On December 7, 2015 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported the presentation of positive clinical and preclinical data describing the activity of its lead oncology drug candidate, selinexor, and its oncology pipeline for the treatment of hematologic malignancies at the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting held December 5-8, 2015 in Orlando, Florida (Press release, Karyopharm, DEC 7, 2015, View Source [SID:1234511225]). Oral and poster presentations representing both company and investigator-sponsored clinical and preclinical studies described data related to selinexor, Karyopharm’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound that inhibits exportin 1 (XPO1). In addition, encouraging preclinical data on other pipeline programs, including a second generation SINE compound, KPT-8602, and a dual acting p21-activated kinase 4 and nicotinamide phosphoribosyltransferase (PAK4/NAMPT) inhibitor, KPT-9274, were presented.

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"Our investigators are highly encouraged by the activity of selinexor in combination with standard of care agents for the treatment of a variety of cancers," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "Data presented at ASH (Free ASH Whitepaper) demonstrate that selinexor is efficacious and often synergistic in combination with other therapeutic agents, including carfilzomib and dexamethasone in refractory multiple myeloma, with Ara-C and idarubicin in relapsed or refractory acute myeloid leukemia (AML), and with fludarabine and cytarabine in pediatric patients with relapsed or refractory acute leukemias. These recent results add to the growing body of evidence seen with selinexor in combinations, including the recently announced preclinical synergy of selinexor with immune checkpoint inhibitors."

"In addition to selinexor, we continue to demonstrate Karyopharm’s commitment and expertise in the field of SINE therapy with encouraging preclinical data presented for KPT-8602, a second generation SINE compound with distinct pharmaceutical properties and the potential for daily dosing. Exciting preclinical data was also presented at ASH (Free ASH Whitepaper) for our novel, first-in-class, dual acting PAK4/NAMPT inhibitor," continued Dr. Shacham.

Selinexor in combination with standard of care agents in multiple myeloma
Preliminary data from an ongoing investigator sponsored trial (IST) of selinexor in combination with carfilzomib and dexamethasone in refractory multiple myeloma (MM) were previously presented at ASH (Free ASH Whitepaper) 2014 and updated today with additional patient data. In light of these data presented by Andrzej Jakubowiak, MD, PhD, from The University of Chicago, with support from the Multiple Myeloma Research Consortium, Amgen Inc. and Karyopharm, Karyopharm plans to initiate a Phase 2/3 clinical study (SCORE) by early 2016 to evaluate the combination of selinexor, carfilzomib and dexamethasone versus carfilzomib and dexamethasone in patients with refractory MM who were previously treated with a proteasome inhibitor and an immunomodulatory agent. In addition, Karyopharm recently initiated a 3-arm Phase 1b/2 clinical study (STOMP) evaluating selinexor plus low dose dexamethasone in combination with the MM backbone therapies with either bortezomib or pomalidomide or lenalidomide. Karyopharm’s commitment to these studies is based upon the growing body of preclinical evidence demonstrating that adding selinexor and dexamethasone to active anti-cancer agents, including proteasome inhibitors and immunomodulatory agents, may provide prolonged clinical benefit and restore drug sensitivity in MM.

"These data demonstrate encouraging efficacy of selinexor, carfilzomib and dexamethasone in heavily pretreated patients with highly refractory multiple myeloma, including patients whose disease is refractory to previous carfilzomib-based combinations, suggesting the potential of this combination to overcome carfilzomib resistance," said Dr. Andrzej J. Jakubowiak from The University of Chicago.

In a poster titled, "Phase 1 MMRC Trial of Selinexor, Carfilzomib (CFZ) and Dexamethasone (DEX) in Relapsed and Relapsed/Refractory Multiple Myeloma," Dr. Jakubowiak and his colleagues demonstrated a 67% overall response rate with the combination of selinexor, carfilzomib and dexamethasone and no unexpected toxicities observed to date. All evaluable patients whose responses were reported at ASH (Free ASH Whitepaper) had MM that was refractory to carfilzomib.

Nine patients with refractory MM were evaluable as of September 30, 2015, had a median age of 67 years and a median of four prior treatment regimens. All patients enrolled were refractory to prior carfilzomib-based treatment. Seven patients were carfilzomib-refractory in their last prior therapy before enrolling on the combination study with selinexor.

Response rates for all enrolled patients were 67% with partial responses (PR) or better, including 22% with very good partial responses (VGPR); 78% had at least minor responses (MR). Responses occurred rapidly within the first one to two cycles. Five of the seven (71%) patients refractory to carfilzomib in their last prior therapy responded with a PR or better.

