On December 6, 2015 Takeda Pharmaceutical Company Limited (TSE: 4502) reported results from the TOURMALINE-MM1 trial presented at the 57th Annual Meeting and Exposition of the American Society of Hematology (ASH) (Free ASH Whitepaper), showing that treatment with NINLARO (ixazomib) capsules is effective in extending progression free survival (PFS) with a manageable tolerability profile in patients with relapsed and/or refractory multiple myeloma (Press release, Takeda, DEC 6, 2015, View Source [SID:1234508434]). The TOURMALINE-MM1 trial is an international, randomized, double-blind, placebo-controlled Phase 3 clinical trial designed to evaluate once-weekly oral ixazomib plus lenalidomide and dexamethasone compared to placebo plus lenalidomide and dexamethasone.

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NINLARO was recently approved by the U.S. Food and Drug Administration (FDA) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. The approval was based on the Phase 3 TOURMALINE-MM1 data, which were highlighted at today’s ASH (Free ASH Whitepaper) press briefing. Ixazomib data will be featured in 18 presentations at this year’s ASH (Free ASH Whitepaper) meeting, including an oral presentation on Phase 2 data from an investigational study evaluating the all-oral combination of ixazomib plus cyclophosphamide and low-dose dexamethasone (ICd) in newly diagnosed multiple myeloma patients.

"The data presented at ASH (Free ASH Whitepaper) this year are the first major output from the comprehensive ixazomib clinical trial program, TOURMALINE, demonstrating Takeda’s ongoing commitment to providing effective and convenient treatment options for patients with multiple myeloma," said Andy Plump, M.D., Ph.D, Takeda Chief Medical and Scientific Officer. "The breadth and depth of the TOURMALINE program allows us to gather important data across a broad range of patients that live with multiple myeloma and to expand on the efficacy and safety profile of our oral proteasome inhibitor, ixazomib. We will continue this and other important clinical trials and look forward to sharing results over the next few years."

The comprehensive ixazomib clinical development program, TOURMALINE, includes a total of five pivotal trials – four investigating every major multiple myeloma patient population and one in light-chain amyloidosis.

Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lenalidomide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase 3 Tourmaline-MM1 Study (Abstract #727)

TOURMALINE-MM1 (n= 722) is the first double-blind, placebo-controlled trial with a proteasome inhibitor and has met the primary endpoint at the first interim analysis. Trial results demonstrate a statistically significant (35%) improvement in PFS, with patients treated in the ixazomib arm living for a significantly longer time without their disease worsening compared to patients in the control arm (20.6 months vs. 14.7 months in control group; Hazard Ratio [HR] 0.742; p = 0.012). Overall response rate (ORR) was 78.3% in the ixazomib arm and median duration of response was 20.5 months, vs. 71.5% and 15 months in the control group. Median PFS in high-risk patients (HR 0.543; HR 0.596 in patients with del(17p)) was similar to that in the overall patient population and in standard-risk patients. Adverse events observed with IRd were consistent with reported safety profiles for the individual agents. The most common gr ≥3 adverse events included neutropenia, anemia, thrombocytopenia, and pneumonia. Gastrointestinal events included diarrhea, nausea, and vomiting. Peripheral neuropathy (PN) rates were 28% in the IRd arm vs. 21% in the control arm, 35% vs. 21% had rash events, 8% vs. 10% had acute renal failure, and 4% vs. 3% had heart failure.

"The TOURMALINE-MM1 trial evaluated ixazomib plus lenalidomide and dexamethasone in some of the most common patient types in the relapsed/refractory multiple myeloma setting who are in urgent need of new treatment options due to the complex nature of this disease. This trial enabled us to gather efficacy and safety data across a large variety of patients such as older patients, patients with moderate renal impairment, light chain disease, and high risk cytogenetics," said lead investigator and presenter Philippe Moreau, M.D., University of Nantes, France."

