Six out of nine pediatric patients with relapsed or refractory Hodgkin lymphoma (HL) (n=5)or systemic anaplastic large cell lymphoma (sALCL) (n=4)achieved complete remission (CR) in multicenter phase I and phase II trials of Brentuximab Vedotin ( SGN-35 and previously called cAC10-vcMMAE; now marketed as Adcetris™ by Millennium: The Takeda Oncology Company and Seattle Genetics, Inc). The remaining three patients achieved stable disease (SD). Five of the 6 patients with CR remained in remission after follow-up that ranged from 3 to more than 15 months.
The was data reported during an oral presentation at the 2011 European Multidisciplinary Cancer Congress, the rebranded European oncology meeting encompassing the 16th ECCO, the 36th ESMO and the 30th ESTRO Congresses as well as the essential contribution of all ECCO’s other Founding Members in partnership – ESSO, EACR, EONS and SIOPE. The meeting is being held from September 23 – 27, in Stockholm, Sweden. The study results were based on a retrospective analysis of pediatric patients between 12 and 17 years who had failed at least one prior chemotherapy regimen.
Cancers of the lymphatic system
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell . The Reed-Sternberg cell generally expresses CD30 . Systemic ALCL is an aggressive type of T-cell non-Hodgkin lymphoma that also expresses CD30.
“Both Hodgkin lymphoma and systemic ALCL are relatively common pediatric lymphomas, but few options are available to patients who relapse or are refractory to treatments,” said Dr. Michelle Fanale, M.D. Anderson Cancer Center, Houston Texas. “It is encouraging that Brentuximab Vedotin resulted in complete remissions in six of nine patients and was generally well tolerated. These data support the further investigation of Brentuximab Vedotin in children and adolescents with CD30-positive lymphomas.”
Brentuximab vedotin is an antibody-drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE). The drug is based on proprietary technology from Seattle Genetics. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.
The marketing authorization application for Brentuximab Vedotin in relapsed or refractory HL and sALCL, filed by Takeda Global Research & Development Centre (Europe), was accepted by the European Medicines Agency in June 2011. Brentuximab Vedotin was granted accelerated approval by the U.S. Food and Drug Administration in August 2011 for the treatment of patients with HL after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates, and the treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. These indications are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with Brentuximab Vedotin. Brentuximab Vedotin has not been approved for the treatment of pediatric patients.
“The approval of Brentuximab Vedotin is a result of more than a decade of research and development by talented scientists and physicians. The company has deep appreciation for the hundreds of patients who participated in ADCETRIS trials, and the passion and determination of the clinicians at sites around the world in investigating this first in a new class of targeted anticancer agents. We are committed to continued clinical investigation through a broad development program for CD30-positive malignancies, including confirmatory trials in front-line Hodgkin and T-cell lymphomas that we have planned in consultation with the FDA,” said Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.
“The marked single agent activity seen with Brentuximab Vedotin, including a high durable complete remission rate, offers an opportunity to improve the treatment paradigm of patients for whom the treatment is indicated,” said Owen A. O’Connor, M.D., Ph.D., Professor, and Director, Division of Hematology and Medical Oncology at NYU Cancer Institute. “Brentuximab Vedotin represents a major advancement in the care of these patients. It is the first drug approved by the FDA for Hodgkin lymphoma in more than 30 years, and provides a new therapeutic alternative for Hodgkin lymphoma and systemic ALCL.”
Brentuximab Vedotin was associated with generally manageable adverse events; the most common, determined as treatment-emergent events occurring in more than 4 patients, were nausea (n=6), peripheral neuropathy (n=6), fatigue (n=5), cough (n=4), mouth and throat pain (n=4), and fever (n=4). Adverse events of Grade 3 or higher were neutropenia (n=3), decrease in white blood cell count (n=1), thrombocytopenia (n=1), catheter site infection (n=1), and hyperesthesia (n=1)
Patients received intravenous Brentuximab Vedotin as a 30-minute outpatient infusion in weekly treatment cycles (3 out of 4 weeks) at doses of 0.8 or 1.2 milligrams per kilogram (mg/kg) or every 3 weeks at doses of 1.2 or 1.8 mg/kg. There were no deaths or discontinuations due to treatment in this subset of pediatric patients.