On November 21, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported the U.S. Food and Drug Administration (FDA) has approved the use of DARZALEX (daratumumab) in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy (Press release, Genmab, NOV 21, 2016, View Source [SID1234516717]). In July 2016, daratumumab was granted a Breakthrough Therapy Designation (BTD) in this patient population. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize DARZALEX.

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Genmab will receive milestone payments totaling USD 65 million from Janssen associated with the first commercial sale of the daratumumab in combination with lenalidomide and dexamethasone and in combination with bortezomib and dexamethasone in the United States. As this will occur quickly after this approval, Genmab is improving its financial guidance for the year. See the Outlook section of this announcement for more information.

"This is an exciting day for patients with multiple myeloma in the U.S., who will now have the opportunity to receive DARZALEX at an earlier point in treatment of their disease," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab. "We believe daratumumab has the potential to become a backbone therapy for multiple myeloma."

The approval was based on data from two Phase III studies: the CASTOR study of daratumumab in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in patients with relapsed or refractory multiple myeloma, and the POLLUX study of daratumumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with relapsed or refractory multiple myeloma.

Data from the Phase I study of daratumumab in combination with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma was also submitted as part of the supplemental Biologics License Application (sBLA) for daratumumab in the newly approved indications in August 2016. The FDA granted a Standard Review for the use of daratumumab in combination with pomalidomide and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received at least two prior therapies, including a proteasome inhibitor and an immunomodulatory agent. The FDA assigned a Prescription Drug User Fee Act (PDUFA) target date of June 17, 2017 for the combination of daratumumab with pomalidomide and dexamethasone.

DARZALEX was initially approved by the FDA in November 2015 for the monotherapy 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 immunomodulatory agent.

OUTLOOK
MDKK Revised Guidance Previous Guidance
Revenue 1,650 — 1,700 1,200 — 1,250
Operating expenses (800) — (850) (800) — (850)
Operating income 825 — 875 375 — 425
Cash position at end of year* 3,650 — 3,750 3,650 — 3,750
*Cash, cash equivalents, and marketable securities

Genmab is improving the 2016 financial guidance it published on November 2, 2016, due to the inclusion of daratumumab milestones totaling USD 65 million. The milestones are associated with the first commercial sale of DARZALEX in combination with lenalidomide and dexamethasone, and bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy in the U.S. following FDA approval in this indication.

Operating Result
We expect our 2016 revenue to be in the range of DKK 1,650 — 1,700 million, an increase of DKK 450 million compared to the previous guidance. We have increased our projected daratumumab milestones to DKK 1,020 million (previously DKK 570 million) due to inclusion of USD 65 million in milestone payments triggered by the first commercial sale of DARZALEX in combination with lenalidomide and dexamethasone, and bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. We expect DARZALEX royalties to remain in the range of DKK 400 — 450 million, based on an estimated USD 500 — 550 million of DARZALEX sales in 2016. The remainder of the revenue mainly consists of Arzerra royalties, DuoBody milestones, and non-cash amortization of deferred revenue.

We anticipate that our 2016 operating expenses will remain in the range of DKK 800 — 850 million.
As a result of the increased revenue, we now expect the operating income for 2016 to be approximately DKK 825 — 875 million, compared to DKK 375 — 425 million in the previous guidance.

Cash Position
There is no change to the projected cash position at the end of 2016 of DKK 3,650 — 3,750 million as we expect to receive payment for the additional milestones shortly after year-end.
Outlook: Risks and Assumptions
In addition to factors already mentioned, the estimates above are subject to change due to numerous reasons, including but not limited to the achievement of certain milestones associated with our collaboration agreements; the timing and variation of development activities (including activities carried out by our collaboration partners) and related income and costs; DARZALEX and Arzerra sales and corresponding royalties to Genmab; fluctuations in the value of our marketable securities; and currency exchange rates. The financial guidance assumes that no significant agreements are entered into during 2016 that could materially affect the results.

