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

Phase 1

Completed

• Conditions: Solid Tumors
• Interventions: Drug: PF-03814735

• Registration Number: NCT00424632
• Lead Sponsor: Pfizer

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.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2006-11
• Study First Submitted: 2007-01-18
• Study First Submitted QC: 2007-01-18
• Study First Posted: 2007-01-19
• Primary Completion: 2009-06
• Study Completion: 2009-06
• Results First Submitted: 2012-03-21
• Results First Submitted QC: 2012-05-07
• Status Verified: 2012-06
• Results First Posted: 2012-06-12
• Last Update Submitted: 2012-06-14
• Last Update Posted: 2012-06-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 57

Inclusion Criteria

• Metastatic solid tumor resistant to standard therapy or for which no standard therapy is available
• Adequate bone marrow, liver and kidney function

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Single arm dose escalation	PF-03814735	-

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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
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.
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).
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.

Trial Locations

Locations (1)

Pfizer Investigational Site; 🇧🇪 Leuven, Belgium