A Phase 1, Open-Label, Dose Escalation Study To Evaluate Safety, Pharmacokinetics And Pharmacodynamics Of PF-00562271 In Patients With Advanced Non-Hematologic Malignancies
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Verastem, Inc.
- Enrollment
- 99
- Locations
- 1
- Primary Endpoint
- Number of Participants With First Cycle Dose Limiting Toxicities (DLTs)
Study Overview
Brief 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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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.
Arms & Interventions
1
Intervention: PF00562271 (Drug)
2
Intervention: PF00562271 (Drug)
3
Intervention: PF00562271 (Drug)
4
Intervention: PF00562271 (Drug)
Outcomes
Primary Outcomes
Number of Participants With First Cycle Dose Limiting Toxicities (DLTs)
Time Frame: Baseline up to Cycle 1 Day 21 (C1.D21)
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
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 Outcomes
- 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(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(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(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(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(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(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(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(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(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)(Baseline up to 12 cycles (cycle=21days))
- Phosphorylated Focal Adhesion Kinase (pFAK)(Baseline (up to 28 days prior to first dose) up to 12 cycles (cycle=21days))
- Phosphorylated Mitogen Activated Pathway Kinase (pMAPK)(Baseline (up to 28 days prior to first dose) up to 12 cycles (cycle=21days))
- Phospho-SRC (pSRC)(Baseline (up to 28 days prior to first dose) up to 12 cycles (cycle=21days))
- Caspase-3(Baseline (up to 28 days prior to first dose) up to 12 cycles (cycle=21days))