New Data Support the Use of Tbo-Filgrastim in Pediatric Patients

On Sunday, December 10, at the American Society of Hematology’s (ASH) 59th Annual Meeting and Exposition in Atlanta, Georgia, Noah Federman, MD, will present research from a phase 2 study on the use of subcutaneous tbo-filgrastim (Granix) in pediatric patients with solid tumors who are undergoing chemotherapy.¹

Chemotherapy-induced neutropenia, a common adverse event related to chemotherapy, can limit optimal dosing and treatment. Tbo-filgrastim, a non-glycosylated recombinant methionyl human granulocyte colony-stimulating growth factor (G-CSF), is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies who are receiving myelosuppressive anticancer therapy associated with clinically significant incidence of febrile neutropenia. Tbo-filgrastim is not technically a biosimilar of filgrastim (Neupogen), as it was approved prior to the establishment of a biosimilar approval pathway in the United States. However, tbo-filgrastim and filgrastim do not differ significantly in terms of pharmacokinetic (PK) parameters, safety, or efficacy.

This phase 2, multicenter, open-label study investigated the safety, tolerability, PK, pharmacodynamics, efficacy, and immunogenicity of tbo-filgrastim in patients aged between 1 month and 16 years who had solid tumors without bone marrow involvement, and who had received at least 1 cycle of myelosuppressive chemotherapy.

Patients (n = 50) were administered a subcutaneous dose of tbo-filgrastim at 5µg per kilogram of body weight once daily. Tbo-filgrastim administration was started at approximately 24 hours after the end of the last chemotherapy treatment, and daily dosing continued until the expected neutrophil nadir has passed and neutrophil count had recovered, but not for more than 14 days.

The most common cancers for which the 2 infants (aged 1 month to 2 years), 30 children (aged 2 years to 12 years), and 18 adolescents (aged 12 years to 16 years) were being treated were rhabdomyosarcoma (14%), neuroblastoma (14%), Ewing tumors (12%), and osteosarcoma (12%). The mean number of doses of tbo-filgrastim administered were 9.2 in children and 7.3 in adolescents. The 2 infant patients received 12 and 14 doses, respectively.

Serious treatment-emergent adverse events (TEAEs) were reported in 24% of patients, with febrile neutropenia (12%), anemia (8%), thrombocytopenia (8%), increased alanine aminotransferase (6%) and increased aspartate aminotransferase (6%) being the most commonly reported. Nine patients experienced treatment-related TEAEs, of which the most common were musculoskeletal and connective tissue disorders (8%), and which were of grade 1 severity. Two patients had increases in liver function enzymes that the investigator considered to be related to tbo-filgrastim and chemotherapy; no clinical symptoms were observed in these events, and both resolved by the end of the study. No deaths or study withdrawal occurred during the study period.

PK parameters of exposure were comparable between age groups. The incidence of severe neutropenia was 52%, and the mean duration of severe neutropenia was 1.8 days. The incidence of febrile neutropenia was 26%. Immunogenicity assessments found that none of the patients had developed anti-drug antibodies to tbo-filgrastim.

The researchers concluded that a daily dose of tbo-filgrastim at 5μg per kilogram of body weight administered to pediatric patients with solid tumors without bone marrow involvement demonstrated a safety profile consistent with the safety profile in adult patients, and that no immunogenic response was observed in this population.

"We are very excited to present the results of the first study of tbo-filgrastim in children,” Federman told The Center for Biosimilars® in an email. “As we all know, chemotherapy-induced neutropenia is a common complication from chemotherapy which may lead to prolonged hospitalization, increased morbidity, and limitation of optimal dosing of chemotherapy and treatment of cancer…G-CSF, while standard of care, is quite expensive, and there is a need for additional agents to expand access.”

At the ASH meeting, he said, “We will be sharing what I believe is quite compelling data to support the use of tbo-filgrastim in children after receiving myelosuppressive chemotherapy and applaud this momentous global collaborative effort in an orphan disease population with few approved medications.”

Reference

1. Federman N, Dragomir MD, Kizyma Z, et al. A phase 2, international, multicenter, prospective clinical trial of subcutaneous tbo-filgrastim in pediatric patients with solid tumors undergoing chemotherapy. Presented at the American Society of Hematology 59th Annual Meeting and Exposition, December 10, 2017; Atlanta, Georgia. Abstract 2271. https://ash.confex.com/ash/2017/webprogram/Paper106027.html