CP-751,871 In Combination With Docetaxel In Advance Non-hematologic Malignancies

Study Overview
=================
Brief Summary
-----------------
This clinical trial is designed to determine the safety, tolerability, pharmacokinetics and pharmacodynamic effects of escalating doses of CP 751,871 given in combination with docetaxel in patients with non-hematologic malignancies for whom docetaxel is a reasonable treatment option.

Official Title
-----------------
A Phase 1b Dose Escalation, Open-label Study Of CP-751,871 In Combination With Docetaxel In Advanced Non-hematologic Malignancies

Conditions
-----------------
Advanced Non-Hematologic Malignancies

Intervention / Treatment
-----------------
* Drug: CP-751,871
* Drug: Docetaxel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age greater than 18 years Documented advanced-stage non-hematologic malignancy for whom docetaxel monotherapy is a reasonable treatment option Eastern Cooperative Oncology Group [ECOG] performance status 0-1 Exclusion Criteria: Significant active cardiac disease Chemotherapy, biological or investigational agents within 4 weeks prior to dosing Inadequate bone marrow, renal, cardiac or liver function

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CP-751,871 combined with docetaxel<br> | Drug: CP-751,871<br>* CP-751,871 was given intravenously [IV] every 3 weeks in escalating doses ranging from 0.1 mg/kg up to 20 mg/kg. Standard doses of Docetaxel were given every 3 weeks with CP-751,871. Study therapy was continued until disease progression, lack of tolerability for up to 17 cycles (approximately 1 year).<br>Drug: Docetaxel<br>* Docetaxel up to 75 mg/m^2 was administered intravenously [IV] on Day 1 of each 3-week dosing cycle.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) |  | Cycle 1 Day 1 through Cycle 1 Day 21 | 
| Recommended Phase 2 Dose (RP2D) |  | Cycle 1 Day 1 through Cycle 1 Day 21 | 
| Area Under the Curve From Time Zero to 25 Hours Postdose (AUC25) of Docetaxel in Cycle 1 | Area under the plasma concentration versus time curve (AUC) from time zero to 25 hours post dose, the nominal time of the last sample (24 hours after end of infusion) | 30 minutes before docetaxel infusion; 30 and 50 minutes after the start of docetaxel infusion; and 30 minutes and 1, 3, 8, and 24 hours after the end of docetaxel infusion | 
| Area Under the Curve From Time Zero to 25 Hours Postdose (AUC25) of Docetaxel in Cycle 4 | Area under the plasma concentration versus time curve (AUC) from time zero to 25 hours post dose, the nominal time of the last sample (24 hours after end of infusion) | 30 minutes before CP-751,871 infusion; 1 hour after the end of CP-751,871 infusion; 30 minutes before docetaxel infusion; 30 and 50 minutes after the start of docetaxel infusion; and 30 minutes and 1, 3, 8, and 24 hours after the end of docetaxel infusion | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Docetaxel in Cycle 1 | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) | 30 minutes before docetaxel infusion; 30 and 50 minutes after the start of docetaxel infusion; and 30 minutes and 1, 3, 8, and 24 hours after the end of docetaxel infusion | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Docetaxel in Cycle 4 | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) | 30 minutes before CP-751,871 infusion; 1 hour after the end of CP-751,871 infusion; 30 minutes before docetaxel infusion; 30 and 50 minutes after the start of docetaxel infusion; and 30 minutes and 1, 3, 8, and 24 hours after the end of docetaxel infusion | 
| Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast(dn)) of Docetaxel in Cycle 1 | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) divided by dose | 30 minutes before docetaxel infusion; 30 and 50 minutes after the start of docetaxel infusion; and 30 minutes and 1, 3, 8, and 24 hours after the end of docetaxel infusion | 
| Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast(dn)) of Docetaxel in Cycle 4 | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) divided by dose | 30 minutes before CP-751,871 infusion; 1 hour after the end of CP-751,871 infusion; 30 minutes before docetaxel infusion; 30 and 50 minutes after the start of docetaxel infusion; and 30 minutes and 1, 3, 8, and 24 hours after the end of docetaxel infusion | 
| Maximum Observed Plasma Concentration (Cmax) of Docetaxel in Cycle 1 |  | 30 minutes before docetaxel infusion; 30 and 50 minutes after the start of docetaxel infusion; and 30 minutes and 1, 3, 8, and 24 hours after the end of docetaxel infusion | 
| Maximum Observed Plasma Concentration (Cmax) of Docetaxel in Cycle 4 |  | 30 minutes before CP-751,871 infusion; 1 hour after the end of CP-751,871 infusion; 30 minutes before docetaxel infusion; 30 and 50 minutes after the start of docetaxel infusion; and 30 minutes and 1, 3, 8, and 24 hours after the end of docetaxel infusion | 
| Dose Normalized Maximum Observed Plasma Concentration (Cmax(dn)) of Docetaxel in Cycle 1 | Maximum Observed Plasma Concentration (Cmax) divided by dose | 30 minutes before docetaxel infusion; 30 and 50 minutes after the start of docetaxel infusion; and 30 minutes and 1, 3, 8, and 24 hours after the end of docetaxel infusion | 
