While 70 to 80% of all newly diagnosed patients with adult Hodgkin lymphoma are typically cured with combination chemotherapy of three or four agents together, there still is a significant number of patients whose disease progresses after initial induction chemotherapy. For these patients, treatment options include additional courses of the same or different chemotherapy regimens followed by an autologous stem cell transplant. However, for patients whose disease returns after an autologous stem cell transplant, there currently are no approved treatment options.

A phase I study in 45 relapsed or refractory Hodgkin lymphoma patients [1] found that more than half of the 28 patients treated at doses ranging from 1.2 mg/kg to 2.7 mg/kg of brentuximab vedotin achieved an objective (measurable) response. Brentuximab vedotin is an investigational antibody-drug conjugate (ADC) that delivers a highly potent chemotherapy agent – monomethyl auristatin E – directly to Hodgkin lymphoma cells and induces cell death via an anti-CD-30 antibody.

Based on these phase I results, researchers led by the City of Hope National Cancer Center in California and The Universit… M. D. Anderson Cancer Center enrolled patients into a phase II, single-arm, multicenter study that was designed to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma who had already undergone an autologous stem cell transplant.[2]

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A total of 102 patients at 26 study centers across the United States received brentuximab vedotin (1.8 mg/kg) every three weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. The primary endpoint of the study was the overall objective response rate. Secondary endpoints included complete response rate, duration of response, progression-free survival, overall survival, and tolerability.

Similar to findings from the phase I study, tumor reduction was demonstrated in 96 patients (94%), and objective response rate was 75%. These findings were validated by an independent review committee. Thirty-four percent of patients achieved a complete remission, and median duration has not yet been reached. Brentuximab vedotin was generally well-tolerated in this patient population, with the majority of adverse events, including peripheral neuropathy, fatigue, and nausea, being grade 1 or 2.

“The responses seen in these heavily pre-treated and refractory patients suggest that, if approved by the Food and Drug Administration, brentuximab vedotin may become an important treatment option for patients with relapsed or refractory Hodgkin lymphoma,” said Robert Chen, MD, Assistant Professor, City of Hope National Medical Center in California. “Additionally, other studies are currently underway to determine if brentuximab vedotin, when used in combination with standard chemotherapy, will also improve outcomes in newly diagnosed patients, potentially changing the treatment paradigm for Hodgkin lymphoma.”

The data of this research was presented during the 52nd Annual Meeting of the American Society of Hematology in Orlando, Florida (December 4 – 7, 2010).

Results from another, unrelated, Phase II Trial of Brentuximab Vedotin (SGN-35) in Relapsed or Refractory ALCL were also presented during the meeting.[3]

The single-arm trial assessed efficacy and safety of single-agent brentuximab vedotin in relapsed or refractory systemic ALCL patients. Patients received 1.8 milligrams per kilogram of brentuximab vedotin every three weeks for up to 16 total doses. The primary endpoint of the trial was overall objective response rate as assessed by an independent central review. Response assessments were based on the rigorous and internationally established Revised Response Criteria for Malignant Lymphoma [4]. Secondary endpoints of the trial included complete response rate, duration of response, progression-free survival, overall survival and tolerability.

The median age of patients in the phase II trial was 52 years. Enrolled patients had received a median of two prior chemotherapy regimens. Sixty-two percent of patients were primary refractory, defined as patients who did not achieve a complete remission to front-line chemotherapy or who relapsed within three months of receiving front-line chemotherapy. Seventy-two percent of patients were anaplastic lymphoma kinase (ALK) negative, generally suggesting a poor prognosis. Twenty-four percent of patients did not respond to any prior treatment, and 26% had failed prior autologous stem cell transplant.

Eighty-six percent of patients achieved an objective response as assessed by an independent central review, including 53% complete remissions and 33% partial remissions. An additional three percent of patients had stable disease, five percent had progressive disease and five percent were not evaluable or were histologically ineligible. A high level of concordance was observed between independently reviewed and investigator-assessed response. Median duration of response and median progression-free survival had not yet been reached. Tumor reductions were achieved in 97% of patients. B-symptoms resolved in 82% of patients in whom such symptoms were present at baseline (14 out of 17). Thirty-one percent of patients remained on treatment. The most common adverse events were nausea (38%), peripheral sensory neuropathy (38%), fatigue (34%), fever (33%) and diarrhea (29%). The most common Grade 3 adverse events were neutropenia (21%), thrombocytopenia (14%), peripheral sensory neuropathy (10%) and anemia (7%).

“Nearly all patients in this trial had reductions in tumor volume, including a remarkable rate of complete remissions,” said Dr. Andrei Shustov, assistant professor of Hematology at the University of Washington School of Medicine and attending physician in the Hematologic Malignancies Program at the Seattle Cancer Care Alliance. “This suggests that brentuximab vedotin has the potential to provide a promising new treatment option for patients with relapsed or refractory systemic ALCL. The data are also supportive of continued clinical evaluation of brentuximab vedotin in earlier lines of ALCL treatment, and in other CD30-positive malignancies.”

“Single-agent activity of this magnitude is rarely seen in oncology. It is particularly impressive when demonstrated in a pretreated disease population,” said Dr. Pier Zinzani, Associate Professor,Institute of Hematology “Seràgnoli” University of Bologna, Italy. “There have been no major treatment advances in relapsed or refractory ALCL in many years. We are excited by the potential of adding brentuximab vedotin to the armamentarium of treatment options.”

Brentuximab vedotin (SGN-35) is being developed by Seattle Genetics is collaborating withMillennium/The Takeda Oncology Company and has received orphan drug designation in the United States and Europe for both Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL).Seattle Genetics has also received Fast Track designation from the FDA for brentuximab vedotin in Hodgkin lymphoma.