Solid Tumors
Conditions
Brief summary
The purpose of this study is to determine the maximum tolerated dose and recommended phase 2 dose of PF-03814735 administered orally as single agent in patients with advanced solid tumors.
Interventions
DRUGPF-03814735
1, 5, and 25 mg gelatin capsules administered orally once a day from day 1 to day 5, or from day 1 to day 10 every 3 weeks until disease progression or unacceptable toxicity.
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Metastatic solid tumor resistant to standard therapy or for which no standard therapy is available * Adequate bone marrow, liver and kidney function
Exclusion criteria
* Brain metastases that are symptomatic and/or require treatment with steroids and/or anticonvulsants, or brain metastases that have been treated within 3 months prior to study start * Myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident in the previous 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Graded According to Common Terminology Criteria Adverse Events (CTCAE), Version 3 | Day 1 up to Day 21 of first cycle | DLT defined as any of the following during the first cycle of treatment and attributable to PF-03814735: Grade (Gr) 4 neutropenia (absolute neutrophil count \[ANC\] \<500 cells/mm\^3) for \>7 days or febrile neutropenia (ANC \<1000/mm\^3, fever ≥38 degrees Celsius; neutropenic infection (ANC \<1000/mm\^3); Gr 4 thrombocytopenia (platelets \<25,000 cells/mm\^3); ≥Gr 3 nausea, vomiting, or diarrhea, despite optimal antiemetic, anti-diarrheal support; ≥20% decrease in left ventricular ejection fraction compared to baseline; other non-hematological toxicity; any Gr ≥3 adverse event; or failure to recover. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time for Maximum Observed Serum Concentration (Tmax) | Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose | — |
| Area Under the Serum Concentration Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) | Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose | Area under the serum concentration time-curve from zero to the last measured concentration. |
| Area Under the Serum Concentration Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 24 Hours (AUCτ). | Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose | — |
| Minimum Observed Serum Trough Concentration (Cmin) | Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose | Cmin defined as the lowest serum concentration observed during the dosing interval. |
| Observed Serum Accumulation Ratio (Rac) | Schedule B Day-5: pre-dose, 0.5, 1, 2, 4, 6, 10, 24, 32, 48, and 72 hours post-dose, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose | Rac was the ratio of Schedule B Cycle 1/Day 9 to Day -5 (Day 9 AUCτ to Day -5 AUCτ). |
| Terminal Half-life (t 1/2) | Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose | Terminal half-life (serum decay half-life) is the time measured for the serum concentration to decrease by one half. |
| Urine Pharmacokinetics | Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose | Urine PK for quantification of unchanged PF-03814375 and any identified metabolites. 24-hour urine collection at 8-hour intervals after the morning dose (Schedule \[Sch\] A Day 4, Sch B Day 9; last sample collected just prior to the morning dose on Sch A Day 5 or Sch B Day 10 in the expanded maximum tolerated dose (MTD) cohort only (≥ 10 participants in Sch A 80 mg and Sch B 50 mg groups). The lower limit of quantification (LLOQ) was 1 nanogram per milliliter (ng/mL). Clinical specimens with concentrations below the LLOQ were to be reported as below the limited of quantification (BLQ) 1 ng/mL. |
| Maximum Observed Serum Concentration (Cmax) | Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose | — |
| Target Modulation by Phosphohistone H3 (pH3) Expression in Tumor Tissue (IHC) | Schedule A Cycle 1 or Cycle 2 /Day 4 or Day 5, Schedule B Cycle 1/Day 9 or Day 10 | pH3 expression is a method to enable the quantification of the proliferative potential of tumor cells. Post-dose tumor tissue sampling occurred after FDG-PET. Biopsies were not to be taken from lesions which were used for PET analysis and were to be taken between 1 and 6 hours after study drug administration. Collected in the expanded MTD cohort only (≥ 10 participants in Sch A 80 mg and Sch B 50 mg groups). |
| Number of Participants With Objective Tumor Response | Every 2 cycles (each cycle=21 days) until disease progression or participant discontinuation; maximum follow-up was from baseline up to 12 cycles | Number of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST). 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 to Progression | Baseline, every 2 cycles (each cycle=21 days) until disease progression or participant discontinuation; maximum follow-up was from baseline up to 12 cycles | Time to Progression defined as the time from the date of enrollment to the date progressive disease first reported. If tumor progression data included more than 1 date, the first date was to be used. TTP = (first date of tumor progression - date of enrollment + 1). Progressive disease: ≥20% increase in sum LD of target lesions from smallest sum LD recorded since treatment start or appearance of ≥1 new lesions. |
