Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Digestive System Diseases

Gland and Hormone Related Diseases

Symptoms and General Pathology

Rare Diseases

Prostatic Neoplasms

Pancreatic Neoplasms

Head and Neck Neoplasms

Tissue Adhesions

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

125 mg twice daily \[BID\] with food, tablet

PF00562271

Pfizer CT.gov Call Center

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.

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

A Phase 1, Open-Label, Dose Escalation Study To Evaluate Safety, Pharmacokinetics And Pharmacodynamics Of PF-00562271 In Patients With Advanced Non-Hematologic Malignancies

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.

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.

Area under the serum concentration time-curve from zero to the last measured concentration; nanograms multiplied by hours per milliliters (ng\*hr/mL).

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 is the time measured for the serum concentration to decrease by one half.

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.

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).

Area under the serum concentration time-curve from zero to the last measured concentration.

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.

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.

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.

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.

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.

Verastem, Inc.

The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

PF-00562271 administered as 5 milligrams (mg) orally (PO) twice a day (BID) without food (w/o food: no food within 2 hours prior to dosing) (escalation cohort).

PF-00562271 5 mg BID

PF-00562271 administered as 10 mg PO BID w/o food (escalation cohort).

PF-00562271 10 mg BID

PF-00562271 administered as 15 mg PO BID w/o food (escalation cohort).

PF-00562271 15 mg BID

PF-00562271 administered as 25 mg PO BID w/o food (escalation cohort).

PF-00562271 25 mg BID

PF-00562271 administered as 35 mg PO BID w/o food (escalation cohort).

PF-00562271 35 mg BID

PF-00562271 administered as 45 mg PO BID w/o food (escalation cohort).

PF-00562271 45 mg BID

PF-00562271 administered as 60 mg PO BID w/o food (escalation cohort).

PF-00562271 60 mg BID

PF-00562271 administered as 75 mg PO BID with food (w/food: regular meal 200 to 800 calories) (expansion cohort).

As of July 2008, participants newly enrolled to the expansion cohort or who restarted treatment after dose delay associated with adverse event(s) were dosed according to intra-participant escalation (up-titration w/food): 75 mg BID week 1; 100 mg BID week 2; 125 mg BID week 3. Participant who was not able to titrate higher than 75 mg BID was reported in the 75 mg BID expansion cohort.

PF-00562271 75 mg BID

PF-00562271 administered as 80 mg PO BID w/o food (escalation cohort).

PF-00562271 80 mg BID

PF-00562271 administered as 100 mg BID w/food (escalation cohort). As of July 2008, participants newly enrolled to expansion cohort or who restarted treatment after dose delay associated with adverse event(s) were dosed according to intra-participant escalation (up-titration w/food): 75 mg BID week 1; 100 mg BID week 2; 125 mg BID week 3. Participants who were not able to titrate higher than 100 mg BID were reported in the 100 mg BID cohort. Escalation and expansion cohorts were combined for reporting.

PF-00562271 100 mg BID

PF-00562271 administered as 105 mg PO BID w/o food (escalation cohort).

PF-00562271 105 mg BID

PF-00562271 administered as 125 mg PO BID w/food (escalation cohort). As of July 2008, participants newly enrolled to expansion cohort or who restarted treatment after dose delay associated with adverse event(s) were dosed according to intra-participant escalation (up-titration w/food): 75 mg BID week 1; 100 mg BID week 2; 125 mg BID week 3.

Additional participants were to be enrolled to the expansion cohort at the maximum tolerated dose (MTD) 125 mg BID (expansion cohort \[E1 or E2\]); E1 cohort United States (US) participants received Midazolam (MDZ) syrup 2 mg per milliliter (mg/mL) as a single PO dose 24 hours prior to first PF-00562271 dose (w/o food 2 hours prior to and after MDZ dosing) and on Cycle 1, Day 21 simultaneously with PF-00562271 dosing (w/food). E1 participants outside the US and E2 participants were not dosed with MDZ.

Escalation and expansion cohorts were combined for reporting.

PF-00562271 125 mg BID

PF-00562271 administered as 150 mg PO BID w/food (escalation cohort).

PF-00562271 150 mg BID

PF-00562271 administered as 125 mg PO once a day (QD) w/o food (escalation cohort).

PF-00562271 125 mg QD

PF-00562271 administered as 175 mg PO QD w/o food (escalation cohort).

PF-00562271 175 mg QD

PF-00562271 administered as 225 mg PO QD w/o food (escalation cohort).

PF-00562271 225 mg QD

PF-00562271 dose escalation administered as 5 mg PO BID up to 150 mg PO BID or 125 mg PO QD up to 225 mg PO QD. Participants in the PF-00562271125 mg BID US E1 cohort administered MDZ 2 mg/mL as a single dose on C1.D1 and C1.D21 prior to PF-00562271 dosing.

