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Gamma Secretase Inhibitors and Modulators

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10 mg, 50 mg or 100 mg tablets. Patients dosed from 20 mg - 500 mg, twice daily

PF-03084014

Pfizer CT.gov Call Center

This is a phase 1, dose escalating study to determine the safety of PF-03084014 in patients with advanced cancer and leukemia

A Trial In Patients With Advanced Cancer And Leukemia

A PHASE I TRIAL OF PF-03084014 IN PATIENTS WITH ADVANCED SOLID TUMOR MALIGNANCY AND T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOBLASTIC LYMPHOMA

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

Any DLT event attributable to PF-03084014 during Cycle 1: non-hematologic toxicities \>= Grade 3 despite optimal care; treatment delay \>=7 days or unable to deliver at least 80% of planned dose due to treatment-related toxicities; Grade 4 neutropenia \>7 days; febrile neutropenia; neutropenic infection; Grade \>=3 thrombocytopenia with bleeding

Any DLT attributable to PF-03084014 at 1st Cycle: non-hematologic toxicities \>= Grade 3 despite optimal care; treatment delay \>=7 days; unable to deliver at least 80% of planned dose; absolute neutrophil count (ANC) \<1000/microliter (uL), or platelet count \<30,000/uL, or hemoglobin \<8 gram/deciliter (g/dL) in a bone marrow with \<5% blasts and no evidence of leukemia or abnormal dysplasia for \>42 days

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of casual relationship. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death, was life-threatening (immediate risk of death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions), and resulted in congenital anomaly/birth defect.

An AE was any untoward medical occurrence in a participant who received study drug. Treatment-related events were those assessed by the investigator as related to study medication. An SAE was any untoward medical occurrence at any dose that: resulted in death, was life-threatening (immediate risk of death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions), and resulted in congenital anomaly/birth defect.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent were events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. CTCAE version 3.0 was used for AE grading: Grade 1 mild AE; Grade 2 moderate AE; Grade 3 severe AE; Grade 4 life-threatening or disabling AE; Grade 5 death related to AE.

An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-related events were those assessed by the investigator as related to study medication. CTCAE version 3.0 was used for AE grading: Grade 1 mild AE; Grade 2 moderate AE; Grade 3 severe AE; Grade 4 life-threatening or disabling AE; Grade 5 death related to AE.

Criteria for potentially important changes in ECG were defined as: maximum (max.) post-dose (post-baseline) time from electrocardiogram Q wave to the corresponding to electrical systole (QT interval) corrected for Fridericia's factor (QTcF), or QT interval corrected for Bazett's factor (QTcB): \<450, 450 -\<480, 480-\<500, and \>=500 msec. Maximum increase (inc.) from baseline in QTcF or QTcB: change (chg) \<30, 30\>=chg\<60, and chg \>=60 msec.

Parameters analyzed included: white blood cell (WBC) count plus differential, absolute (abs) neutrophil count, platelets, hemoglobin, sodium, potassium, bicarbonate, chloride, blood urea nitrogen, creatinine, glucose, uric acid, calcium, phosphate, magnesium, total protein, albumin, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), partial prothrombin time/international normalized ratio (PTT/INR). Urinalysis: pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrites. Pregnancy test: Serum or urine pregnancy test for women of childbearing potential. There were no changes in urine protein among the solid tumor and T-ALL/LBL participants that were clinically significant. Clinical significance was judged by the investigator.

Cmax was the maximum observed serum concentration.

Cmax(dn) was calculated by maximum observed serum concentration (Cmax) divided by administered dose.

AUCtau was area under the serum concentration-time profile from time 0 to tau (dosing interval). CV is the coefficient of variation.

AUCtau (dn) was calculated by area under the serum concentration-time profile from time 0 to tau (dosing interval) (AUCtau) divided by administered dose. NE is not estimable.

Tmax was the time to reach maximum serum concentration (Cmax).

