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

Phase 1

Terminated

Conditions: Advanced Non-Hematologic Malignancies

Interventions: Drug: PF-04605412

Registration Number: NCT00915278

Lead Sponsor: Pfizer

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 33

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
PF-04605412	PF-04605412	-

Primary Outcome Measures

Name	Time	Method
Number of Participants With Dose-limiting Toxicities (DLT)	Baseline up to 6 weeks PF-04605412	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.

Secondary Outcome Measures

Name	Time	Method
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 Extrapolated Infinite Time [AUC (0 - 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	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).
Serum Decay Half-Life (t1/2)	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 is the time measured for the plasma concentration to decrease by one half.
Volume of Distribution at Steady State (Vss)	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 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.
Systemic Clearance (CL)	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	CL is a quantitative measure of the rate at which a drug substance is removed from the body.
Number of Participants Positive for Anti-PF04605412 Antibodies	Baseline up to end of treatment	Serum samples were analyzed for anti-drug antibodies (ADA) or human anti-human antibodies (HAHA). This was used to evaluate immunogenicity.
Number of Participants With pFAK Expression	Predose and postdose	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against pFAK.
Number of Participants With Caspase 3 Expression	Predose and postdose	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Caspase 3.
Number of Participants With Ki67 Expression	Predose and postdose	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Ki67.
Area Under the Curve From Time Zero to Last Quantifiable 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 serum concentration time-curve from zero to the last measured concentration (AUClast).
Objective Response - Number of Participants With Objective Response	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	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.
Percent Change in Transfer Constant (Ktrans) From Baseline to Cycle 1 Day 15	Screening, and 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.
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
Percent Change in Initial Area Under the Curve (IAUC)	Screening, and Cycle 1 Day 15	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).
Number of Participants With Tissue Macrophage Infiltration	Predose and postdose	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against tissue macrophages.
Number of Participants With Integrin Alpha 5 Beta 1 Expression	Predose and postdose	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against integrin alpha 5 beta 1.
Number of Participants With CD68 Expression	Predose and postdose	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies CD68.
Number of Participants With CD31 Expression	Predose and postdose	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD31.
Number of Participants With Perforin Expression	Predose and postdose	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Perforin.
Number of Participants With Granzyme B Expression	Predose and postdose	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Granzyme B.
Number of Participants With CD56 Expression	Predose and postdose	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD56.
Number of Participants With CD16 Expression	Predose and postdose	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD16.