| Duration of Response | Every 2 cycles (each cycle=21 days) until disease progression or participant discontinuation; maximum follow-up was from baseline up to 12 cycles | Duration of responses based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST. 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. |
| Germ Line Polymorphism of Candidate Genes Targeted by PF-03814735 | Schedule A Cycle 1 or Cycle 2 /Day 4 or Day 5, Schedule B Cycle 1/Day 9 or Day 10 (each cycle=21 days) | Percentage of germ line polymorphism cell expression in relation to clinical response. Responses include CR: disappearance of all target lesions; PR: ≥30% decrease in sum of LD of target lesions referencing baseline sum LD; Progressive disease: ≥20% increase in sum LD of target lesions from smallest sum LD recorded since Tx start or appearance of ≥1 new lesions; Stable disease: neither sufficient shrinkage to=PR nor sufficient increase to=PD during first 6 weeks after Tx start referencing smallest sum LD since Tx start. |
| Aurora Gene Somatic Mutations/Amplification and Pathway Genes in Tumor Tissue | Schedule A Cycle 1 or Cycle 2 /Day 4 or Day 5, Schedule B Cycle 1/Day 9 or Day 10 (each cycle=21 days) | Percentage of aurora gene somatic mutations/amplification and pathway genes in relation to clinical response. Responses include CR: disappearance of all target lesions; PR: ≥30% decrease in sum of longest dimensions (LD) of target lesions referencing baseline sum LD; Progressive disease: ≥20% increase in sum LD of target lesions from smallest sum LD recorded since Tx start or appearance of ≥1 new lesions; Stable disease: neither sufficient shrinkage to=PR nor sufficient increase to=PD during first 6 weeks after Tx start referencing smallest sum LD since Tx start. |
| Summary of Tumor Metabolism Assessed by Positron Emission Tomography With F-18-fluorodeoxyglucose (FDG-PET) | Baseline (Schedule A or Schedule B Day -7) and Schedule A Cycle 1/Day 3 or Day 4, Schedule B Cycle 1/Day 8 or 9 | FTD-PET measured as standardized uptake volume (SUV) values corrected for lean body mass. Change from baseline categorized according to European Organization for Research and Treatment for Cancer (EORTC) criteria: Partial Metabolic Response (PMR): SUV value during treatment \<75 percent (%) of baseline value; Progressive Metabolic Disease (PMD): SUV value during treatment \>125% of baseline value; Stable Metabolic Disease (SMD): change in SUV value between PMR and PMD. Collected in the expanded MTD cohort only (≥ 10 participants in Sch A 80 mg and Sch B 50 mg groups). |
Countries
Belgium, United States
Participant flow
Pre-assignment details
59 participants enrolled and 57 sequentially assigned to treatment in Schedule A or B of study treatment. Schedule A: starting dose was 5 milligrams per day (mg/day) and dose was escalated up to 100 mg/day. Schedule B: starting dose determined based on occurrence of dose limiting toxicities and maximum tolerated dose in Schedule A.
Participants by arm
| Arm | Count |
|---|---|
| PF-03814735 (Schedule A) Participants received daily dosing of PF-03814735 of 5, 10, 20, 40, 60, 80, or 100 mg administered PO every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis. | 32 |
| PF-03814735 (Schedule B) Participants received daily dosing of PF-03814735 of 40, 50, or 60 mg administered PO every morning on an empty stomach for 10 consecutive days out of 21-day cycles on an outpatient basis. | 25 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 2 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
| Overall Study | Global deterioration of health status | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Objective progression or relapse | 1 | 1 | 1 | 2 | 2 | 13 | 7 | 3 | 12 | 4 |
| Overall Study | Other | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | PF-03814735 (Schedule A) | PF-03814735 (Schedule B) | Total |
|---|---|---|---|
| Age Continuous | 63.6 years STANDARD_DEVIATION 9 | 58.2 years STANDARD_DEVIATION 10.2 | 61.2 years STANDARD_DEVIATION 9.8 |
| Sex: Female, Male Female | 18 Participants | 13 Participants | 31 Participants |
| Sex: Female, Male Male | 14 Participants | 12 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 1 / 1 | 4 / 4 | 3 / 3 | 15 / 15 | 7 / 7 | 3 / 3 | 15 / 16 | 6 / 6 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 | 1 / 1 | 1 / 4 | 1 / 3 | 4 / 15 | 2 / 7 | 0 / 3 | 5 / 16 | 0 / 6 |
Outcome results
Primary
Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Graded According to Common Terminology Criteria Adverse Events (CTCAE), Version 3
DLT defined as any of the following during the first cycle of treatment and attributable to PF-03814735: Grade (Gr) 4 neutropenia (absolute neutrophil count \[ANC\] \<500 cells/mm\^3) for \>7 days or febrile neutropenia (ANC \<1000/mm\^3, fever ≥38 degrees Celsius; neutropenic infection (ANC \<1000/mm\^3); Gr 4 thrombocytopenia (platelets \<25,000 cells/mm\^3); ≥Gr 3 nausea, vomiting, or diarrhea, despite optimal antiemetic, anti-diarrheal support; ≥20% decrease in left ventricular ejection fraction compared to baseline; other non-hematological toxicity; any Gr ≥3 adverse event; or failure to recover.