About the CASTOR study
The Phase III CASTOR study included 498 patients who had relapsed or refractory multiple myeloma. Patients were randomized to receive either daratumumab combined with subcutaneous bortezomib (a type of chemotherapy, called a proteasome inhibitor) and dexamethasone (a corticosteroid), or bortezomib and dexamethasone alone. The study met the primary endpoint of improving progression free survival (PFS); Hazard Ratio (HR) = 0.39, 95% CI 0.28-0.53, p<0.0001. The median PFS for patients treated with daratumumab has not been reached, compared to median PFS of 7.2 months for patients who did not receive daratumumab.

Daratumumab also significantly increased the overall response rate (ORR) (79% vs. 60%, p<0.0001), including doubling rates of complete response (CR) or better (18% vs. 9%) and rates of very good partial response (VGPR) or better (57% vs. 28%). The most common grade 3 or 4 adverse events in patients treated with daratumumab in combination with bortezomib and dexamethasone compared to those who only received bortezomib and dexamethasone were thrombocytopenia (47% vs 35%), anemia (13% vs 14%) and neutropenia (15% vs 5%). Daratumumab-associated infusion-related reactions were reported in 45% of patients, were mostly grade 1/2, and occurred predominantly during the first infusion. This is consistent with the reported safety profile of daratumumab monotherapy and background bortezomib/dexamethasone therapy.

About the POLLUX study
The Phase III POLLUX study enrolled 569 patients who had relapsed or refractory multiple myeloma. Patients were randomized to receive either daratumumab combined with lenalidomide (an immunomodulatory drug) and dexamethasone (a corticosteroid), or lenalidomide and dexamethasone alone. The study met the primary endpoint of improving progression-free survival (PFS) (Hazard Ratio (HR) = 0.37; 95% CI 0.27-0.52; p<0.0001) for patients treated with daratumumab versus patients who did not receive daratumumab. Patients who received treatment with daratumumab in combination with lenalidomide and dexamethasone had a 63% reduction in risk of their disease progressing, compared to those who did not receive daratumumab. The median PFS for patients treated with daratumumab in combination with lenalidomide and dexamethasone has not been reached, compared to an estimated median PFS of 18.4 months for patients who received lenalidomide and dexamethasone alone. Additionally, daratumumab significantly increased ORR (91% vs. 75%, p<0.0001, including doubling rates of CR or better (42% vs. 19%), as well as rates of VGPR or better (75% vs. 43%). The most common grade 3 or 4 adverse events in patients treated with daratumumab in combination with lenalidomide and dexamethasone versus those who received only lenalidomide and dexamethasone were neutropenia (53% vs 40%), thrombocytopenia (13% vs 15%), and anemia (13% vs 19%). Daratumumab-associated infusion-related reactions occurred in 48% of patients, were mostly grade 1/2, and occurred predominantly during the first infusion. Overall, the safety profile was consistent with known toxicities of daratumumab monotherapy and combination therapy of lenalidomide and dexamethasone.

Both the CASTOR study and the POLLUX study were published in The New England Journal of Medicine in August 2016 and October 2016 respectively.

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 30,330 new patients are expected to be diagnosed with multiple myeloma and approximately 12,650 people are expected to die from the disease in the U.S. in 2016.3 Globally, it was estimated that 124,225 people would be diagnosed and 87,084 would 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 proteasome inhibitors or immunomodulatory agents, have poor prognoses and few treatment options.6

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.7 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe for use as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. 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,7,8 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,7,8 antibody-dependent cellular phagocytosis9,10 and antibody-dependent cellular cytotoxicity.7,8 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and subsets of regulatory T cells (Tregs) and B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs and Bregs were accompanied by increases in CD4+ and CD8+
T cell numbers in both the peripheral blood and bone marrow.7,11

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, non-Hodgkin’s lymphoma and solid tumors.

IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS – None
WARNINGS AND PRECAUTIONS
Infusion Reactions — DARZALEX can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Interference with Serological Testing – Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.

Neutropenia – DARZALEX may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX is recommended. Consider supportive care with growth factors.

Thrombocytopenia – DARZALEX may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions.

Interference with Determination of Complete Response – Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions — In patients who received DARZALEX in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: neutropenia (92%), thrombocytopenia (73%), upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse events was 49%. Serious adverse reactions were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%) and pyrexia (3%).

In patients who received DARZALEX in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: thrombocytopenia (90%), neutropenia (58%), peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse events was 42%. Serious adverse reactions were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%).

