A Study Of PF-03732010 In Patients With Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
P-cadherin may play a part in tumor growth; PF-03732010 is a new drug that inhibits P-cadherin. This study will test how well the drug is tolerated, and what effects there might be. Blood will also be taken to measure the amount of drug in blood.

Official Title
-----------------
A Phase 1 Pharmacokinetic And Pharmacodynamic Study Of PF-03732010 In Patients With Advanced Solid Tumors

Conditions
-----------------
Neoplasms

Intervention / Treatment
-----------------
* Drug: PF-03732010


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Advanced solid tumors refractory to (or intolerant of) established therapy known to provide clinical benefit, or for which there is no standard therapy Age >= 18 years of age Adequate bone marrow function as defined by: absolute neutrophil count (ANC) ≥1500/uL, hemoglobin ≥ 9 g/dL, platelets > 100,000/uL Adequate liver function as defined by: bilirubin < 1.5 x ULN, AST, ALT and ALP < 2.5 x ULN, or < 5 x ULN with documented liver and/or bone metastases Serum creatinine < 1.5 x ULN ECOG status 0-1 Availability of biopsy tumor tissue (or fine needle aspirate) for testing of P-cadherin expression Tumor tissue (or fine needle aspirate) showing over-expression of P-cadherin Must be able to give written informed consent Be able to comply with scheduled study visits, treatment plans, laboratory tests and other procedures Exclusion Criteria: Chemotherapy, radiotherapy, or any investigational cancer therapy within 4 weeks of study entry Patients with carcinomatous meningitis or untreated brain metastases. History of significant low platelet count, and/or bleeding disorders, requiring medical or surgical intervention History of significant bleeding episodes within 6 months, unless the source of bleeding has been resected

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: PF-03732010<br>Single Arm study | Drug: PF-03732010<br>* IV infusion. Escalating dose levels, starting at 0.5 mg/kg to Maximum Tolerated Dose. Cycle length of 4 weeks for first cycle, and 2 weekly for subsequently cycles was originally explored, yet based on emerging PK data the Cycle 1 duration is 2 weeks and then weekly. Number of Cycles: Until Progression or unacceptable toxicity develops.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) |  | Baseline up to end of treatment (EOT) or withdrawal assessed up to Day 7 of last cycle | 
| Recommended Phase-2 Dose (RP2D) |  | Baseline up to EOT or withdrawal assessed up to Day 7 of last cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-28 Day)] | AUC (0-28 day)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-28 day). | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | 
| Time to Reach Maximum Observed Serum Concentration (Tmax) |  | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | 
| Minimum Observed Serum Trough Concentration (Cmin) |  | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | 
| Maximum Observed Serum Concentration (Cmax) |  | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-14 Day)] | AUC (0-14)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-14 day). | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | 
| Clearance (CL) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | 
| Apparent Volume of Distribution (Vd) | 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. | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | 
| Number of Participants With Objective Response of Complete Response or Partial Response | Number of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. PR are those with at least 30 percent decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. | Baseline to disease progression or 4 weeks after the first dose and then every 6 weeks up to Week 37 |