Seven patients were evaluable for dose limiting toxicity (DLT) and no DLTs were reported. A maximum tolerated dose (MTD) has not yet been established, and none of the patients discontinued the study due to adverse events (AEs). The AEs were reversible and manageable with supportive care. Grade 3/4 AEs were predominantly hematological and included thrombocytopenia (67%), neutropenia (44%), lymphopenia (22%) and anemia (22%). The most common grade 3/4 non-hematologic AE was fatigue (22%).

Additionally, in two posters titled, "Selinexor is an Effective Cancer Treatment in Hypoxic Conditions and Synergizes with Proteasome Inhibitors to Treat Drug Resistant Multiple Myeloma," and "Combination Therapy of Selinexor with Bortezomib or Carfilzomib Overcomes Drug Resistance to Proteasome Inhibitors (PI) in Human Multiple Myeloma," Karyopharm researchers and collaborators demonstrated the potential of selinexor to synergize with proteasome inhibitors to overcome drug resistance.

Selinexor combinations in acute myeloid leukemia (AML)
Clinical data presented at ASH (Free ASH Whitepaper) demonstrated the activity and tolerability of selinexor in combination with standard of care agents in the AML setting; a Phase 2 trial investigating the efficacy and tolerability of arabinoside cytosine (Ara-C) and idarubicin in combination with selinexor in "fit" patients with relapsed and/or refractory AML and a Phase 1 study determining the safety and efficacy of selinexor in combination with fludarabine and cytarabine in pediatric patients with relapsed and/or refractory acute leukemia.

"Acute myeloid leukemia is the most frequent cause of leukemia-related death. While complete response rates can be as high as 80% in patients undergoing initial induction chemotherapy, the majority of AML patients will relapse with a bleak prognosis. As there is currently no standard-of-care regimen for these patients, a great unmet medical need exists for new treatment options such as selinexor," said Walter Fiedler, MD of the University Medical Center Hamburg-Eppendorf, Germany, the lead investigator for the study.

In a poster titled, "SAIL: Selinexor, ARA-C and Idarubicin: An Effective and Tolerable Combination in Patients with Relapsed/Refractory AML: A Multicenter Phase II Study," Karyopharm researchers in collaboration with Dr. Fiedler demonstrated that Ara-C and idarubicin in combination with selinexor has the potential to achieve significant response rates, particularly in this heavily pretreated patient population, without unexpected toxicities observed to date. Importantly, these responses enabled the majority of patients to proceed to allogeneic stem cell transplantation.

As of June 16, 2015, 20 patients with relapsed/refractory AML were evaluable for efficacy and toxicity. Median age was 59 (range 22-78) years. On average, patients received approximately 3.5 (range 1-6) prior therapies, all including intensive chemotherapy.
Overall response rate (ORR) was 60% (45% of patients achieved complete response (CR), 5% of patients achieved complete response with incomplete count recovery (CRi) and 10% of patients achieved PR). Sixty percent of patients treated received or were planned for stem cell transplantation or donor lymphocyte infusion.

The most frequent non-hematologic AEs were vomiting, diarrhea, nausea, fatigue, anorexia and neutropenic fever. One treatment-related death occurred wherein a patient with grade 4 thrombocytopenia developed a subarachnoid hemorrhage, which is common in relapsed AML due to intensive chemotherapy and is a less frequent consequence of single-agent selinexor treatment.
This trial will be expanded further, and has provided the basis for several front-line and other combination therapies for the treatment of AML.

In a poster titled "Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination with Fludarabine and Cytarabine (AraC) in Pediatric Patients with Relapsed or Refractory Leukemia," Karyopharm researchers in collaboration with Jeffrey E. Rubnitz, MD of St. Jude Children’s Research Hospital demonstrated that selinexor given in combination with fludarabine and cytarabine is tolerable in pediatric patients with relapsed acute leukemia. Most patients demonstrated XPO1 target inhibition with encouraging response rates which will be further explored in the Phase 2 portion of this trial.
Eighteen children or adolescents with relapsed or refractory acute leukemia (prior therapies included intensive chemotherapy combinations) completed at least one cycle of selinexor and were evaluable for safety; four treated at dose level 1 (30 mg/m2), three at dose level 2 (40 mg/m2), six at dose level 3 (55 mg/m2), and five at dose level 4 (70 mg/m2). Two DLTs of cerebellar toxicity were observed at dose level 4 (70 mg/m2), thereby establishing a maximum tolerated dose (MTD) of 55 mg/m2. The most common grade 3 or 4 non-hematologic toxicity related to selinexor was asymptomatic hyponatremia, which was observed in 13 patients and easily corrected in all cases.

