Phase I/II study of single-agent lenvatinib in children and adolescents with refractory or relapsed solid malignancies and young adults with osteosarcoma (ITCC-050)☆

Abstract

Background We report results from the phase I dose-finding and phase II expansion part of a multicenter, open-label study of single-agent lenvatinib in pediatric and young adult patients with relapsed/refractory solid tumors, including osteosarcoma and radioiodine-refractory differentiated thyroid cancer (RR-DTC) ( NCT02432274 ). Patients and methods The primary endpoint of phase I was to determine the recommended phase II dose (RP2D) of lenvatinib in children with relapsed/refractory solid malignant tumors. Phase II primary endpoints were progression-free survival rate at 4 months (PFS-4) for patients with relapsed/refractory osteosarcoma; and objective response rate/best overall response for patients with RR-DTC at the RP2D. Results In phase I, 23 patients (median age, 12 years) were enrolled. With lenvatinib 14 mg/m 2 , three dose-limiting toxicities (hypertension, n = 2; increased alanine aminotransferase, n = 1) were reported, establishing 14 mg/m 2 as the RP2D. In phase II, 31 patients with osteosarcoma (median age, 15 years) and 1 patient with RR-DTC (age 17 years) were enrolled. For the osteosarcoma cohort, PFS-4 (binomial estimate) was 29.0% [95% confidence interval (CI) 14.2% to 48.0%; full analysis set: n = 31], PFS-4 by Kaplan–Meier estimate was 37.8% (95% CI 20.0% to 55.4%; full analysis set) and median PFS was 3.0 months (95% CI 1.8-5.4 months). The objective response rate was 6.7% (95% CI 0.8% to 22.1%). The patient with RR-DTC had a best overall response of partial response. Some 60.8% of patients in phase I and 22.6% of patients in phase II (with osteosarcoma) had treatment-related treatment-emergent adverse events of grade ≥3. Conclusions The lenvatinib RP2D was 14 mg/m 2 . Single-agent lenvatinib showed activity in osteosarcoma; however, the null hypothesis could not be rejected. The safety profile was consistent with previous tyrosine kinase inhibitor studies. Lenvatinib is currently being investigated in osteosarcoma in combination with chemotherapy as part of a randomized, controlled trial ( NCT04154189 ), in pediatric solid tumors in combination with everolimus ( NCT03245151 ), and as a single agent in a basket study with enrollment ongoing ( NCT04447755 ).

Origin and Therapies of Osteosarcoma

“…A clinical trial is also underway to test the activity of Lenvatinib (targeting VEGFR, PDGFR, KIT, FGFR and RET) in relapsed patients (NCT02432274). The first published results from 31 patients show a 4-month PFS of 29% [ 273 ]. Finally, Pazopanib, a second-generation MTKi targeting VEGF, PDGFR and KIT, showed positive effects in 3 patients with relapsed OS for the second time, appearing to stabilize disease progression and thus prolong patient survival [ 274 ].…”

Challenges of Systemic Therapy Investigations for Bone Sarcomas

“…A large number of tyrosine kinase inhibitors (TKIs) have been investigated in the 21st century for many malignant diseases, both hematologic diseases and solid tumors, including osteosarcoma. There have been many prospective phase II trials of TKIs as treatments for osteosarcoma, such as sorafenib with or without everolimus, apatinib, regorafenib, cabozantinib and lenvatinib [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ], mainly targeting vascular endothelial growth factor receptor (VEGFR) and its downstream signaling pathway ( Table 1 ).…”

Lenvatinib dose, efficacy, and safety in the treatment of multiple malignancies

“…Specifically, in adults, lenvatinib plus pembrolizumab is being evaluated in patients with gastric cancer, colorectal cancer, glioblastoma, biliary tract cancer, melanoma, hepatocellular carcinoma, non-small cell lung cancer, head and neck cancer, and urothelial carcinoma [ 80 ]. Importantly, lenvatinib is also being assessed for the treatment of pediatric solid tumors as a monotherapy, in combination with everolimus, or in combination with chemotherapy [ 81 – 83 ]. The dosing paradigm employed in these studies mirrors the strategy used in adults of starting at the recommended lenvatinib dose and modifying as necessary based on adverse events; the recommended doses for lenvatinib monotherapy, lenvatinib with everolimus, and lenvatinib with chemotherapy are equivalent to those in adults [ 81 – 83 ].…”

“…Importantly, lenvatinib is also being assessed for the treatment of pediatric solid tumors as a monotherapy, in combination with everolimus, or in combination with chemotherapy [ 81 – 83 ]. The dosing paradigm employed in these studies mirrors the strategy used in adults of starting at the recommended lenvatinib dose and modifying as necessary based on adverse events; the recommended doses for lenvatinib monotherapy, lenvatinib with everolimus, and lenvatinib with chemotherapy are equivalent to those in adults [ 81 – 83 ]. As the amount of data supporting the therapeutic profile of lenvatinib continues to grow, it is important for clinicians to review dosing paradigms associated with each indication to benefit and manage patients most effectively.…”