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)☆

N Gaspar, Q Campbell-Hewson, S Gallego Melcon, F Locatelli, R Venkatramani, S Hecker-Nolting, M Gambart, F Bautista, E Thebaud, I Aerts, B Morland, C Rossig, A Canete Nieto, A Longhi, C Lervat, N Entz-Werle, S J Strauss, P Marec-Berard, C E Okpara, C He, L Dutta, M Casanova, N Gaspar, Q Campbell-Hewson, S Gallego Melcon, F Locatelli, R Venkatramani, S Hecker-Nolting, M Gambart, F Bautista, E Thebaud, I Aerts, B Morland, C Rossig, A Canete Nieto, A Longhi, C Lervat, N Entz-Werle, S J Strauss, P Marec-Berard, C E Okpara, C He, L Dutta, M Casanova

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/m2, three dose-limiting toxicities (hypertension, n = 2; increased alanine aminotransferase, n = 1) were reported, establishing 14 mg/m2 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/m2. 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).

Keywords: lenvatinib; osteosarcoma; pediatric; solid tumors; tyrosine kinase inhibitors.

Conflict of interest statement

Disclosure SGM: personal fees from Loxo Oncology, Bayer, and EUSA Pharma, outside the submitted work. FL: consultant or advisory role for Novartis, Amgen, Bellicum Pharmaceuticals, and Pfizer; honoraria for speaking at symposia from Amgen, Novartis, bluebird bio, Miltenyi, Bellicum Pharmaceuticals, and Jazz Pharmaceuticals. FB: consultant or advisory role for Bayer, Amgen, Roche, Sanofi, and EUSA Pharma; honoraria for speaking at symposia from Amgen and Jazz Pharmaceuticals; support for attending symposia from Takeda, EUSA Pharma, Shire, and Jazz Pharmaceuticals. CR: consultant or advisory role for Amgen, Bristol Myers Squibb (BMS), Celgene, Genentech, Novartis, Pfizer, and Roche. ACN: personal fees from Bayer and EUSA Pharma, outside of the submitted work. AL: nonfinancial support and ‘other’ from PharmaMar; grants and nonfinancial support from Takeda, during the conduct of the study. SJS: consultant or advisory role for Lilly outside the submitted work. CO: employee of Eisai Ltd. CH: employee of Eisai Inc. LD: employee of Eisai Inc. MC: advisory roles for AstraZeneca, Bayer, BMS, Eisai, Lilly, and Roche outside the submitted work. All other authors have declared no conflicts of interest.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Phase I/II study of lenvatinib in children, adolescents, and young adults (up to 25 years of age with osteosarcoma) with relapsed or refractory solid tumors. BOR, best overall response; DLT, dose-limiting toxicity; DTC, differentiated thyroid cancer; ETP, etoposide; IFM, ifosfamide; LEN, lenvatinib; ORR, objective response rate; PD, progressive disease; PFS-4, progression free survival at 4 months; RD, recommended dose; TiTE-CRM, time to event continual reassessment method. a The phase I part of this study also included a dose-finding cohort for the combination of lenvatinib and chemotherapy in patients with osteosarcoma (cohort 3A) and the phase II part included an expansion cohort for the combination of lenvatinib and chemotherapy in patients with osteosarcoma (cohort 3B). These cohorts are not shown in this figure, and the results from these cohorts will be published separately. b Secondary endpoints included safety and toxicity, BOR, ORR, complete response (CR), partial response (PR), duration of response (DOR), PFS, time to progression (TTP), and disease control rate [DCR; CR + PR + durable stable disease (SD) ≥7 weeks]. c Additional secondary endpoints in phase I/II were identification of blood and tumor biomarkers, population-based pharmacokinetic (PK) parameters and the efficacy of lenvatinib as determined by OS. Exploratory endpoints included assessment of the relationship of lenvatinib exposure to clinical response.
Figure 2
Figure 2
CONSORT diagram for (A) phase I and (B) phase II. a Patients confirmed to meet eligibility requirements. b Patients who were 2 to <6 years of age were required to enter a 3-week run-in period, and received lenvatinib 5 mg/m2 to confirm tolerability before being assigned to a dose level. Of the two patients who entered the run-in period, one was enrolled at lenvatinib 11 mg/m2 and one was enrolled at lenvatinib 14 mg/m2. c Patients who were still receiving study drug or who were in survival follow-up at the cut-off date.
Figure 3
Figure 3
Maximum change in sum of diameters of target lesions in (A) phase I and (B) phase II patients with osteosarcoma.

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