Interim results from a phase I clinical trial of brentuximab vedotin(SGN-35, Adcetris™, Seattle Genetics/Millennium: The Takeda Oncology Company) in combination with chemotherapy for the treatment of newly diagnosed advanced stage Hodgkin lymphoma (HL) patients were presentedAnas Younes, MD, Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center at the 53rd annual meeting of the American Society of Hematology on December 10-13, 2011 in San Diego, CA. 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 (HL) and non-Hodgkin lymphoma (NHL). 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.

Therapeutic options
According to the American Cancer Society, more than 8,800 cases of Hodgkin lymphoma will be diagnosed in the United States during 2011 and approximately 1,300 people will die from the disease. Globally, there are more than 30,000 cases of Hodgkin lymphoma diagnosed each year. Although front-line combination chemotherapy can result in durable response rates, up to 30% of these patients relapse or are refractory to front-line treatment and have few therapeutic options beyond ASCT.

Phase I brentuximab vedotin concomitantly with ABVD or AVD
In the phase I trial, patients received brentuximab vedotin concomitantly with either ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) or AVD, which removes bleomycin from the regimen. The trial was designed to establish the safety profile and maximum tolerated dose when adding brentuximab vedotin to ABVD or AVD.

ADC Bio
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MabPlex
 

Mechanism of Action
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), utilizing Seattle Genetics’ proprietary technology. MMAE is a synthetic antineoplastic agent which inhibits cell division by blocking the polymerisation of tubulin. Because of its toxicity, it cannot be used as a drug itself. Instead, it is linked to a monoclonal antibody which directs it to cancer cells. 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. Once the conjugate has entered a tumor cell, it is cleaved by cathepsin, activating the antimitotic mechanism.

Study protocol
The trial included a total of 44 patients treated with front-line therapy with this drug combined with ABVD or AVD in patients with newly diagnosed advanced stage hodgkin lymphoma. Twenty-five patients were treated in brentuximab vedotin plus ABVD cohorts and 19 in the brentuximab vedotin plus AVD cohorts. All patients were previously untreated with Stage IIa bulky disease or Stage IIb-IV Hodgkin lymphoma. No dose-limiting toxicity was observed at the maximum planned dose of brentuximab vedotin (1.2 milligrams per kilogram [mg/kg] every two weeks). To date, no pulmonary toxicity events have been observed in the brentuximab vedotin plus AVD cohorts. Ten out of 25 patients (40%) in the brentuximab vedotin plus ABVD cohorts had an event of pulmonary toxicity, including three Grade 3 and two Grade 4 events. This compares to an overall rate of pulmonary toxicity with bleomycin-based regimens reported in published literature of 10 to 25% [1,2].

Adverse events
Concomitant use of brentuximab vedotin with bleomycin is not recommended due to an increased incidence of pulmonary adverse events. Patients are no longer being treated on the ABVD cohorts of the study. Among the 10 patients experiencing a pulmonary toxicity event in the ABVD combination cohorts, seven discontinued bleomycin and completed treatment with brentuximab vedotin plus AVD.

Across all treatment cohorts, the most common adverse events were neutropenia (77%), nausea (66%), peripheral sensory neuropathy (48%), fatigue (43%) and vomiting (43%). Grade 3 or higher adverse events were neutropenia (77%), anemia (14%), febrile neutropenia (11%) and pulmonary toxicity (11%, all in the ABVD cohorts). No Grade 3 or 4 adverse events of peripheral neuropathy have been observed to date.

Among 25 patients in the brentuximab vedotin plus ABVD cohorts, all 15 patients who completed front-line therapy on study achieved a complete remission; five patients were unevaluable because they withdrew from the study prior to completing a full course of therapy and five patients were in ongoing treatment. All patients in the brentuximab vedotin plus AVD cohorts are in ongoing treatment and response results are not yet available. Thirty-six of 37 evaluable patients in both study arms had negative interim PET scans after Cycle 2 as assessed by central review, including 22 out of 22 (100%) in the ABVD cohorts and 14 out of 15 (93%) in the AVD cohorts.

Enhance traditional chemotherapy
“Front-line Hodgkin lymphoma is a setting in which a core research strategy for decades has been to enhance the activity of traditional chemotherapy regimens while reducing the significant toxicities and long-term side effects of such regimens. For example, bleomycin is commonly associated with an increased risk of pulmonary complications that have been shown to have a negative impact on the outcome of patients with Hodgkin lymphoma,” said Dr. Anas Younes, Professor of Medicine and Director, Clinical Investigation and Translational Research Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center. “Data from this trial support further evaluation of ADCETRIS administered concomitantly with AVD in previously untreated Hodgkin lymphoma patients.”

In this open-label trial, cohorts of patients received escalating doses of brentuximab vedotin ranging from 0.6 mg/kg to 1.2 mg/kg every two weeks concomitantly with ABVD or a dose of 1.2 mg/kg every two weeks concomitantly with AVD. The median age of patients across all cohorts of the trial was 32.5 years. Enrollment of a total of 51 patients to the trial is complete, including 25 in the brentuximab vedotin plus ABVD cohorts and 26 in the brentuximab vedotin plus AVD cohorts.

Ongoing trials planned
Seattle Genetics and Millennium: The Takeda Oncology Company are jointly developing brentuximab vedotin. The companies are planning a phase III clinical trial in advanced stage front-line Hodgkin lymphoma patients. The randomized trial will compare progression-free survival in patients receiving brentuximab vedotin in combination with AVD to patients receiving ABVD alone.

Marketing approval
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. The indications for brentuximab vedotin 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 use in any front-line setting and is not approved for use outside the United States. Patients who are receiving strong CYP3A4 inhibitors concomitantly with Brentuximab vedotin should be closely monitored for adverse reactions.

Program: Oral and Poster Abstracts
Type: Oral
Abstract: 955 Frontline Therapy with Brentuximab Vedotin Combined with ABVD or AVD in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma
Session: 624. Lymphoma – Therapy with Biologic Agents, excluding Pre-Clinical Models: Novel Biologic Approaches to Aggressive and Hodgkin Lymphoma
When: Tuesday, December 13, 2011: 7:30 AM
Where: Room 6B (San Diego Convention Center).