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

Advanced Non-Hematologic Malignancies Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00915278
• Other study ID #: B1001001
• Status: Terminated
• Phase: Phase 1
• First received: June 3, 2009
• Last updated: February 25, 2014
• Start date: September 2009
• Est. completion date: January 2013

Study information

• Verified date: February 2014
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 33
• Est. completion date: January 2013
• Est. primary completion date: January 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Advanced Non-Hematologic Malignancies

Intervention

Drug:
• PF-04605412
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

Locations

Country	Name	City	State
United Kingdom	Pfizer Investigational Site	North Cheam	Surrey
United Kingdom	Pfizer Investigational Site	Sutton	Surrey
United Kingdom	Pfizer Investigational Site	Tooting	London
United States	Pfizer Investigational Site	Nashville	Tennessee
United States	Pfizer Investigational Site	Nashville	Tennessee
United States	Pfizer Investigational Site	Nashville	Tennessee
United States	Pfizer Investigational Site	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Number of Participants With Tissue Macrophage Infiltration	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against tissue macrophages.	Predose and postdose	No
Secondary	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	No
Secondary	Number of Participants With CD68 Expression	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies CD68.	Predose and postdose	No
Secondary	Number of Participants With Granzyme B Expression	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Granzyme B.	Predose and postdose	No
Secondary	Number of Participants With CD56 Expression	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD56.	Predose and postdose	No
Secondary	Number of Participants With CD16 Expression	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD16.	Predose and postdose	No
Secondary	Number of Participants With pFAK Expression	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against pFAK.	Predose and postdose	No
Secondary	Number of Participants With CD31 Expression	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD31.	Predose and postdose	No
Secondary	Number of Participants With Caspase 3 Expression	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Caspase 3.	Predose and postdose	No
Secondary	Number of Participants With Ki67 Expression	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Ki67.	Predose and postdose	No
Secondary	Number of Participants With Perforin Expression	Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Perforin.	Predose and postdose	No

External Links

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