The TOURMALINE-MM1 trial is currently ongoing. Patients continue to be treated to progression in this trial and will be evaluated for long-term outcomes.

Takeda has submitted additional review applications for ixazomib to regulatory authorities around the world, including the European Medicines Agency (EMA), based on the TOURMALINE-MM1 data.

Randomized Phase 2 Study of the All-Oral Combination of Investigational Proteasome Inhibitor (PI) Ixazomib Plus Cyclophosphamide and Low-Dose Dexamethasone (ICd) in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Who Are Transplant-Ineligible (Abstract #26)

Takeda also presented preliminary data from an open-label, multicenter, Phase 2 study that investigates the all-oral triplet combination of ixazomib plus cyclophosphamide and low-dose dexamethasone (ICd) as a first line therapy for patients not eligible for transplant. Preliminary data demonstrated comparable activity across treatment arms with a manageable toxicity profile in line with previous ixazomib studies and with manageable myelosuppression. This is the first study to assess ICd for the frontline treatment of multiple myeloma.

The Phase 2 study (n = 70) randomized patients receiving ixazomib, low-dose dexamethasone and two different doses of cyclophosphamide 300 mg/m2 (ICd-300, n = 36) or 400 mg/m2 (ICd-400, n = 34), with a mean duration follow-up of 7.0 months in both arms. Preliminary results across treatment arms demonstrated best unconfirmed complete response plus very good partial response (CR+VGPR) of 27% (ICd-300) and 23% (ICd-400), as well as early overall response rates (ORR) of 80% (ICd-300) and 73% (ICd-400). Toxicity was manageable in both the ICd-300 and ICd-400 arms, but toxicity rates appeared higher with ICd-400. Thrombocytopenia events occurred in 5 patients (no gr ≥3) in the ICd-300 arm and 4 patients (3 gr ≥3) in the ICd-400 arm. Most common adverse events (>15% all patients) included anemia, neutropenia, nausea, PN, diarrhea, vomiting, constipation, and fatigue. Most common gr ≥3 adverse events were neutropenia, anemia and pneumonia; no Grade 3 PN was observed.

"Research has shown that the combination of a proteasome inhibitor with cyclophosphamide and dexamethasone is active in patients with multiple myeloma. As treatment practices for multiple myeloma can vary across regions, it is important that we gain an understanding of the utility of ixazomib in a number of combination settings," said lead investigator and presenter Meletios A. Dimopoulos, M.D., National and Kapodistrian University of Athens, School of Medicine. "Preliminary data suggest that this may be a viable all-oral triplet regimen. We are committed to gathering additional data of ixazomib in this investigational setting."

About NINLARO (ixazomib) capsules
NINLARO (ixazomib) is the first and only oral proteasome inhibitor approved by the U.S. Food and Drug Administration (FDA) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO is administered orally, once-weekly on days 1, 8, and 15 of a 28-day treatment cycle. NINLARO is currently under review by the European Medicines Agency (EMA) and was granted an accelerated assessment by the Committee for Medicinal Products for Human Use (CHMP). NINLARO also received Breakthrough Therapy status by the U.S. FDA for relapsed or refractory systemic light-chain (AL) amyloidosis, a related ultra orphan disease, in 2014.

The TOURMALINE clinical development program further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with multiple myeloma worldwide and the healthcare professionals who treat them. Five global Phase 3 trials are ongoing:

· TOURMALINE-MM1, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma

· TOURMALINE-MM2, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma

· TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)

· TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT

· TOURMALINE-AL1, investigating ixazomib plus dexamethasone vs. physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis

In addition to the TOURMALINE program, a large number of investigator initiated studies are evaluating ixazomib for patients globally.

For additional information on the ongoing Phase 3 studies please visit www.clinicaltrials.gov. To learn more about NINLARO, please visit www.NINLARO.com or call 1-844-N1POINT (1-844-617-6468).

