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).

Molecular biology of rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is one of the most common extracranial solid tumours in children. Embryonal and alveolar subtypes of RMS present completely different genetic abnormalities. Embryonal RMS (eRMS) is characterised by loss of heterozygosity on the short arm of chromosome 11 (11p15.5), suggesting inactivation of a tumour-suppressor gene. In contrast, the majority (80-85%) of the alveolar RMS (aRMS) have the reciprocal chromosomal translocations 't(2;13)(q35;q14) or t(1;13)(p36;q14). t(2;13) appears in approximately 70% of patients with the alveolar subtype. The molecular counterpart of this translocation consists of the generation of a chimeric fusion gene involving the /PAX3/ gene located in chromosome 2 and a member of the fork-head family, /FOXO1/ (formerly /FKHR/), located in chromosome 13. A less frequent variant translocation t(1;13) involves another PAX family gene, /PAX7/, located in chromosome 1 and /FOXO1/ and is present in 10-15% of cases of the alveolar subtype in RMS. Recently, many studies focused on cancer have demonstrated the great potential of the genomic approach based on tumour expression profiles. These technologies permit the identification of new regulatory pathways. Molecular detection of minimal disease by a sensitive method could contribute to better treatment stratification in these patients. In RMS, the advances in the knowledge of the biological characteristics of the tumour are slowly translated into the clinical management of children with this tumour.

Natural killer cell function in children with malignant solid neoplasias.

Natural killer (NK) cell numbers and lytic activity were determined in 40 children with various types of solid malignant neoplasias and in 25 control children by NKH-1 monoclonal antibody and cytotoxicity against K562 target cells, respectively. Patients were analyzed at the time of diagnosis before initiation of therapy and followed over a median time of 15.8 months. Mean NK cell numbers and lytic activity were similar among different types of tumor analyzed. Patients with localized disease (stages I, II; n = 25) also showed values not statistically different from those of patients in advanced disease (stages III, IV; n = 15). According to their response to therapy, patients were divided into three groups: group 1 (complete remission; n = 28), group 2 (partial remission; n = 5), and group 3 (progression of disease; n = 6). Patients in group 3 showed at the time of diagnosis a mean NK activity significantly lower than that of patients in groups 1 and 2 and control children (P = 0.007). The defect in NK cell lytic capacity in vitro observed in patients with progressive disease suggests that NK cells play a role in the control of neoplastic growth in vivo and may imply that some children with refractory progressive disease can benefit from immunomodulation destined to improve the lytic potential of NK cells.

Non-Hodgkin's lymphoma after liver transplantation: response to chemotherapy.

An increased incidence of lymphoproliferative disorders in immunosuppressed organ transplant recipients has long been recognised. Lymphoproliferative disorders occur in 2% of orthotopic liver transplant patients. Different therapies have been used, but the optimal treatment remains unknown. Relatively little information is available on experience with cytotoxic chemotherapy. Three children who developed Burkitt-like, non-Hodgkin's lymphomas after liver transplantation are described. The disease failed to regress after initial management, which included a reduction in immunosuppression. With cytotoxic chemotherapy all three achieved complete remission, which continued 36+, 35+, and 16+ months after diagnosis. Results suggest that in selected cases chemotherapy can be safe in late-onset lymphomas appearing after solid organ transplantation.

[Non-Hodgkins lymphoma in childhood, preliminary results of the LSA2 L2 protocol modified by high-dose methotrexate]. / Linfoma no Hodgkin en la infancia, resultados preliminares del protocolo LSA2 L2 modificado con metotrexate a altas dosis.

From january 1982 to january 1986 we treated 23 pediatric patients who had non Hodgkin's lymphoma, with a new therapeutic protocol. This protocol is based on the LSA2 L2, modified during the induction phase with high-dose methotrexate and increasing of intrathecal therapy. Nineteen patients (83%) were in stages III and IV and the 47.4% were in stage IV. The distribution according to histology was: 10 Burkitt's undifferentiated lymphomas; 2 non-Burkitt's undifferentiated lymphomas; 5 lymphoblastic lymphomas convoluted-cells; 5 lymphoblastic lymphoma non-convoluted cells and 1 indeterminate lymphoma. The follow-up oscillated between 6 months and 4 years. The total survival rate is 82.6% with a 100% survival in stages I, II and III and 63.5% in stage IV. The survival according histology is 91.7% for undifferentiated lymphomas and 70% for lymphoblastic lymphomas; the actuarial survival rates in the two groups at 30 months are 87% and 55% respectively (p greater than 0.10). We concluded that adding high-dose methotrexate to the LSA2 L2 protocol improve the survival rate in undifferentiated lymphomas and in a less extent in lymphoblastic lymphomas, without significant toxicity. This new protocol is mainly indicated in undifferentiated and indeterminate non-Hodgkin's lymphomas.

Late recurrent metastasis in Wilms' tumour.

Recurrence of Wilms' tumour after 5 years of disease-free survival is rare. We present the case of a 26-year-old man who had been diagnosed of Wilms' tumour at the age of 6 years treated by surgery, chemotherapy, and radiotherapy and who remained disease free for 8 years, after which lung metastases were detected. Second complete remission was attained with surgery and chemotherapy and 20 years after initial diagnosis he again presented with lung metastases, similarly achieving complete remission with surgery and second-line chemotherapy. The clinical and biological aspects of late metastasis in this neoplasm are discussed.

[Neuroblastoma IV-S. A series of 7 cases]. / Neuroblastomas IV-S. Serie de siete casos.

A review of the findings in seven cases of stage IV-S neuroblastoma, that have been observed between 1966 and 1984. Patients under one year stage IV-S neuroblastoma have a favorable prognosis; survival rate was 71%. Primary tumor in some may be relatively small. Chemotherapy and radiation therapy may not be necessary in the management of certain children.