Cmax was the maximum observed serum concentration. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant. CV is the coefficient of variation.

Tmax was the time to reach maximum serum concentration (Cmax). Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.

AUCtau was area under the serum concentration-time profile from time 0 to tau (dosing interval). Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired concentration of a drug. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.

Serum decay half-life (t1/2) is the time measured for the serum concentration to decrease by one half. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.

Cmin was the minimum serum concentration. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.

Cavg was the average serum concentration at steady state. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.

Accumulation was calculated as AUCtau at steady state (Cycle 1 Day 21) divided by AUCtau after a single dose on Cycle 1 Day 1. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.

AUCtau (dn) was calculated by area under the serum concentration-time profile from time 0 to tau (dosing interval) (AUCtau) divided by administered dose. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.

Cmax(dn) was calculated by maximum observed serum concentration (Cmax) divided by administered dose. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.

AUCtau was area under the serum concentration-time profile from time 0 to tau (dosing interval).

AUCtau(dn) was calculated by area under the serum concentration-time profile from time 0 to tau (dosing interval) (AUCtau) divided by administered dose.

AUCtau was area under the serum concentration-time profile from time 0 to tau (dosing interval). Data for this outcome measure was planned to be analyzed for two arms only.

AUCtau(dn) was calculated by area under the serum concentration-time profile from time 0 to tau (dosing interval) (AUCtau) divided by administered dose. Data for this outcome measure was planned to be analyzed for two arms only.

Cmax was the maximum observed serum concentration. Data for this outcome measure was planned to be analyzed for two arms only.

Cmax(dn) was calculated by maximum observed serum concentration (Cmax) divided by administered dose. Data for this outcome measure was planned to be analyzed for two arms only.

Tmax was the time to reach maximum serum concentration (Cmax). Data for this outcome measure was planned to be analyzed for two arms only.

Objective response (OR) was defined as confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0). Confirmed CR defined as disappearance of all target lesions. Confirmed PR defined as \>=30% decrease in sum of the longest dimensions (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST. Confirmed responses are those that persist on repeat imaging study \>=4 weeks after initial documentation of response.

Time from Cycle 1 Day 1 to first documentation of disease progression. Progression was defined as per RECIST version 1.0, as a 20% increase in the sum of the longest diameter of target lesions, or target lesions over nadir, uneuivocal progression of non-target disease, or the appearance of new lesions. TTP (months) was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 30.

Time from the first documentation of OR to objective disease progression or death due to any cause. DR was only calculated for participants with an OR. DR (months) was calculated as (date of first documentation of objective progression or death minus date of first documentation of PR or CR plus 1) divided by 30.

PFS was defined as the time from Cycle 1 Day 1 to date of first documentation of progression or death due to any cause. Progression was defined as per RECIST version 1.0, as a 20% increase in the sum of the longest diameter of target lesions, or target lesions over nadir, unequivocal progression of non-target disease, or the appearance of new lesions. PFS (months) was calculated as (the first event date minus the date of first dose of study medication plus 1) divided by 30.

OR was adapted from International Working Group Response Criteria for Acute Myeloid Leukemia (AML). The response categories of interest were CR, complete response with incomplete hematopoietic recovery (CRi), and PR. CR: ANC \>1500/microliter (uL), no circulating blasts. Platelets \>100,000/uL, \<5% marrow blast cells, no extramedullary disease, bone marrow cellularity \>20% with tri-lineage hematopoiesis and \<5% marrow blast cells, none of which were neoplastic; CRi: same as CR but ANC may be \>1500/uL or platelet count \>100,000/uL, no requirement on bone marrow cellularity; PR: same as CR but bone marrow with \>= 50% reduction of leukemia blast cells and an absolute blast count between 5% and 25%.

