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.

On August 27, 2015 Exelixis, Inc. (NASDAQ:EXEL) reported that Swissmedic, the Swiss licensing and supervisory authority of Switzerland, has approved cobimetinib for use in combination with vemurafenib as a treatment for patients with advanced melanoma (Press release, Exelixis, AUG 27, 2015, View Source [SID:1234507351]). Cobimetinib is a selective inhibitor of MEK that was discovered by Exelixis and is the subject of a worldwide collaboration agreement between Exelixis and Genentech, a member of the Roche Group. The trade name for cobimetinib in Switzerland is Cotellic.

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Roche’s Swiss regulatory submission for cobimetinib was based on data from coBRIM, the phase 3 pivotal trial of cobimetinib and vemurafenib conducted in 495 patients with previously untreated unresectable, locally advanced or metastatic melanoma with a BRAF V600 mutation. The resulting approval is the first for cobimetinib worldwide, and additional regulatory applications are under review in other territories. Genentech filed its New Drug Application (NDA) for cobimetinib with the U.S. Food and Drug Administration (FDA) in December 2014 and the Prescription Drug User Fee Act date is November 11, 2015. Separately, Roche filed a Marketing Authorization Application with the European Medicines Agency in late 2014, and Roche anticipates a regulatory decision before the end of 2015.

"The Swiss regulatory approval of cobimetinib is an important advance for melanoma patients, physicians, and caregivers," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "Exelixis congratulates our partner Roche on this first approval for the product, and we look forward to additional regulatory decisions in the United States and European Union, which are anticipated later this year."

After discovering cobimetinib internally, Exelixis advanced the product to investigational new drug (IND) status. In late 2006, the company entered into its worldwide collaboration with Genentech, under which Exelixis received initial upfront and milestone payments for signing the agreement and submitting the IND. Following the determination of the maximum tolerated dose in phase 1 by Exelixis, Genentech exercised its option to further develop cobimetinib. Under the terms of the collaboration, Exelixis is eligible to receive royalties on sales of cobimetinib outside the United States. If cobimeitnib is approved in the United States, Exelixis is entitled to an initial equal share of U.S. profits and losses, which will decrease as sales increase, and will share in U.S. marketing and commercialization costs. In November 2013, Exelixis exercised its option to co-promote cobimetinib in the United States and, under the terms of the agreement, the company is prepared to field up to 25 percent of the U.S. sales force.

Dr. Morrissey continued: "As the second approved product to have been discovered at Exelixis, cobimetinib represents a major achievement for our company and for all of the employees, past and present, who contributed to the program since its inception. Our agreement with Genentech and Roche enables Exelixis to participate meaningfully in the product’s commercialization. This includes receiving royalties on ex-U.S. sales and sharing in the profits in the U.S., where our team is fully prepared to co-promote cobimetinib with Genentech pending regulatory approval. Exelixis is excited to be working with Genentech and Roche to ensure that the commercialization phase of our cobimetinib partnership mirrors the productivity and success seen during the compound’s discovery and clinical development."

About the coBRIM study

The pivotal coBRIM study is an international, randomized, double-blind, placebo-controlled, phase 3 study evaluating the safety and efficacy of the combination therapy. A total of 495 patients with unresectable, locally advanced or metastatic melanoma with a BRAF V600 mutation were randomized to receive vemurafenib once daily at the approved dosage and either cobimetinib or a placebo for 3 weeks followed by one week off cobimetinib/placebo. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent. Investigator-assessed progression-free survival (PFS) was the primary endpoint. Secondary endpoints include PFS by independent review committee, objective response rate, overall survival, duration of response and other safety, pharmacokinetic and quality of life measures.1

The Swissmedic approval was based on an updated analysis of the coBRIM study data that showed that patients with previously untreated BRAF V600 mutation-positive advanced melanoma live a median of more than a year (12.3 months) without progression of their disease (progression-free survival, PFS) on combination therapy with cobimetinib and vemurafenib, and 7.2 months on vemurafenib monotherapy.2,3 Patients responded better to treatment with cobimetinib and vemurafenib than those given vemurafenib alone. In this updated analysis, the objective response rate (ORR) of the cobimetinib and vemurafenib combination was 70 percent (compared to 50 percent for vemurafenib monotherapy).2 With further follow-up from the primary analysis, the complete response rate was 15 percent. The safety profile of cobimetinib and vemurafenib was consistent with safety data previously reported from the phase 1b BRIM7 study. The most common adverse events in the combination arm were diarrhea, rash, nausea, fever, sun sensitivity, liver lab abnormalities, elevated creatine phosphokinase (CPK, an enzyme released by muscles) and vomiting.

