A Safety Study Of A Monoclonal Antibody Against A5B1 Integrin In Solid Tumors

Study Overview
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Brief Summary
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Dose finding study of the MoaB PF-04605412 directed against the alpha5beta1 integrin. Main objective is to define the MTD (maximum tolerated dose) or MAD (maximum administrable dose) in cancer patients pre treated or unresponsive to standard therapies.

Official Title
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A Phase 1 Safety, Pharmacokinetic And Pharmacodynamic Study Of The Anti-A5B1 Integrin Monoclonal Antibody PF-04605412 Administered Intravenously To Adult Patients With Advanced Or Metastatic Solid Tumors

Conditions
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Advanced Non-Hematologic Malignancies

Intervention / Treatment
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* Drug: PF-04605412


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed advanced measurable or evaluable solid tumors unresponsive to currently available therapies, or for which there is no curative therapy Eastern Cooperative Oncology Group (ECOG) performance status 0 and 1 Life expectancy more than12 weeks Adequate bone marrow, liver and renal function Exclusion Criteria: Known brain metastasis Chemotherapy, radiotherapy, or any investigational cancer therapy within 4 weeks of start of screening procedures Major surgical procedure within 4 weeks of start of screening procedures Active bleeding disorder, including gastrointestinal bleeding, as evidenced by hematemesis, significant hemoptysis or melena in the past 6 months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-04605412<br> | Drug: PF-04605412<br>* PF-04605412 will be administered as 2 hr IV infusion every 4 or 2 weeks. Start dose is 7.5 mg. Multiple doses are foreseen. Treatment will continue until intolerable toxicity, progression of disease or patient's refusal<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities (DLT) | DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity,any >= Grade 3 adverse event (AE) graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], version 3.0 without a clear alternative explanation to study treatment relationship occurring during the first 6 weeks of treatment with PF-04605412. DLT was used to determine maximum tolerated dose (MTD) in this study. | Baseline up to 6 weeks PF-04605412 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentration (Cmax) |  | Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1 | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Area under the serum concentration time-curve from zero to the last measured concentration (AUClast). | Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1 | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] | AUC (0 - inf)= Area under the serum concentration versus time curve (AUC) from time zero (predose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf). | Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1 | 
| Serum Decay Half-Life (t1/2) | Serum decay half-life is the time measured for the plasma concentration to decrease by one half. | Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1 | 
| Time to Reach Maximum Observed Serum Concentration (Tmax) |  | Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1 | 
| Systemic Clearance (CL) | CL is a quantitative measure of the rate at which a drug substance is removed from the body. | Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1 | 
| Volume of Distribution at Steady State (Vss) | 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. | Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1 | 
| Number of Participants Positive for Anti-PF04605412 Antibodies | Serum samples were analyzed for anti-drug antibodies (ADA) or human anti-human antibodies (HAHA). This was used to evaluate immunogenicity. | Baseline up to end of treatment | 
| Objective Response - Number of Participants With Objective Response | Number of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST. Confirmed responses are those that persist on repeat imaging study ≥4 weeks after initial documentation of response. Per RECIST v1.0: CR defined as disappearance of all target lesions and non-target lesions. PR defined as ≥30% decrease in sum of the longest diameters dimensions (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions. | Baseline up to 6 weeks after the first infusion of PF-04605412 (end of Cycle 2) and approximately every 6 weeks thereafter only in the absence of progressive disease | 
| Percent Change in Transfer Constant (Ktrans) From Baseline to Cycle 1 Day 15 | Percent change in Ktrans for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from baseline to Cycle 1 day 15 aimed at defining the effect of PF-04605412 on tumor vasculature. | Screening, and Cycle 1 Day 15 | 
| Percent Change in Initial Area Under the Curve (IAUC) | Percent change in the IAUC for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from baseline to Cycle 1 Day 15. IAUC reflects the contrast distribution volume (extravascular extracellular space) in addition to contrast delivery and transport across the vascular endothelium. An IAUC value of zero indicates the absence of disease (ie, no leakage of the contrast agent into the synovial volume); therefore, an increase in this parameter indicates worsening disease (ie, greater permeability of the synovial membrane). | Screening, and Cycle 1 Day 15 | 
| Number of Participants With Tissue Macrophage Infiltration | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against tissue macrophages. | Predose and postdose | 
| Number of Participants With Integrin Alpha 5 Beta 1 Expression | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against integrin alpha 5 beta 1. | Predose and postdose | 
| Number of Participants With CD68 Expression | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies CD68. | Predose and postdose | 
| Number of Participants With Granzyme B Expression | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Granzyme B. | Predose and postdose | 
| Number of Participants With CD56 Expression | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD56. | Predose and postdose | 
| Number of Participants With CD16 Expression | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD16. | Predose and postdose | 
| Number of Participants With pFAK Expression | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against pFAK. | Predose and postdose | 
| Number of Participants With CD31 Expression | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD31. | Predose and postdose | 
| Number of Participants With Caspase 3 Expression | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Caspase 3. | Predose and postdose | 
| Number of Participants With Ki67 Expression | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Ki67. | Predose and postdose | 
| Number of Participants With Perforin Expression | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Perforin. | Predose and postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoplasms, monoclonal antibody, PF-04605412, advanced metastatic solid tumors