Twelve patients were evaluable for response. The ORR was 67%. Four patients achieved CR, 2 CRi, and two had a PR. Seven of the eight patients with objective responses underwent subsequent stem cell transplantation.
Inhibition of XPO1 was assessed by quantitative real-time polymerase chain reaction, or qRT-PCR, of XPO1 mRNA, which is upregulated in response to selinexor. Thirteen of the first fourteen patients enrolled on the trial demonstrated at least two-fold induction of XPO1 mRNA, which persisted for at least 48 hours, indicating prolonged inhibition of the protein by selinexor.

Optimizing selinexor dose
Karyopharm researchers also presented data establishing 60mg as the most appropriate selinexor dose for both efficacy and tolerability across many of the hematologic cancers as well as preclinical data on Karyopharm’s emerging oncology pipeline including KPT-8602, a second generation SINE compound, and KPT-9274, Karyopharm’s novel, first-in-class, dual acting PAK4/NAMPT inhibitor.

In an oral presentation titled, "Safety, Efficacy, and Determination of the Recommended Phase 2 Dose for the Oral Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330)," Karyopharm researchers and Christine Chen, MD, of the Princess Margaret Cancer Center demonstrated that while efficacy was comparable, doses of selinexor from 45-65mg (median 60mg) were better tolerated than doses greater than 65mg and showed less weight loss, fewer incidence of high grade adverse events, and greater numbers of days on study.

266 heavily pretreated patients with MM, non-Hodgkin’s lymphoma, AML, and other hematological malignancies were divided into three groups of evaluable patients: those that received 4-44mg (median 30mg), 45-65mg (median 60mg) and > 65mg (70-160mg; median 90mg) for comparison of safety and efficacy endpoints.
Patients in the 4-44mg and 45-65mg groups remained on study longer than those receiving > 65mg, with average treatment duration of 120 days versus 90 days, respectively. Overall efficacy appeared superior in the 45-65mg dose group across multiple hematologic indications.

The most common AEs were nausea (63%), fatigue (62%), anorexia (57%), vomiting (38%), which were mostly grade 1/2, and thrombocytopenia (41%), which was mostly grade 3/4, but with very low rates of bleeding. The incidence of certain selinexor-related high grade (3/4) AEs was less in patients receiving 45-65mg selinexor vs those receiving > 65mg.
These data from Karyopharm’s extensive Phase 1 selinexor experience with selinexor corroborate our findings that a flat dose of 60mg is the most appropriate selinexor dose for both efficacy and tolerability in several settings, including older patients with AML. However, as is the case for many other anti-cancer drugs, certain indications will be treated with different doses.
Karyopharm’s new oncology pipeline candidates

In two oral presentations titled, "Nuclear Export Inhibitor KPT-8602 is Highly Active Against Leukemic Blasts and Leukemia-Initiating Cells in Patient-Derived Xenograft Models of AML" and "Next Generation XPO1 Inhibitor Shows Improved Efficacy and In Vivo Tolerability in Hematologic Malignancies" and a poster titled "Next Generation XPO1 Inhibitor KPT-8602 for the Treatment of Drug-Resistant Multiple Myeloma," Karyopharm researchers and collaborators demonstrated the potential of this second generation SINE compound for higher and/or more frequent dosing with KPT-8602 compared with selinexor. Based on these data, Karyopharm plans to initiate a focused Phase 1 MM study with KPT-8602 in the first quarter of 2016.

Finally, in two posters titled, "In Vitro and In Vivo Anti-Leukemic Effects of PAK4 Allosteric Modulators in Acute Myeloid Leukemia: Promising Results Justifying Further Development" and "Dissecting Signaling Network Responses to PAK4 Allosteric Modulators in Cell Subsets within Primary Human Acute Myeloid Leukemia Samples," encouraging preclinical activity was reported with KPT-9274 (PAK4/NAMPT inhibitor) and based on these data, Karyopharm plans to initiate clinical development in patients with heavily pretreated solid tumors or lymphoma in the first half of 2016.

