Phase I Study to Evaluate the Tolerability, Efficacy, and Safety of Pazopanib in Combination with PCI-24781 in Patients with Metastatic Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- PZP115891, PCI-24781
- Conditions
- Metastatic Solid Tumors
- Sponsor
- Pamela Munster
- Enrollment
- 90
- Locations
- 1
- Primary Endpoint
- Dose limiting toxicity (DLT)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This is a open-label non-randomized, dose escalation and expansion Phase Ia/Ib study to determine the safety, tolerability and maximum tolerated dose (MTD) of pazopanib in combination with PCI-24781 in patients with advanced solid tumors.
Detailed Description
Study rationale/purpose 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 progression-free survival (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.
Investigators
Pamela Munster
Professor, Department of Medicine (Hematology/Oncology), UCSF
University of California, San Francisco
Eligibility Criteria
Inclusion Criteria
- •Patients must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to adhere with treatment and followup.
- •Age ≥ 18 years
- •Phase Ia: Patients must have histologically or cytologically documented metastatic solid tumor malignancies. Phase Ib: Patients must have histologically or cytologically confirmed locally advanced, solid tumor malignancies of one of the following tumor types:
- •Renal cell carcinoma (N = 20 patients) (Cohort A)
- •Non-anaplastic thyroid carcinoma (N = 20 patients) (Cohort B) Documentation of histology from a primary or metastatic site is allowed.
- •Soft tissue sarcoma (N = 20 patients) (Cohort C). Patients must have progressed in a prior line of therapy.
- •Ovarian carcinoma (N = 20 patients) (Cohort D)
- •Measurable disease by RECIST 1.1
- •Phase Ia: Patients may have de novo metastatic disease, or documented progression despite any number of prior therapies. Patients must have no curative or other effective therapeutic options available. Phase Ib: Patients may have had any number of prior treatments, or prior pazopanib.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
Exclusion Criteria
- Not provided
Arms & Interventions
Panobinostat with PC124871
Intervention: PZP115891, PCI-24781
Outcomes
Primary Outcomes
Dose limiting toxicity (DLT)
Time Frame: up to 4 weeks
A dose limiting toxicity (DLT) will be defined as any predetermined adverse events occurring during Cycle 1 when association to therapy that is part of this study is related or possibly related
Maximum Tolerated Dose (MTD)
Time Frame: up to 4 weeks
The maximum tolerated dose (MTD) will be defined as the highest tested dose level at which less than 33% of patients experience DLT in Cycle 1
Secondary Outcomes
- Establish the half-life of PCI-24781, pazopanib and the combination of the two drugs.(up to 2 months)
- Establish the area under the curve (AUC) of PCI-24781, pazopanib and the combination of the two drugs.(up to 2 months)
- Objective response rate (ORR)(approximately 4 months)
- Establish the volume of distribution of PCI-24781, pazopanib and the combination of the two drugs.(up to 2 months)
- Establish the bioavailability of PCI-24781, pazopanib and the combination of the two drugs.(up to 2 months)
- Establish the clearance of PCI-24781, pazopanib and the combination of the two drugs.(up to 2 months)
- Overall survival (OS)(Up to 1 year)
- Duration of Response (DoR)(Up to 1 year)
- Clinical Benefit Rate (CBR)(approximately 4 months)
- Progression-free Survival (PFS)(Up to 1 year)