In patients who received DARZALEX as monotherapy, the most frequently reported adverse reactions (incidence ≥20%) were: neutropenia (60%), thrombocytopenia (48%), infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).

DRUG INTERACTIONS
Effect of Other Drugs on daratumumab: The coadministration of lenalidomide or bortezomib with DARZALEX did not affect the pharmacokinetics of daratumumab.

Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX with bortezomib did not affect the pharmacokinetics of bortezomib.

On November 21, 2016 CTI BioPharma Corp. (CTI) (NASDAQ and MTA: CTIC) reported that data from the randomized Phase 3 PERSIST-2 clinical trial comparing the investigational agent pacritinib, an oral multikinase inhibitor, with physician-specified best available therapy (BAT), including ruxolitinib, for treatment of patients with myelofibrosis whose baseline platelet counts are less than 100,000 per microliter will be presented in a late-breaking oral presentation at the upcoming 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, being held December 3-6 in San Diego, CA (Press release, CTI BioPharma, NOV 21, 2016, View Source [SID1234516716]).

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Myelofibrosis is associated with significantly reduced quality of life and shortened survival. Spleen enlargement (splenomegaly) is a common and debilitating symptom of myelofibrosis. As the disease progresses, the body slows production of important blood cells and within one year of diagnosis the incidence of disease-related thrombocytopenia (very low blood platelet counts), severe anemia and red blood cell transfusion requirements increase significantly.

Details of the PERSIST-2 presentation, two additional poster presentations regarding pacritinib, as well as poster presentations highlighting PIXUVRI (pixantrone) and tosedostat, are below. Full abstracts can be accessed on the ASH (Free ASH Whitepaper) website at www.hematology.org.

PERSIST-2 Oral Presentation

Results of the PERSIST-2 Phase 3 Study of Pacritinib (PAC) Versus Best Available Therapy (BAT), Including Ruxolitinib (RUX), in Patients with Myelofibrosis (MF) and Platelet Counts Less Than 100,000/µL
First Author: John Mascarenhas, M.D., Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
Date/Time: Tuesday, December 6 at 8:30 a.m. PT
Location: Hall AB
Oral Session: Late-Breaking Abstracts
Abstract #LBA-5

Poster Presentations

Pacritinib

Relationship of JAK2V617F Allelic Burden (AB) to Demographics, Disease Characteristics, and Response to Therapy in PERSIST-1, A Randomized Phase 3 Study of Pacritinib (PAC) Versus Best Available Therapy (BAT) in Patients (Pts) with Primary and Secondary Myelofibrosis (MF)First Author: Alessandro M. Vannucchi, M.D., CRIMM, AOU Careggi, University of Florence, Florence, Italy
Date/Time: Sunday, December 4 at 6:00-8:00 p.m. PT
Location: Hall GH
Poster Session: 634. Myeloproliferative Syndromes: Clinical: Poster II
Abstract #3131

Pacritinib Targets IRAK1 and Shows Synergy with HDAC and BET Inhibitors in Acute Myeloid Leukemia
First Author: Anupriva Agarwal, Ph.D., Knight Cancer Institute, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR
Date/Time: Sunday, December 4 at 6:00-8:00 p.m. PT
Location: Hall GH
Poster Session: 802. Chemical Biology and Experimental Therapeutics: Poster II
Abstract #3514

Pixantrone

The Combination of Pixantrone, Etoposide, Bendamustine and, in CD20+ Tumors, Rituximab (PREBEN) Shows Promising Feasibility/Efficacy in Heavily Pre-Treated Aggressive Lymphomas of B- And T-Cell Phenotype – Results of the Pre-Trial Experience Leading to a Nordic Phase 1/2 Study (the PREBEN Trial)
First Author: Michael R. Clausen, M.D., Hematology, Aarhus University Hospital, Aarhus, Denmark
Date/Time: Saturday, December 3 at 5:30-7:30 pm PT
Location: Hall GH
Poster Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma – Clinical Studies: Poster I
Abstract #1782

Tosedostat

A Phase 1 Dose-Escalation Study of the Class 1 Selective Histone Deacetylase Inhibitor CHR-3996 in Combination with Tosedostat for Patients with Relapsed, Refractory Multiple Myeloma: Results of the MUK Three Trial
First Author: Rakesh Popat, MBBS, Ph.D., University College London Hospitals NHS Foundation Trust, London, UK
Date/Time: Sunday, December 4 at 6:00-8:00 p.m. PT
Location: Hall GH
Poster Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
Abstract #3321