The RFS of CR was defined as the time from the date of first attaining CR to the date of relapse or death from any cause, whichever occurred first. Similarly, the RFS of CR + CRi (or RFS of CR + CRi + PR) was defined as the time from the date of first attaining CR + CRi (or CR + CRi + PR) to the date of relapse or death from any cause, whichever occurred first.

PBR was the maximum percentage of peripheral blast count reduction for each participant who received at least one dose of study medication. PBR was derived by the Sponsor from percentage of peripheral blood Blast Count reported by sites.

Gene expression analysis in tumor biopsies was done using cDNA prepared from RNA extracted from tumor biopsies. Gene expression was measured by custom Taqman low density array (TLDA) cards run on Applied Biosystems 7900HT Fast Real-Time polymerase chain reaction (PCR) system. Changes from baseline were calculated as ratios to baseline. Only Hes4 gene showed consistent down modulation across dosing cohorts (150 mg and 220 mg BID) and therefore results were reported for Hes4 only. Data for this outcome measure was planned to be analyzed for two arms only.

Ribonucleic acid (RNA) was extracted from peripheral blood and used as a template to synthesize complementary deoxyribonucleic acid (cDNA). Gene expression in cDNA was measured by custom Taqman low density array (TLDA) cards run on Applied Biosystems 7900HT Fast Real-Time polymerase chain reaction (PCR) system. Changes from baseline were calculated as ratios to baseline. Results were reported Only for Hes4 as this was the only gene to show consistent down modulation across dosing cohorts (150 mg and 220 mg).

Notch intracellular domain (NICD) levels was measured in peripheral blood mononuclear cell (PBMC) pellets using a validated enzyme-linked immunosorbent assay (ELISA).

Notch intracellular domain (NICD) was to be measured in bone marrow monoculear cell (BMMC) cell pellets using a validated ELISA.

Pfizer

Same event may appear as AE and SAE, what is presented are distinct events. Event may be categorized as serious in 1 participant and non-serious in another participant or 1 participant may have experienced both serious and non-serious event. The safety analysis set includes all enrolled participants who received at least 1 dose of study medication.

PF-03084014 20 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, participants with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

PF-03084014 20 mg BID in Solid Tumor Participants

PF-03084014 40 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, participants with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

PF-03084014 40 mg BID in Solid Tumor Participants

PF-03084014 80 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, participants with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

PF-03084014 80 mg BID in Solid Tumor Participants

PF-03084014 100 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, participants with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

PF-03084014 100 mg BID in Solid Tumor Participants

PF-03084014 130 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, participants with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

PF-03084014 130 mg BID in Solid Tumor Participants

PF-03084014 150 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, participants with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

PF-03084014 150 mg BID in Solid Tumor Participants

PF-03084014 150 mg was administered orally BID to participants with T-ALL/LBL as single agent for 21 days per cycle continuously (except for Cycle 1). On Cycle 1 Day 21, only the morning dose was administered, followed by a 7-day washout interval.

PF-03084014 150 mg BID in T-ALL/LBL Participants

PF-03084014 220 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, participants with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

PF-03084014 220 mg BID in Solid Tumor Participants

PF-03084014 330 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, participants with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

PF-03084014 330 mg BID in Solid Tumor Participants

PF-03084014 was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, participants with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

PF-03084014 in Solid Tumor Participants

PF-03084014 in T-ALL/LBL Participants

Total

Age, Continuous

Sex: Female, Male

Study components related to combination therapy with dexamethasone were removed due to operational/scientific reasons. Due to halting of T-AA/LBL participant's enrollment; limited number of evaluable participants, PBR and RFS data was not collected.

Pfizer ClinicalTrials.gov Call Center

PF-03084014 20 mg was administered orally BID to participants with solid tumors as single agent for 21 days per cycle continuously (except for Cycle 1). On Cycle 1 Day 21, only the morning dose was administered, followed by a 7-day washout interval.

PF-03084014 40 mg was administered orally BID to participants with solid tumors as single agent for 21 days per cycle continuously (except for Cycle 1). On Cycle 1 Day 21, only the morning dose was administered, followed by a 7-day washout interval.