Time frame: Day 1 up to Day 21 of first cycle
Population: Safety population: Same as the As-treated population, defined as all patients enrolled in the study that received at least 1 dose of the study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-03814735 5 mg (Schedule A) | Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Graded According to Common Terminology Criteria Adverse Events (CTCAE), Version 3 | 0 participants |
| PF-03814735 10 mg (Schedule A) | Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Graded According to Common Terminology Criteria Adverse Events (CTCAE), Version 3 | 0 participants |
| PF-03814735 20 mg (Schedule A) | Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Graded According to Common Terminology Criteria Adverse Events (CTCAE), Version 3 | 0 participants |
| PF-03814735 40 mg (Schedule A) | Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Graded According to Common Terminology Criteria Adverse Events (CTCAE), Version 3 | 0 participants |
| PF-03814735 60 mg (Schedule A) | Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Graded According to Common Terminology Criteria Adverse Events (CTCAE), Version 3 | 0 participants |
| PF-03814735 80 mg (Schedule A) | Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Graded According to Common Terminology Criteria Adverse Events (CTCAE), Version 3 | 1 participants |
| PF-03814735 100 mg (Schedule A) | Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Graded According to Common Terminology Criteria Adverse Events (CTCAE), Version 3 | 2 participants |
| PF-03814735 40 mg (Schedule B) | Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Graded According to Common Terminology Criteria Adverse Events (CTCAE), Version 3 | 0 participants |
| PF-03814735 50 mg (Schedule B) | Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Graded According to Common Terminology Criteria Adverse Events (CTCAE), Version 3 | 1 participants |
| PF-03814735 60 mg (Schedule B) | Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Graded According to Common Terminology Criteria Adverse Events (CTCAE), Version 3 | 2 participants |
Secondary
Area Under the Serum Concentration Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 24 Hours (AUCτ).
Time frame: Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose
Population: PK parameter analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-03814735 5 mg (Schedule A) | Area Under the Serum Concentration Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 24 Hours (AUCτ). | 2.957 mcg*hr/mL | — |
| PF-03814735 10 mg (Schedule A) | Area Under the Serum Concentration Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 24 Hours (AUCτ). | 10.09 mcg*hr/mL | — |
| PF-03814735 20 mg (Schedule A) | Area Under the Serum Concentration Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 24 Hours (AUCτ). | 17.68 mcg*hr/mL | — |
| PF-03814735 40 mg (Schedule A) | Area Under the Serum Concentration Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 24 Hours (AUCτ). | 22.99 mcg*hr/mL | Geometric Coefficient of Variation 17 |
| PF-03814735 60 mg (Schedule A) | Area Under the Serum Concentration Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 24 Hours (AUCτ). | 47.95 mcg*hr/mL | Geometric Coefficient of Variation 62 |
| PF-03814735 80 mg (Schedule A) | Area Under the Serum Concentration Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 24 Hours (AUCτ). | 49.33 mcg*hr/mL | Geometric Coefficient of Variation 58 |
| PF-03814735 100 mg (Schedule A) | Area Under the Serum Concentration Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 24 Hours (AUCτ). | 57.96 mcg*hr/mL | Geometric Coefficient of Variation 45 |
| PF-03814735 40 mg (Schedule B) | Area Under the Serum Concentration Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 24 Hours (AUCτ). | 22.69 mcg*hr/mL | — |
| PF-03814735 50 mg (Schedule B) | Area Under the Serum Concentration Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 24 Hours (AUCτ). | 22.08 mcg*hr/mL | Geometric Coefficient of Variation 90 |
| PF-03814735 60 mg (Schedule B) | Area Under the Serum Concentration Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 24 Hours (AUCτ). | 37.15 mcg*hr/mL | Geometric Coefficient of Variation 66 |
| PF-03814735 60 mg (Schedule B) | Area Under the Serum Concentration Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 24 Hours (AUCτ). | 24.12 mcg*hr/mL | Geometric Coefficient of Variation 24 |
Secondary
Area Under the Serum Concentration Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast)
Area under the serum concentration time-curve from zero to the last measured concentration.
