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

This study has been terminated.
(The study was terminated on 26 February 2013. Risk-benefit assessment is no longer positive and does not support further development)
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT00915278
First received: June 3, 2009
Last updated: February 25, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Advanced Non-Hematologic Malignancies
Drug: PF-04605412
Phase 1

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

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Number of Participants With Dose-limiting Toxicities (DLT) [ Time Frame: Baseline up to 6 weeks PF-04605412 ] [ Designated as safety issue: Yes ]
    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:
  • 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 ] [ Designated as safety issue: No ]
  • Area Under the Curve From Time Zero to Last Quantifiable 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 ] [ Designated as safety issue: No ]
    Area under the serum concentration time-curve from zero to the last measured concentration (AUClast).

  • Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - 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 ] [ Designated as safety issue: No ]
    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) [ 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 ] [ Designated as safety issue: No ]
    Serum decay half-life is the time measured for the plasma concentration to decrease by one half.

  • 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 ] [ Designated as safety issue: No ]
  • Systemic Clearance (CL) [ 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 ] [ Designated as safety issue: No ]
    CL is a quantitative measure of the rate at which a drug substance is removed from the body.

  • Volume of Distribution at Steady State (Vss) [ 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 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants Positive for Anti-PF04605412 Antibodies [ Time Frame: Baseline up to end of treatment ] [ Designated as safety issue: Yes ]
    Serum samples were analyzed for anti-drug antibodies (ADA) or human anti-human antibodies (HAHA). This was used to evaluate immunogenicity.

  • Objective Response - Number of Participants With Objective Response [ 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 ] [ Designated as safety issue: No ]

    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 [ Time Frame: Screening, and Cycle 1 Day 15 ] [ Designated as safety issue: No ]
    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.

  • Percent Change in Initial Area Under the Curve (IAUC) [ Time Frame: Screening, and Cycle 1 Day 15 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Predose and postdose ] [ Designated as safety issue: No ]
    Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against tissue macrophages.

  • Number of Participants With Integrin Alpha 5 Beta 1 Expression [ Time Frame: Predose and postdose ] [ Designated as safety issue: No ]
    Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against integrin alpha 5 beta 1.

  • Number of Participants With CD68 Expression [ Time Frame: Predose and postdose ] [ Designated as safety issue: No ]
    Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies CD68.

  • Number of Participants With Granzyme B Expression [ Time Frame: Predose and postdose ] [ Designated as safety issue: No ]
    Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Granzyme B.

  • Number of Participants With CD56 Expression [ Time Frame: Predose and postdose ] [ Designated as safety issue: No ]
    Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD56.

  • Number of Participants With CD16 Expression [ Time Frame: Predose and postdose ] [ Designated as safety issue: No ]
    Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD16.

  • Number of Participants With pFAK Expression [ Time Frame: Predose and postdose ] [ Designated as safety issue: No ]
    Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against pFAK.

  • Number of Participants With CD31 Expression [ Time Frame: Predose and postdose ] [ Designated as safety issue: No ]
    Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD31.

  • Number of Participants With Caspase 3 Expression [ Time Frame: Predose and postdose ] [ Designated as safety issue: No ]
    Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Caspase 3.

  • Number of Participants With Ki67 Expression [ Time Frame: Predose and postdose ] [ Designated as safety issue: No ]
    Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Ki67.

  • Number of Participants With Perforin Expression [ Time Frame: Predose and postdose ] [ Designated as safety issue: No ]
    Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Perforin.


Enrollment: 33
Study Start Date: September 2009
Study Completion Date: January 2013
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PF-04605412 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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00915278

Locations
United States, Pennsylvania
Pfizer Investigational Site
Philadelphia, Pennsylvania, United States, 19111
United States, Tennessee
Pfizer Investigational Site
Nashville, Tennessee, United States, 37232
Pfizer Investigational Site
Nashville, Tennessee, United States, 37232-5536
Pfizer Investigational Site
Nashville, Tennessee, United States, 37232-7610
United Kingdom
Pfizer Investigational Site
Tooting, London, United Kingdom, SW17 0QT
Pfizer Investigational Site
North Cheam, Surrey, United Kingdom, SM3 9DW
Pfizer Investigational Site
Sutton, Surrey, United Kingdom, SM2 5PT
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided

Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00915278     History of Changes
Other Study ID Numbers: B1001001
Study First Received: June 3, 2009
Results First Received: February 25, 2014
Last Updated: February 25, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
Neoplasms
monoclonal antibody
PF-04605412
advanced metastatic solid tumors

Additional relevant MeSH terms:
Neoplasms
Antibodies
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 28, 2014