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Study Of PF-00562271, Including Patients With Pancreatic, Head And Neck, Prostatic Neoplasms

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Verastem, Inc.
ClinicalTrials.gov Identifier:
NCT00666926
First received: March 26, 2008
Last updated: March 14, 2013
Last verified: March 2013
History of Changes
  Purpose

Phase 1 safety, pharmacokinetics, and pharmacodynamics trial of the focal adhesion kinase (FAK) inhibitor PF-00562271 in patients with positive Positron Emission Tomography [PET] scans due to advanced non-hematologic malignancies, including pancreatic, head and neck, and prostatic neoplasms, and patients with other malignancies appropriate for serial biopsy. Screening consists of a Fluorodeoxyglucose Positron Emission Tomography [FDG-PET] and tumor imaging, medical history, physical examination, Eastern Cooperative Oncology Group [ECOG] performance status, blood draws, a pregnancy test for female patients of childbearing potential. Treatment consists of PF00562271 tablets continued until progression of disease, unacceptable toxicity, or patient request. Evaluations for bioactivity are measured by serial FDG-PET and blood tests for biomarkers related to FAK and PYK2 kinase activities.


Condition Intervention Phase
Head and Neck Neoplasm
Prostatic Neoplasm
Pancreatic Neoplasm
 Drug: PF00562271
 Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1, Open-Label, Dose Escalation Study To Evaluate Safety, Pharmacokinetics And Pharmacodynamics Of PF-00562271 In Patients With Advanced Non-Hematologic Malignancies

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Verastem, Inc.:

Primary Outcome Measures:
  • Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) [ Time Frame: Baseline up to Cycle 1 Day 21 (C1.D21) ] [ Designated as safety issue: No ]
    At least possibly attributable to study treatment (Tx): Grade (Gr) 4 neutropenia (absolute neutrophil count [ANC] <500 cells/mm^3) for >7 days or Gr 3 febrile neutropenia (ANC <1000/mm^3, fever ≥38 degrees Celsius; Gr 4 thrombocytopenia (platelets <25,000 cells/mm^3); Gr ≥3 non-hematologic toxicity despite adequate medical intervention; Gr ≥3 confirmed prolonged QTc interval (>500 milliseconds [msec]); confirmed cardiac troponin I ≥99 percentile of reference range; Tx related toxicities with failure to receive ≥18 days Tx in 21-day cycle or inability to resume current dose level ≤14 days.

  • Percentage of Participants With Tumor Metabolic Response (Reduction of ≥15%) in Positron Emission Tomography With F-18-fluorodeoxyglucose (FDG-PET) [ Time Frame: Baseline, C1.D14 ] [ Designated as safety issue: No ]
    Metabolic response demonstrated in any tumor reduction of ≥15% in tumor FDG standardized uptake value (SUV) in Cycle 1; based on the recommendations of the European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Participant must have had a baseline PET with at least 1 tumor lesion demonstrating an FDG SUV of ≥5.