Time frame: Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose
Population: Data was not summarized as the development of the compound was discontinued.
Secondary
Aurora Gene Somatic Mutations/Amplification and Pathway Genes in Tumor Tissue
Percentage of aurora gene somatic mutations/amplification and pathway genes in relation to clinical response. Responses include CR: disappearance of all target lesions; PR: ≥30% decrease in sum of longest dimensions (LD) of target lesions referencing baseline sum LD; Progressive disease: ≥20% increase in sum LD of target lesions from smallest sum LD recorded since Tx start or appearance of ≥1 new lesions; Stable disease: neither sufficient shrinkage to=PR nor sufficient increase to=PD during first 6 weeks after Tx start referencing smallest sum LD since Tx start.
Time frame: Schedule A Cycle 1 or Cycle 2 /Day 4 or Day 5, Schedule B Cycle 1/Day 9 or Day 10 (each cycle=21 days)
Population: Data was not summarized as the development of the compound was discontinued.
Secondary
Duration of Response
Duration of responses based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST. 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 frame: Every 2 cycles (each cycle=21 days) until disease progression or participant discontinuation; maximum follow-up was from baseline up to 12 cycles
Population: Data was not summarized as the development of the compound was discontinued.
Secondary
Germ Line Polymorphism of Candidate Genes Targeted by PF-03814735
Percentage of germ line polymorphism cell expression in relation to clinical response. Responses include CR: disappearance of all target lesions; PR: ≥30% decrease in sum of LD of target lesions referencing baseline sum LD; Progressive disease: ≥20% increase in sum LD of target lesions from smallest sum LD recorded since Tx start or appearance of ≥1 new lesions; Stable disease: neither sufficient shrinkage to=PR nor sufficient increase to=PD during first 6 weeks after Tx start referencing smallest sum LD since Tx start.
Time frame: Schedule A Cycle 1 or Cycle 2 /Day 4 or Day 5, Schedule B Cycle 1/Day 9 or Day 10 (each cycle=21 days)
Population: Data was not summarized as the development of the compound was discontinued.
Secondary
Maximum Observed Serum Concentration (Cmax)
Time frame: Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose
Population: Pharmacokinetic (PK) parameter analysis set: Enrolled participants who received at least 1 dose of study treatment who had at least 1 of the PK parameters of interest estimated in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-03814735 5 mg (Schedule A) | Maximum Observed Serum Concentration (Cmax) | 0.1920 mcg/mL | — |
| PF-03814735 10 mg (Schedule A) | Maximum Observed Serum Concentration (Cmax) | 0.6470 mcg/mL | — |
| PF-03814735 20 mg (Schedule A) | Maximum Observed Serum Concentration (Cmax) | 0.9010 mcg/mL | — |
| PF-03814735 40 mg (Schedule A) | Maximum Observed Serum Concentration (Cmax) | 1.965 mcg/mL | Geometric Coefficient of Variation 35 |
| PF-03814735 60 mg (Schedule A) | Maximum Observed Serum Concentration (Cmax) | 3.724 mcg/mL | Geometric Coefficient of Variation 30 |
| PF-03814735 80 mg (Schedule A) | Maximum Observed Serum Concentration (Cmax) | 3.773 mcg/mL | Geometric Coefficient of Variation 43 |
| PF-03814735 100 mg (Schedule A) | Maximum Observed Serum Concentration (Cmax) | 4.106 mcg/mL | Geometric Coefficient of Variation 46 |
| PF-03814735 40 mg (Schedule B) | Maximum Observed Serum Concentration (Cmax) | 1.470 mcg/mL | — |
| PF-03814735 50 mg (Schedule B) | Maximum Observed Serum Concentration (Cmax) | 1.957 mcg/mL | Geometric Coefficient of Variation 36 |
| PF-03814735 60 mg (Schedule B) | Maximum Observed Serum Concentration (Cmax) | 2.786 mcg/mL | Geometric Coefficient of Variation 50 |
| PF-03814735 60 mg (Schedule B) | Maximum Observed Serum Concentration (Cmax) | 2.087 mcg/mL | Geometric Coefficient of Variation 24 |
Secondary
Minimum Observed Serum Trough Concentration (Cmin)
Cmin defined as the lowest serum concentration observed during the dosing interval.
