Clinical trial NCT00932126: This Is The First Study Using Escalating Doses Of PF-03758309, An Oral Compound, In Patients With Advanced Solid Tumors
Official title: Phase 1, Open Label, Dose-Escalation, Safety, Pharmacokinetic And Pharmacodynamic Study Of Single Agent PF-03758309, An Oral PAK4 Inhibitor, In Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Advanced Solid Tumors
Keywords: Phase 1 dose escalation dose finding pharmacokinetic and pharmacodynamic study
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2009-07-03
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is the first study using PF-03758309, an oral compound, in patients with advanced solid tumors. In this study different doses of PF-03758309 will be administered to different groups of patients. The study will assess the compound's safety, the blood levels of PF-03758309 during the treatment and the effect of the compound on the tumor cells.

Detailed description: The study was prematurely terminated on 26Jul2011 due to the undesirable PK characteristics of PF-03758309 and the lack of an observed dose-response relationship. There were no safety concerns that contributed to the study termination.

Eligibility criteria: Inclusion Criteria:

* Advanced/metastatic solid tumor that is resistant to standard therapy or for which no standard therapy is available.
* ECOG (Eastern Cooperative Oncology Group) Performance Status (PS) must be 0 or 1.
* Adequate bone marrow, liver and kidney function.

Exclusion Criteria:

* Patients with known brain metastases.
* Previous high dose chemotherapy requiring stem cell rescue.
* Prior irradiation to \>25% of the bone marrow.
* Active bacterial, fungal or viral infection including hepatitis B (HBV), hepatitis C (HCV).
* Current active treatment in another clinical study.
* Pregnancy or breast feeding.
* Active inflammatory gastrointestinal disease, chronic diarrhea (unless related to underlying malignancy or prior related treatment) or history of abdominal fistula, gastrointestinal perforation, peptic ulcer disease, or intra-abdominal abscess within 6 months prior to study enrollment.

Primary outcomes:
measure: Number of Participants With Cycle 1 Dose-limiting Toxicities (DLT)
timeFrame: Baseline (up to 30 days prior to first study drug administration) till 28 days after the last treatment administration (end of Cycle 1 [28 days])
Secondary outcomes:
measure: Number of Participants With Objective Response
timeFrame: Baseline until the date of first documented progression or discontinuation from the study due to any cause, assessed every 2 months until when the last participant was discontinued due to disease progression in Month 27 of the study
measure: Time to Tumor Progression (TTP)
timeFrame: Baseline until the date of first documented progression or discontinuation from the study due to any cause, assessed every 2 months until when the last participant was discontinued due to disease progression in Month 27 of the study
measure: Duration of Response
timeFrame: Baseline until the date of first documented progression or discontinuation from the study due to any cause, assessed every 2 months until when the last participant was discontinued due to disease progression in Month 27 of the study
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: predose, 0.5, 1, 2, 3, 5, 8, 10, 24 and 48 hours post dose, on Cycle 1 Day 8 and Cycle 2-4 Day 1 at pre-dose and 2 hours post morning dose, and on Cycle 1 Day 15 at predose, 0.5, 1, 2, 3, 5, 8 and 10 hours post morning dose
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax)
timeFrame: predose, 0.5, 1, 2, 3, 5, 8, 10, 24 and 48 hours post dose, on Cycle 1 Day 8 and Cycle 2-4 Day 1 at pre-dose and 2 hours post morning dose, and on Cycle 1 Day 15 at predose, 0.5, 1, 2, 3, 5, 8 and 10 hours post morning dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
timeFrame: predose, 0.5, 1, 2, 3, 5, 8, 10, 24 and 48 hours post dose, on Cycle 1 Day 8 and Cycle 2-4 Day 1 at pre-dose and 2 hours post morning dose, and on Cycle 1 Day 15 at predose, 0.5, 1, 2, 3, 5, 8 and 10 hours post morning dose
measure: Area Under the Concentration-Time Curve From Time 0 to 12 Hours Post Morning Dose [AUC(0-12)]
timeFrame: pre-dose and 12 hours post morning dose
measure: Minimum Observed Plasma Trough Concentration (Cmin)
timeFrame: predose, 0.5, 1, 2, 3, 5, 8, 10, 24 and 48 hours post dose, and on Cycle 1 Day 15 at predose, 0.5, 1, 2, 3, 5, 8 and 10 hours post morning dose
measure: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)
timeFrame: predose, 0.5, 1, 2, 3, 5, 8, 10, 24 and 48 hours post dose, and on Cycle 1 Day 15 at predose, 0.5, 1, 2, 3, 5, 8 and 10 hours post morning dose
measure: PAK (p21 Activated Kinase)-Related Pathway Molecule Expression Modulation by PF-03758309 in Tumor and Surrogate Tissue
timeFrame: Screening, 0, 2, 4, and 72 hours post dose Cycle 2 Day 8. A 6th sample of hair follicle could be requested at 6 or 8 hours post-dose if necessary. For fresh tumor tissue, baseline and between Day 8 and 22 of Cycle 1 in participants with accessible tumors
measure: Baseline Tumor Expression of PAK-related Pathway Molecules and Other Known Biomarkers
timeFrame: Baseline
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: Pfizer Investigational Site
state: California
city: Aurora
country: United States
facility: Pfizer Investigational Site
state: Colorado
city: East Melbourne
country: Australia
facility: Pfizer Investigational Site
state: Victoria
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Mpilla GB, Uddin MH, Al-Hallak MN, Aboukameel A, Li Y, Kim SH, Beydoun R, Dyson G, Baloglu E, Senapedis WT, Landesman Y, Wagner KU, Viola NT, El-Rayes BF, Philip PA, Mohammad RM, Azmi AS. PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus. Mol Cancer Ther. 2021 Oct;20(10):1836-1845. doi: 10.1158/1535-7163.MCT-20-1105. Epub 2021 Jul 12.