Secondary Outcome Measures:
  • Maximum Serum Concentration (Cmax): PF-00562271 C0.D1, C1.D1 [ Time Frame: Escalation cohorts: C0.D1 0 hour (0 hr=pre-dose PF-00562271), and 0.5, 1, 2, 4, 6, 8, 12, 24, 48 hrs post dose; Expansion E1 US cohort: C1.D1 0 hr (prior to MDZ dose); E1 non-US and E2 cohort: C1.D1 0 hr and 0.5, 1, 2, 4 hrs post C1.D1 morning (am) dose ] [ Designated as safety issue: No ]
  • Maximum Serum Concentration (Cmax): PF-00562271 C1.D14 [ Time Frame: Escalation and Expansion E1 and E2 cohorts: C1.D14 0 hour (0 hr=pre-dose PF-00562271), and 0.5, 1, 2, 4, 6, 8, 12 (if BID) or 24 (if QD) hrs post am dose ] [ Designated as safety issue: No ]
  • Time to Reach Maximum Observed Serum Concentration (Tmax): PF-00562271 C0.D1, C1.D1 [ Time Frame: Escalation cohorts: C0.D1 0 hour (0 hr=pre-dose PF-00562271), and 0.5, 1, 2, 4, 6, 8, 12, 24, 48 hrs post dose; Expansion E1 US cohort: C1.D1 0 hr (prior to MDZ dose); E1 non-US and E2 cohort: C1.D1 0 hr and 0.5, 1, 2, 4 hrs post C1.D1 am dose ] [ Designated as safety issue: No ]
  • Time to Reach Maximum Observed Serum Concentration (Tmax): PF-00562271 C1.D14 [ Time Frame: Escalation and Expansion E1 and E2 cohorts: C1.D14 0 hour (0 hr=pre-dose PF-00562271), and 0.5, 1, 2, 4, 6, 8, 12 (if BID) or 24 (if QD) hrs post am dose ] [ Designated as safety issue: No ]
  • Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast): PF-00562271 C0.D1, C1.D1 [ Time Frame: Escalation cohorts: C0.D1 0 hour (0 hr=pre-dose PF-00562271), and 0.5, 1, 2, 4, 6, 8, 12, 24, 48 hrs post dose; Expansion E1 US cohort: C1.D1 0 hr (prior to MDZ dose); E1 non-US and E2 cohort: C1.D1 0 hr and 0.5, 1, 2, 4 hrs post C1.D1 am dose ] [ Designated as safety issue: No ]
    Area under the serum concentration time-curve from zero to the last measured concentration; nanograms multiplied by hours per milliliters (ng*hr/mL).

  • Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf): PF-00562271 C0.D1, C1.D1 [ Time Frame: Escalation cohorts: C0.D1 0 hour (0 hr=pre-dose PF-00562271), and 0.5, 1, 2, 4, 6, 8, 12, 24, 48 hrs post dose; Expansion E1 US cohort: C1.D1 0 hr (prior to MDZ dose); E1 non-US and E2 cohort: C1.D1 0 hr and 0.5, 1, 2, 4 hrs post C1.D1 am dose ] [ Designated as safety issue: No ]
    AUCinf = area under the serum concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).

  • Serum Decay Half-life (t 1/2): PF-00562271 C0.D1, C1.D1 [ Time Frame: Escalation cohorts: C0.D1 0 hour (0 hr=pre-dose PF-00562271), and 0.5, 1, 2, 4, 6, 8, 12, 24, 48 hrs post dose; Expansion E1 US cohort: C1.D1 0 hr (prior to MDZ dose); E1 non-US and E2 cohort: C1.D1 0 hr and 0.5, 1, 2, 4 hrs post C1.D1 am dose ] [ Designated as safety issue: No ]
    Serum decay half-life is the time measured for the serum concentration to decrease by one half.

  • Apparent Oral Clearance (CL/F): PF-00562271 C0. D1, C1.D1 [ Time Frame: Escalation cohorts: C0.D1 0 hour (0 hr=pre-dose PF-00562271), and 0.5, 1, 2, 4, 6, 8, 12, 24, 48 hrs post dose; Expansion E1 US cohort: C1.D1 0 hr (prior to MDZ dose); E1 non-US and E2 cohort: C1.D1 0 hr and 0.5, 1, 2, 4 hrs post C1.D1 am dose ] [ Designated as safety issue: No ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

  • Minimum Observed Serum Trough Concentration (Cmin): PF-00562271 C1.D14 [ Time Frame: Escalation and Expansion E1 and E2 cohorts: C1.D14 0 hour (0 hr=pre-dose PF-00562271), and 0.5, 1, 2, 4, 6, 8, 12 (if BID) or 24 (if QD) hrs post am dose ] [ Designated as safety issue: No ]
  • Area Under the Curve From Time Zero to the End of the Dosing Interval (AUCtau): PF-00562271 C1.D14 [ Time Frame: Escalation and Expansion E1 and E2 cohorts: C1.D14 0 hour (0 hr=pre-dose PF-00562271), and 0.5, 1, 2, 4, 6, 8, 12 (if BID) or 24 (if QD) hrs post am dose ] [ Designated as safety issue: No ]
  • Observed Accumulation Ratio (Rac): PF-00562271 C1.D14 [ Time Frame: Escalation (Esc) cohort: C0.D1: 0 hr, and 0.5, 1, 2, 4, 6, 7,12 hrs post dose; Expansion (Exp) cohort: C0:D1: 0 hr, and 1, 2, 4, 8 hrs post dose; Esc and Exp cohorts: C1.D14 0 hour, and 0.5, 1, 2, 4, 6, 8, 12 (if BID) or 24 (if QD) hrs post am dose ] [ Designated as safety issue: No ]
    Rac was the ratio of the Day 14 AUC0-tau (0 hour to last dose interval) and AUC during the corresponding time period after the lead-in dose (AUCtau C1.D14/AUCtau C0.D1).