About the Phase 3 Development Program of Pacritinib

Pacritinib was evaluated in two Phase 3 clinical trials, known as the PERSIST program, for patients with myelofibrosis, with one trial in a broad set of patients without limitations on platelet counts, the PERSIST-1 trial; and the other in patients with low platelet counts, the PERSIST-2 trial. In August 2014, pacritinib was granted Fast Track designation by the FDA for the treatment of intermediate and high risk myelofibrosis including, but not limited to, patients with disease-related thrombocytopenia (low platelet counts); patients experiencing treatment-emergent thrombocytopenia on other JAK2 inhibitor therapy; or patients who are intolerant of, or whose symptoms are not well controlled (sub-optimally managed) on other JAK2 therapy.

Clinical studies under the CTI BioPharma investigational new drug (IND) for pacritinib are currently subject to a full clinical hold issued by the U.S. Food and Drug Administration in February 2016.

About Pacritinib

Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. The JAK family of enzymes is a central component in signal transduction pathways, which are critical to normal blood cell growth and development, as well as inflammatory cytokine expression and immune responses. Mutations in these kinases have been shown to be directly related to the development of a variety of blood-related cancers, including myeloproliferative neoplasms, leukemia and lymphoma. In addition to myelofibrosis, the kinase profile of pacritinib suggests its potential therapeutic utility in conditions such as acute myeloid leukemia, or AML, myelodysplastic syndrome, or MDS, chronic myelomonocytic leukemia, or CMML, and chronic lymphocytic leukemia, or CLL, due to its inhibition of c-fms, IRAK1, JAK2 and FLT3.

About PIXUVRI (pixantrone)

PIXUVRI is a novel aza-anthracenedione with unique structural and physiochemical properties. PIXUVRI was structurally designed so that it cannot bind iron and perpetuate oxygen radical production or form a long-lived hydroxyl metabolite — both of which are the putative mechanisms for anthracycline induced acute and chronic cardiotoxicity.

In May 2012, the European Commission granted conditional marketing authorization for PIXUVRI as a monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive NHL. The benefit of PIXUVRI treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy. The Summary of Product Characteristics (SmPC) has the full prescribing information, including the safety and efficacy profile of PIXUVRI in the approved indication. The SmPC is available at www.pixuvri.eu. PIXUVRI does not have marketing approval in the United States.

About Tosedostat

Tosedostat is an investigational oral aminopeptidase inhibitor that has demonstrated anti-tumor responses in blood-related cancers and solid tumors in Phase 1-2 clinical trials. Tosedostat is currently being evaluated in multiple Phase 2 clinical trials for the treatment of patients with AML or high-risk MDS. Tosedostat is not approved or commercially available.

On November 21, 2016 Stemline Therapeutics, Inc. (Nasdaq:STML) reported the oral presentation of clinical data from its ongoing Phase 2 trial of SL-701 in patients with second-line glioblastoma (GBM) (Press release, Stemline Therapeutics, NOV 21, 2016, View Source [SID1234516715]). The Phase 2 results were delivered by David A. Reardon, M.D., Clinical Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute and Professor of Medicine, Harvard Medical School, at the Society for Neuro-Oncology (SNO) annual meeting in Scottsdale, AZ this past Friday, November 18, at 6:20 PM ET. SL-701 is a subcutaneously delivered immunotherapy designed to generate a long-term T cell response against GBM.

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David A. Reardon, M.D., the lead investigator of the study, commented, "We are observing encouraging clinical activity, including major responses, some with promising durability, from the combination of SL-701 and bevacizumab." Dr. Reardon continued, "These preliminary findings are consistent with a potential long-term immunotherapeutic benefit of SL-701 as a large majority of treated patients remain alive and the trial has not reached a median overall survival." Dr. Reardon concluded, "We look forward to following our patients and reporting longer-term survival and response data as the trial matures. In parallel, we are evaluating additional combination regimens and the design of a potential pivotal trial."