Important Safety Information

WARNINGS AND PRECAUTIONS
· Thrombocytopenia has been reported with NINLARO. During treatment, monitor platelet counts at least monthly, and consider more frequent monitoring during the first three cycles. Adjust dosing as needed. Platelet nadirs occurred between Days 14-21 of each 28-day cycle and recovered to baseline by the start of the next cycle.

· Gastrointestinal Toxicities, including diarrhea, constipation, nausea and vomiting, were reported with NINLARO and may occasionally require the use of antidiarrheal and antiemetic medications, and supportive care. Adjust dosing for severe symptoms.
· Peripheral Neuropathy (predominantly sensory) was reported with NINLARO. Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.

· Peripheral Edema was reported with NINLARO. Monitor for fluid retention. Investigate for underlying causes when appropriate and provide supportive care as necessary. Adjust dosing as needed.

· Cutaneous Reactions: Rash, most commonly maculo-papular and macular rash, was reported with NINLARO. Manage rash with supportive care or with dose modification.

· Hepatotoxicity has been reported with NINLARO. Monitor hepatic enzymes regularly during treatment and adjust dosing as needed

· Embryo-fetal Toxicity: NINLARO can cause fetal harm. Women should be advised of the potential risk to a fetus, to avoid becoming pregnant, and to use contraception during treatment and for an additional 90 days after the final dose of NINLARO.

ADVERSE REACTIONS
The most common adverse reactions occurring in greater than or equal to 20% of patients treated with NINLARO were diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting and back pain.

SPECIAL POPULATIONS
· Hepatic Impairment: Reduce the NINLARO starting dose to 3mg in patients with moderate or severe hepatic impairment
· Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease requiring dialysis. NINLARO is not dialyzable.
· Lactation: Advise women to discontinue nursing while on NINLARO.

DRUG INTERACTIONS: Avoid concomitant administration of NINLARO with strong CYP3A inducers.

INDICATION
NINLARO (ixazomib) is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

Please see the accompanying full Prescribing Information for NINLARO.

About Multiple Myeloma
Multiple myeloma is a cancer of the plasma cells, which are found in the bone marrow. In multiple myeloma, a group of plasma cells, or myeloma cells, becomes cancerous and multiplies, increasing the number of plasma cells to a higher than normal level. Because plasma cells circulate widely in the body, they have the potential to affect many bones in the body, possibly resulting in compression fractures, lytic bone lesions and related pain. Multiple myeloma can cause a number of serious health problems affecting the bones, immune system, kidneys and red blood cell count, with some of the more common symptoms including bone pain and fatigue, a symptom of anemia. Multiple myeloma is a rare form of cancer, with more than 26,000 new cases in the U.S. and 114,000 new cases globally per year.

On December 6, 2015 Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) reported the presentation of results from a Washington University-sponsored Phase 1 trial of vosaroxin plus azacitidine in patients with myelodysplastic syndrome, and from an analysis of the Company’s Phase 3 VALOR trial of vosaroxin and cytarabine in relapsed/refractory acute myeloid leukemia (AML) at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida (Press release, Sunesis, DEC 6, 2015, View Source;p=RssLanding&cat=news&id=2120408 [SID:1234508433]). The posters, titled "A Phase I Study of Vosaroxin plus Azacitidine for Patients with Myelodysplastic Syndrome" (publication number 1686) and "Baseline Predictors of Mortality in Patients with Relapsed or Refractory Acute Myeloid Leukemia Treated with Vosaroxin Plus Cytarabine or Placebo plus Cytarabine in the Phase 3 VALOR Study" (publication number 2560) are available at www.sunesis.com.

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A Phase I Study of Vosaroxin Plus Azacitidine for Patients with Myelodysplastic Syndrome

In a Phase 1/2, open label, dose-escalation trial sponsored by the Washington University School of Medicine, patients with MDS who may have received up to three prior cycles of hypomethylating agent-based therapy were given vosaroxin and azacitidine for a maximum of six cycles. The Phase 1 portion of the study was designed to determine the maximum tolerated dose and dose limiting toxicity of the combination. Other endpoints include best response, safety, tolerability, and event-free, progression-free, disease-free and overall survival.

