NCT NCT02109445)

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

3 participants

Primary outcome timeframe

Cycle 1 (28 days)

Results posted on

2019-01-10

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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.
Overall Study STARTED	3
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	3

Reasons for withdrawal

Reasons for withdrawal
Measure	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.
Overall Study Symptomatic deterioration	2
Overall Study Adverse Event	1

Baseline Characteristics

Study Of PF-03084014 In Combination With Gemcitabine And Nab-Paclitaxel In Patients With Metastatic Pancreatic Adenocarcinoma Not Previously Treated With Anticancer Therapies

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	PF-03084014+Nab-Paclitaxel+Gemcitabine n=3 Participants 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.
Age, Continuous	64.3 years STANDARD_DEVIATION 4.7 • n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants
Sex: Female, Male Male	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	PF-03084014 + Nab-Paclitaxel + Gemcitabine n=2 Participants 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.
Number of Participants With Dose-limiting Toxicities (DLTs) in Cycle 1	2 participants

PRIMARY outcome

Timeframe: 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.

Overall survival was the duration from randomization to death. For participants who are alive, overall survival was censored at the last contact.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	PF-03084014 + Nab-Paclitaxel + Gemcitabine n=3 Participants 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.
Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment in Phase 1 All-causality TEAEs	3 participants
Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment in Phase 1 Treatment-related TEAEs	3 participants
Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment in Phase 1 Grade 3 or 4 TEAEs	3 participants

SECONDARY outcome

Timeframe: Baseline up to 28-35 days post last administration of study drug

Population: No participants were analyzed since Phase 2 was not performed.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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\[if urine tested positive for blood or protein\]).

Outcome measures

Outcome measures
Measure	PF-03084014 + Nab-Paclitaxel + Gemcitabine n=3 Participants 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.
Number of Participants With Laboratory Abnormalities in Phase 1	3 participants

SECONDARY outcome

Timeframe: 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.

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\[if urine tested positive for blood or protein\]).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Following parameters were analyzed for examination of vital signs: systolic and diastolic blood pressure, heart rate, weight and body surface area.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	PF-03084014 + Nab-Paclitaxel + Gemcitabine n=3 Participants 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.
Number of Participants With Worsening QTc Results in Phase 1	NA participants Results were all outside of the toxicity range and could not be evaluated.

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	PF-03084014 + Nab-Paclitaxel + Gemcitabine n=3 Participants 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.
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 nanogramhour/milliliter (nghr/mL) Geometric Coefficient of Variation NA The Geometric Coefficient of Variation is not calculable as there was one evaluable participant.
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 nanogramhour/milliliter (nghr/mL) Geometric Coefficient of Variation 913
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 nanogramhour/milliliter (nghr/mL) Geometric Coefficient of Variation NA The Geometric Coefficient of Variation is not calculable as there was one evaluable participant.
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 nanogramhour/milliliter (nghr/mL) Geometric Coefficient of Variation 11
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 nanogramhour/milliliter (nghr/mL) Geometric Coefficient of Variation 9
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 nanogramhour/milliliter (nghr/mL) Geometric Coefficient of Variation NA The Geometric Coefficient of Variation is not calculable as there was one evaluable participant.
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 nanogramhour/milliliter (nghr/mL) Geometric Coefficient of Variation NA The Geometric Coefficient of Variation is not calculable as there was one evaluable participant.
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 nanogramhour/milliliter (nghr/mL) Geometric Coefficient of Variation 172
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 nanogramhour/milliliter (nghr/mL) Geometric Coefficient of Variation 176
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 nanogramhour/milliliter (nghr/mL) Geometric Coefficient of Variation NA The Geometric Coefficient of Variation is not calculable as there was one evaluable participant.

SECONDARY outcome

Timeframe: Cycle 1 Day 1 till end of last cycle

Population: As Phase 2 was not performed, no participants were analyzed for this outcome measure.

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).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	PF-03084014 + Nab-Paclitaxel + Gemcitabine n=3 Participants 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.
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
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) Geometric Coefficient of Variation NA The Geometric Coefficient of Variation is not calculable as there was one evaluable participant.
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
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) Geometric Coefficient of Variation NA The Geometric Coefficient of Variation is not calculable as there was one evaluable participant.
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
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) Geometric Coefficient of Variation NA The Geometric Coefficient of Variation is not calculable as there was one evaluable participant.