Selinexor single-agent hematologic studies enrollment updates
Karyopharm is actively enrolling patients in four later phase clinical studies evaluating single-agent selinexor: one in older patients with relapsed/refractory AML (SOPRA study), the second in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) (SADAL study), the third in patients with MM (STORM study) and the fourth in patients with Richter’s transformation (SIRRT study). Interim data are expected from the SOPRA and STORM studies in the middle of 2016. In conjunction with discussions with the U.S. Food and Drug Administration (FDA), Karyopharm has amended the protocol for its ongoing Selinexor Against Diffuse Aggressive Lymphoma (SADAL) study in patients with heavily pretreated DLBCL to remove dexamethasone from the regimen and evaluate selinexor as a single-agent in this patient population and to adjust SADAL’s inclusion and exclusion criteria. The study will continue to compare 60mg and 100mg twice weekly doses of selinexor with 100 patients per arm. Based on these amendments, the company expects to report top-line data from this study in the first quarter of 2017.

About selinexor
Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding to and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. Over 1,300 patients have been treated with selinexor in company and investigator-sponsored Phase 1 and Phase 2 clinical trials in advanced hematologic malignancies and solid tumors. Karyopharm has initiated four later-phase clinical trials of selinexor, including one in older patients with AML (SOPRA), one in patients with Richter’s transformation (SIRRT), one in patients with DLBCL (SADAL) and a single-arm trial of selinexor and lose-dose dexamethasone in patients with MM (STORM). Karyopharm plans to initiate a Phase 2/3 clinical study (SCORE) in early 2016 to evaluate the combination of selinexor, carfilzomib and dexamethasone versus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma who were previously treated with a proteasome inhibitor and an immunomodulatory drug. In solid tumors, Karyopharm plans to initiate a randomized, placebo-controlled Phase 2/3 trial of selinexor to treat liposarcoma during the fourth quarter of 2015. Additional Phase 1 and Phase 2 studies are ongoing or currently planned, including multiple studies in combination with one or more approved therapies in a variety of tumor types to further inform the company’s clinical development priorities for selinexor. The latest clinical trial information for selinexor is available at www.clinicaltrials.gov.

On December 7th, 2015 Servier reproted that Novartis has exercised an option to expand its research agreement to include anti-Mcl-1 drug candidates (Press release, Servier, DEC 7, 2015, View Source [SID:1234508830]). Mcl-1, one of the most frequently amplified genes in cancer cells, is involved in cancer cell survival, but no selective and potent inhibitor has been developed yet.

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In 2014 the companies entered into a strategic global collaboration to develop and commercialize specific Bcl-2 inhibitors from Servier research programs that are partnered with Vernalis (Press Release, May 2014). These molecules are inducing apoptosis in cancer cells by neutralizing anti-apoptotic proteins of the Bcl-2 family.

Under the terms of the collaboration expansion, Servier and Novartis now extend their collaboration to co-develop and commercialize anti-Mcl-1 drug candidates. Servier remains responsible for research activities on the whole apoptosis program and will share responsibilities with Novartis to conduct preclinical development and worldwide clinical development programs. Commercialization rights to products arising from the collaboration will be allocated between the parties on a geographic basis.

Jean-Pierre Abastado, Ph.D., Director of the Center of Therapeutic Innovation in Oncology at Servier, said: "We are excited to expand our collaboration with Novartis. For many years we have worked to discover compounds inhibiting Bcl-2 family members whose deregulation plays a major role in the aberrant survival of cancer cells. Our ultimate goal is to bring these innovative therapies targeting apoptosis to patients suffering from cancers."

Emmanuel Canet, M.D., Ph.D., President of Servier R&D commented that "this significant collaboration with one of the leaders in the field today reinforces Servier innovative approach in oncology research and its commitment to provide cancer patients with novel options to treat blood cancers as well as solid tumors."

About Mcl-1 target and Bcl-2 protein family

Mcl-1 is part of a closely related group of proteins known as the ‘Bcl-2 family’ are crucial inhibitors of apoptosis, the programmed cell death. Deregulations of this protein family play a major role in the aberrant survival of cancer cells. Pro-survival Bcl-2 family members have been recognized as attractive therapeutic targets in oncology for more than twenty years but drug discovery research on this class of targets is particularly challenging and requires innovative chemistry supported by structural biology. Both hematological malignancies and solid tumors could be targeted by these novel drug candidates.

