On March 9, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported it has reached a USD 5 million milestone in its daratumumab collaboration with Janssen Biotech, Inc. (Janssen) (Press release, Genmab, MAR 9, 2016, View Source [SID:1234509440]).

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This is the second milestone payment triggered by progress in the ongoing Phase II study ("Carina" LYM2001) of daratumumab in NHL. The study evaluates daratumumab monotherapy in three different types of NHL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL). This milestone is related to progress in the arm of the study treating patients with FL.

"The daratumumab study in NHL is now underway, and we are very pleased to have achieved milestones for progress in two of the disease areas included in the study, FL and DLBCL," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab. "We remain optimistic about the therapeutic potential of daratumumab in indications outside of multiple myeloma."

Daratumumab has received Orphan Drug designation from the US FDA for DLBCL, MCL and FL.

About the LYM2001 study
This Phase II study (NCT02413489) is a three arm (DLBCL, FL, MCL), open-label multicenter study which will enroll up to 210 patients with relapsed or refractory non-Hodgkin’s lymphoma. Patients in the study will be treated with daratumumab monotherapy. The primary endpoint of the study is overall response rate. The safety profile of daratumumab in these diseases will also be assessed.

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States 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.1 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. For more information, visit www.DARZALEX.com.

Daratumumab is a 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 is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,1,2 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,1,2 antibody-dependent cellular phagocytosis3,4 and antibody-dependent cellular cytotoxicity.1,2 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and a subset of regulatory T cells (Tregs) both of which express CD38. These reductions in MDSCs and Tregs were paralleled by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.1

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and 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’s lymphoma.

On March 09, 2016 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported the publication of results from the ONTIME trial of intravenous (IV) rigosertib in higher-risk myelodysplastic syndromes (HR-MDS) in the top-tier, peer-reviewed journal, Lancet Oncology (Press release, Onconova, MAR 9, 2016, View Source [SID:1234509436]). The article, titled, "Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial," currently appears in the online edition, and will appear in an upcoming print issue of the journal.

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The ONTIME trial was a randomized clinical study in HR-MDS patients following the failure of hypomethylating agents (HMAs). Overall survival was the primary endpoint in this international study of 299 patients. Although there was a trend to improvement in overall survival with IV rigosertib, no statistically significant difference was observed in the intention-to-treat (ITT) analysis between treatment and control (best supportive care, BSC) arms. Analyses in multiple clinically-important subgroups suggested that rigosertib may provide a meaningful survival benefit over BSC in some HR-MDS patients, including those with primary HMA failure (i.e., never benefited from first-line treatment with HMAs). Additionally, those HR-MDS patients who were classified as Very High Risk by the International Prognostic Scoring System (Revised), and patients with monosomy 7 or trisomy 8 chromosomal aberrations, showed encouraging overall survival results with rigosertib. Collectively, these results helped define a more homogenous patient population for a new Phase 3 study of IV rigosertib, referred to as INSPIRE, which was initiated by Onconova in the fourth quarter of 2015.

"This publication presents peer-reviewed results of the ONTIME trial with insights into the complexity of MDS, particularly in patients whose disease has failed the available HMA therapies," said Guillermo Garcia-Manero, MD, Chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center, and lead author of the paper. "Rigosertib was well tolerated in patients with a high unmet medical need who have no approved therapeutic options. We are impressed by the trend to notable efficacy in well-defined, well-balanced subgroups of HR-MDS patients with very poor prognosis. Based on these findings, we have designed the new Phase 3 INSPIRE study with IV rigosertib, which is currently enrolling patients."

Steven Fruchtman, MD, Chief Medical Officer of Onconova added, "The INSPIRE trial is now open at multiple sites in the U.S., and we intend to initiate sites in Canada, Europe, Israel, and Australia. In addition, we are pleased that our commercial partner for Japan and Korea, SymBio Pharmaceuticals, Ltd., will also shortly begin enrolling patients for this study in Japan. We believe that publication of the ONTIME results in Lancet Oncology serves to highlight an important unmet medical need and the ongoing Phase 3 INSPIRE trial, and broadens the awareness of this pivotal study among physicians and patients."

