Phase I Tolerability, Efficacy, and Safety Study of Pazopanib in Combination With PCI-24781 in Patients With Metastatic Solid Tumors
This is a open-label non-randomized, dose escalation and expansion Phase Ia/b study to determine the safety, tolerability and maximum tolerated dose (MTD) of pazopanib in combination with PCI-24781 in patients with advanced solid tumors.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Study to Evaluate the Tolerability, Efficacy, and Safety of Pazopanib in Combination With PCI-24781 in Patients With Metastatic Solid Tumors|
- To determine the maximum tolerated dose (MTD) of pazopanib in combination with PCI-24781 in patients with advanced solid tumors [ Time Frame: Patients will be followed for the duration of treatement, an expected average of 4 months. ] [ Designated as safety issue: Yes ]
- To establish the pharmacokinetics profile of PCI-24781, pazopanib and the combination of the two drugs. [ Time Frame: PK sampling through the first 2 months of treatment. ] [ Designated as safety issue: No ]
- To obtain a preliminary assessment of efficacy as measured by the clinical benefit rate=CR+PR+SD, objective response proportion, and progression-free survival [ Time Frame: Patients will have efficacy evaluations at 2- month intervals while on treatment, an expected average of 4 months. ] [ Designated as safety issue: No ]
|Study Start Date:||May 2012|
|Estimated Study Completion Date:||October 2015|
|Estimated Primary Completion Date:||October 2014 (Final data collection date for primary outcome measure)|
|Experimental: Panobinostat with PC124871||
Drug: PZP115891, PCI-24781
PCI-24781: oral, 30 to 75 mg/m2 b.i.d. Cycle 1, Days -7 to -4 and Cycle 1 and ongoing - Days 1-5, 8-12, 15-19
PZP115891: oral, 400 - 800 mg qd 28 days per cycle
Pazopanib is a potent, multi-targeted tyrosine kinase inhibitor44 of VEGFR-1, -2, -3, PDGFR-α and -β and c-kit approved for metastatic renal cell carcinoma based on phase III data showing a significant prolongation of PFS (5 mos in pretreated patients and 8.3 mos in treatment-naïve patients). In addition recent data was presented this year, but is not yet published, with treatment-refractory sarcoma patients that showed a PFS was significantly prolonged from a median of 20 vs. 7 weeks. As can occur with all antiangiogenic agents, resistance to pazopanib may develop. Epigenetic modification with HDAC inhibitors may overcome drug resistance by causing an increase in accessibility of DNA to chemotherapeutic agents and may therefore significantly potentiate their cytotoxicity. Combination trials with chemotherapy agents are ongoing (clinicaltrials.gov.) To our knowledge, a combination trial of HDACi with anti-angiogenesis agents has not yet been performed and represents an unmet medical need.
PCI-24781 is a pan HDAC inhibitor. In cell lines tested, up-regulation and down-regulation of genes known to result in changes with signal transduction, oxidation, metabolic changes, apoptosis, proliferation, differentiation and angiogenesis were seen. In addition, ongoing single agent and combination trials have shown the drug to be effective and well-tolerated.
Hypothesis: Combining an antiangiogenic agent, such as pazopanib, with an epigenetic modifier, such as histone deacetylase inhibitor (HDACi) PCI-24781, can increase the efficacy of pazopanib as well as overcome development of resistance to pazopanib.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01543763
|Contact: Pamela Munster, MDfirstname.lastname@example.org|
|United States, California|
|UCSF Helen Diller Family Comprehensive Cancer Center||Recruiting|
|San Francisco, California, United States, 94143|
|Contact: Paula Fiermonte 415-885-7605 FiermonteP@cc.ucsf.edu|
|Principal Investigator: Pamela Munster, MD|
|Principal Investigator:||Pamela Munster, MD||University of California, San Francisco|