Date: 2016-01-07
Type of information: Publication of results in a medical journal
phase: 2
Announcement: publication of results in The Lancet
Company: Janssen Biotech, a J&J company (USA - NJ) Genmab (Denmark)
Product: daratumumab
Action
mechanism: monoclonal antibody. Daratumumab is a human CD38 monoclonal antibody with broad-spectrum killing activity. Daratumumab is in clinical development for multiple myeloma. It targets the CD38 molecule which is highly expressed on the surface of multiple myeloma cells and may also have potential in other cancers on which CD38 is expressed, including diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, plasma cell leukemia, acute myeloid leukemia, follicular lymphoma and mantle cell lymphoma. Daratumumab has been granted Breakthrough Therapy Designation from the FDA for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double refractory to a PI and an IMiD. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize daratumumab.
Disease: multiple myeloma patients who have received at least three different lines of therapy including both a proteasome inhibitor and an immunomodulatory agent (IMiD) or who are double refractory to a proteasome inhibitor and an IMiD
Therapeutic area: Cancer - Oncology - Rare diseases
Country: Canada, Spain, USA
Trial
details: The Sirius MMY2002 study enrolled 124 patients who have received at least three prior lines of therapy, including both a proteasome inhibitor and an IMiD, or who are double refractory to a proteasome inhibitor and an IMiD. Examples of proteasome inhibitors are bortezomib or carfilzomib and examples of IMiD agents are pomalidomide or lenalidomide. Part 1 defined an optimal daratumumab regimen going forward, while part 2 was an expansion, based on the optimal regimen determined in Part 1. The primary objective of the study was to define the optimal dose and dosing schedule, to determine the efficacy of two treatment regimens of daratumumab as measured by overall response rate (ORR), and to further characterize the safety of daratumumab as a single agent. (NCT01985126)
Latest
news: * On January 7, 2016, Genmab announced The Lancet has published data from the Phase II study (Sirius MMY2002) of daratumumab in patients with relapsed and refractory multiple myeloma. Patients that received 16 mg/kg of daratumumab had a median of five prior lines of therapy and 95.3% were refractory to both proteasome inhibitors (PIs) and immunomodulatory drugs, which are current standard of care treatments for multiple myeloma. The data showed a 29.2% overall response rate (31 of 106), including three stringent complete responses, ten very good partial responses, and 18 partial responses in patients treated with 16 mg/kg of daratumumab. The median time to response was one month among patients who responded to treatment. Median duration of response was 7.4 months, and median progression free survival was 3.7 months. The 12-month overall survival rate was 64.8% and at a subsequent cutoff, median overall survival was 17.5 months. Daratumumab was well tolerated, with fatigue (40%) and anemia (33%) of any grade as the most common adverse events (AEs). No drug-related AEs led to treatment discontinuation. * On May 30, 2015, Genmab announced that data from the international, multi-center, open-label, two-part, single-arm Phase 2 MMY2002 (SIRIUS) trial show treatment with daratumumab achieved an overall response rate (ORR) of 29.2 percent (95% CI, 20.8-38.9), as assessed by an independent review committee, in heavily pre-treated patients with multiple myeloma. The ORR was consistent among the pre-specified subgroups based on age, prior lines of therapy, type of myeloma and baseline renal function. Median duration of response was 7.4 months (95% CI, 5.5-not estimable). Ninety-five percent of patients in the study were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD). Patients received a median of five prior lines of therapy, including a PI and an IMiD. No patients discontinued treatment due to infusion-related reactions (IRRs) and 4.7 percent of patients discontinued treatment due to adverse events (AEs), none of which were considered drug-related. Janssen Research & Development, LLC (Janssen) announced the data will be presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL. In part one of this ongoing international, multi-center, open-label, two-part, single-arm study, 34 patients were randomized to receive either 8 mg/kg of daratumumab once every four weeks (Q4W) or 16mg/kg once a week (QW) for eight weeks, then once every two weeks (Q2W) for 16 weeks and once every four weeks (Q4W) following, until disease progression or unacceptable toxicity. In part two, 90 additional patients were enrolled to receive 16 mg/kg of daratumumab on the same dosing schedule as in part one. Results are reported for all patients in parts one and two treated with 16 mg/kg of daratumumab (n=106). Very good partial response (VGPR) or better was achieved in 12 percent (95% CI, 7-20) of patients, with three stringent complete responses (sCR) (95% CI, 0.6-8.0) and 10 very good partial responses (VGPR) (95% CI, 4.6-16.7) reported. Median overall survival (OS) has not been reached, and the estimated one-year overall survival rate is 65 percent. The median progression-free survival was 3.7 months. After a median follow up of 9.4 months, 45.2 percent of responders remain on therapy. Serious AEs occurred in 30 percent of patients. The most common AEs were fatigue (39.6 percent), anemia (33 percent), nausea (29.2 percent), thrombocytopenia (25.5 percent), neutropenia (22.6 percent), back pain (22.6 percent) and cough (20.8 percent). Five patients (4.7 percent) discontinued treatment due to AEs, none of which were considered drug-related. Infusion-related reactions (IRR) were reported in 42.5 percent of patients and were predominantly grade 1 or 2 (4.7 percent grade 3; no grade 4 reported). These occurred mainly during the first infusion. The most common IRRs included nasal congestion (12 percent), throat irritation (7 percent), cough, dyspnea, chills and vomiting (6 percent each) - all of which were treated with standard of care and slower infusion rates. * On February 3, 2015, Genmab announced preliminary results from the Phase II study of daratumumab in double refractory multiple myeloma conducted by its collaboration partner Janssen Biotech. The overall response rate (ORR) in the study was 29.2% in the 16 mg/kg dosing group and the median duration of response was 7.4 months as determined by an Independent Review Committee (IRC). The study evaluated multiple myeloma patients who have received at least three different lines of therapy including both a proteasome inhibitor and an immunomodulatory agent (IMiD) or who are double refractory to a proteasome inhibitor and an IMiD. This is the indication for which daratumumab was granted Breakthrough Therapy Designation from the FDA in May 2013. Daratumumab showed a manageable safety profile. The data will be discussed with health authorities at upcoming meetings, pending their agreement.Genmab also looks forward to presenting additional data of this trial at a key upcoming medical conference this year.
In November 2015, the FDA approved Darzalex™ (daratumumab) injection for intravenous infusion for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent. A marketing application with data from the Sirius study and data from four other studies was submitted to the European Medicines Agency (EMA) by Janssen in September 2015 and was subsequently granted accelerated assessment.
