Phase 1b study of galunisertib and ramucirumab in patients with advanced hepatocellular carcinoma
James J Harding1,2, Richard K Do1,2, Amin Yaqubie1
1Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Background:
Preclinical data suggest that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β signaling interact to stimulate angiogenesis and suppress antitumor immune responses. Thus, combined inhibition of both pathways may offer greater antitumor activity compared with VEGF-targeted antiangiogenic monotherapy against hepatocellular carcinoma (HCC).
Methods:
This is a multicenter, open-label, phase 1b study of galunisertib, an inhibitor of TGF-β receptor 1, and ramucirumab, an anti-VEGF receptor 2 antibody, in patients with advanced HCC aiming to define the maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics (PK), antitumor efficacy, and plasma alpha-fetoprotein and TGF-β kinetics. Dose escalation employed a 3 + 3 design. Patients received galunisertib at 80 mg (cohort 1) or 150 mg (cohort 2) orally twice a day on days 1-14 of a 28-day cycle combined with ramucirumab 8 mg/kg intravenously every 2 weeks.
Results:
Eight patients were enrolled: three in cohort 1 and five in cohort 2 (two patients were unevaluable due to rapid disease progression and replaced). No dose-limiting toxicities were observed. Treatment-related adverse events (AEs) of any grade in ≥2 patients included nausea (25%) and vomiting (25%). There was one Grade 3 treatment-related AE, a cerebrovascular accident possibly related to ramucirumab. Galunisertib exposure was dose-proportional and not affected by ramucirumab. The RECIST version 1.1 objective response rate and disease control rate were 0% and 12.5%, respectively.
Conclusion:
Combination therapy was safe and tolerable and displayed favorable PK. The MTD was established at galunisertib at 150 mg orally twice a day and ramucirumab 8 mg/kg intravenously every 2 weeks. The results do not support the preclinical hypothesis that blocking TGFβ signaling enhances efficacy of VEGF-targeted therapy; thus further clinical development was halted for the combination of galunisertib and ramucirumab.
Insights
This phase 1b study combined galunisertib (TGF-β inhibitor) and ramucirumab (VEGF inhibitor) for advanced hepatocellular carcinoma (HCC). The combination was safe but did not show enhanced antitumor activity, halting further development.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Preclinical data suggest synergistic effects of inhibiting vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-β) signaling in hepatocellular carcinoma (HCC).
- Combined inhibition may enhance antitumor activity compared to VEGF-targeted monotherapy.
Purpose of the Study:
- To evaluate the safety and tolerability of combining galunisertib (TGF-β receptor 1 inhibitor) with ramucirumab (anti-VEGF receptor 2 antibody) in advanced HCC.
- To determine the maximum tolerated dose (MTD) and assess pharmacokinetics (PK), antitumor efficacy, and biomarker kinetics.
Main Methods:
- A multicenter, open-label, phase 1b study using a 3+3 dose escalation design.
- Patients received escalating doses of galunisertib (80 mg or 150 mg BID) with ramucirumab (8 mg/kg IV every 2 weeks).
- Safety, PK, objective response rate (ORR), and disease control rate (DCR) were assessed.
Main Results:
- Eight patients were enrolled; no dose-limiting toxicities were observed.
- The MTD was established at galunisertib 150 mg BID and ramucirumab 8 mg/kg IV every 2 weeks.
- The ORR was 0% and DCR was 12.5%; common adverse events included nausea and vomiting.
Conclusions:
- The combination of galunisertib and ramucirumab was safe and tolerable in advanced HCC patients.
- The combination did not support the preclinical hypothesis of enhanced efficacy, leading to the discontinuation of further clinical development for this combination.