| Dose Normalized Maximum Observed Plasma Concentration (Cmax(dn)) of Docetaxel in Cycle 4 | Maximum Observed Plasma Concentration (Cmax) divided by dose | 30 minutes before CP-751,871 infusion; 1 hour after the end of CP-751,871 infusion; 30 minutes before docetaxel infusion; 30 and 50 minutes after the start of docetaxel infusion; and 30 minutes and 1, 3, 8, and 24 hours after the end of docetaxel infusion | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Docetaxel in Cycle 1 |  | 30 minutes before docetaxel infusion; 30 and 50 minutes after the start of docetaxel infusion; and 30 minutes and 1, 3, 8, and 24 hours after the end of docetaxel infusion | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Docetaxel in Cycle 4 |  | 30 minutes before CP-751,871 infusion; 1 hour after the end of CP-751,871 infusion; 30 minutes before docetaxel infusion; 30 and 50 minutes after the start of docetaxel infusion; and 30 minutes and 1, 3, 8, and 24 hours after the end of docetaxel infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Occurrence of Human Anti-human Antibody (HAHA) Response to CP-751,871 | The development of HAHA is considered clinically relevant when temporally associated to the onset of adverse events or a significant decrease in the plasma concentrations of CP-751,871. The positive value is defined as ≥3.32. | 30 minutes predose at each cycle, End of Study (28 days after the last CP-751,871 infusion), and 150 days after the last CP-751,871 infusion | 
| Number of Participants With Objective Response (OR) | Number of participants with OR 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. | Baseline, every 2 months (approximately 7-10 days prior to the start of the next dose) up to Cycle 17 (1 cycle = 21 days) | 
| Time to Tumor Progression (TTP) | Time in weeks from start of study treatment to first documentation of objective tumor progression or death due to cancer, whichever comes first. TTP was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 7. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]) | Baseline, every 2 months (approximately 7-10 days prior to the start of the next dose) up to Cycle 17 (1 cycle = 21 days) | 
| Circulating Tumor Cells (CTCs), CTCs Expressing Insulin-like Growth Factor 1 Receptor (IGF-1R), and Circulating Endothelial Cells (CECs) |  | Predose on Day 1 and on Day 8 of each cycle, and End of Study (28 days after the last CP-751,871 infusion) | 
| Systemic Clearance (CL) of CP-751,871 in Cycle 1 | CL is a quantitative measure of the rate at which a drug substance is removed from the body. | 30 minutes prior to the Cycle 1 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 1 CP-751,871 infusion; and 30 minutes prior to the Cycle 2 CP-751,871 infusion (Day 22) | 
| Systemic Clearance (CL) of CP-751,871 in Cycle 4 | CL is a quantitative measure of the rate at which a drug substance is removed from the body. | 30 minutes prior to the Cycle 4 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 4 CP-751,871 infusion; and 30 minutes prior to the Cycle 5 CP-751,871 infusion (Day 22) | 
| Maximum Observed Plasma Concentration (Cmax) of CP-751,871 in Cycle 1 |  | 30 minutes prior to the Cycle 1 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 1 CP-751,871 infusion; and 30 minutes prior to the Cycle 2 CP-751,871 infusion (Day 22) | 
| Maximum Observed Plasma Concentration (Cmax) of CP-751,871 in Cycle 4 |  | 30 minutes prior to the Cycle 4 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 4 CP-751,871 infusion; and 30 minutes prior to the Cycle 5 CP-751,871 infusion (Day 22) | 
| Area Under the Curve From Time Zero (Day 1) to Day 22 (AUC(0-d22)) of CP-751,871 in Cycle 1 | Area under the plasma concentration versus time curve (AUC) from time zero (Day 1) to Day 22, where Day 22 is the nominal time (504 hours) of the predose sample for the next cycle. | 30 minutes prior to the Cycle 1 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 1 CP-751,871 infusion; and 30 minutes prior to the Cycle 2 CP-751,871 infusion (Day 22) | 
| Area Under the Curve From Time Zero (Day 1) to Day 22 (AUC(0-d22)) of CP-751,871 in Cycle 4 | Area under the plasma concentration versus time curve (AUC) from time zero (Day 1) to Day 22, where Day 22 is the nominal time (504 hours) of the predose sample for the next cycle. | 30 minutes prior to the Cycle 4 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 4 CP-751,871 infusion; and 30 minutes prior to the Cycle 5 CP-751,871 infusion (Day 22) | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of CP-751,871 in Cycle 1 | Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf). | 30 minutes prior to the Cycle 1 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 1 CP-751,871 infusion; and 30 minutes prior to the Cycle 2 CP-751,871 infusion (Day 22) | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of CP-751,871 in Cycle 4 | Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf). | 30 minutes prior to the Cycle 4 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 4 CP-751,871 infusion; and 30 minutes prior to the Cycle 5 CP-751,871 infusion (Day 22) | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of CP-751,871 in Cycle 1 | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) | 30 minutes prior to the Cycle 1 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 1 CP-751,871 infusion; and 30 minutes prior to the Cycle 2 CP-751,871 infusion (Day 22) | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of CP-751,871 in Cycle 4 | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) | 30 minutes prior to the Cycle 4 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 4 CP-751,871 infusion; and 30 minutes prior to the Cycle 5 CP-751,871 infusion (Day 22) | 