  • Maximum Serum Concentration (Cmax): MDZ [ Time Frame: C0.D1, C1.D21 Expansion cohort E1 US sites only: 0 hr (prior to MDZ dosing) and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hrs post MDZ dose ] [ Designated as safety issue: No ]
  • Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast): MDZ [ Time Frame: C0.D1, C1.D21 Expansion cohort E1 US sites only: 0 hr (prior to MDZ dosing) and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hrs post MDZ dose ] [ Designated as safety issue: No ]
    Area under the serum concentration time-curve from zero to the last measured concentration.

  • Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf): MDZ [ Time Frame: C0.D1, C1.D21 Expansion cohort E1 US sites only: 0 hr (prior to MDZ dosing) and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hrs post MDZ dose ] [ Designated as safety issue: No ]
    AUCinf = area under the serum concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).

  • Time to Reach Maximum Observed Serum Concentration (Tmax): MDZ [ Time Frame: C0.D1, C1.D21 Expansion cohort E1 US sites only: 0 hr (prior to MDZ dosing) and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hrs post MDZ dose ] [ Designated as safety issue: No ]
  • Serum Decay Half-life (t 1/2): MDZ [ Time Frame: C0.D1, C1.D21 Expansion cohort E1 US sites only: 0 hr (prior to MDZ dosing) and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hrs post MDZ dose ] [ Designated as safety issue: No ]
    Serum decay half-life is the time measured for the serum concentration to decrease by one half.

  • Apparent Oral Clearance (CL/F): MDZ [ Time Frame: C0.D1, C1.D21 Expansion cohort E1 US sites only: 0 hr (prior to MDZ dosing) and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hrs post MDZ dose ] [ Designated as safety issue: No ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

  • Percentage of Participants With Best Overall Response as Measured Using the Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Baseline up to 12 cycles (cycle=21days) ] [ Designated as safety issue: No ]
    Best response recorded from start of treatment (Tx) until disease progression. Complete response: disappearance of all target lesions. Partial response: ≥30% decrease in sum of longest dimensions (LD) of target lesions referencing baseline sum LD. Progressive disease: ≥20% increase in sum LD of target lesions from smallest sum LD recorded since Tx start or appearance of ≥1 new lesions. Stable disease: neither sufficient shrinkage to=PR nor sufficient increase to=PD during first 6 weeks after Tx start referencing smallest sum LD since Tx start.

  • Phosphorylated Focal Adhesion Kinase (pFAK) [ Time Frame: Baseline (up to 28 days prior to first dose) up to 12 cycles (cycle=21days) ] [ Designated as safety issue: No ]
    Analysis of tumor specimens to assess FAK-related biomarkers for potential predictors of response markers to PF-00562271; FAK is overexpressed in a variety of human cancers. For dose escalation cohorts and expansion cohort E1, pre-treatment tumor biopsy collected between Day -28 and first PF-00562271 dose and on-treatment tumor biopsy collected 2 to 8 hours after PF-00562271 dose during Cycle 1 between day 12 and 16. In addition, up to 10 participants in cohort E2 were to be enrolled for serial biopsies.