Time frame: Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose
Population: PK parameter analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-03814735 5 mg (Schedule A) | Minimum Observed Serum Trough Concentration (Cmin) | 0.05440 mcg/mL | — |
| PF-03814735 10 mg (Schedule A) | Minimum Observed Serum Trough Concentration (Cmin) | 0.2330 mcg/mL | — |
| PF-03814735 20 mg (Schedule A) | Minimum Observed Serum Trough Concentration (Cmin) | 0.3110 mcg/mL | — |
| PF-03814735 40 mg (Schedule A) | Minimum Observed Serum Trough Concentration (Cmin) | 0.4521 mcg/mL | Geometric Coefficient of Variation 27 |
| PF-03814735 60 mg (Schedule A) | Minimum Observed Serum Trough Concentration (Cmin) | 1.019 mcg/mL | Geometric Coefficient of Variation 105 |
| PF-03814735 80 mg (Schedule A) | Minimum Observed Serum Trough Concentration (Cmin) | 1.061 mcg/mL | Geometric Coefficient of Variation 86 |
| PF-03814735 100 mg (Schedule A) | Minimum Observed Serum Trough Concentration (Cmin) | 1.410 mcg/mL | Geometric Coefficient of Variation 58 |
| PF-03814735 40 mg (Schedule B) | Minimum Observed Serum Trough Concentration (Cmin) | 0.4950 mcg/mL | — |
| PF-03814735 50 mg (Schedule B) | Minimum Observed Serum Trough Concentration (Cmin) | 0.3901 mcg/mL | Geometric Coefficient of Variation 271 |
| PF-03814735 60 mg (Schedule B) | Minimum Observed Serum Trough Concentration (Cmin) | 0.6636 mcg/mL | Geometric Coefficient of Variation 178 |
| PF-03814735 60 mg (Schedule B) | Minimum Observed Serum Trough Concentration (Cmin) | 0.4217 mcg/mL | Geometric Coefficient of Variation 61 |
Secondary
Number of Participants With Objective Tumor Response
Number of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST). 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 frame: Every 2 cycles (each cycle=21 days) until disease progression or participant discontinuation; maximum follow-up was from baseline up to 12 cycles
Population: Data was not summarized as the development of the compound was discontinued.
Secondary
Observed Serum Accumulation Ratio (Rac)
Rac was the ratio of Schedule B Cycle 1/Day 9 to Day -5 (Day 9 AUCτ to Day -5 AUCτ).
Time frame: Schedule B Day-5: pre-dose, 0.5, 1, 2, 4, 6, 10, 24, 32, 48, and 72 hours post-dose, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose
Population: PK parameter analysis set. N=number of participants in the indicated population contributing to the mean.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-03814735 5 mg (Schedule A) | Observed Serum Accumulation Ratio (Rac) | 1.054 ratio | Geometric Coefficient of Variation 28 |
| PF-03814735 10 mg (Schedule A) | Observed Serum Accumulation Ratio (Rac) | 1.503 ratio | Geometric Coefficient of Variation 44 |
| PF-03814735 20 mg (Schedule A) | Observed Serum Accumulation Ratio (Rac) | 1.247 ratio | Geometric Coefficient of Variation 27 |
Secondary
Summary of Tumor Metabolism Assessed by Positron Emission Tomography With F-18-fluorodeoxyglucose (FDG-PET)
FTD-PET measured as standardized uptake volume (SUV) values corrected for lean body mass. Change from baseline categorized according to European Organization for Research and Treatment for Cancer (EORTC) criteria: Partial Metabolic Response (PMR): SUV value during treatment \<75 percent (%) of baseline value; Progressive Metabolic Disease (PMD): SUV value during treatment \>125% of baseline value; Stable Metabolic Disease (SMD): change in SUV value between PMR and PMD. Collected in the expanded MTD cohort only (≥ 10 participants in Sch A 80 mg and Sch B 50 mg groups).