Thirteen patients were enrolled in the dose-escalation phase and five of twenty planned patients have been enrolled in the expansion cohort to date. At the initial dose of 50 mg/m2/day vosaroxin, 2 of 6 patients experienced a DLT (grade 4 hyperbilirubinemia, and grade 4 neutropenia >42 days). The vosaroxin dose was de-escalated to 34 mg/m2/day, resulting in 1 of 6 patients with a DLT (grade 4 mucositis). Of the 18 patients enrolled to date, 16 completed ≥1 cycle and are evaluable for response. Best response for each patient was as follows: stable disease, n=3; stable disease with hematologic improvement (HI)-neutrophils, n=2; marrow complete remission (CR), n=4; marrow CR with HI-platelets; n=2; marrow CR with HI-neutrophils, n=1; marrow CR with HI-erythroid, n=1; and marrow CR with HI-platelets and neutrophils, n=1; and CR, n=1. One patient had progressive disease (PD). Of the 16 evaluable patients, 6 have proceeded to allogenic stem cell transplant and 3 are actively undergoing study treatment. The major non-hematologic toxicities of febrile neutropenia, infections, and mucositis were expected based on the disease population and prior experiences with vosaroxin.

"Hypomethlyating agents are the mainstay of treatment for myelodysplastic syndromes, yet these agents alone produce remissions in a minority of patients and are typically not curative," said Meagan A. Jacoby, M.D., Ph.D., Assistant Professor, Division of Oncology, Washington University School of Medicine, and principal investigator of the study. "The combination of vosaroxin and azacitidine show promising activity with response rates comparable or better than those generally observed with azacitidine alone. Additionally, the transplant rate observed is encouraging in this patient population with a median age of 66 years. We look forward to additional patient accrual and follow up from this study."

Baseline Predictors of Mortality in Patients with Relapsed or Refractory Acute Myeloid Leukemia Treated with Vosaroxin Plus Cytarabine or Placebo Plus Cytarabine in the Phase 3 VALOR Study

Treatment-related mortality (TRM) score is a prognostic scoring system to predict risk of 30-day mortality with intensive treatment protocols in patients with newly diagnosed AML (Walter, 2011, J Clin Oncol 29:4417-4424). The "simplified TRM" score includes age, performance status (PS), platelet count, serum albumin, type of AML (secondary vs primary), white blood cell count, blast percentage in the peripheral blood, and serum creatinine. In a retrospective analysis, TRM and other criteria were used to evaluate risk of early mortality in patients with relapsed or refractory acute myeloid leukemia treated with vosaroxin plus cytarabine or placebo plus cytarabine in Sunesis’ randomized, double-blind, placebo-controlled Phase 3 VALOR trial.

A total of 705 patients from VALOR were included in the safety population (355 treated with vosaroxin/cytarabine and 350 treated with placebo/cytarabine). Rates of 30-day (7.9% vs 6.6%, respectively) and 60-day (19.7% vs 19.4%, respectively) mortality in VALOR were comparable between vosaroxin plus cytarabine and placebo plus cytarabine arms. Several individual baseline factors independently predicted risk of early mortality, including ECOG performance status, hemoglobin, bilirubin and albumin levels, intermediate or high bone marrow blasts, and prior myelodysplastic syndrome. The previously validated TRM score for predicting early mortality in newly diagnosed AML was also predictive of mortality in this relapsed/refractory population. Vosaroxin/cytarabine treatment and age were not significant predictors of early mortality.

