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A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
Phase I Trial of Dabrafenib and Pazopanib in BRAF Mutated Advanced Malignancies
Sigurdis Haraldsdottir1, Filip Janku1, Ming Poi1
1Sigurdis Haraldsdottir, Ming Poi, Cynthia Timmers, Susan Geyer, Larry J. Schaaf, Jennifer Sexton, Lai Wei, Jennifer Thurmond, Erin M. Bertino, Kari Kendra, Amir Mortazavi, Mitch Phelps, and Manisha H. Shah, Ohio State University Medical Center, Columbus, OH; Sigurdis Haraldsdottir, Stanford University, Stanford, CA; Filip Janku, Vivianne Velez-Bravo, Vanda M. Stepanek, and Vivek Subbiah, University of Texas MD Anderson Cancer Center, Houston, TX; and Susan Geyer, University of South Florida, Tampa, FL.
Purpose:
Several tumor types carry BRAF mutations and vascular endothelial growth factor pathway upregulation. Resistance mechanisms to BRAF inhibitors can include platelet-derived growth factor-β upregulation. Dabrafenib, a BRAF inhibitor, and pazopanib, a multikinase inhibitor that targets vascular endothelial growth factor and platelet-derived growth factor, have not been combined previously. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of the combination.
Patients And Methods:
Patients with any advanced BRAF mutated malignancy with adequate organ function were eligible. Prior use of dabrafenib or pazopanib was not allowed. Dosages started at dabrafenib 50 mg twice a day and pazopanib 400 mg daily on dose level (DL) 1, with maximum dosages of 150 mg twice a day and 800 mg daily on DL5. Pharmacokinetics and BRAF V600E plasma clone were measured, and efficacy was evaluated by imaging and tumor markers every 8 weeks.
Results:
Twenty-three patients with 11 different tumor histologies were enrolled in five DLs. Two dose-limiting toxicities were observed-a grade 3 bowel perforation on DL3 and grade 3 arthralgia on DL5. Common drug-related adverse events included nausea (52%), skin papules (43%), diarrhea (39%), hand-foot syndrome (30%), anemia (26%), rash (22%), vomiting (22%), hypophosphatemia (22%), and transaminitis (22%). Five patients (22%) experienced a partial response, including low-grade ovarian serous carcinoma, thyroid cancer, and glioblastoma multiforme, and two patients (appendiceal and thyroid cancer) had stable disease > 6 months. Pharmacokinetic measurements revealed pazopanib levels < 17.5 μg/mL in 80% of treated patients at steady state, particularly at DL5. BRAF V600E plasma copies correlated with response and progression.
Conclusion:
Combination dabrafenib and pazopanib had no unexpected toxicities, and durable partial responses were observed at DL3 or greater. Dose escalation beyond DL5 may be considered as pazopanib levels were suboptimal as a result of drug interaction with dabrafenib.
Insights
This phase I study combined dabrafenib and pazopanib in advanced BRAF-mutated cancers. The combination showed manageable toxicities and durable partial responses, suggesting potential for further dose escalation.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- BRAF mutations are prevalent in various cancers.
- Resistance to BRAF inhibitors can involve platelet-derived growth factor-β (PDGF-β) upregulation.
- Pazopanib targets vascular endothelial growth factor (VEGF) and PDGF pathways.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, and pharmacodynamics of combining dabrafenib and pazopanib.
- To determine the maximum tolerated dose (MTD) of the combination therapy.
- To assess preliminary efficacy in patients with advanced BRAF-mutated malignancies.
Main Methods:
- Phase I clinical trial enrolling patients with advanced BRAF-mutated cancers.
- Dose escalation study with dabrafenib and pazopanib across five dose levels (DLs).
- Safety, pharmacokinetic, pharmacodynamic, and efficacy assessments were performed.
Main Results:
- Twenty-three patients with 11 tumor types were enrolled.
- Common adverse events included nausea, skin papules, and diarrhea.
- Partial responses were observed in 22% of patients, including ovarian serous carcinoma, thyroid cancer, and glioblastoma.
- Suboptimal pazopanib levels were noted, potentially due to drug interaction.
Conclusions:
- Combination dabrafenib and pazopanib demonstrated no unexpected toxicities.
- Durable partial responses were achieved at dose level 3 and higher.
- Further dose escalation may be considered, addressing potential drug interactions affecting pazopanib levels.
