On August 26, 2015 Janssen Research & Development, LLC reported data from the multicenter, two-part, open-label Phase 1/2 GEN501 study published in The New England Journal of Medicine show daratumumab, an investigational, human anti-CD38 monoclonal antibody, demonstrated a tolerable safety profile as a monotherapy in patients with multiple myeloma who had relapsed after or were refractory (resistant) to at least two or more prior lines of therapy, including proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), chemotherapy and autologous stem cell transplantation (Press release, Johnson & Johnson, AUG 27, 2015, View Source [SID:1234507357]). Daratumumab also demonstrated a 36 percent overall response rate (ORR) in patients treated with a 16 mg/kg dose, with responses improving (or “deepening”) over time. Patients enrolled in the study had a median of four prior lines of therapy and 64 percent were refractory to both PIs and IMiDs.

Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by excess growth and survival of malignant plasma cells.1 Patients who are refractory to both PIs and IMiDs have a poor prognosis, with an estimated median overall survival of nine months.2

“What is impressive about this study is that daratumumab monotherapy induced durable responses that improved, or deepened, over time and 65 percent of responding patients remained in remission at 12 months,” said lead author Henk M. Lokhorst, M.D., Ph.D., Department of Haematology, VU University Medical Center, Amsterdam, Netherlands. “These findings speak to the potential of daratumumab as an option for patients with multiple myeloma who no longer respond to existing therapies.”

The GEN501 trial had a two-part study design. In Part 1, 32 patients were treated with escalating doses and no maximum tolerated dose was identified. In Part 2, 72 patients were enrolled in a dose expansion cohort and received either 8 mg/kg (30 patients) or 16 mg/kg (42 patients) of daratumumab at various schedules until disease progression or unmanageable toxicity to optimize doses identified in Part 1. Following this study, 16 mg/kg was chosen as the dose to be used in all daratumumab clinical trials.

Patients had a median of four prior lines of therapy and 79 percent were refractory to their last therapy, including both lenalidomide and bortezomib (64 percent). Additionally, 76 percent of patients previously received an autologous stem cell transplant. The primary endpoint for this trial was safety. Secondary endpoints were pharmacokinetics, objective response according to the International Myeloma Working Group (IMWG) uniform response criteria for myeloma, relative reductions in the levels of M protein and free light chains, time to disease progression, duration of response, progression-free survival and overall survival.

In the 16 mg/kg cohort, the ORR was 36 percent (11 partial responses, two very good partial responses and two complete responses) and 10 percent in the 8 mg/kg cohort (three partial responses). The two complete responses were confirmed with the use of a novel assay. Median progression-free survival was 5.6 months (95% CI: 4.2, 8.1) and 65 percent (95% CI: 28, 86) of responders remained in remission at 12 months.

“These data were part of our recent submission package to the FDA for daratumumab. Our hope is that daratumumab will offer a new treatment for patients with multiple myeloma who are greatly in need of new options,” said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen. “We are confident in our comprehensive development plan for daratumumab, which includes studying the medicine in earlier lines of therapy, both as a single agent and in combination with existing therapies.”

In the 16 mg/kg cohort, serious adverse events (AEs) occurred in 33 percent of patients. Infusion-related reactions (IRRs) occurred in 71 percent of patients in both the 8 mg/kg and 16 mg/kg cohorts, and all were grades 1 and 2, except for the occurrence of grade 3 reactions in one patient. The majority of IRRs occurred during the first infusion, with notably fewer during subsequent infusions. No patient discontinued treatment due to an IRR. The most common AEs in either treatment group were fatigue, allergic rhinitis and pyrexia (fever). The most frequent hematologic AE was neutropenia (abnormally low levels of neutrophils, a type of white blood cell), which occurred in 12 percent of patients (n=5) in the 16 mg/kg cohort. Grade 3 or 4 AEs were reported in 26 percent of patients in the 16 mg/kg cohort, with pneumonia (n=5) and thrombocytopenia (abnormally low levels of platelets in the blood; n=4) as the most common in both the 8 mg/kg and 16 mg/kg cohorts.

On July 9, 2015, Janssen completed the rolling submission of its Biologic License Application (BLA) for daratumumab to the FDA for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an IMiD, or who are double refractory to a PI and an IMiD. Daratumumab received Breakthrough Therapy Designation from the FDA for this patient population in May 2013. The regulatory submission for daratumumab will be primarily supported by data from the Phase 2 MMY2002 (SIRIUS) monotherapy study presented in May/June 2015 at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), along with additional data from four other studies, including GEN501.

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement which granted Janssen an exclusive license to develop, manufacture and commercialize daratumumab. If approved, daratumumab would be commercialized in the U.S. by Janssen Biotech, Inc.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.1 Multiple myeloma is the third most common blood cancer in the U.S., behind only leukemia and lymphoma.3 Approximately 26,850 new patients will be diagnosed with multiple myeloma, and approximately 11,240 people will die from the disease in the U.S. in 2015.4 Globally, it is estimated that 124,225 people will be diagnosed and 87,084 will die from the disease in 2015.5,6 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.7 Patients who relapse after treatment with standard therapies, including PIs or IMiDs, have poor prognoses and few treatment options.2

About Daratumumab
Daratumumab is an investigational human monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through multiple immune-mediated mechanisms,8 including complement-dependent cytotoxicity,8 antibody-dependent cellular phagocytosis9 and antibody-dependent cellular cytotoxicity,8 as well as via induction of apoptosis.10 Five Phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin lymphoma.