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

Prostatic Neoplasm Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00666926
• Other study ID #: A8031001
• Status: Completed
• Phase: Phase 1
• First received: March 26, 2008
• Last updated: March 14, 2013
• Start date: December 2005
• Est. completion date: April 2009

Study information

• Verified date: March 2013
• Source: Verastem, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 99
• Est. completion date: April 2009
• Est. primary completion date: April 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Head and Neck Neoplasm
• Head and Neck Neoplasms
• Neoplasms
• Pancreatic Neoplasm
• Pancreatic Neoplasms
• Prostatic Neoplasm
• Prostatic Neoplasms

Intervention

Drug:
• PF00562271
125 mg twice daily [BID] with food, tablet
• PF00562271
125 mg BID with food, tablet
• PF00562271
125 mg BID with food, tablet
• PF00562271
125 mg BID with food, tablet

Locations

Country	Name	City	State
Australia	Pfizer Investigational Site	East Melbourne	Victoria
Canada	Pfizer Investigational Site	Toronto	Ontario
United States	Pfizer Investigational Site	Aurora	Colorado
United States	Pfizer Investigational Site	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Verastem, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With First Cycle Dose Limiting Toxicities (DLTs)	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.	Baseline up to Cycle 1 Day 21 (C1.D21)	No
Primary	Percentage of Participants With Tumor Metabolic Response (Reduction of =15%) in Positron Emission Tomography With F-18-fluorodeoxyglucose (FDG-PET)	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.	Baseline, C1.D14	No
Secondary	Maximum Serum Concentration (Cmax): PF-00562271 C0.D1, C1.D1		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	No
Secondary	Maximum Serum Concentration (Cmax): PF-00562271 C1.D14		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	No
Secondary	Time to Reach Maximum Observed Serum Concentration (Tmax): PF-00562271 C0.D1, C1.D1		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	No
Secondary	Time to Reach Maximum Observed Serum Concentration (Tmax): PF-00562271 C1.D14		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	No
Secondary	Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast): PF-00562271 C0.D1, C1.D1	Area under the serum concentration time-curve from zero to the last measured concentration; nanograms multiplied by hours per milliliters (ng*hr/mL).	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	No
Secondary	Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf): PF-00562271 C0.D1, C1.D1	AUCinf = area under the serum concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8).	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	No
Secondary	Serum Decay Half-life (t 1/2): PF-00562271 C0.D1, C1.D1	Serum decay half-life is the time measured for the serum concentration to decrease by one half.	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	No
Secondary	Apparent Oral Clearance (CL/F): PF-00562271 C0. D1, C1.D1	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.	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	No
Secondary	Minimum Observed Serum Trough Concentration (Cmin): PF-00562271 C1.D14		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	No
Secondary	Area Under the Curve From Time Zero to the End of the Dosing Interval (AUCtau): PF-00562271 C1.D14		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	No
Secondary	Observed Accumulation Ratio (Rac): PF-00562271 C1.D14	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).	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	No
Secondary	Maximum Serum Concentration (Cmax): MDZ		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	No
Secondary	Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast): MDZ	Area under the serum concentration time-curve from zero to the last measured concentration.	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	No
Secondary	Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf): MDZ	AUCinf = area under the serum concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8).	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	No
Secondary	Time to Reach Maximum Observed Serum Concentration (Tmax): MDZ		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	No
Secondary	Serum Decay Half-life (t 1/2): MDZ	Serum decay half-life is the time measured for the serum concentration to decrease by one half.	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	No
Secondary	Apparent Oral Clearance (CL/F): MDZ	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.	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	No
Secondary	Percentage of Participants With Best Overall Response as Measured Using the Response Evaluation Criteria in Solid Tumors (RECIST)	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.	Baseline up to 12 cycles (cycle=21days)	No
Secondary	Phosphorylated Focal Adhesion Kinase (pFAK)	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.	Baseline (up to 28 days prior to first dose) up to 12 cycles (cycle=21days)	No
Secondary	Phosphorylated Mitogen Activated Pathway Kinase (pMAPK)	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.	Baseline (up to 28 days prior to first dose) up to 12 cycles (cycle=21days)	No
Secondary	Phospho-SRC (pSRC)	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.	Baseline (up to 28 days prior to first dose) up to 12 cycles (cycle=21days)	No
Secondary	Caspase-3	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.	Baseline (up to 28 days prior to first dose) up to 12 cycles (cycle=21days)	No

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