Time frame: Baseline (Schedule A or Schedule B Day -7) and Schedule A Cycle 1/Day 3 or Day 4, Schedule B Cycle 1/Day 8 or 9
Population: Data was not summarized as the development of the compound was discontinued.
Secondary
Target Modulation by Phosphohistone H3 (pH3) Expression in Tumor Tissue (IHC)
pH3 expression is a method to enable the quantification of the proliferative potential of tumor cells. Post-dose tumor tissue sampling occurred after FDG-PET. Biopsies were not to be taken from lesions which were used for PET analysis and were to be taken between 1 and 6 hours after study drug administration. Collected in the expanded MTD cohort only (≥ 10 participants in Sch A 80 mg and Sch B 50 mg groups).
Time frame: Schedule A Cycle 1 or Cycle 2 /Day 4 or Day 5, Schedule B Cycle 1/Day 9 or Day 10
Population: Data was not summarized as the development of the compound was discontinued.
Secondary
Terminal Half-life (t 1/2)
Terminal half-life (serum decay half-life) is the time measured for the serum concentration to decrease by one half.
Time frame: Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose
Population: Half-life (t ½) was not reported for multiple-dose data since the 24-hour sampling period was not long enough to adequately characterize t ½.
Secondary
Time for Maximum Observed Serum Concentration (Tmax)
Time frame: Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose
Population: PK parameter analysis set
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| PF-03814735 5 mg (Schedule A) | Time for Maximum Observed Serum Concentration (Tmax) | 2.00 hours | — |
| PF-03814735 10 mg (Schedule A) | Time for Maximum Observed Serum Concentration (Tmax) | 1.00 hours | — |
| PF-03814735 20 mg (Schedule A) | Time for Maximum Observed Serum Concentration (Tmax) | 24.0 hours | — |
| PF-03814735 40 mg (Schedule A) | Time for Maximum Observed Serum Concentration (Tmax) | 1.50 hours | Full Range 144 |
| PF-03814735 60 mg (Schedule A) | Time for Maximum Observed Serum Concentration (Tmax) | 2.00 hours | Full Range 79 |
| PF-03814735 80 mg (Schedule A) | Time for Maximum Observed Serum Concentration (Tmax) | 2.00 hours | Full Range 63 |
| PF-03814735 100 mg (Schedule A) | Time for Maximum Observed Serum Concentration (Tmax) | 2.00 hours | Full Range 56 |
| PF-03814735 40 mg (Schedule B) | Time for Maximum Observed Serum Concentration (Tmax) | 2.00 hours | — |
| PF-03814735 50 mg (Schedule B) | Time for Maximum Observed Serum Concentration (Tmax) | 1.00 hours | Full Range 79 |
| PF-03814735 60 mg (Schedule B) | Time for Maximum Observed Serum Concentration (Tmax) | 2.00 hours | Full Range 59 |
| PF-03814735 60 mg (Schedule B) | Time for Maximum Observed Serum Concentration (Tmax) | 1.50 hours | Full Range 61 |
Secondary
Time to Progression
Time to Progression defined as the time from the date of enrollment to the date progressive disease first reported. If tumor progression data included more than 1 date, the first date was to be used. TTP = (first date of tumor progression - date of enrollment + 1). Progressive disease: ≥20% increase in sum LD of target lesions from smallest sum LD recorded since treatment start or appearance of ≥1 new lesions.
Time frame: Baseline, every 2 cycles (each cycle=21 days) until disease progression or participant discontinuation; maximum follow-up was from baseline up to 12 cycles
Population: Data was not summarized as the development of the compound was discontinued.
Secondary
Urine Pharmacokinetics
Urine PK for quantification of unchanged PF-03814375 and any identified metabolites. 24-hour urine collection at 8-hour intervals after the morning dose (Schedule \[Sch\] A Day 4, Sch B Day 9; last sample collected just prior to the morning dose on Sch A Day 5 or Sch B Day 10 in the expanded maximum tolerated dose (MTD) cohort only (≥ 10 participants in Sch A 80 mg and Sch B 50 mg groups). The lower limit of quantification (LLOQ) was 1 nanogram per milliliter (ng/mL). Clinical specimens with concentrations below the LLOQ were to be reported as below the limited of quantification (BLQ) 1 ng/mL.
Time frame: Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose
Population: Data was not summarized as the development of the compound was discontinued.