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.

PF-03814735

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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.

Phase 1 Study Of Aurora Kinase Inhibitor PF-03814735 In Patients With Advanced Solid Tumors

A Phase 1, Open Label, Multi-Center, Accelerated Dose-Escalation, Pharmacokinetic And Pharmacodynamic Trial Of The Oral Single Agent Aurora Kinase Inhibitor PF-03814735 In Patients With Advanced Solid Tumors For Whom No Standard Therapy Is Available

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.

Area under the serum concentration time-curve from zero to the last measured concentration.

Cmin defined as the lowest serum concentration observed during the dosing interval.

Rac was the ratio of Schedule B Cycle 1/Day 9 to Day -5 (Day 9 AUCτ to Day -5 AUCτ).

Terminal half-life (serum decay half-life) is the time measured for the serum concentration to decrease by one half.

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.

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).

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 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 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 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.

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.

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.

Pfizer

The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Participants received daily dosing of PF-03814735 of 5 milligrams (mg) administered orally (PO) every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis.

PF-03814735 5 mg (Schedule A)

Participants received daily dosing of PF-03814735 of 10 mg administered PO every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis.

PF-03814735 10 mg (Schedule A)

Participants received daily dosing of PF-03814735 of 20 mg administered PO every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis.

PF-03814735 20 mg (Schedule A)

Participants received daily dosing of PF-03814735 of 40 mg administered PO every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis.

PF-03814735 40 mg (Schedule A)

Participants received daily dosing of PF-03814735 of 60 mg administered PO every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis.

PF-03814735 60 mg (Schedule A)

Participants received daily dosing of PF-03814735 of 80 mg administered PO every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis.

PF-03814735 80 mg (Schedule A)

Participants received daily dosing of PF-03814735 of 100 mg administered PO every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis.

PF-03814735 100 mg (Schedule A)

Participants received daily dosing of PF-03814735 of 40 mg administered PO every morning on an empty stomach for 10 consecutive days out of 21-day cycles on an outpatient basis.

PF-03814735 40 mg (Schedule B)

Participants received daily dosing of PF-03814735 of 50 mg administered PO every morning on an empty stomach for 10 consecutive days out of 21-day cycles on an outpatient basis.

PF-03814735 50 mg (Schedule B)

Participants received daily dosing of PF-03814735 of 60 mg administered PO every morning on an empty stomach for 10 consecutive days out of 21-day cycles on an outpatient basis.

PF-03814735 60 mg (Schedule B)

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.

PF-03814735 (Schedule A)

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.

PF-03814735 (Schedule B)

Total

Age Continuous

Sex: Female, Male

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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.

Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Graded According to Common Terminology Criteria Adverse Events (CTCAE), Version 3

Participant was randomized to receive daily dosing of PF-03814735 50 mg administered PO every morning on an empty stomach for 10 consecutive days out of 21-day cycles on an outpatient basis. However, participant had reduced dose of 25 mg beginning on Cycle 1 Day 1 of treatment.

PF-03814735 25 mg (Schedule B)

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.

Maximum Observed Serum Concentration (Cmax)

Participant was randomized to receive daily dosing of PF-03814735 of 50 mg administered PO every morning on an empty stomach for 10 consecutive days out of 21-day cycles on an outpatient basis. However, participant had reduced dose of 25 mg beginning on Cycle 1 Day 1 of treatment.

Time for Maximum Observed Serum Concentration (Tmax)

Data was not summarized as the development of the compound was discontinued.

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 Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 24 Hours (AUCτ).

Minimum Observed Serum Trough Concentration (Cmin)

PK parameter analysis set. N=number of participants in the indicated population contributing to the mean.

Observed Serum Accumulation Ratio (Rac)

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.

Spots Global Cancer Trial Database for Phase 1 Study Of Aurora Kinase Inhibitor PF-03814735 In Patients With Advanced Solid Tumors

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