About the cobimetinib and vemurafenib Combination

Cobimetinib is a selective inhibitor that blocks the activity of MEK, a protein kinase that is part of a key pathway (the RAS-RAF-MEK-ERK pathway) that promotes cell division and survival. This pathway is frequently activated in human cancers including melanoma, where mutation of one of its components (BRAF) causes abnormal activation in about 50 percent of tumors. About 50 percent of patients with BRAF mutation positive melanoma experience a tumor response when treated with a BRAF inhibitor, however development of resistance and subsequent tumor progression limits treatment benefit. Clinical and preclinical analyses indicated that reactivation of the MEK-ERK pathway may underlie development of resistance to BRAF inhibitors in many progressing tumors, and that co-treatment with a BRAF and MEK inhibitor delays the emergence of resistance in the preclinical setting, providing the rationale for testing the combination of vemurafenib and cobimetinib in clinical trials. In addition to the combination with vemurafenib in melanoma, cobimetinib is also being investigated in combination with several investigational medicines, including an immunotherapy, in several tumor types, including non-small cell lung cancer, colorectal cancer, triple-negative breast cancer and melanoma.

About Melanoma and its BRAF V600 Mutation-Positive Form

Melanoma is the less common, but more serious category of skin cancer that starts in the skin’s pigment producing cells known as melanocytes. According to the American Cancer Society, approximately five percent of skin cancer diagnoses are melanoma, but melanoma accounts for a large majority of skin cancer deaths. In recent years, there have been significant advances in treatment for metastatic melanoma and people with the disease have more options. However, it continues to be a serious health issue with a high unmet need and a steadily increasing incidence over the past 30 years. It is projected that approximately half of all melanomas, and eight percent of solid tumors, contain a mutation of the BRAF protein. BRAF is a key component of the RAS-RAF-MEK-ERK pathway involved in normal cell growth and survival. However, mutations that keep the BRAF protein in an active state may cause excessive signaling in the pathway, leading to uncontrolled cell growth and survival. The BRAF V600 mutation-positive form of melanoma is associated with high-risk characteristics of the disease, including early onset, the absence of chronic skin damage, and decreased survival.

On August 27, 2015 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported that it has filed Clinical Trial Applications (CTAs) with the United Kingdom, German and Austrian regulatory agencies for IV rigosertib as a treatment in higher-risk myelodysplastic syndromes (HR-MDS) patients after failure of a hypomethylating agent (HMA) therapy (Press release, Onconova, AUG 27, 2015, View Source [SID:1234507348]). Upon clearance of the CTAs and the recently updated U.S. IND submission, Onconova intends to initiate a single randomized controlled pivotal Phase 3 trial, designated 04-30 or "INSPIRE", in patients with HR-MDS whose prior therapy with an HMA has failed. Additional filings in other European countries and in Japan are expected to follow shortly.

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"These filings follow our recent updated IND submission to the U.S. FDA," said Ramesh Kumar, Ph.D., President and CEO of Onconova. "Together, acceptance of these regulatory filings will allow Onconova to initiate a single global pivotal trial for IV rigosertib in HR-MDS. We anticipate enrollment in the new Phase 3 study will begin in the second half of 2015."

Per a development and licensing agreement with Baxalta (formerly the BioScience business of Baxter International Inc.), which grants Baxalta commercialization rights to rigosertib in the European Union and other countries in Europe, the company has elected to and Baxalta will fulfill its obligation under the agreement to pay for half of the costs for the trial of rigosertib in HR-MDS up to a specified cap.

Onconova has partnered with SymBio Pharmaceuticals, Ltd. for clinical development of rigosertib in Japan and Korea. SymBio plans to participate in the global Phase 3 trial by enrolling patients in Japan, which should accelerate the timing of regulatory filings in Japan and Korea.