PF-03084014 80 mg was administered orally BID to participants with solid tumors as single agent for 21 days per cycle continuously (except for Cycle 1). On Cycle 1 Day 21, only the morning dose was administered, followed by a 7-day washout interval.

PF-03084014 100 mg was administered orally BID to participants with solid tumors as single agent for 21 days per cycle continuously (except for Cycle 1). On Cycle 1 Day 21, only the morning dose was administered, followed by a 7-day washout interval.

PF-03084014 130 mg was administered orally BID to participants with solid tumors as single agent for 21 days per cycle continuously (except for Cycle 1). On Cycle 1 Day 21, only the morning dose was administered, followed by a 7-day washout interval.

PF-03084014 150 mg was administered orally BID to participants with solid tumors as single agent for 21 days per cycle continuously (except for Cycle 1). On Cycle 1 Day 21, only the morning dose was administered, followed by a 7-day washout interval.

PF-03084014 220 mg was administered orally BID to participants with solid tumors as single agent for 21 days per cycle continuously (except for Cycle 1). On Cycle 1 Day 21, only the morning dose was administered, followed by a 7-day washout interval.

PF-03084014 330 mg was administered orally BID to participants with solid tumors as single agent for 21 days per cycle continuously (except for Cycle 1). On Cycle 1 Day 21, only the morning dose was administered, followed by a 7-day washout interval.

Solid tumor participants enrolled for dose-escalation who started treatment and who did not have first cycle major treatment deviations (including less than 80% of the planned dose of PF-03084014 in Cycle 1 for reasons other than treatment-related toxicities) were evaluable for DLTs.

Number of Solid Tumor Participants With First-Cycle Dose-Limiting Toxicity (DLT)

PF-03084014 150 mg was administered orally BID to participants with T-cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma (T-ALL/LBL) as single agent for 21 days per cycle continuously (except for Cycle 1). On Cycle 1 Day 21, only the morning dose was administered, followed by a 7-day washout interval.

T-ALL/LBL participants enrolled for dose-escalation who started treatment and who did not have first cycle major treatment deviations (including less than 80% of the planned dose of PF-03084014 in Cycle 1 for reasons other than treatment-related toxicities) were evaluable for DLTs.

Number of T-ALL/LBL Participants With First-Cycle DLT

No. of Participants With AEs

No. of Participants With SAEs

No. of Participants Discontinued PF-03084014

No. of Participants Temp. Discontinued Treatment

No. of Participants With Dose Reduction Due to AEs

PF-03084014 20 mg was administered orally twice daily (BID) to participants with solid tumors as single agent for 21 days per cycle continuously (except for Cycle 1). On Cycle 1 Day 21, only the morning dose was administered, followed by a 7-day washout interval.

All participants who received at least 1 dose of study medication.

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causality)

No.of Participants With Dose Reduction Due to AEs

Number of Participants With TEAEs (Treatment-Related)

Any AEs, Grade 1

Any AEs, Grade 2

Any AEs, Grade 3

Any AEs, Grade 4

Any AEs, Grade 5

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causality) by Severity (by Maximum Common Terminology Criteria for Adverse Events [CTCAE] Grade)

Missing or Unknown

Number of Participants With TEAEs (Treatment-Related) by Severity (by Maximum CTCAE Grade)

Max. QTcB interval <450 msec

Max. QTcB interval 450-<480 msec

Max. QTcB interval 480-<500 msec

Max. QTcB interval >=500 msec

Max. QTcF interval <450 msec

Max. QTcF interval 450-<480 msec

Max. QTcF interval 480-<500 msec

Max. QTcF interval >=500 msec

Max. QTcB interval inc. from baseline chg<30 msec

Max. QTcB interval inc. from baseline 30=<chg<60

Max. QTcB interval inc. from baseline chg>=60 msec

Max. QTcF interval inc. from baseline chg<30 msec

Max. QTcF interval inc. from baseline 30=<chg<60

Max. QTcF interval inc. from baseline chg>=60 msec

Number of Participants With Potentially Clinical Significant Categorical Changes From Baseline in Electrocardiogram (ECG) Findings in QTc Interval

