Low-Dose Metronomic Topotecan and Pazopanib (TOPAZ) in Children with Relapsed or Refractory Solid Tumors: A C17 Canadian Phase I Clinical Trial

Oral metronomic topotecan represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib in targeting angiogenesis. A phase I and pharmacokinetic (PK) study of this combination was performed in children with relapsed/refractory solid tumors. Oral topotecan and pazopanib were each administered daily without interruption in 28-day cycles at five dose levels (0.12 to 0.3 mg/m2 topotecan and 125 to 160 mg/m2 pazopanib powder for oral suspension (PfOS)), with dose escalation in accordance with the rolling-six design. PK studies were performed on day 1 and at steady state. Thirty patients were enrolled, with 26 evaluable for dose-limiting toxicity (DLT), with median age 12 years (3–20). Toxicities were generally mild; the most common grade 3/4 adverse events related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphopenia (11%), AST elevation (11%), and lipase elevation (11%). Only two cycle 1 DLTs were observed on study, both at the 0.3/160 mg/m2 dose level comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle 1 required treatment discontinuation. The best response was stable disease in 10/25 patients (40%) for a median duration of 6.4 (1.7–45.1) months. The combination of oral metronomic topotecan and pazopanib is safe and tolerable in pediatric patients with solid tumors, with a recommended phase 2 dose of 0.22 mg/m2 topotecan and 160 mg/m2 pazopanib. No objective responses were observed in this heavily pre-treated patient population, although 40% did achieve stable disease for a median of 6 months. While this combination is likely of limited benefit for relapsed disease, it may play a role in the maintenance setting

Low-Dose Metronomic Topotecan and Pazopanib (TOPAZ) in Children with Relapsed or Refractory Solid Tumors: A C17 Canadian Phase I Clinical Trial

Oral metronomic topotecan represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib in targeting angiogenesis. A phase I and pharmacokinetic (PK) study of this combination was performed in children with relapsed/refractory solid tumors. Oral topotecan and pazopanib were each administered daily without interruption in 28-day cycles at five dose levels (0.12 to 0.3 mg/m2 topotecan and 125 to 160 mg/m2 pazopanib powder for oral suspension (PfOS)), with dose escalation in accordance with the rolling-six design. PK studies were performed on day 1 and at steady state. Thirty patients were enrolled, with 26 evaluable for dose-limiting toxicity (DLT), with median age 12 years (3–20). Toxicities were generally mild; the most common grade 3/4 adverse events related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphopenia (11%), AST elevation (11%), and lipase elevation (11%). Only two cycle 1 DLTs were observed on study, both at the 0.3/160 mg/m2 dose level comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle 1 required treatment discontinuation. The best response was stable disease in 10/25 patients (40%) for a median duration of 6.4 (1.7–45.1) months. The combination of oral metronomic topotecan and pazopanib is safe and tolerable in pediatric patients with solid tumors, with a recommended phase 2 dose of 0.22 mg/m2 topotecan and 160 mg/m2 pazopanib. No objective responses were observed in this heavily pre-treated patient population, although 40% did achieve stable disease for a median of 6 months. While this combination is likely of limited benefit for relapsed disease, it may play a role in the maintenance setting

New World Health Organization recommendations for care of preterm or low birth weight infants: health policy

Approximately 11% of infants are born preterm, and complications of prematurity are the most common cause of death in children aged under five years. Almost one million preterm infants die each year across low, high and middle income countries. In 2021, the World Health Organization (WHO) convened a Guideline Development Group (GDG) to examine evidence and formulate recommendations for care of preterm or low birthweight (LBW) infants according to WHO Guideline Review Committee (GRC) criteria. GRADE methods were used to assess the certainty of evidence and the GDG developed judgements using the DECIDE (Developing and Evaluating Communication strategies to support Informed Decisions and practice based on Evidence) framework. Twenty-five recommendations were made; 11 recommendations were new, and 16 were for preventive and promotive care. Kangaroo Mother Care (KMC) was recommended to start immmediately after birth as routine care for all preterm or LBW newborns (except for critically ill infants who are in shock, unable to breath spontaneously after resuscitation, or require ventilatory support) both in the facility and at home. New recommendations were also made for caffeine to treat apnoea and for extubation; family involvement in routine care for preterm or LBW infants; and for post-discharge home-visit follow-up care. New recommendations were also made to consider use of probiotics, emollient therapy, caffeine for prevention of apnoea, continuous positive airway pressure (CPAP) immediately after birth (with or without respiratory distress) in infants less than 32 weeks gestational age; and for family support to enable the care of preterm or LBW infants. The recommendations confirm the pivotal role of preventive and promotive care for preterm and LBW infants, especially the importance of keeping the baby and mother together, and empowering and supporting families to care for their preterm or LBW infant. WHO is now working to help scale up care for small and sick newborns, including organizational shifts in all ‘health system building blocks’ such as infrastructure, commodities, workforce and monitoring. Funding: Nil