SL-701 Phase 2 Trial
The SL-701 Phase 2 trial enrolled second-line GBM patients and was comprised of a single-agent stage (Stage 1; n=46) and a combination stage which evaluated SL-701 with bevacizumab (Stage 2; n=28).

SL-701 was found to be safe and well-tolerated, and demonstrated clinical activity, including major responses, in second-line GBM when used alone or in combination with bevacizumab.

Key efficacy outcomes observed to date with the overall program include:

Combination activity in second-line GBM
SL-701 + poly-ICLC + bevacizumab (Phase 2 trial, Stage 2; n=21 evaluable)
Major responses (n=7; 2 complete responses [CR] and 5 partial responses [PR])
4 confirmed with 2nd response assessment
2 with pending 2nd response assessment
1 progressed prior to 2nd response assessment
Response duration encouraging, with several responses of 6 months-plus in duration, all ongoing
Overall survival appears promising; median not reached and data continue to mature
Single agent activity in relapsed/refractory GBM
SL-701 + GM-CSF + Imiquimod (Phase 2 trial, Stage 1; n=42 evaluable)
1 partial response (PR) of 13+ months duration, ongoing
2 stable diseases (SD) of 18+ and 20+ months duration, both ongoing
Earlier versions of SL-701 + poly-ICLC (Phase 1 trial)
Major responses in second- and third-line GBM
Patients continue to be followed for response and survival, and additional clinical data updates are expected next year, as well as immunocorrelative analyses.

The full presentation is now available on the Stemline website, under the "Scientific Presentations" tab (see link: View Source).

On November 21, 2016 Kite Pharma, Inc. (Nasdaq:KITE) reported that data from the interim analysis of the pivotal ZUMA-1 trial of KTE-C19 in patients with chemorefractory aggressive non-Hodgkin lymphoma (NHL) have been accepted as an oral late-breaking presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) 58th Annual Meeting in San Diego, CA, on December 6, 2016 (Press release, Kite Pharma, NOV 21, 2016, View Source [SID1234516710]). The abstract was one of only six accepted in this category and will be included in the December 1 online issue of Blood.

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"Outcomes for patients with aggressive NHL depend on whether their disease is sensitive to chemotherapy. The ZUMA-1 study was designed to support registration of KTE-C19 by enrolling a well-defined chemorefractory patient population," said Jeff Wiezorek, M.D., Senior Vice President of Clinical Development of Kite. "We are pleased with the outcome of the study to date and thank the patients and investigators for their participation in the first positive pivotal study in CAR-T therapy."

The abstract, titled "KTE-C19 (anti-CD19 CAR T Cells) Induces Complete Remissions in Patients with Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Results from the Pivotal Phase 2 ZUMA-1," will be presented by Sattva S. Neelapu, M.D., Associate Professor at the University of Texas MD Anderson Cancer Center, Houston, TX.

Session Information

Session Name: Late-Breaking Abstracts Session
Session Date: Tuesday, December 6, 2016
Session Time: 7:30 AM – 9:00 AM PT
Presentation Time: 8:45 AM PT
Room: San Diego Convention Center, Hall AB

This oral presentation will feature interim results from the ZUMA-1 Phase 2 trial. In September 2016, Kite announced ZUMA-1 positive interim topline results (objective response rate 79 percent; complete remission rate 52 percent) from 62 patients with 3 months of follow-up in both Cohort 1 and Cohort 2. Cohort 1 included patients with DLBCL, and Cohort 2 enrolled patients with transformed follicular lymphoma (TFL) and primary mediastinal B-cell lymphoma (PMBCL). Details of data available at the time of interim analysis, including 93 patients who had the opportunity to be followed for one month, will be presented in the late-breaker presentation on December 6, 2016. Cohort 2 data will be covered in a separate oral presentation on December 5, 2016: Abstract #998, A Phase 2 Multicenter Trial of KTE-C19 (anti-CD19 CAR T Cells) in Patients with Chemorefractory Primary Mediastinal B-Cell Lymphoma (PMBCL) and Transformed Follicular Lymphoma (TFL): Interim Results From ZUMA-1, View Source

About KTE-C19

Kite Pharma’s lead product candidate, KTE-C19, is an investigational therapy in which a patient’s T cells are engineered to express a CAR to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias, and redirect the T cells to kill cancer cells. KTE-C19 has been granted Breakthrough Therapy Designation status for diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL) by the U.S. Food and Drug Administration (FDA) and Priority Medicines (PRIME) regulatory support for DLBCL in the EU.