Hemoglobin

Lymphocytes (abs)

Neutrophils (abs)

Platelets

Bicarbonate

Bilirubin

Creatinine

Hypercalcaemia

Hyperglycaemia

Hyperkalaemia

Hypermagnesaemia

Hypernatraemia

Hypoalbuminaemia

Hypocalcaemia

Hypoglycaemia

Hypokalaemia

Hypomagnesaemia

Hyponatraemia

Hypophosphataemia

PF-03084014 20, 40, 80, 100, 150, 220, 330 mg was administered orally BID to participants with solid tumors as single agent for 21 days per cycle continuously (except for Cycle 1). On Cycle 1 Day 21, only the morning dose was administered, followed by a 7-day washout interval.

Number of Participants With Laboratory Tests Abnormalities Meeting the Criteria of Potential Clinical Concern (Hematology and Chemistries, All Cycles)

All treated participants who had at least 1 of the PK parameters of interest. N=number of participants evaluable for this outcome measure (OM).

Maximum Observed Serum Concentration (Cmax) After a Single Dose on Cycle 1 Day 1

All treated participants who had at least 1 of the PK parameters of interest. N=number of participants evaluable for this OM.

Dose-normalized Cmax [Cmax (dn)] After a Single Dose on Cycle 1 Day 1

All treated participants who had at least 1 of the PK parameters of interest. Overall Number of Participants Analyzed (N) =number of participants evaluable for this outcome measure (OM).

Area Under the Time-Concentration Curve From Time 0 to the Dosing Interval (AUCtau) After a Single Dose on Cycle 1 Day 1

Dose-normalized AUCtau [AUCtau (dn) ] After a Single Dose on Cycle 1 Day 1

Time to Reach Cmax (Tmax) After a Single Dose on Cycle 1 Day 1

All participants who had at least 6 days of uninterrupted dosing prior to the Cycle 1 Day 21 PK assessment. The 6-day duration was chosen based on the observed terminal half-life of PF-03084014. N=number of participants evaluable for this OM.

Cmax After Multiple Dose on Cycle 1 Day 21

All participants who had at least 6 days of uninterrupted dosing prior to the Cycle 1 Day 21 PK assessment. The 6-day duration was chosen based on the observed terminal half-life of PF-03084014. N=number of participants evaluable for this OM

Time to Reach Cmax (Tmax) After Multiple Dose on Cycle 1 Day 21

AUCtau After Multiple Dose on Cycle 1 Day 21

Apparent Volume of Distribution (Vz/F) on Cycle 1 Day 21

Serum Decay Half-Life (t1/2) After Multiple Dose on Cycle 1 Day 21

Apparent Oral Clearance (CL/F) on Cycle 1 Day 21

Minimum Observed Serum Concentration (Cmin) After Multiple Dose on Cycle 1 Day 21

Average Serum Concentration (Cavg) at Steady State on Cycle 1 Day 21

Accumulation Ratio (Rac) on Cycle 1 Day 21

Dose-normalized AUCtau [AUCtau (dn)] After Multiple Dose on Cycle 1 Day 21

Dose-normalized Cmax [Cmax (dn)] After Multiple Dose on Cycle 1 Day 21

PF-03084014 150 mg was administered orally BID to participants with solid tumors as single agent for 21 days per cycle continuously (except for Cycle 1=28 days \[with a 7-day washout\]). On Cycle 1 Day 1 and Cycle 2 Day 1, only the morning dose was administered. Each participant was to serve as their own control in which PF-03084014 was administered in the morning under either "fed" or "fasted" conditions on Day 1 of Cycle 1 and Cycle 2. The testing order for fed versus fasted conditions was as follows: The first 6 participants in this sub-study were tested under fed followed by fasted conditions, the next 6 participants were tested under fasted followed by fed conditions.