Entire Study Population

Age Continuous

Sex: Female, Male

PET and RECIST Response Analysis Sets as defined in Protocol Amendment 3 dated 20Mar2007 are reported in Basic Results per the revised definitions in Statistical Analysis Plan version 2 dated 11Apr2008.

Mitchell Keegan

PF-00562271 administered as 75 mg PO BID with food (w/food: regular meal 200 to 800 calories) (escalation cohort).

As of July 2008, participants newly enrolled to expansion cohort or who restarted treatment after dose delay associated with adverse event(s) were dosed according to intra-participant escalation (up-titration): 75 mg BID week 1; 100 mg BID week 2; 125 mg BID week 3. Participant who was not able to titrate higher than 75 mg BID was reported in the 75 mg BID cohort.

PF-00562271 administered as 100 mg BID w/food (escalation cohort). As of July 2008, participants newly enrolled to expansion cohort or who restarted treatment after dose delay associated with adverse event(s) were dosed according to intra-participant escalation (up-titration): 75 mg BID week 1; 100 mg BID week 2; 125 mg BID week 3. Participants who were not able to titrate higher than 100 mg BID were reported in the 100 mg BID cohort.

PF-00562271 administered as 125 mg PO BID w/food (escalation cohort). As of July 2008, participants newly enrolled to expansion cohort or who restarted treatment after dose delay associated with adverse event(s) were dosed according to intra-participant escalation (up-titration): 75 mg BID week 1; 100 mg BID week 2; 125 mg BID week 3.

Additional participants were to be enrolled to the expansion cohort at the maximum tolerated dose (MTD) 125 mg BID (expansion cohort \[E1 or E2\]); E1 cohort United States (US) participants received Midazolam (MDZ) syrup 2 mg per milliliter (mg/mL) as a single PO dose 24 hours prior to first PF-00562271 dose (w/o food 2 hours prior to and after MDZ dosing) and on Cycle 1, Day 21 simultaneously with PF-00562271 dosing (w/food). E1 participants outside the US and E2 participants were not dosed with MDZ.

Safety analysis set: All enrolled participants who started treatment.

Number of Participants With First Cycle Dose Limiting Toxicities (DLTs)

PF-00562271 administered as 125 mg PO BID w/food (escalation cohort). As of July 2008, participants newly enrolled to expansion cohort or who restarted treatment after dose delay associated with adverse event(s) were dosed according to intra-participant escalation (up-titration w/food): 75 mg BID week 1; 100 mg BID week 2; 125 mg BID week 3.

Additional participants were to be enrolled to the expansion cohort at the maximum tolerated dose (MTD) 125 mg BID (expansion cohort \[E1 or E2\]); E1 cohort United States (US) participants received Midazolam (MDZ) syrup 2 mg per milliliter (mg/mL) as a single PO dose 24 hours prior to first PF-00562271 dose (w/o food 2 hours prior to and after MDZ dosing) and on Cycle 1, Day 21 simultaneously with PF-00562271 dosing (w/food). E1 participants outside the US and E2 participants were not dosed with MDZ.

Participants in the 125 mg BID expansion cohort with at least 1 dose of study treatment, at least 1 lesion with an SUV ≥5 at baseline, and an on-study PET assessment C1.D14 (Day 13 up to Day 17).

Percentage of Participants With Tumor Metabolic Response (Reduction of ≥15%) in Positron Emission Tomography With F-18-fluorodeoxyglucose (FDG-PET)

PF-00562271 administered as 125 mg PO BID w/food (escalation cohort). As of July 2008, participants newly enrolled to expansion cohort or who restarted treatment after dose delay associated with adverse event(s) were dosed according to intra-participant escalation (up-titration): 75 mg BID week 1; 100 mg BID week 2; 125 mg BID week 3.

PF-00562271 administered as 75 mg PO BID with food w/food. As of July 2008, participants newly enrolled to the expansion cohort or who restarted treatment after dose delay associated with adverse event(s) were dosed according to intra-participant escalation (up-titration w/food): 75 mg BID week 1; 100 mg BID week 2; 125 mg BID week 3. Participant who was not able to titrate higher than 75 mg BID was reported in the 75 mg BID expansion cohort.

PF-00562271 75 mg BID (Expansion Cohort)

PF-00562271 administered as 100 mg PO BID w/food. As of July 2008, participants newly enrolled to expansion cohort or who restarted treatment after dose delay associated with adverse event(s) were dosed according to intra-participant escalation (up-titration w/food): 75 mg BID week 1; 100 mg BID week 2; 125 mg BID week 3. Participants who were not able to titrate higher than 100 mg BID were reported in the 100 mg BID cohort.

PF-00562271 100 mg BID (Expansion Cohort)

PF-00562271 administered as 125 mg PO BID w/food. As of July 2008, participants newly enrolled to expansion cohort or who restarted treatment after dose delay associated with adverse event(s) were dosed according to intra-participant escalation (up-titration w/food): 75 mg BID week 1; 100 mg BID week 2; 125 mg BID week 3.