| Plasma Decay Half-Life (t1/2) of CP-751,871 in Cycle 1 | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | 30 minutes prior to the Cycle 1 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 1 CP-751,871 infusion; and 30 minutes prior to the Cycle 2 CP-751,871 infusion (Day 22) | 
| Plasma Decay Half-Life (t1/2) of CP-751,871 in Cycle 4 | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | 30 minutes prior to the Cycle 4 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 4 CP-751,871 infusion; and 30 minutes prior to the Cycle 5 CP-751,871 infusion (Day 22) | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of CP-751,871 in Cycle 1 |  | 30 minutes prior to the Cycle 1 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 1 CP-751,871 infusion; and 30 minutes prior to the Cycle 2 CP-751,871 infusion (Day 22) | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of CP-751,871 in Cycle 4 |  | 30 minutes prior to the Cycle 4 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 4 CP-751,871 infusion; and 30 minutes prior to the Cycle 5 CP-751,871 infusion (Day 22) | 
| Volume of Distribution at Steady State (Vss) of CP-751,871 in Cycle 1 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. | 30 minutes prior to the Cycle 1 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 1 CP-751,871 infusion; and 30 minutes prior to the Cycle 2 CP-751,871 infusion (Day 22) | 
| Volume of Distribution at Steady State (Vss) of CP-751,871 in Cycle 4 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. | 30 minutes prior to the Cycle 4 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 4 CP-751,871 infusion; and 30 minutes prior to the Cycle 5 CP-751,871 infusion (Day 22) | 
| Apparent Volume of Distribution (Vz/F) of CP-751,871 in Cycle 1 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | 30 minutes prior to the Cycle 1 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 1 CP-751,871 infusion; and 30 minutes prior to the Cycle 2 CP-751,871 infusion (Day 22) | 
| Volume of Distribution (Vz) of CP-751,871 in Cycle 1 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. | 30 minutes prior to the Cycle 1 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 1 CP-751,871 infusion; and 30 minutes prior to the Cycle 2 CP-751,871 infusion (Day 22) | 
| Apparent Volume of Distribution (Vz/F) of CP-751,871 in Cycle 4 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | 30 minutes prior to the Cycle 4 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 4 CP-751,871 infusion; and 30 minutes prior to the Cycle 5 CP-751,871 infusion (Day 22) | 
| Volume of Distribution (Vz) of CP-751,871 in Cycle 4 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. | 30 minutes prior to the Cycle 4 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 4 CP-751,871 infusion; and 30 minutes prior to the Cycle 5 CP-751,871 infusion (Day 22) | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of CP-751,871 in Cycle 1 | Area under the plasma concentration versus time curve (AUC) from time zero to tau, the dosing interval, where tao is the actual time of the predose sample for the next cycle. | 30 minutes prior to the Cycle 1 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 1 CP-751,871 infusion; and 30 minutes prior to the Cycle 2 CP-751,871 infusion (Day 22) | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of CP-751,871 in Cycle 4 | Area under the plasma concentration versus time curve (AUC) from time zero to tau, the dosing interval, where tao is the actual time of the predose sample for the next cycle. | 30 minutes prior to the Cycle 4 CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of the Cycle 4 CP-751,871 infusion; and 30 minutes prior to the Cycle 5 CP-751,871 infusion (Day 22) | 
| Observed Accumulation Ratio (Rac) of CP-751,871 | AUCtao of Cycle 4 divided by AUC(0-d22) of Cycle 1 | 30 minutes prior to CP-751,871 infusion; 1 hour, and 1 (Day 2), 3 (Day 4) and 7 (Day 8) days post end of CP-751,871 infusion; and 30 minutes prior to the next cycle CP-751,871 infusion (Day 22) in Cycle 1 and Cycle 4 | 
| Observed Concentration of CP-751,871 at Day 22 (Cday22) of Cycle 1 and 4 | Cday22 is the measured CP-751,871 plasma concentration in blood sample collected at Day 22. | Cycle 1: 30 minutes prior to the Cycle 2 CP-751,871 infusion (this is Day 22 for Cycle 1); Cycle 4: 30 minutes prior to the Cycle 5 CP-751,871 infusion (this is Day 22 for Cycle 4) | 
| Time of Last Quantifiable Time Point (Tlast) of CP-751,871 in Cycle 1 and Cycle 4 | Blood samples were collected at timepoints prespecified in the study protocol. Tlast of CP-751,871 was the last time point when blood sample collected was quantifiable for CP-751,871. | Cycle 1 and 4: prior to CP-751,871 infusion, at 1 hour post CP-751,871 infusion, and at 1, 3, 7 days post end of docetaxel infusion | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
non-hematologic cancer, advanced solid tumors, prostrate cancer