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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT00424632
First received: January 18, 2007
Last updated: June 14, 2012
Last verified: June 2012
  Purpose

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.


Condition Intervention Phase
Solid Tumors
Drug: PF-03814735
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Graded According to Common Terminology Criteria Adverse Events (CTCAE), Version 3 [ Time Frame: Day 1 up to Day 21 of first cycle ] [ Designated as safety issue: Yes ]
    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:
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Area Under the Serum Concentration Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) [ 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 ] [ Designated as safety issue: No ]
    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). [ 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 ] [ Designated as safety issue: No ]
  • Minimum Observed Serum Trough Concentration (Cmin) [ 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 ] [ Designated as safety issue: No ]
    Cmin defined as the lowest serum concentration observed during the dosing interval.

  • Observed Serum Accumulation Ratio (Rac) [ 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 ] [ Designated as safety issue: No ]
    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) [ 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 ] [ Designated as safety issue: No ]
    Terminal half-life (serum decay half-life) is the time measured for the serum concentration to decrease by one half.

  • Urine Pharmacokinetics [ 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 ] [ Designated as safety issue: No ]
    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) [ 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 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Schedule A Cycle 1 or Cycle 2 /Day 4 or Day 5, Schedule B Cycle 1/Day 9 or Day 10 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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.


Enrollment: 57
Study Start Date: November 2006
Study Completion Date: June 2009
Primary Completion Date: June 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single arm dose escalation Drug: PF-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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00424632

Locations
United States, Tennessee
Pfizer Investigational Site
Nashville, Tennessee, United States, 37203
Belgium
Pfizer Investigational Site
Leuven, Belgium, 3000
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided by Pfizer

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00424632     History of Changes
Other Study ID Numbers: A9491001
Study First Received: January 18, 2007
Results First Received: March 21, 2012
Last Updated: June 14, 2012
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Neoplasms

ClinicalTrials.gov processed this record on July 28, 2014