  • Phosphorylated Mitogen Activated Pathway Kinase (pMAPK) [ Time Frame: Baseline (up to 28 days prior to first dose) up to 12 cycles (cycle=21days) ] [ Designated as safety issue: No ]
    Analysis of tumor specimens to assess FAK-related biomarkers for potential predictors of response markers to PF-00562271; MAPK regulates activities of several transcription factors. A defect in MAPK pathway leads to uncontrolled cell growth. For dose escalation cohorts and expansion cohort E1, pre-treatment tumor biopsy collected between Day -28 and first PF-00562271 dose and on-treatment tumor biopsy collected 2 to 8 hours after PF-00562271 dose during Cycle 1 between day 12 and 16. In addition, up to 10 participants in cohort E2 were to be enrolled for serial biopsies.

  • Phospho-SRC (pSRC) [ Time Frame: Baseline (up to 28 days prior to first dose) up to 12 cycles (cycle=21days) ] [ Designated as safety issue: No ]
    Analysis of tumor specimens to assess FAK-related biomarkers for potential predictors of response markers to PF-00562271; SRC proto-oncogenes are regulators of growth and differentiation of eukaryotic cells and are implicated in development of human tumors. For dose escalation cohorts and expansion cohort E1, pre-treatment tumor biopsy collected between Day -28 and first PF-00562271 dose; on-treatment tumor biopsy collected 2 to 8 hours after PF-00562271 dose during Cycle 1 between day 12 and 16. In addition, up to 10 participants in cohort E2 were to be enrolled for serial biopsies.

  • Caspase-3 [ Time Frame: Baseline (up to 28 days prior to first dose) up to 12 cycles (cycle=21days) ] [ Designated as safety issue: No ]
    Analysis of tumor specimens to assess FAK-related biomarkers for potential predictors of response markers to PF-00562271; sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. For dose escalation cohorts and expansion cohort E1, pre-treatment tumor biopsy collected between Day -28 and first PF-00562271 dose and on-treatment tumor biopsy collected 2 to 8 hours after PF-00562271 dose during Cycle 1 between day 12 and 16. In addition, up to 10 participants in cohort E2 were to be enrolled for serial biopsies.


Enrollment: 99
Study Start Date: December 2005
Study Completion Date: April 2009
Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: PF00562271
125 mg twice daily [BID] with food, tablet
Experimental: 2 Drug: PF00562271
125 mg BID with food, tablet
Experimental: 3 Drug: PF00562271
125 mg BID with food, tablet
Experimental: 4 Drug: PF00562271
125 mg BID with food, tablet

  Eligibility

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

Inclusion Criteria:

  • Pancreatic, head and neck, and prostatic neoplasms, and patients with non-hematologic malignancies who have tumor appropriate for serial biopsy.
  • Adequate organ function, including bilirubin less than 1.5 x ULN, and [Eastern Cooperative Oncology Group] ECOG performance status of 0-2.

Exclusion Criteria:

  • Clinically significant gastrointestinal abnormalities, requirement for systemic anticoagulants or potent CYP 3A4 inhibitors, and history of clinically significant cardiac or pulmonary disorders.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00666926

Locations
United States, Colorado
Pfizer Investigational Site
Aurora, Colorado, United States, 80045
United States, Tennessee
Pfizer Investigational Site
Nashville, Tennessee, United States, 37203
Australia, Victoria
Pfizer Investigational Site
East Melbourne, Victoria, Australia, 3002
Canada, Ontario
Pfizer Investigational Site
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
Verastem, Inc.
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
To obtain contact information for a study center near you, click here.  This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party: Verastem, Inc.
ClinicalTrials.gov Identifier: NCT00666926     History of Changes
Other Study ID Numbers: A8031001
Study First Received: March 26, 2008
Results First Received: May 11, 2012
Last Updated: March 14, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Verastem, Inc.:
Pancreatic Neoplasm
Head and Neck neoplasm
Prostatic neoplasms; Focal Adhesion Kinase
 Phase 1
Pharmacodynamics
FDG-PET

Additional relevant MeSH terms:
Neoplasms
Head and Neck Neoplasms
Pancreatic Neoplasms
Prostatic Neoplasms
Neoplasms by Site
Digestive System Neoplasms
Endocrine Gland Neoplasms
 Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Genital Neoplasms, Male
Urogenital Neoplasms
Genital Diseases, Male
Prostatic Diseases

ClinicalTrials.gov processed this record on May 16, 2013