Additional participants were to be enrolled to the expansion cohort at the maximum tolerated dose (MTD) 125 mg BID (expansion cohort \[E1 or E2\]); E1 cohort United States (US) participants received Midazolam (MDZ) syrup 2 mg per milliliter (mg/mL) as a single PO dose 24 hours prior to first PF-00562271 dose (w/o food 2 hours prior to and after MDZ dosing) and on Cycle 1, Day 21 simultaneously with PF-00562271 dosing (w/food). E1 participants outside the US and E2 participants were not dosed with MDZ.

PF-00562271 125 mg BID (Expansion Cohort)

Pharmacokinetic (PK) parameter analysis set: all participants with at least 1 dose of study treatment and at least 1 of the PK parameters of interest estimated in at least 1 treatment period. Escalation cohorts: Cycle 0 48 hours post dose timepoint = C1.D1.

Maximum Serum Concentration (Cmax): PF-00562271 C0.D1, C1.D1

Maximum Serum Concentration (Cmax): PF-00562271 C1.D14

PF-00562271 administered as 100 mg BID w/food (escalation cohort). As of July 2008, participants newly enrolled to the expansion cohort or who restarted treatment after dose delay associated with adverse event(s) were dosed according to intra-participant escalation (up-titration): 75 mg BID week 1; 100 mg BID week 2; 125 mg BID week 3. Participants who were not able to titrate higher than 100 mg BID were reported in the 100 mg BID cohort.

PK parameter analysis set. Escalation cohorts: Cycle 0 48 hours post dose timepoint = C1.D1.

Time to Reach Maximum Observed Serum Concentration (Tmax): PF-00562271 C0.D1, C1.D1

Time to Reach Maximum Observed Serum Concentration (Tmax): PF-00562271 C1.D14

Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast): PF-00562271 C0.D1, C1.D1

Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf): PF-00562271 C0.D1, C1.D1

Serum Decay Half-life (t 1/2): PF-00562271 C0.D1, C1.D1

Apparent Oral Clearance (CL/F): PF-00562271 C0. D1, C1.D1

Minimum Observed Serum Trough Concentration (Cmin): PF-00562271 C1.D14

Area Under the Curve From Time Zero to the End of the Dosing Interval (AUCtau): PF-00562271 C1.D14

Observed Accumulation Ratio (Rac): PF-00562271 C1.D14

Participants in the PF-00562271 125 mg BID cohort who received MDZ (test) administered prior to PF-00562271 (reference) dosing.

C0.D1 (n=11)

C1.D21 (n=8)

N=participants in the PK parameter analysis set who received MDZ dosing prior to PF-00562271 in the 125 mg BID cohort; (n)=number of participants with analyzable data at observation.

Maximum Serum Concentration (Cmax): MDZ

Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast): MDZ

C1.D21 (n=5)

Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf): MDZ

Time to Reach Maximum Observed Serum Concentration (Tmax): MDZ

Serum Decay Half-life (t 1/2): MDZ

Apparent Oral Clearance (CL/F): MDZ

Complete response

Partial response

Stable disease

Progressive disease

Indeterminate

RECIST response analysis set: all enrolled participants who had an adequate baseline tumor assessment, measureable disease and who started treatment. N=number of participants with evaluable data at observation.

Percentage of Participants With Best Overall Response as Measured Using the Response Evaluation Criteria in Solid Tumors (RECIST)

Data was not summarized as samples were processed and analyzed later than 3 days after collection and thus the data were considered unusable.

Phosphorylated Focal Adhesion Kinase (pFAK)

Phosphorylated Mitogen Activated Pathway Kinase (pMAPK)

Phospho-SRC (pSRC)

Caspase-3

PF-00562271 administered as 125 mg PO BID w/food (escalation cohort). As of July 2008, participants newly enrolled to expansion cohort or who restarted treatment after dose delay associated with adverse event(s) were dosed according to intra-participant escalation (up-titration w/food): 75 mg BID week 1; 100 mg BID week 2; 125 mg BID week 3.

Additional participants were to be enrolled to the expansion cohort at the maximum tolerated dose (MTD) 125 mg BID (expansion cohort \[E1 or E2\]); E1 cohort United States (US) participants received Midazolam (MDZ) syrup 2 mg per milliliter (mg/mL) as a single PO dose 24 hours prior to first PF-00562271 dose (w/o food 2 hours prior to and after MDZ dosing) and on Cycle 1, Day 21 (C1.D21) simultaneously with PF-00562271 dosing (w/food). E1 participants outside the US and E2 participants were not dosed with MDZ.

Escalation and expansion cohorts were combined for reporting.

Spots Global Cancer Trial Database for Study Of PF-00562271, Including Patients With Pancreatic, Head And Neck, Prostatic Neoplasms

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Study Description

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