About INSPIRE

The INternational Study of Phase III IV RigosErtib, or INSPIRE, is based on guidance received from the U.S. Food and Drug Administration and European Medicines Agency and derives from the findings of the ONTIME Phase 3 trial. INSPIRE is a multi-center, randomized controlled study to assess the efficacy and safety of IV rigosertib in HR-MDS patients under 80 years of age who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first nine months of initiation of HMA treatment. This time frame optimizes the opportunity to respond to treatment with an HMA prior to declaring treatment failure, as per NCCN Guidelines.1 The trial will enroll approximately 225 patients randomized at a 2:1 ratio into two treatment arms: IV rigosertib plus Best Supportive Care versus Physician’s Choice plus Best Supportive Care. The primary endpoint of INSPIRE is overall survival and an interim analysis is anticipated. Full details of the INSPIRE trial, such as inclusion and exclusion criteria, as well as secondary endpoints, can be found on clinicaltrials.gov (NCT02562443).

About Rigosertib

Rigosertib is a small molecule inhibitor of cellular signaling and acts as a Ras mimetic. These effects of rigosertib appear to be mediated by direct binding of the compound to the Ras-binding domain (RBD) found in many Ras effector proteins, including the Raf kinases and PI3K. The initial therapeutic focus for rigosertib is myelodysplastic syndromes (MDS), a group of bone marrow disorders characterized by ineffective formation of blood cells that often converts into acute myeloid leukemia (AML). Clinical trials for rigosertib are being conducted at leading institutions in the United States, Europe, and the Asia-Pacific region. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan.

On March 9, 2016 Medivation, Inc. (NASDAQ: MDVN) reported that the U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold on the Investigational New Drug (IND) application for pidilizumab (MDV9300) in hematological malignancies and confirmed that the Phase II clinical trial in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), as well as other studies that cross reference the IND, may now proceed (Press release, Medivation, MAR 9, 2016, View Source [SID:1234509435]). The partial clinical hold was not related to any safety concerns.

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The investigator brochure, protocols, and informed consent documents related to the Phase II trial have satisfactorily been revised to reflect the Company’s understanding that PD-1 (Programmed Death-1) is not the target of pidilizumab. No patients had yet been enrolled in the trial, which commenced in late 2015. Patients who were receiving pidilizumab through investigator-sponsored trials have continued to receive treatment and those investigators have been informed to update their protocols and informed consent documents to state that pidilizumab is not an anti-PD-1 antibody.

"We are delighted that the FDA has lifted the partial clinical hold and that we may proceed with our potentially pivotal trial in this area of high unmet medical need," said David Hung, M.D., Founder, President & Chief Executive Officer of Medivation. "As we move forward, we also are working to determine the compound’s exact binding mechanism which, we believe, modulates the body’s innate immune response and differentiates it from the heavily crowded immuno-oncology space that targets the adaptive side of immunity."

The Company also intends to submit an amendment to the Chemistry, Manufacturing and Controls (CMC) section of the IND in the second quarter to provide for larger manufacturing lot sizes to better support the current and planned clinical activities for pidilizumab, which is intended for development in other hematologic malignancies, such as multiple myeloma. As such, the DLBCL trial is targeted to resume in the second half of this year.

About the Phase II Trial
The international, open-label, Phase II trial of pidilizumab is expected to enroll approximately 180 patients with an incomplete response following salvage therapy or autologous stem cell transplantation for relapsed or refractory CD20+ DLBCL, transformed indolent lymphoma, or primary mediastinal B-cell lymphoma. The patients will be assessed in two parallel cohorts of approximately 90 patients each: one cohort will enroll patients who have received an autologous stem cell transplant, and the second cohort will enroll patients who have received salvage chemotherapy, but who are ineligible for transplant. Pidilizumab will be administered at a dose of 200 mg by IV infusion. The primary endpoint of the trial is best overall response rate.