"The rate of early mortality in patients treated for acute myeloid leukemia reflects a balance of efficacy and safety outcomes," said Dr. Jeffrey Lancet, Senior Member and Professor of Oncologic Sciences at the H. Lee Moffitt Cancer Center, Tampa, Florida. "The ability to assess increased risk of early mortality in this disease would provide valuable information in guiding treatment decisions. Based on this analysis, patient selection for future studies of vosaroxin and other intensive regimens in the AML setting may benefit from use of these predictive factors."

About QINPREZO (vosaroxin)
QINPREZO (vosaroxin) is an anti-cancer quinolone derivative (AQD), a class of compounds that has not been used previously for the treatment of cancer. Preclinical data demonstrate that vosaroxin both intercalates DNA and inhibits topoisomerase II, resulting in replication-dependent, site-selective DNA damage, G2 arrest and apoptosis. Both the U.S. Food and Drug Administration (FDA) and European Commission have granted orphan drug designation to vosaroxin for the treatment of AML. Additionally, vosaroxin has been granted fast track designation by the FDA for the potential treatment of relapsed or refractory AML in combination with cytarabine. Vosaroxin is an investigational drug that has not been approved for use in any jurisdiction.
The trademark name QINPREZO is conditionally accepted by the FDA and the EMA as the proprietary name for the vosaroxin drug product candidate.

On December 6, 2015 Seattle Genetics, Inc. (Nasdaq: SGEN) reported clinical data with denintuzumab mafodotin (SGN-CD19A; 19A) in B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL) and B-lineage acute lymphocytic leukemia (B-ALL), presented 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 6, 2015, View Source;p=RssLanding&cat=news&id=2120410 [SID:1234508431]). Preclinical data from a novel antibody-drug conjugate (ADC) program called SGN-CD19B in B-cell malignancies will also be featured in an oral presentation. About 85 percent of non-Hodgkin lymphomas (NHL) are B-cell lineage, and CD19 is broadly expressed across all subtypes of B-cell malignancies. These two ADCs, 19A and SGN-CD19B, both target CD19 and utilize two of Seattle Genetics’ proprietary payloads, monomethyl auristatin F (MMAF) and a pyrrolobenzodiazepine (PBD) dimer, respectively. The company has initiated the first of two planned phase 2 trials of 19A in DLBCL and plans to advance SGN-CD19B into a phase 1 trial in 2016.

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"Data presented at ASH (Free ASH Whitepaper) from our 19A phase 1 trial in non-Hodgkin lymphoma show encouraging objective response rates, particularly in relapsed DLBCL patients, and a tolerability profile that we believe supports further investigation as part of novel regimens. Based on these data, we recently initiated a phase 2 trial in relapsed DLBCL, and plan to initiate a phase 2 trial in frontline DLBCL during 2016," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "CD19 is an attractive target for NHL, and there is a clear need for potent, safe and convenient therapies that can be used to improve outcomes for patients."

With more than 15 years of experience and innovation, Seattle Genetics is the leader in developing ADCs, a technology designed to harness the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. More than 25 ADCs in clinical development utilize Seattle Genetics’ proprietary ADC technology.

A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in Relapsed/Refractory B-Lineage Non-Hodgkin Lymphoma (Abstract #182, oral presentation on Sunday, December 6, 2015 at 7:45 a.m.)

Data were reported from 62 patients with relapsed or refractory NHL, including 54 patients with DLBCL, five patients with mantle cell lymphoma and three patients with grade 3 follicular lymphoma. Of the 62 patients, 37 patients (60 percent) were refractory to their last therapy and 25 patients (40 percent) were relapsed. Sixteen patients (26 percent) had received a prior autologous stem cell transplant. The median age of patients was 65 years.

