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).

Host feeding patterns of Culex vishnui sub group of mosquitoes in Dibrugarh district of Assam.

The host feeding patterns of three species of mosquitoes belonging to vishnui sub group, Culex tritaeniorhynchus, Culex vishnui and Culex pseudovishnui, the most prevalent species in Dibrugarh district were determined by analysing their blood meals. All 3 species were found be essentially zoophilic. High percentage of pig feeding was observed in Culex tritaeniorhynchus (40 per cent) and Culex vishnui (35.3 per cent) in comparison to other prevalent species in this area. In contrast Culex pseudovishnui another member of this group was not attracted to pigs (0.4 per cent). Few human feeds were recorded for Culex tritaeniorhynchus (0.4 per cent), Culex vishnui (0.4 per cent) and Culex pseudovishnui (0.8 per cent), indicating their occasional contact with human hosts. Considering the importance of this group as proven vectors of Japanese encephalitis the relevance of these results to JE transmission in this area are discussed.

Anopheline fauna of parts of Tirap district, Arunachal Pradesh with reference to malaria transmission.

In a survey on the anopheline fauna in highly malaria endemic areas of the Tirap district of Arunachal Pradesh, 7476 anophelines belonging to 17 species were collected, including seven species of anophelines which are recognized malaria vectors in India. Anopheles tessellatus and A. jamesii were recorded for the first time in this area. The parasitological survey revealed that the area was endemic for malaria particularly P. falciparum, the slide positivity rate and slide falciparum rate being 25.63 and 19.21 per cent respectively. On dissection of 10 anopheles species, malarial infection was detected in two viz., A. minimus and A. dirus.

Genotoxic effect of smoke-dried meat extract in Swiss albino mice using sperm head shape abnormality test.

The genotoxic effect of an extract of smoke-dried meat was assayed by employing in vivo sperm head shape abnormality. A significant dose responsive mutagenic effect was observed using the sperm head shape abnormality test. The result indicates that higher doses i.e., 100 and 200 mg/kg body wt. of smoke meat extract, significantly induced sperm head shape abnormality as compared to lower doses i.e., 20 mg/kg body wt. and control.

Epidemiological observations on malaria in some parts of Tengakhat PHC, Dibrugarh district, Assam.

A three year study carried out in 44 villages (pop. 17,938) reveals seasonal transmission of malaria i.e., from June to November. The incidence of malaria was high in the year 1988 in comparison to that of 1987 and 1989. P. falciparum was the predominant species. The population living in forest fringe areas were more prone to malaria than the rest. Anopheles nigerrimus, An. kochi, An. karwari and An. philippinensis were most abundant among the 16 anopheline species collected. Known vectors of malaria such as An. minimus, An. philippinensis, An. annularis and An. dirus were detected. An. dirus was incriminated as vector during this study.

Incrimination of Anopheles dirus as a vector of malaria in Dibrugarh district, Assam.

Anopheles nigerrimus, A. vagus, A. dirus, A. karwari and A. kochi were the most abundant species among 12 anopheline species collected during the course of entomological studies carried out from July to September, 1988 in an area endemic for malaria under Tengakhat PHC of Dibrugarh district, Assam. Sporozoites were detected in the salivary glands of one specimen of A. dirus, Peyton & Harrison (A. balabacensis) which constituted about 18.11 per cent of the total anopheline collection.

The importance of Anopheles dirus (A. balabacensis) as a vector of malaria in northeast India.

Anopheles dirus (A. balabacensis) is the most prevalent among twelve anopheline species collected during the course of entomological studies carried out in Changlang district of Arunachal Pradesh during July and August, 1988. It is observed to be a forest species and is found to breed in small stagnant water pools completely or partially shaded by plants in the open jungle. Sporozoites have been detected in several specimens of A. dirus (A. balabacensis) supporting its role in transmission of malaria in forest areas.