Dr. Marachelian and her team have demonstrated that there is a new treatment that is equivalent to a product that has been manufactured for commercial use and should be made available to patients outside of clinical trials.
Principal investigator Araz Marachelian, MD, of Children’s Hospital Los Angeles (CHLA), and colleagues at pediatric academic centers across the United States have been studying immunotherapy for 2 decades. Dr. Marachelian and her team have demonstrated that there is a new treatment that is equivalent to a product that has been manufactured for commercial use and should be made available to patients outside of clinical trials.
Dinutuximab (Unituxin™; ch14.18), is a monoclonal antibody that targets disialoganglioside (GD2), which has demonstrated improved survival in patients with high-risk neuroblastoma. The Children’s Oncology Group (COG) conducted a randomized, phase III trial of dinutuximab and found that children treated with the dinutuximab experienced event-free survival (EFS) and improved overall survival (OS) compared with patients who did not receive the immunotherapy. This study was published January 20, 2016, in Cancer Chemotherapy and Pharmacology.
Neuroblastoma most commonly arises in and around the adrenal glands, which have similar origins to nerve cells and sit atop the kidneys. However, neuroblastoma can also develop in other areas of the abdomen and in the chest, neck, and near the spine, where groups of nerve cells exist and accounts for approximately 7% of cancers in children younger than 15 years.
Nearly half of patients present with metastatic disease and have a 5-year EFS of less than 50%. While patients do respond to treatments such as chemotherapy, radiation, surgery, and autologous stem cell transplantation (ASCT), 5-year EFS survival rates are less than 50%, so it was pivotal for new treatment options to become available outside of clinical trials.
The primary objective of this study was to compare the pharmacokinetics of dinutuximab manufactured by National Cancer Institute (NCI) and United Therapeutics Corporation (UTC). The secondary objective was to compare how patients tolerated the doses and to determine its level of safety.
Patients were randomly assigned 1:1 to receive either ch14.18-UTC or ch14.18-NCI during cycles 1 and 2, followed by ch14.18 from the other product during cycles 3 through 5. Eligible patients were randomly assigned between 56 and 105 days after ASCT, and also radiotherapy, if necessary.
To be considered eligible, 28 patients who were 8 years old or younger had been diagnosed with high-risk neuroblastoma, and had completed standard induction therapy, surgery, myeloablative therapy, ASCT, and local radiotherapy to the primary tumor if indicated. The patients received equivalent ch14.18-UTC or ch14.18-NCI doses. Despite comparable protein content, nominal doses differed: 17.5 mg/m2/day (ch14.18-UTC) and 25 mg/m2/day (ch14.18-NCI). Patients received one product during therapy cycles 1 and 2, the other during cycles 3–5. Ch14.18 pharmacokinetic profile characterization used population modeling (NONMEM® version 7.2).
Because of the study complexity and data limitations, a model-based approach was used to assess the pharmacokinetic comparability of ch14.18-UTC and ch14.18-NCI.
All patients received at least one dose of ch14.18 and were included in the safety analysis. Seven patients discontinued the study prior to completion of the planned 6 cycles due to disease progression (n = 2), adverse events (n = 2), or withdrawal of consent (n = 1). Two patients received cycles 1–5 in the United States and returned to their home country to complete cycle 6. Ch14.18 was administered over a median duration of 11 hours (range 10–20 hours).
The researchers concluded that the ch14.18-UTC dose of 17.5 mg/m2 is comparable to the ch14.18-NCI dose of 25 mg/m2 in terms of systemic exposure and with no notable safety and tolerability differences. “After a two year study that compared commercially manufactured dinutuximab to the material produced by NCI, we see no difference in how patients metabolize or respond to the treatment,” said Dr. Marachelian in a CHLA press release.
Side effects included pyrexia (100%), hypoalbuminemia (96%), hypokalemia (96%), hyponatremia (82%), cough (75%), increased ALT (68%), anemia (68%), hypocalcemia (68%), pain (68%), pruritus (68%), increased AST (64%), hypertriglyceridemia (64%), and abdominal pain (61%), but were considered tolerable.
Through the New Approaches to Neuroblastoma Therapy (NANT) consortium, Dr. Marachelian is currently leading two active trials investigating the use of dinutuximab in combination with other agents.