The primary endpoints of the ongoing clinical trial are to estimate the maximum tolerated dose and evaluate the safety and tolerability of 19A. In addition, the trial is evaluating antitumor activity, pharmacokinetics, progression-free survival and overall survival. In this study, patients receive 19A either every three weeks or every six weeks. Patients with stable disease or better are eligible to continue treatment with 19A. Key findings from an oral presentation by Craig Moskowitz, M.D. Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, include:

The maximum tolerated dose was not exceeded after escalating to 6 milligrams per kilogram (mg/kg) every three weeks.
Of the 60 patients evaluable for response, 23 patients (38 percent) achieved an objective response, including 14 patients (23 percent) with a complete remission and nine patients (15 percent) with a partial remission. Thirteen patients (22 percent) achieved stable disease and 24 patients (40 percent) had disease progression.

Antitumor activity appeared to be higher in relapsed patients. Of the 25 relapsed patients, 15 patients (60 percent) achieved an objective response, including 10 patients (40 percent) with a complete remission. In the 23 relapsed patients who responded, median duration of response was 47.1 weeks. Among all relapsed patients, median progression-free survival was 25.1 weeks and median overall survival was 56.7 weeks.

The most common adverse events of any grade occurring in more than 15 percent of patients were blurred vision (63 percent); dry eye (53 percent); fatigue, keratopathy and photophobia (39 percent each). Ocular symptoms were reported in more than 70 percent of patients. Symptoms were mostly Grade 1/2 and were managed with steroid eye drop treatment and dose modifications. Eighty-eight percent of patients with Grade 3 or 4 keratopathy experienced improvement and/or resolution within a median of five weeks.

A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in Adults with Relapsed or Refractory B-Lineage Acute Leukemia (B-ALL) and Highly Aggressive Lymphoma (Abstract #1328, poster presentation on Saturday, December 5, 2015)

Data were reported from 72 adult patients with relapsed or refractory B-ALL and highly aggressive lymphomas, including B-cell lymphoblastic lymphoma (B-LBL) and Burkitt lymphoma. The median age of adult patients was 45 years and the median number of prior systemic therapies was two, with 20 patients (28 percent) having received a prior allogeneic stem cell transplant.

The primary endpoints of the ongoing clinical trial are to estimate the maximum tolerated dose and to evaluate the safety of 19A. In addition, the trial is evaluating antitumor activity, pharmacokinetics, progression-free survival and overall survival. In this dose-escalation study, patients received 19A in Schedule A (40 patients) at 0.3 to 3 mg/kg weekly or Schedule B (32 patients) at 4 to 6 mg/kg every three weeks. Key findings include:

Of the 56 B-ALL adult patients evaluable for response, six patients (19 percent) treated weekly achieved a composite complete remission (complete remission or complete remission with incomplete platelet or blood recovery) and nine patients (38 percent) treated every three weeks achieved a composite complete remission. The median duration of response was 27 weeks. Fifty-four percent of patients across both schedules achieved cytoreduction of greater than 50 percent.

In the ten patients with Philadelphia chromosome positive (Ph+) B-ALL, five patients (50 percent) achieved a complete remission and one patient (10 percent) had a partial remission. Ph+ B-ALL represents 20 to 30 percent of adult patients and carries a dismal prognosis, with higher rates of relapse and lower overall survival.

The maximum tolerated dose was not reached in patients treated weekly and was identified at 5 mg/kg in patients treated every three weeks.

The most common adverse events of any grade occurring in 25 percent or more of patients treated weekly (40 patients) or every three weeks (32 patients), respectively, were nausea (63 and 41 percent), fatigue (58 and 47 percent), fever (55 and 50 percent), headache (45 and 38 percent) and anemia (43 and 22 percent).

In the study, 43 patients (60 percent) developed ocular symptoms, of which 91 percent were Grade 1/2. These included blurred vision (39 percent), dry eye (25 percent) and photophobia (19 percent). Ocular symptoms were managed with steroid eye drop treatment and dose modifications. Keratopathy was observed in 34 patients, of whom 22 patients had Grade 3/4 events. The majority of patients with Grade 3/4 events had improvement or resolution with a median time of approximately four weeks.
The 19A phase 1 clinical trials are ongoing. Separately, a randomized phase 2 trial has recently initiated evaluating 19A in combination with R-ICE chemotherapy for second-line DLBCL. In addition, a phase 2 clinical trial in frontline DLBCL is planned to begin in 2016. More information about the 19A clinical trials, including enrolling centers, is available by visiting www.clinicaltrials.gov.