On November 21, 2016 DelMar Pharmaceuticals, Inc. (NASDAQ: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported the Company’s presentations at the CNS Anticancer Drug Discovery and Development Conference and Society for NeuroOncology Annual meeting, which was held November 16-20, 2016 in Scottsdale, Arizona (Press release, DelMar Pharmaceuticals, NOV 21, 2016, http://ir.delmarpharma.com/news/detail/838/delmar-pharmaceuticals-delivers-an-address-and-presents-an-overview-of-upcoming-gbm-trials-with-val-083-at-the-cns-anticancer-drug-discovery-development-conference-and-society-for-neurooncology-annual-meeting [SID1234516708]).

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During the conference, DelMar’s chairman and CEO, Jeffrey Bacha, delivered an oral address during CNS Anticancer Drug Discovery and Development sessions. Mr. Bacha described DelMar’s research and recent clinical trial results and how these data position VAL-083 as a potential solution for newly diagnosed GBM patients whose cancer exhibits features, such as a high expression of MGMT, implicated in resistance to currently approved chemotherapy.

"It was an honor to be invited to share and discuss our research with leaders in the global neuro-oncology community," stated Mr. Bacha. "Overcoming the unique challenges in treating brain tumors requires cooperation among experts across a range of medical and scientific disciplines. We look forward to continuing to advance VAL-083 as a potential new chemotherapy in collaboration with leading cancer centers and researchers."

DelMar also provided an overview of three upcoming clinical trials with VAL-083 for the treatment of chemo-resistant GBM. A copy of the company’s poster presentation entitled ‘Clinical Trials of VAL-083 in Patients with Chemo-Resistant Glioblastoma’ can be viewed at View Source The planned trials include:

1. A pivotal, randomized multi-center Phase 3 study measuring survival outcomes compared to a "physicians’ choice" control for the treatment of bevacizumab-failed GBM. A summary of the proposed clinical trial design includes:

Approximately 180 patients with histologically confirmed recurrent GBM who have failed both standard chemo-radiation and bevacizumab will be randomized in a 2:1 fashion to receive either VAL-083 or a commonly used salvage chemotherapy;
The proposed study is projected to be enrolled at approximately 25 centers;
The proposed primary endpoint is overall survival (OS);
The proposed statistical design between the two arms of the study is 90% power, and is proposed to include an interim analysis at 50% events for futility with O’Brien-Fleming superiority boundary and non-binding, gamma (-5) futility boundary; and
The estimated length of the proposed study is less than two years from initiation.
The proposed trial design is subject to feedback from the FDA and other regulatory authorities. DelMar plans to submit the protocol to the FDA in coming weeks.

2. An open label, single-arm, biomarker-driven, Phase 2 study of VAL-083 in patients with MGMT-unmethylated, bevacizumab-naïve recurrent GBM (clinicaltrials.gov identifier: NCT02717962)

This single arm, biomarker-driven study will enroll 48 patients to determine if treatment of MGMT-unmethylated recurrent glioblastoma with VAL-083 improves overall survival (OS), compared to historical reference control;
The lomustine arm of the recently published EORTC26101 trial will serve as the reference control; and
The study is initially being enrolled at the University of Texas MD Anderson Cancer Center as a single center trial, but may be expanded to include additional centers.
This trial is being conducted in collaboration with the University of Texas MD Anderson Cancer Center ("MDACC"). The MDACC Institutional Review Board (IRB) has approved the protocol for this Phase II Study, and DelMar has completed a formal site initiation visit. DelMar and MDACC anticipate commencing enrollment and initiating patient treatment in the coming weeks.