On December 7 AstraZeneca reported plans to test a digital support service for women undergoing treatment for recurrent platinum-sensitive high-grade ovarian cancer in clinical trials of cediranib plus olaparib (Press release, AstraZeneca, DEC 7, 2015, https://www.astrazeneca.com/our-company/media-centre/press-releases/2015/AstraZeneca-and-Voluntis-to-test-companion-mobile-app-in-ovarian-cancer-studies-07122015.html [SID:1234508600]). Voluntis has developed the service in close clinical collaboration with AstraZeneca and the US National Cancer Institute (NCI). It is delivered through a smartphone app paired with a web portal to help clinicians and patients manage side effects of hypertension and diarrhoea sometimes associated with combination therapy with cediranib and olaparib. Such side effects are traditionally described to care teams through manual, time-consuming and non-digitised channels.

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The app will be tested as a companion device in three separate clinical trials sponsored by the NCI beginning in the first quarter of 2016, under a Cooperative Research and Development Agreement between the NCI and AstraZeneca. This approach illustrates a clear focus on understanding the patient journey when developing therapeutic solutions. The service will also serve as a pilot within AstraZeneca’s broader strategy of using digital technology to complement treatment and to improve patient outcomes.

Antoine Yver, Head of Oncology, Global Medicines Development at AstraZeneca, said: "Empowering patients with this smartphone-based app gives them greater control of their treatment and management of their response. The support it provides can further reduce medication dose modification and discontinuation rates and help maintain patients on therapy to improve their treatment outcome."

Pierre Leurent, Chief Executive Officer of Voluntis, said: "We are delighted to be partnering with AstraZeneca for this project. AstraZeneca has a strong focus on the use of companion devices in drug development. Their approach, combined with our technological, medical and regulatory expertise provides the perfect synergy to create a personalised therapeutic solution that goes beyond the pill to best serve the needs of patients and their health care providers."

NOTES TO EDITORS

About cediranib

Cediranib is a highly potent, selective, orally-administered inhibitor of VEGF-1, -2 and -3 receptors. It has been shown to inhibit angiogenesis and lymphangiogenesis in the vascularization of platinum sensitive tumor types. In July 2015, cediranib filing was accepted by the European Medicines agency and awarded Orphan Drug status for the treatment of platinum sensitive relapse ovarian cancer. Cediranib also in development, in combination with Lynparza (olaparib), for platinum sensitive relapse ovarian cancer and platinum resistant relapse ovarian cancer.

About olaparib

Olaparib is an innovative, first-in-class oral poly ADP-ribose polymerase (PARP) inhibitor that exploits tumour DNA repair pathway deficiencies to preferentially kill cancer cells. This mode of action gives olaparib the potential for activity in a range of tumour types with DNA repair deficiencies. Olaparib is the first PARP inhibitor to be approved for patients with germline BRCA-mutated advanced ovarian cancer, and has been launched in the U.S. and Europe, with ongoing regulatory submissions across multiple markets. In addition to ovarian cancer, AstraZeneca is investigating the full potential of olaparib in multiple tumour types, with Phase III studies in second line gastric cancer, BRCA-mutated pancreatic cancer and adjuvant and metastatic BRCA-mutated breast cancers underway.

About Voluntis

Pioneering therapeutic companion software, Voluntis innovates healthcare by embedding connectivity in therapeutics and medical intelligence in software. Dedicated to managing chronic conditions, Voluntis’ companion software aim to enable treatment personalisation, to support team-care coordination and to improve real-world outcomes. Harnessing its proprietary technology, Voluntis has developed digital solution for diabetes, respiratory diseases, cancer, anticoagulation treatments and haemophilia. Voluntis is headquartered in Paris, France, and has offices in Boston, USA. For more information, visit www.voluntis.com.

On December 7, 2015 ZIOPHARM Oncology, Inc. (Nasdaq:ZIOP), a biopharmaceutical company focused on new cancer immunotherapies, reported that results from its CD19-specific CAR T-cell therapy programs were presented at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida (Press release, Ziopharm, DEC 7, 2015, View Source [SID:1234508482]). The presentation (Abstract 862), titled "Pre-Emptive Donor Lymphocyte Infusion with CD19-Directed, CAR-Modified T Cells Infused after Allogeneic Hematopoietic Cell Transplantation for Patients with Advanced CD19+ Malignancies" was presented by lead author Partow Kebriaei, M.D., Associate Professor, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, in an oral session, and is available at www.ziopharm.com. The investigational therapies infusing T cells genetically modified to express a CD19-specific chimeric antigen receptor (CAR), described in the presentation, were exclusively licensed to ZIOPHARM and its collaboration partner, Intrexon Corporation (NYSE:XON), through an agreement with MD Anderson.

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"This study, which was initially designed to test the safety and tolerability of the Sleeping Beauty platform, a system for the non-viral genetic modification of cells, appears to show a survival benefit with a doubling of overall survival compared to historical controls," said Dr. Richard Champlin, Chair, Department of Stem Cell Transplantation and Cellular Therapy at MD Anderson. "This is the measure of clinical success for a post-transplant therapy, where the contribution of either treatment is difficult to discern in early follow-up. Also promising was the absence of GvHD among HLA-mismatched CAR+ T-cell recipients, even at large doses, which supports infusing third-party T cells."

In the two separate trials described in Dr. Kebriaei’s presentation, patient-derived (autologous) or donor-derived (allogeneic) CAR-modified T cells targeting CD19 were administered to recipients with advanced CD19+ malignancies after hematopoietic stem-cell transplantation (HSCT). The studies employed the Sleeping Beauty system, a cost-effective non-viral two plasmid electroporation method to stably express CAR in T cells.

Seven patients with advanced non-Hodgkin lymphoma (NHL) were treated with autologous cells, all of whom remained alive and six of whom remained in complete remission at a median 25.5 months of follow-up translating to a three-year progression free survival (PFS) of 83% and a three-year overall survival (OS) of 100%.

Nineteen patients with advanced acute lymphoblastic leukemia and NHL were treated with allogeneic T cells. One-year PFS among these patients was 53% and one-year OS was 63%. Among eight patients who received donor-derived T cells after haploidentical HSCT, all remained alive and six remained in complete remission after a median of 5.2 months of follow up, translating to a one-year PFS of 75% and OS of 100%.

No infusion related or late toxicity was observed in any recipients. A mild elevation in cytokines was observed, without cytokine storm. Autologous and allogeneic cells survived an average of 201 and 51 days, respectively.

A graft-versus-host disease (GvHD) rate of 11% was observed among recipients receiving donor-derived CAR+ T cells which did not differ from controls. Because of this low rate of GvHD, a complication associated with allogeneic HSCT, administration of up to 108/m2 genetically modified haploidentical T cells was possible. This lays the groundwork for infusing HLA-mismatched CAR+ T cells as an off-the-shelf broadly-accessible therapeutic.

"Sleeping Beauty, which is among the fastest technologies to go from bench to bedside, was a critical innovation of this trial," said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of ZIOPHARM. "In addition to demonstrating safety and durable responses, it provides us a pathway for testing new CARs, co-expressing CAR with other molecules, and to do so at relatively low cost in the setting of both patient-derived and third-party derived products. We look forward to the new trial initiated at MD Anderson using Sleeping Beauty-modified T cells expressing a next-generation CD19-specific CAR in active CD19+ lymphoid malignancies."

Results from the haploidentical population were also presented separately in an oral presentation, titled "Donor-derived CD19-specific CAR+ T-cell therapy after haploidentical hematopoietic stem-cell transplantation," by Dr. Cooper, at the Haplo2015 Symposium, December 3, 2015, in Orlando, Florida. The presentation is available at www.ziopharm.com.

On December 7, 2015 Seattle Genetics, Inc. (Nasdaq: SGEN) reported data presentations evaluating ADCETRIS (brentuximab vedotin) in frontline non-Hodgkin lymphoma at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in Orlando, Florida, December 5-8, 2015 (Press release, Seattle Genetics, DEC 7, 2015, View Source;p=RssLanding&cat=news&id=2120760 [SID:1234508481]). The data include an oral presentation highlighting updated results from an ongoing phase 2 clinical trial evaluating ADCETRIS in combination with chemotherapy for newly diagnosed, high risk diffuse large B-cell lymphoma (DLBCL) patients. In addition, a poster presentation highlights a three-year durability analysis from a phase 1 clinical trial of ADCETRIS in combination with chemotherapy for the treatment of newly diagnosed peripheral T-cell lymphoma, also known as mature T-cell lymphoma (MTCL), patients. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma and is expressed on several types of non-Hodgkin lymphoma.

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"There is a significant need to improve frontline treatment options in aggressive non-Hodgkin lymphomas. In particular, newly diagnosed patients with high-intermediate and high-risk DLBCL and MTCL have estimated three-year progression-free survival rates of approximately 55 percent and 30 percent, respectively," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "ADCETRIS has demonstrated high complete remission and progression-free survival rates when added to frontline chemotherapy regimens for DLBCL and MTCL. Our efforts to redefine frontline therapy for these diseases are part of our goal to establish ADCETRIS as the foundation of care for all CD30-expressing lymphomas."

ADCETRIS is currently not approved for the treatment of frontline DLBCL and MTCL. For more information about the clinical trials, including enrolling centers, visit www.clinicaltrials.gov.

Brentuximab Vedotin with RCHOP as Frontline Therapy in Patients with High-Intermediate/High-Risk Diffuse Large B-Cell Lymphoma (DLBCL): Results from an Ongoing Phase 2 Study (Abstract #814, oral presentation on Monday, December 7, 2015 at 5:15 p.m.)

Updated interim results were reported from an ongoing phase 2 clinical trial evaluating ADCETRIS in combination with the standard of care regimen consisting of rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP) in frontline high-intermediate and high-risk DLBCL. Patients were randomized to receive standard dose RCHOP with either 1.2 milligrams per kilogram (mg/kg) or 1.8 mg/kg of ADCETRIS. The trial was designed to assess antitumor activity and the safety profile of ADCETRIS plus RCHOP in these patients. Exploratory endpoints included CD30 expression measured by immunohistochemistry (IHC) testing and the relationship between CD30 expression and response.

Data were reported from 51 frontline DLBCL patients with a median age of 67 years. Seventy-one percent of patients in the trial had stage IV disease, 37 percent were considered high-risk and 63 percent were considered high-intermediate risk. Key findings presented by Christopher Yasenchak, M.D., Willamette Valley Cancer Institute and Research Center/US Oncology Research, include:

Of 25 evaluable patients who had CD30-expressing disease (one percent expression or greater), 21 patients (84 percent) obtained an objective response, including 19 patients (76 percent) with a complete remission and two patients (eight percent) with a partial remission. The estimated progression-free survival rate for CD30-positive patients at both 12 and 15 months was 83 percent.
Subsets of patients known to have a poor prognosis appear to have favorable outcomes:

Eleven patients with CD30-positive activated B-cell like (ABC) DLBCL had a complete remission rate of 73 percent (eight of 11 patients). The estimated progression-free survival rate for these patients at both 12 and 15 months was 80 percent.
Six patients with Epstein-Barr virus (EBV)-positive lymphoma had a complete remission rate of 83 percent (five of six patients). The estimated progression-free survival rate for these patients at 12 months was 83 percent.

The most common treatment-emergent adverse events of any grade were fatigue and peripheral sensory neuropathy (63 percent each), diarrhea and nausea (57 percent each), and neutropenia and vomiting (37 percent each).The most common Grade 3 or 4 adverse events were febrile neutropenia (31 percent), neutropenia (33 percent) and anemia (24 percent). Based on an increased rate of Grade 3 peripheral neuropathy observed in the first 10 patients treated on the 1.8 mg/kg arm, remaining patients were treated with 1.2 mg/kg of ADCETRIS.

Based on these data, the phase 2 trial has been amended to add a randomized cohort exploring the activity and safety of ADCETRIS plus RCHP (without vincristine) versus RCHOP in frontline patients with CD30-expressing high-intermediate or high-risk DLBCL. Separately, a randomized phase 2 trial is also ongoing evaluating rituximab and bendamustine with or without ADCETRIS in relapsed or refractory DLBCL.

Frontline Treatment of CD30+ Peripheral T-cell Lymphomas with Brentuximab Vedotin in Combination with CHP: 3-Year Durability and Survival Follow-up (Abstract #1537, poster presentation on Saturday, December 5, 2015)

Data were reported from 26 frontline MTCL patients who received the combination regimen of ADCETRIS plus cyclophosphamide, doxorubicin and prednisone (CHP). Patients who achieved at least a partial remission with combination therapy were eligible to receive continued single-agent ADCETRIS treatment. The median age of patients was 56 years. Nineteen patients (73 percent) had a subtype of MTCL called systemic anaplastic large cell lymphoma (sALCL), including 16 patients (62 percent) with anaplastic lymphoma kinase (ALK) negative disease, which is typically associated with a poor prognosis. Seven patients had a diagnosis of other types of MTCL. The majority of patients had advanced stage disease and were considered high risk.

Updated key findings based on a median observation time of 38.7 months from first dose of therapy include:

The estimated three-year progression-free survival rate was 52 percent, with no patients receiving a consolidative stem cell transplant in first remission. There have been no progression events since the previous presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in September 2014. The estimated median progression-free survival has not yet been reached.
The estimated three-year overall survival rate was 80 percent.

