This notice was prepared by the Clinical Pharmacology Review Team including Jingyu (Jerry) Yu, Ph.D., Clinical Pharmacology and Pharmacometrics Reviewer; Liang Zhao, Ph.D., Team Leader, Division of Pharmacometrics; and Hong Zhao, Ph.D., Team Leader, Division of Clinical Pharmacology V, Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.
On March 10, 2015, the U. S. Food and Drug Administration (FDA) approved dinutuximab (Unituxin, United Therapeutics Corporation), in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. Unituxin is a disialoganglioside, GD2-binding chimeric monoclonal antibody (mAb) that binds cell surface GD2 and induces cell lysis of GD2-expressing cells through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The recommended dose of Unituxin is 17.5 mg/m2/day administered as an intravenous infusion over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles. Cycles 1, 3, 5 are 24 days in duration and cycles 2 and 4 are 32 days in duration. Verification of adequate hematologic, respiratory, hepatic, and renal function is required prior to initiation of each Unituxin course and premedication with analgesics, antihistamines, antipyretics combined with hydration is required prior to initiation of each Unituxin infusion.
The approval was based on a significantly improved event free survival (EFS) in 113 patients with high-risk neuroblastoma. Patients were 11 months to 15 years of age (median age 3.8 years). The number of EFS events (%) was 33 (29%) for the Unituxin and 13-cis-retinoic acid (RA) arm and 50 (44%) for RA alone [hazard ratio for EFS (years): 0.57; 95% CI: 0.37 to 0.89; p=0.01]. The most common adverse reactions (ARs) observed in Unituxin/RA-treated patients were primarily gastrointestinal, hematologic, electrolyte, hepatic and infusion reaction related. A detailed list can be found in the prescribing information linked below. Across clinical studies, 17% of patients tested positive for anti-dinutuximab binding antibodies. Neutralizing antibodies were detected in 3.6% of these patients.
The mean (range) terminal half-live of dinutuximab is estimated to be 10 (6 to 33) days based on a population pharmacokinetic analysis of a clinical study where Unituxin was administered in combination with RA in 27 children with high-risk neuroblastoma [age (mean±SD): 3.9±1.9 years]. Dinutuximab clearance increased with body size. No formal pharmacokinetic studies were conducted in patients with renal or hepatic impairment. Dinutuximab is not expected to have enzyme- or transporter-based drug-drug interactions.
Full prescribing information is available at go.usa.gov/3aGzP. The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the Agency's Drugs@FDA website (go.usa.gov/3aGzz).
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