"We completed a Phase 1 trial for oral rigosertib (SyB C-1101) in relapsed or refractory MDS last June and expect to complete the ongoing Phase 1 trial for IV rigosertib (SyB L-1101) in the treatment of relapsed or refractory HR-MDS patients this October. After consulting with the PMDA (Japanese Pharmaceuticals and Medical Devices Agency), it is our plan to participate in the global 04-30 trial, and to begin enrolling patients in Japan for this unmet medical need in HR-MDS," added Mr. Fuminori Yoshida, President and CEO of SymBio.

"Onconova is appreciative of the continued collaborations with Baxalta and SymBio to advance the INSPIRE Trial," continued Dr. Kumar. "We look forward to working closely with our partners in the development of IV rigosertib in HR-MDS in Europe and in Japan."

The INSPIRE Trial will enroll HR-MDS patients who had progressed on, or failed to respond to, previous treatment with an HMA. The primary endpoint of this study is overall survival, and an interim analysis is anticipated. This randomized trial of approximately 225 patients will be conducted at about 100 sites globally. Enrollment in this trial is expected to begin later this year.

On August 27, 2015 Genmab A/S (OMX: GEN) reported the New England Journal of Medicine (NEJM) has published the full data set from the initial Phase I/II study with daratumumab monotherapy treating patients with relapsed or refractory multiple myeloma (Press release, Genmab, AUG 27, 2015, View Source [SID:1234507347]).

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Patients that received 16 mg/kg in part 2 of the study had a median of 4 prior lines of therapy and 64% of these patients were refractory to both proteasome inhibitors (PIs) and immunomodulatory (IMiD) drugs, which are current standard of care treatments for multiple myeloma. The data showed a 36% response rate in the 16 mg/kg group in part 2 of the study, with responses that deepened over time. Sixty five percent of patients in this group that responded to treatment were progression-free twelve months following the start of treatment. For all patients in part 2, pneumonia and thrombocytopenia were the most common grade 3/4 adverse events (AEs; ≥5%). Infusion-related reactions were mild with no dose-dependent adverse events. In part 1 of the study, no maximum tolerated dose was identified up to 24 mg/kg.

Following this study, 16 mg/kg was chosen as the dose to be used in future daratumumab clinical studies. Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab.

"Patients who have relapsed or refractory multiple myeloma currently have very limited treatment options. The results from this first-in-human study of daratumumab, presented in full in The NEJM, show an impressive response rate and duration of response, particularly when you consider that patients in the study had received a large number of prior treatments," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

Data from this study has been included in the Biologics License Application (BLA) submitted by Janssen to the U.S. Food and Drug Administration for daratumumab as a treatment for patients with multiple myeloma who have received at least three prior lines of therapy including both a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double refractory to a PI and an IMiD. The BLA submission was completed on July 9th 2015.

About the study
This two-part, Phase I/II, open-label study enrolled 32 patients in part 1, and 72 patients in part 2, 42 of which were in the 16 mg/kg dose group. Part 1 was a dose-escalation study with patients receiving weekly doses of daratumumab between 0.005 and 24 mg/kg of daratumumab.

In part 2, 8 mg/kg and 16 mg/kg daratumumab were administered with different schedules. The primary endpoint of the study was safety. Secondary endpoints were pharmacokinetics, objective response according to International Myeloma Working Group (IMWG) uniform response criteria for myeloma, relative reductions in M-protein and free light chains, time to progression, response duration, progression-free and overall survival.

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., after leukemia and lymphoma.2 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 2015.3 Globally, it is estimated that 124,225 people will be diagnosed and 87,084 will die from the disease in 2015.4 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.5 Patients who relapse after treatment with standard therapies, including PIs or IMiDs, have poor prognoses and few treatment options.6

About daratumumab
Daratumumab is an investigational human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It induces rapid tumor cell death through multiple immune-mediated mechanisms7, including complement-dependent cytotoxicity7, antibody-dependent cellular phagocytosis8 and antibody-dependent cellular cytotoxicity7, as well as via induction of apoptosis9 . Five Phase III 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. Daratumumab has been granted Breakthrough Therapy Designation from the US FDA.