The observed three-year progression-free survival and overall survival rates of 52 and 80 percent compare favorably to historical three-year progression-free survival and overall survival rates for frontline MTCL of approximately 30 and 40 percent, respectively.
The most common adverse events of any grade occurring in more than 30 percent of patients were nausea and peripheral sensory neuropathy (69 percent each), diarrhea (62 percent), fatigue (58 percent) and hair loss (54 percent). The most common Grade 3 or higher adverse events occurring in more than 10 percent of patients were febrile neutropenia (31 percent), neutropenia (23 percent), anemia (15 percent) and pulmonary embolism (12 percent).

Seventy-three percent of patients (19 of 26) experienced peripheral neuropathy, the majority of which was Grade 1 or 2. Ninety-five percent of these patients had complete resolution or some improvement of their symptoms at last follow-up with a median time to resolution of 1.3 months.

A global phase 3 study called ECHELON-2 is currently enrolling patients. The ECHELON-2 trial is a randomized, double-blind, placebo-controlled, multi-center trial designed to investigate A+CHP versus CHOP as frontline therapy in patients with CD30-positive MTCL. Approximately 450 patients (approximately 225 patients per treatment arm) will be randomized to receive A+CHP or CHOP every three weeks for six to eight cycles.

About ADCETRIS

ADCETRIS is being evaluated broadly in more than 70 ongoing clinical trials, including the phase 3 ALCANZA trial and two additional phase 3 studies, ECHELON-1 in frontline classical HL and ECHELON-2 in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing malignancies, including B-cell lymphomas.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS for intravenous injection has received approval from the FDA for three indications: (1) regular approval for the treatment of patients with classical HL after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (2) regular approval for the treatment of classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (3) accelerated approval for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Health Canada granted ADCETRIS approval with conditions for relapsed or refractory HL and sALCL.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive HL following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. ADCETRIS has received marketing authorization by regulatory authorities in more than 55 countries. See important safety information below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

About Seattle Genetics

Seattle Genetics is a biotechnology company focused on the development and commercialization of innovative antibody-based therapies for the treatment of cancer. Seattle Genetics is leading the field in developing antibody-drug conjugates (ADCs), a technology designed to harness the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. The company’s lead product, ADCETRIS (brentuximab vedotin) is a CD30-targeted ADC that, in collaboration with Takeda Pharmaceutical Company Limited, is commercially available in more than 55 countries, including the U.S., Canada, Japan and members of the European Union. Additionally, ADCETRIS is being evaluated broadly in more than 70 ongoing clinical trials in CD30-expressing malignancies. Seattle Genetics is also advancing a robust pipeline of clinical-stage programs, including vadastuximab talirine (SGN-CD33A; 33A), denintuzumab mafodotin (SGN-CD19A; 19A), SGN-LIV1A, SGN-CD70A, ASG-22ME, ASG-15ME and SEA-CD40. Seattle Genetics has collaborations for its ADC technology with a number of leading biotechnology and pharmaceutical companies, including AbbVie, Agensys (an affiliate of Astellas), Bayer, Genentech, GlaxoSmithKline and Pfizer. More information can be found at www.seattlegenetics.com.

ADCETRIS (brentuximab vedotin) U.S. Important Safety Information

BOXED WARNING
Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS (brentuximab vedotin).

Contraindication
ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.

Anaphylaxis and infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy.
Hematologic toxicities: Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with ADCETRIS. Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.
Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Closely monitor patients during treatment for the emergence of possible bacterial, fungal or viral infections.

Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment.

Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment.

Hepatotoxicity: Serious cases of hepatotoxicity, including fatal outcomes, have occurred with ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first dose of ADCETRIS or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.

Pulmonary Toxicity: Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, some with fatal outcomes, have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.

Serious dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Embryo-fetal toxicity: Fetal harm can occur. Advise pregnant women of the potential hazard to the fetus.

Most Common Adverse Reactions:

ADCETRIS was studied as monotherapy in 160 patients with relapsed classical HL and sALCL in two uncontrolled single-arm trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

ADCETRIS was studied in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT in a placebo-controlled randomized trial. The most common adverse reactions (≥20%) in the ADCETRIS-treatment arm (167 patients), regardless of causality, were neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea.

Drug Interactions:
Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations:
MMAE exposure and adverse reactions are increased in patients with moderate or severe hepatic impairment or severe renal impairment. Avoid use.