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

Phase 1TerminatedNCT00915278

Pfizer33 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Advanced Non-Hematologic Malignancies

Interventions

PF-04605412DRUG

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (7)

Pfizer Investigational Site

Philadelphia, Pennsylvania, United States

Pfizer Investigational Site

Nashville, Tennessee, United States

Pfizer Investigational Site

Nashville, Tennessee, United States

Pfizer Investigational Site

Nashville, Tennessee, United States

Outcomes

Primary Outcomes

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.

Time frame: Baseline up to 6 weeks PF-04605412

Secondary Outcomes

Maximum Observed Serum Concentration (Cmax)

Time frame: 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).

Time frame: 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).

Time frame: 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.

Time frame: 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

Data from ClinicalTrials.gov

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Pfizer Investigational Site

Tooting, London, United Kingdom

Pfizer Investigational Site

North Cheam, Surrey, United Kingdom

Pfizer Investigational Site

Sutton, Surrey, United Kingdom

Time to Reach Maximum Observed Serum Concentration (Tmax)

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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.