SECONDARY outcome

Timeframe: Cycle 1 Day 1 till end of last cycle

Population: As Phase 2 was not performed, no participants were analyzed for this outcome measure.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	PF-03084014 + Nab-Paclitaxel + Gemcitabine n=3 Participants 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.
Systemic Clearance (CL) of Nab-paclitaxel in Phase 1 Day 1 (n=3)	37.88 liter (L)/hour (hr) Geometric Coefficient of Variation 25
Systemic Clearance (CL) of Nab-paclitaxel in Phase 1 Day 15 (n=1)	38.60 liter (L)/hour (hr) Geometric Coefficient of Variation NA The Geometric Coefficient of Variation is not calculable as there was one evaluable participant.

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	PF-03084014 + Nab-Paclitaxel + Gemcitabine n=3 Participants 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.
Systemic Clearance (CL) of Gemcitabine in Phase 1 Day 1 (n=3)	5.434 liter (L)/minute (min) Geometric Coefficient of Variation 165
Systemic Clearance (CL) of Gemcitabine in Phase 1 Day 15 (n=1)	8.160 liter (L)/minute (min) Geometric Coefficient of Variation NA The Geometric Coefficient of Variation is not calculable as there was one evaluable participant.

SECONDARY outcome

Timeframe: Cycle 1 Day 1 till end of last cycle

Population: As Phase 2 was not performed, no participants were analyzed for this outcome measure.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	PF-03084014 + Nab-Paclitaxel + Gemcitabine n=3 Participants 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.
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 Interval 0.517 to 4.13
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 Range is not applicable as there is only a single evaluable participant at this time point.
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 Interval 0.517 to 0.583
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 Range is not applicable as there is only a single evaluable participant at this time point.
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 Interval 0.25 to 0.533
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 Range is not applicable as there is only a single evaluable participant at this time point.

SECONDARY outcome

Timeframe: Cycle 1 Day 1 till end of last cycle

Population: As Phase 2 was not performed, no participants were analyzed for this outcome measure.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	PF-03084014 + Nab-Paclitaxel + Gemcitabine n=3 Participants 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.
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
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 Geometric Coefficient of Variation NA The Geometric Coefficient of Variation is not calculable as there was one evaluable participant.
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
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 Geometric Coefficient of Variation NA The Geometric Coefficient of Variation is not calculable as there was one evaluable participant.

SECONDARY outcome

Timeframe: Cycle 1 Day 1 till end of last cycle

Population: As Phase 2 was not performed, no participants were analyzed for this outcome measure.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	PF-03084014 + Nab-Paclitaxel + Gemcitabine n=3 Participants 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.
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
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 Standard Deviation NA The Standard Deviation is not calculable as there was one evaluable participant.
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
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 Standard Deviation NA The Standard Deviation is not calculable as there was one evaluable participant.

SECONDARY outcome

Timeframe: Cycle 1 Day 1 till end of last cycle

Population: As Phase 2 was not performed, no participants were analyzed for this outcome measure.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	PF-03084014 + Nab-Paclitaxel + Gemcitabine n=1 Participants 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.
Number of Participants With Objective Response (OR) in Phase 1	0 participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Overall survival was the duration from randomization to death. For participants who are alive, overall survival was censored at the last contact.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome data not reported

Adverse Events

PF-03084014+Nab-Paclitaxel+Gemcitabine

Serious events: 2 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	PF-03084014+Nab-Paclitaxel+Gemcitabine n=3 participants at risk 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.
Gastrointestinal disorders Vomiting	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Investigations Alanine aminotransferase increased	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Investigations Aspartate aminotransferase increased	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.

Other adverse events

Other adverse events
Measure	PF-03084014+Nab-Paclitaxel+Gemcitabine n=3 participants at risk 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.
Gastrointestinal disorders Ascites	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Gastrointestinal disorders Nausea	66.7% 2/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Gastrointestinal disorders Vomiting	66.7% 2/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
General disorders Chills	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
General disorders Fatigue	100.0% 3/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
General disorders Mucosal inflammation	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Infections and infestations Candida infection	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Injury, poisoning and procedural complications Fall	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Investigations Alanine aminotransferase increased	66.7% 2/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Investigations Aspartate aminotransferase increased	66.7% 2/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Investigations Blood bilirubin increased	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Metabolism and nutrition disorders Decreased appetite	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Metabolism and nutrition disorders Failure to thrive	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Metabolism and nutrition disorders Hypokalaemia	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Metabolism and nutrition disorders Hypophosphataemia	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Nervous system disorders Dizziness	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Psychiatric disorders Anxiety	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Psychiatric disorders Depression	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Psychiatric disorders Hallucination	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Respiratory, thoracic and mediastinal disorders Cough	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Respiratory, thoracic and mediastinal disorders Pleural effusion	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.
Skin and subcutaneous tissue disorders Rash	33.3% 1/3 • Baseline through and including 28 calendar days after the last administration of the investigational product.

Additional Information

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Pfizer, Inc

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER