Safety, tolerability and pharmacokinetics of crizotinib in combination with cytotoxic chemotherapy for pediatric patients with refractory solid tumors or anaplastic large cell lymphoma (ALCL): a Children’s Oncology Group phase 1 consortium study (ADVL1212)

Exceptional response to the ALK and ROS1 inhibitor lorlatinib and subsequent mechanism of resistance in relapsed ALK F1174L-mutated neuroblastoma

“…No mutations in TP53 or other reported neuroblastoma-associated genes, including ATRX, NRAS , or PTPN1 , were identified ( Pugh et al 2013 ). As the patient's family opted against traveling for a clinical trial, ALK-targeted therapy was initiated to treat the progressive disease with the first-generation ALK inhibitor crizotinib (240 mg/m 2 /dose given twice daily), together with the standard cytotoxic chemotherapy regimen of cyclophosphamide (250 mg/m 2 /dose days 1–5) and topotecan (0.75 mg/m 2 /dose days 1–5) as per COG study ADVL1212 Arm C ( Greengard et al 2020 ). The mandible tumor progressed through this regimen during cycle 1 and palliative radiation therapy (3400 cGy) was given to the mandible to prevent airway obstruction.…”

“…Despite these preclinical data, our patient's cancer progressed through crizotinib combined with topotecan and cyclophosphamide. Combining chemotherapy with crizotinib has been tested in a pilot pediatric clinical trial (COG trial ADVL1212) ( Greengard et al 2020 ) to determine a recommended phase 2 dose. Five neuroblastoma patients enrolled on the trial with one achieving a CR (received crizotinib in combination with vincristine and doxorubicin) and another experiencing prolonged stable disease (received crizotinib with topotecan and cyclophosphamide).…”

Pursuing Precision: Receptor Tyrosine Kinase Inhibitors for Treatment of Pediatric Solid Tumors

“…The median time lag from first-in-human to first-in-child trials for oncology agents is 6.5 years [ 160 ], although efforts are underway to hasten access of new drugs to children in the US as well as in developing countries [ 161 , 162 ]. Another access issue is drug formulation, as some younger children may have difficulty with therapy unless an oral solution is available, and even then this may not be tolerable [ 130 ]. As our knowledge base grows, we are now able to identify particular mutations which may respond only to second-generation or third-generation agents.…”

“…Given that cumulative toxicity may be a larger issue with RTK inhibitors and given that demonstration of a steep dose–response curve may be less clear with these drugs, some investigators have advocated for establishing an optimal biological dose (OBD) that identifies the lowest dose at which the desired biological effect is observed [ 129 ]. Understanding the activity of RTK inhibitors at a range of dosing may be important when combining these agents with chemotherapy backbones since lower doses are often necessary to maintain tolerability [ 27 , 51 , 130 ]. In other settings, the dose of RTK inhibitors may be increased until some secondary side effect occurs.…”

Notable therapeutic response in a patient with systemic juvenile xanthogranuloma with KIF5B‐ALK fusion

“…Crizotinib has been administered for paediatric patients with anaplastic large cell lymphoma (ALCL) and solid tumours, including neuroblastoma, and its tolerability and safety have been established. 13,14 Alectinib was reported to show favourable clinical activity and was well tolerated by paediatric patients with ALK-positive ALCL that progressed under conventional chemotherapy. 15,16 In addition, alectinib had superior CNS activity and significantly delayed the progression of CNS metastases as compared with crizotinib in patients with advanced ALK-positive NSCLC.…”