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

Study Overview
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Brief Summary
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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.

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

Conditions
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Head and Neck Neoplasm, Prostatic Neoplasm, Pancreatic Neoplasm

Intervention / Treatment
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* Drug: PF00562271
* Drug: PF00562271
* Drug: PF00562271
* Drug: PF00562271


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: PF00562271<br>* 125 mg twice daily [BID] with food, tablet<br>|
| Experimental: 2<br> | Drug: PF00562271<br>* 125 mg BID with food, tablet<br>|
| Experimental: 3<br> | Drug: PF00562271<br>* 125 mg BID with food, tablet<br>|
| Experimental: 4<br> | Drug: PF00562271<br>* 125 mg BID with food, tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). | 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). | 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatic Neoplasm, Head and Neck neoplasm, Prostatic neoplasms; Focal Adhesion Kinase, Phase 1, Pharmacodynamics, FDG-PET