Lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma (ITCC-050): a multicentre, open-label, multicohort, phase 1/2 study

Background: Tyrosine kinase inhibitors have shown activity in osteosarcoma and might enhance the efficacy of chemotherapy. We aimed to determine the recommended phase 2 dose and antitumour activity of lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma. // Methods: This multicentre, open-label, multicohort, phase 1/2 trial was done at 17 hospitals in six countries. Eligible patients were aged 2–25 years, had relapsed or refractory osteosarcoma, measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Lansky play–performance score or Karnofsky performance score of 50% or higher, up to one previous VEGF or VEGF receptor-targeted therapy, and a life expectancy of at least 3 months. This study includes a combination dose-finding phase 1 part (cohort 3A) and a phase 2 combination expansion in patients with osteosarcoma (cohort 3B). Lenvatinib was administered orally at a starting dose of 11 mg/m2 per day, capped at 24 mg per day, and etoposide (100 mg/m2 per day) plus ifosfamide (3000 mg/m2 per day) were administered intravenously on days 1–3 of each 21-day cycle for a maximum of five cycles. Lenvatinib monotherapy continued after these five cycles until disease progression, toxic effects, or patient choice to discontinue. The phase 1 primary endpoint was to determine the recommended phase 2 dose by evaluating dose-limiting toxicity and the phase 2 primary endpoint was progression-free survival at 4 months. Progression-free survival was measured in the full analysis set, which included all patients enrolled for efficacy outcomes; safety was assessed in all patients who received any study drug. This study is registered with ClinicalTrials.gov, NCT02432274. // Findings: 30 patients were screened for enrolment into cohort 3A between May 9, 2016, and June 3, 2019, and 22 patients for enrolment into cohort 3B between Sept 13, 2018, and July 18, 2019. Eight patients from cohort 3A and two from cohort 3B were ineligible for enrolment in the study. In phase 1, dose-limiting toxicities were observed in three patients (one in the lenvatinib 11 mg/m2 combination group and two in the 14 mg/m2 combination group) and the recommended phase 2 dose was determined as lenvatinib 14 mg/m2 per day (with daily dose cap of 24 mg) and etoposide 100 mg/m2 per day plus ifosfamide 3000 mg/m2 per day administered intravenously on days 1–3 of each 21-day cycle for a maximum of five cycles. 35 patients from phase 1 (cohort 3A; n=15) and phase 2 (cohort 3B; n=20) were treated at the recommended phase 2 dose and their results were pooled. Progression-free survival at 4 months was 51% (95% CI 34–69) in 18 of 35 patients per the binomial estimate. The most common grade 3–4 treatment-emergent adverse events were neutropenia (27 [77%] of 35), thrombocytopenia (25 [71%]), anaemia (19 [54%]), and decreased white blood cell count (19 [54%]). 26 [74%] of 35 patients had serious treatment-emergent adverse events and no treatment-related deaths occurred. // Interpretation: Lenvatinib with etoposide plus ifosfamide shows promising antitumour activity with no new safety signals in patients with refractory and relapsed osteosarcoma. These findings warrant further investigation in an ongoing randomised phase 2 study (NCT04154189)

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)

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)

Incidence and prognostic value of tumour cells detected by RT–PCR in peripheral blood stem cell collections from patients with Ewing tumour

To retrospectively evaluate the incidence of tumour cell contamination of peripheral blood stem cell (PBSC) collections and to correlate these data with the clinical outcome after high-dose chemotherapy (HDCT) with stem cell rescue in patients with a high-risk Ewing tumour. Peripheral blood stem cell collections obtained from 171 patients were analysed. Tumour contamination was assessed by reverse transcriptase–polymerase chain reaction (RT–PCR). The files of 88 patients who underwent HDCT followed by PBSC reinfusion were reviewed in detail, and their outcome compared to the PBSC RT–PCR results. Seven of 88 PBSC collections (8%) contained tumour cells as detected by RT–PCR. Peripheral blood stem cells were collected after a median of five cycles of chemotherapy. No clinical factor predictive of tumour cell contamination of PBSC harvest could be identified. Event-free survival (EFS) and overall survival (OS) of the whole study population were 45.3 % and 51.8 % at 3 years from the date of the graft, respectively. Forty-five patients relapsed with a median time of 15 months after graft, only four of whom had tumour cell contamination of the PBSC harvest. Tumour cell contamination of PBSC collection is rare and does not seem to be associated with a significantly poorer EFS or OS in this high-risk population

Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. Methods We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry). Results We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively;P-value < 5x10(-8)) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84x10(-8)). Conclusions: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. Impact Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci

Implementation of a program based on adapted physical activity and recommendations for second cancers prevention for adolescents and young adults with cancer

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Percutaneous cryotherapy for pain treatment of spindle cell hemangioendothelioma of the hand

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Radiofrequency Ablation of Metastases from Osteosarcoma in Patients Under 25 Years: The SCFE Experience

International audienceBACKGROUND:Radiofrequency ablation (RFA) has demonstrated its effectiveness in controlling metastases measuring less than 3 cm in several adult malignancies but not yet in osteosarcoma. We report our experience of RFA in the treatment of metastases in adolescents and young adults (AYA) with osteosarcoma.PROCEDURE:Sixteen patients treated for osteosarcoma in French Society of Childhood Cancer centers had undergone an RFA procedure between 2006 and 2012.RESULTS:Thirteen sessions were performed in 10 patients to treat 22 lung metastases. Seven patients were in complete remission at last follow up (range 19-51 months; median, 24 months after RFA). None had a recurrence at RFA sites. We report three cases each of hemoptysis and pneumothorax. Eight sessions were performed in seven patients to treat bone lesions. PROCEDURE was intended as: curative for a small metastatic lesion (n = 3, all in remission more than 3 years after); local control of small bone lesions in multi-metastatic diseases (n = 3); analgesia (n = 1). Complications included one first-degree burn, one fracture, and one soft tissue infection.CONCLUSIONS:RFA is feasible in AYA with osteosarcoma. It efficiently achieved local control of small peripheral lung metastases. Its role in the curative care of small secondary bone lesions remains to be confirmed