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

Study Overview
=================
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.

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

Conditions
-----------------
Solid Tumors

Intervention / Treatment
-----------------
* Drug: PF-03814735


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm dose escalation<br> | Drug: PF-03814735<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 1 up to Day 21 of first cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Area under the serum concentration time-curve from zero to the last measured concentration. | 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 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) | Cmin defined as the lowest serum concentration observed during the dosing interval. | 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 | 
| 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). | 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 | 
| 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. | 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 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. | 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 | 
| 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). | 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 | 
| 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). | Schedule A Cycle 1 or Cycle 2 /Day 4 or Day 5, Schedule B Cycle 1/Day 9 or Day 10 | 
| 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. | 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 | 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. | Baseline, 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 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. | Every 2 cycles (each cycle=21 days) until disease progression or participant discontinuation; maximum follow-up was from baseline up to 12 cycles | 
| 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. | 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) | 
| 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. | 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) |