3. An open label, single-arm, biomarker-driven, Phase 2 study of VAL-083 and radiation therapy patients in newly diagnosed MGMT-unmethylated GBM

This single-arm trial will enroll up to 30 newly diagnosed (temozolomide-naïve) GBM patients to examine whether VAL-083 is active in patients with newly diagnosed GBM with MGMT-unmethylated compared to historical control;
If successful, data from the trial will serve as a lead-in to a global randomized Phase II/III clinical trial of VAL-083 in newly diagnosed GBM patients with MGMT-unmethylated;
Progression free survival (PFS) will serve as the primary endpoint to assess VAL-083 treatment activity;
The study will also confirm the safety and tolerability of VAL-083 in combination with a standard-of-care radiation regimen; and
The study will initially be enrolled at the Sun-Yat Sen University (Guangzhou, China) as a single center trial, but may be expanded to include additional centers.
This trial is being conducted in collaboration with Guangxi Wuzhou Pharmaceutical (Group) Co. Under the terms of the company’s collaboration agreement Guangxi Wuzhou Pharmaceuticals is providing drug product and funding for the trial. The Sun-Yat Sen University Clinical Review Committee has approved the protocol and DelMar is completing the final remaining regulatory steps required for initiation of the trial and expects to begin enrollment in early 2017.

In a separate poster presentation, DelMar provided additional non-clinical data regarding VAL-083’s unique anti-cancer mechanism and potential combination therapies. DelMar’s poster presentation, entitled ‘Molecular Mechanisms of Dianhydrogalactitol (VAL-083) in Overcoming GBM Chemo-resistance’ can be viewed on the company’s website at: View Source

In summary, DelMar’s data indicates that:

The mechanism of action of VAL-083 is distinct from other alkylating agents used in the treatment of CNS tumors;
VAL-083 induces irreparable DNA double strand breaks, irreversible S/G2-phase arrest and activation of the homologous recombination DNA repair pathway;
VAL-083’s cytotoxic activity is MGMT-independent and able to overcome TMZ-resistance in GBM cancer stem cells and non-stem cells in vitro;
VAL-083 potentiates radiation in GBM cancer stem cells in vitro;
VAL-083’s activity appears independent of p53; and
VAL-083 displays synergy with a number of agents used in the treatment of GBM and other CNS tumors, including temozolomide, topoisomerase inhibitors, and platinum-based chemotherapy.
"These data are particularly valuable because they demonstrate the potential to combine VAL-083 with topoisomerase inhibitors, which are regularly used in the treatment of recurrent GBM," added Mr. Bacha. "Topoisomerase inhibitors such as irinotecan and etoposide have a relatively narrow therapeutic window and require cells to be in the ‘S-phase’ of the cell cycle for activity. Because VAL-083 causes cell-cycle arrest in the S-phase these data suggest an opportunity to combine VAL-083 with a lower and better tolerated dose of a topoisomerase inhibitor while maintaining or improving efficacy."

About Glioblastoma Multiforme (GBM)
Glioblastoma multiforme (GBM) is the most common and most malignant form of brain cancer. Approximately 15,000 people are diagnosed with GBM each year in the U.S., with similar incidence in Europe. Standard of care is surgery, followed by either radiation therapy, or radiation therapy combined with temozolomide. Approximately 60 percent of GBM patients treated with temozolomide experience tumor progression within one year. More than half of glioblastoma patients will fail the currently approved therapies and face a very poor prognosis.

About VAL-083
VAL-083 is a "first-in-class," small-molecule chemotherapeutic. In more than 40 Phase I and II clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated clinical activity against a range of cancers including lung, brain, cervical, ovarian tumors and leukemia both as a single-agent and in combination with other treatments.

DelMar’s research has demonstrated that VAL-083 is active against GBM cell lines that are resistant to standard-of-care chemotherapy due to features such as high expression of MGMT, in vitro.

DelMar presented data from its Phase I/II clinical trial in refractory GBM at the 2016 American Association of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual meeting demonstrating that the median survival of 22 patients receiving an assumed therapeutic dose of VAL-083 (≥20mg/m2) was 8.35 months following Avastin (bevacizumab) failure compared to published literature where survival of approximately two to five months has been reported.

VAL-083 has received an orphan drug designation in Europe for the treatment of malignant gliomas and the U.S. FDA Office of Orphan Products has granted an orphan designation to VAL-083 for the treatment of glioma, medulloblastoma and ovarian cancer.

DelMar believes that data from its upcoming clinical trials, if successful, will form the basis of a new paradigm in the treatment for all GBM patients who fail, or whose tumors exhibit features that make them unlikely to respond to currently available chemotherapy.

Further details can be found at View Source