Phase I Study of Ramucirumab Plus Merestinib in Previously Treated Metastatic Colorectal Cancer: Safety, Preliminary Efficacy, and Pharmacokinetic Findings
Mené sur des patients atteints d'un cancer colorectal de stade métastatique, cet essai de phase I évalue la dose maximale tolérée du ramucirumab en combinaison avec le mérestinib et analyse les caractéristiques pharmacocinétiques de cette combinaison, après l'échec de traitements à base d'oxaliplatine et/ou d'irinotécan
Background : This study evaluated safety, preliminary efficacy, and pharmacokinetics of ramucirumab plus merestinib in patients with MCR previously treated with oxaliplatin and/or irinotecan. Methods : Open‐label phase Ia/b study comprising 3+3 dose‐limiting toxicity (DLT) observation and expansion parts. Treatment was ramucirumab 8 mg/kg on days 1 and 15 and merestinib 80 mg once daily (QD; 28‐day cycle). Primary objective was safety and tolerability. Secondary objectives were pharmacokinetics and preliminary antitumor activity. Exploratory objective was biomarker associations. Results : Safety findings: DLT (proteinuria) of 7 phase Ia patients (the expansion part started at the initial recommended dose level); 16 patients (70%) with grade ≥3 treatment‐emergent adverse events (TEAEs); 10 patients (43%) with grade ≥3 treatment‐related TEAEs. The most common grade ≥3 treatment‐related TEAEs were fatigue (4 patients [17%]) and increased blood alkaline phosphatase, diarrhea, and hypertension (2 patients each [9%]). One patient discontinued treatment because of cholestatic hepatitis. Geometric mean trough concentrations at cycle 1, day 15, were ramucirumab, 24.8
μg/mL; merestinib, 130 ng/mL. No complete or partial response was seen; 12 patients (52%) achieved stable disease. Median progression
‐free survival was 3.3 months (95% confidence interval [CI]: 1.6–4.4). Median overall survival was 8.9 months (95% CI: 3.5–12.7). There were no associations between genetic alterations and efficacy.
Conclusion
:
Ramucirumab plus merestinib is tolerable and may have clinical benefit in biomarker
‐unselected, heavily pretreated patients with mCRC.
The Oncologist 2020