SGN-CD19B, a Pyrrolobenzodiazepine (PBD)-Based Anti-CD19 Drug Conjugate, Demonstrates Potent Preclinical Activity Against B-Cell Malignancies (Abstract #594, oral presentation on Monday, December 7, 2015 at 11:45 a.m.)

A preclinical analysis evaluated the activity of SGN-CD19B, a new ADC consisting of an anti-CD19 antibody attached to a highly potent DNA binding agent called a PBD dimer, in multiple B-cell malignancy models. Data to be presented in an oral session demonstrate that SGN-CD19B exhibits antitumor activity against a broad panel of CD19-expressing B-cell malignancies, inducing durable tumor regressions and improved survival in multiple preclinical models of NHL and B-ALL. Based on these data, a phase 1 clinical trial evaluating SGN-CD19B in NHL is planned to start in 2016.

About Denintuzumab Mafodotin (SGN-CD19A)

Denintuzumab mafodotin (SGN-CD19A; 19A) is an ADC targeting CD19, a protein expressed broadly on B-cell malignancies. 19A is comprised of an anti-CD19 monoclonal antibody linked to a synthetic cell-killing agent, monomethyl auristatin F (MMAF). The ADC is designed to be stable in the bloodstream, and to release its cytotoxic agent upon internalization into CD19-expressing tumor cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing the antitumor activity.

About Non-Hodgkin Lymphoma

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and NHL. NHL is further categorized into indolent (low-grade) or aggressive, including DLBCL. DLBCL is the most common type of NHL. According to the American Cancer Society, more than 71,000 cases of NHL were to be diagnosed in the United States during 2015 and more than 19,000 people would die from the disease.

About Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia, also called acute lymphocytic leukemia or ALL, is an aggressive type of cancer of the bone marrow and blood that progresses rapidly without treatment. In ALL, lymphoblasts, which are malignant, immature white blood cells, multiply and crowd out normal cells in the bone marrow. ALL is the most common type of cancer in children. According to the American Cancer Society, more than 6,000 people will be diagnosed with ALL during 2015 and more than 1,400 would die from the disease.

On December 6, 2015 Novartis reported that findings from an ongoing Phase IIa study to evaluate the safety and efficacy of investigational chimeric antigen receptor T cell (CART) therapy CTL019 in certain types of relapsed or refractory (r/r) non-Hodgkin lymphoma will be presented in an oral session at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting (Press release, Novartis, DEC 6, 2015, View Source [SID:1234508429]). The study, conducted by the University of Pennsylvania’s Perelman School of Medicine (Penn), found an overall response rate (ORR) at three months of 47% (7/15) in adult patients with r/r diffuse large B-cell lymphoma (DLBCL) and an ORR of 73% (8/11) in adult patients with follicular lymphoma (FL) [1]. Results will be presented in an oral session at ASH (Free ASH Whitepaper) on Sunday, December 6 (Abstract #183, 8 a.m.) [1].

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"These data add to the growing body of clinical evidence on CTL019 and illustrate its potential benefit in the treatment of relapsed and refractory non-Hodgkin lymphoma, a disease with few effective options," said lead investigator Stephen Schuster, M.D., Associate Professor, Division of Hematology/Oncology at the University of Pennsylvania, Abramson Cancer Center. "We look forward to continuing this study to further understand longer-term patient response."

