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Pexidartinib and standard neoadjuvant therapy in the adaptively randomized I-SPY2 trial for early breast cancer
Hope S Rugo1, Mike Campbell2, Christina Yau2
1University of California San Francisco, Box 1710, San Francisco, CA, 94143, USA. hope.rugo@ucsf.edu.
Purpose:
We investigated the small-molecule receptor tyrosine kinase-inhibitor of colony-stimulating factor-1 receptor pexidartinib in the stage II/III breast cancer in the I-SPY2 platform trial.
Methods:
I-SPY2 is an adaptive platform trial that features multiple arms of experimental agents administered on a background of standard neoadjuvant therapy with paclitaxel and adriamycin/cyclophosphamide, followed by definitive surgery. The adaptive randomization engine preferentially assigns patients based upon cumulative performance of each agent in a given breast cancer subtype based on hormone receptor and HER2 receptor status. The study endpoint is pathologic complete response.
Results:
A total of 9 participants were randomized to receive pexidartinib with neoadjuvant paclitaxel before enrollment was halted due to a serious adverse event of vanishing bile duct syndrome. No participants received a full course of the study drug.
Conclusion:
Although there remains interest in agents targeting CSF-1, hepatic toxicity appears to be a limiting factor for their use in early breast cancer.
Trial Registration:
NCT01042379 ( www.
Clinicaltrials:
gov/ct2/show/NCT01042379 ).
Insights
Pexidartinib, a CSF-1 receptor inhibitor, was tested in early breast cancer but halted due to severe liver toxicity. This hepatic toxicity limits the use of CSF-1 targeting agents in this patient population.
Area of Science:
- Oncology
- Pharmacology
Background:
- The I-SPY2 trial is an adaptive platform evaluating novel therapies for high-risk, early-stage breast cancer.
- Colony-stimulating factor-1 receptor (CSF-1R) signaling is implicated in breast cancer progression.
Purpose of the Study:
- To investigate the efficacy and safety of pexidartinib, a CSF-1R inhibitor, in patients with stage II/III breast cancer.
- To assess pexidartinib's role as a neoadjuvant therapy in breast cancer within the I-SPY2 platform trial.
Main Methods:
- The I-SPY2 trial utilizes an adaptive randomization design, assigning patients to treatment arms based on tumor subtype (hormone receptor and HER2 status).
- Pexidartinib was administered in combination with standard neoadjuvant chemotherapy (paclitaxel and adriamycin/cyclophosphamide).
- The primary endpoint was pathologic complete response.
Main Results:
- Nine participants were randomized to the pexidartinib arm.
- The study was halted prematurely due to a serious adverse event of vanishing bile duct syndrome.
- No participants completed the full course of pexidartinib.
Conclusions:
- Hepatotoxicity is a significant concern for CSF-1R inhibitors, potentially limiting their clinical application in early breast cancer.
- Despite interest in targeting CSF-1 signaling, safety issues may outweigh benefits in this setting.
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