PF-03084014 220 mg was administered orally BID to participants with solid tumors as single agent for 21 days per cycle continuously (except for Cycle 1=28 days \[with a 7-day washout\]). On Cycle 1 Day 1 and Cycle 2 Day 1, only the morning dose was administered. Each participant was to serve as their own control in which PF-03084014 was administered in the morning under either "fed" or "fasted" conditions on Day 1 of Cycle 1 and Cycle 2. The testing order for fed versus fasted conditions was as follows: The first 6 participants in this sub-study were tested under fed followed by fasted conditions, the next 6 participants were tested under fasted followed by fed conditions.

Solid tumor participants who were enrolled in the food-effect sub-study, were treated and had evaluable PK data under both fed and fasted states.

AUCtau in the Fasted State for Solid Tumor Participants

AUCtau in the Fed State for Solid Tumor Participants

Cmax in the Fasted State for Solid Tumor Participants

Cmax in the Fed State for Solid Tumor Participants

PF-03084014 150 mg or 220 mg was administered orally BID to participants with solid tumors as single agent for 21 days per cycle continuously (except for Cycle 1=28 days \[with a 7-day washout\]). On Cycle 1 Day 1 and Cycle 2 Day 1, only the morning dose was administered. Each participant was to serve as their own control in which PF-03084014 was administered in the morning under either "fed" or "fasted" conditions on Day 1 of Cycle 1 and Cycle 2. The testing order for fed versus fasted conditions was as follows: The first 6 participants in this sub-study were tested under fed followed by fasted conditions, the next 6 participants were tested under fasted followed by fed conditions.

Solid tumor participants who were enrolled in the food-effect sub-study, were treated and had evaluable PK data under both fed and fasted states. Due to the limited number of evaluable participants (7 at 150 mg BID and 4 at 220 mg BID for Cmax) and a generally dose-proportional exposure (AUCtau and Cmax), data were combined for the 2 dose levels.

Dose-normalized AUCtau [AUCtau(dn)] in the Fasted State for Solid Tumor Participants

Solid tumor participants who were enrolled in the food-effect sub-study, started treatment and had evaluable PK data under both fed and fasted states. Due to the limited number of evaluable participants (7 at 150 mg BID and 4 at 220 mg BID for Cmax) and a generally dose-proportional exposure (AUCtau and Cmax), data were combined for 2 dose levels.

Dose-normalized AUCtau [AUCtau(dn)] in the Fed State for Solid Tumor Participants

Participants who were enrolled in the food-effect sub-study, started treatment and had evaluable PK data under both fed and fasted states. Due to the limited number of evaluable participants (9 at 150 mg BID and 4 at 220 mg BID for Cmax) and a generally dose-proportional exposure (AUCtau and Cmax), data were combined for the 2 dose levels.

Dose-normalized Cmax [Cmax(dn)] in the Fasted State for Solid Tumor Participants

Solid tumor participants who were enrolled in the food-effect sub-study, were treated and had evaluable PK data under both fed and fasted states. Due to the limited number of evaluable participants (9 at 150 mg BID and 4 at 220 mg BID for Cmax) and a generally dose-proportional exposure (AUCtau and Cmax), data were combined for the 2 dose levels.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Trial In Patients With Advanced Cancer And Leukemia	NCT00878189	Neoplasms by Hi...	PF-03084014	16 Years -	Pfizer
A Trial In Patients With Advanced Cancer And Leukemia	NCT00878189	Neoplasms by Hi...	PF-03084014	16 Years -	Pfizer

Spots Global Cancer Trial Database for phase 1 dose escalation study in advanced solid tumor malignancy and leukemia