A phase Ib study of a PI3Kinase inhibitor BKM120 in combination with panitumumab in patients with KRAS wild-type advanced colorectal cancer
Background Resistance to Epidermal Growth Factor inhibition (EGFRi) in patients with KRAS wild-type (wt) Colorectal Cancer (CRC) may occur as a result of PI3K/AKT/mTOR signaling. We conducted a study to establish the recommended phase II dose (RP2D) and response rate of panitumumab, an EGFRi, plus BKM120, a PI3K inhibitor, in advanced CRC. Methods Patients with chemotherapy refractory KRAS wt CRC, who were EGFRi naive were enrolled. A 3 + 3 dose escalation design was utilized. The starting dose of panitumumab was 6 mg/kg iv every 2 weeks with BKM120 at 60 mg oral daily. Results Nineteen patients were treated and 17 were evaluable for response. The starting dose was not tolerable (mucositis, fatigue). At dose level (DL) 1, three of six patients discontinued treatment due to toxicity, DL − 1 had no significant toxicity. Panitumumab 6 mg/kg iv q 2 weeks with BKM120 60 mg given 5 out of 7 days per week was declared the RP2D. One patient (5.9%) who was PTEN and PIK3CA negative by IHC had a partial response, seven had stable disease, and nine had disease progression. Conclusion Panitumumab (6 mg/kg iv q 2 weeks) with BKM120 60 mg given 5 out of 7 days per week was declared the RP2D. Toxicities including fatigue, rash and mucositis. There was little evidence of activity in this biomarker unselected cohort.
KeywordsMetastatic colon cancer Panitumumab BKM120 Phase 1
CCTG is supported by the Canadian Cancer Society Research Institute to the Canadian Cancer Trials Group (grant #021039).
This study was carried out by the Canadian Cancer Trials Group. Novartis provided BKM120 and partial financial support for the trial.
Compliance with ethical standards
Conflict of interest
R Goodwin: Honorarium Novartis, Honorarium Amgen.
D Jonker: No conflicts of interest.
E. Chen: No conflicts of Interest.
H Kennecke: No Conflicts of Interest.
M Cabanero: No conflicts of Interest.
M Tsao: No conflicts of interest.
M Vickers: No Conflicts of Interest.
C Bohemier: No Conflicts of Interest.
H Lim: No conflicts of Interest.
H Ritter: No Conflicts of Interest.
D Tu: No Conflicts of Interest.
L Seymour: Funding to support conduct of the trial.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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