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Establishment of a Primary Culture of Patient-derived Soft Tissue Sarcoma
Published on: April 11, 2018
A Phase I Study of Ganetespib and Ziv-Aflibercept in Patients with Advanced Carcinomas and Sarcomas
Robert Meehan1, Shivaani Kummar2, Khanh Do2
1Early Clinical Trials Development Program, Developmental Therapeutics Clinic, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA.
Lessons Learned:
The combination of the antiangiogenic agent ziv-aflibercept and the heat shock protein 90 inhibitor ganetespib was associated with several serious and unexpected adverse events and was not tolerable on the dosing schedule tested.Studies such as these emphasize the importance of considering overlapping toxicities when designing novel treatment combination regimens.
Background:
Although inhibition of angiogenesis is an effective strategy for cancer treatment, acquired resistance to antiangiogenic therapy is common. Heat shock protein 90 (Hsp90) is a molecular chaperone that regulates various oncogenic signaling pathways involved in acquired resistance and has been shown to play a role in angiogenesis. Combining an antiangiogenic agent with an Hsp90 inhibitor has therefore been proposed as a strategy for preventing resistance and improving antitumor activity. We conducted a single-arm phase I study evaluating the combination of ziv-aflibercept, an antiangiogenic drug, with the Hsp90 inhibitor ganetespib.
Methods:
Adult patients were eligible if they had recurrent or metastatic gastrointestinal carcinomas, nonsquamous non-small cell lung carcinomas, urothelial carcinomas, or sarcomas that had progressed after at least one line of standard therapy. Ziv-aflibercept was administered intravenously on days 1 and 15, and ganetespib was administered intravenously on days 1, 8, and 15, of each 28-day cycle.
Results:
Five patients were treated with the combination. Although three patients achieved stable disease, study treatment was associated with several serious and unexpected adverse events.
Conclusion:
The dose escalation phase of this study was not completed, but the limited data obtained suggest that this combination may be too toxic when administered on this dosing schedule.
Insights
The combination of ziv-aflibercept and ganetespib showed serious adverse events in a phase I study for advanced cancers. This combination was not tolerable on the tested dosing schedule, highlighting the need to consider overlapping toxicities in novel treatment regimens.
Area of Science:
- Oncology
- Cancer Therapeutics
- Clinical Trials
Background:
- Antiangiogenic therapy is effective but resistance is common.
- Heat shock protein 90 (Hsp90) inhibition may overcome resistance and enhance antitumor activity.
- Combining antiangiogenic agents with Hsp90 inhibitors is a proposed strategy to improve cancer treatment.
Purpose of the Study:
- To evaluate the safety and tolerability of combining ziv-aflibercept with ganetespib in patients with advanced solid tumors.
- To assess the preliminary efficacy of this combination regimen.
Main Methods:
- A single-arm, phase I study was conducted.
- Adult patients with recurrent or metastatic gastrointestinal carcinomas, nonsquamous non-small cell lung carcinomas, urothelial carcinomas, or sarcomas were enrolled.
- Ziv-aflibercept and ganetespib were administered intravenously on specific days within 28-day cycles.
Main Results:
- Five patients were treated with the combination therapy.
- Three patients achieved stable disease.
- The combination was associated with several serious and unexpected adverse events.
Conclusions:
- The combination of ziv-aflibercept and ganetespib was not tolerable on the tested dosing schedule.
- The dose escalation was not completed due to toxicity.
- Further studies should carefully consider overlapping toxicities when designing combination regimens.
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