The study findings include 26 adult patients (15 with DLBCL and 11 with FL) who were evaluable for response. The study found that three patients with DLBCL who achieved a partial response (PR) to treatment at three months converted to complete response (CR) by six months. In addition, three patients with FL who achieved a PR to treatment at three months converted to CR by six months. One DLBCL patient with a PR to treatment at three months experienced disease progression at six months after treatment. One FL patient with a PR to treatment at three months who remained in PR at nine months experienced disease progression at approximately 12 months after treatment. Median progression-free survival (PFS) was 11.9 months for patients with FL and 3.0 months for patients with DLBCL.

In the study, four patients developed cytokine release syndrome (CRS) of grade 3 or higher. CRS has been observed after CTL019 infusion when the engineered cells become activated and multiply in the patient’s body. During CRS, patients typically experience varying degrees of flu-like symptoms with high fevers, nausea, muscle pain, and in some cases, low blood pressure and breathing difficulties. Neurologic toxicity occurred in two patients, including one grade three episode of delirium and one possibly related grade five encephalopathy [1].

In contrast to typical small molecule or biologic therapies, CTL019 is specifically manufactured for each individual patient. A patient’s T cells are collected through a specialized blood draw called leukapheresis and then transferred to the Novartis manufacturing facility in Morris Plains, New Jersey. There the cells are reprogrammed to hunt cancer and other B-cells expressing CD19. The patient’s own modified cells are then transferred back to the treatment center where they are administered to the patient.

A poster presentation on December 6, 6-8 p.m., will report on how the successful transfer of cell processing technology from Penn to the Novartis cell manufacturing center in Morris Plains has enabled the scale-up of CTL019 production (Abstract #3100) [2]. The Morris Plains facility is the first FDA-approved Good Manufacturing Practices quality site for a cell therapy production in the US and is now processing cells to support ongoing Phase II multi-center global studies of CTL019 in specific leukemias and lymphomas.

"The company’s investment in our state-of-the-art manufacturing facility has given us the capacity and scalability needed to support our growing global clinical trial program," said Usman Azam, MD, Global Head, Cell & Gene Therapies Unit, Novartis Pharmaceuticals. "Novartis is proud to be the first healthcare company to initiate Phase II CART therapy trials in the US, Europe, Canada and Australia. This is a significant step forward in our mission to help address unmet medical needs of patients." A list of participating trial centers is available at View Source (link is external).

Because CTL019 is an investigational therapy, the safety and efficacy profile has not yet been established. Access to investigational therapies is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the therapy. Because of uncertainty of clinical trials, there is no guarantee that CTL019 will ever be commercially available anywhere in the world.

On December 6, 2015 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company focused on re-engaging the body’s immune system to revolutionize the treatment of cancer, reported, in partnership with its collaborators, that clinical data from a chimeric antigen receptor (CAR) T cell product candidate, JCAR014, demonstrated encouraging clinical responses in patients with relapsed or refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) (Press release, Juno, DEC 6, 2015, View Source;p=RssLanding&cat=news&id=2120411 [SID:1234508428]). Results will be presented in an oral presentation today at the 54th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Orlando.

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In addition, a poster presentation highlighted clinical data from JCAR018, a CAR T cell product candidate targeting CD22 that demonstrated preliminary safety and clinical activity in pediatric and young adult r/r B-cell acute lymphoblastic leukemia (ALL) patients.

"Complete responses and the durability of those responses are key efficacy parameters in both NHL and CLL. The early data reported today are highly encouraging and suggest that our CD19-directed CAR T product candidates have the potential to have a meaningful impact for patients with these difficult-to-treat diseases," said Mark Frohlich, M.D., Executive Vice President, Development and Portfolio Strategy. "Our CD22-directed CAR T product candidate, JCAR018, has shown encouraging early signs of activity from the study in pediatric patients with r/r ALL, where CD19 epitope loss with treatment appears to be of increasing relevance. We look forward to more data in 2016 as we continue to treat patients at the current and higher dose levels."

In an oral presentation on Sunday, December 6, 2015, Cameron J. Turtle, MBBS, Ph.D. of the Fred Hutchinson Cancer Research Center will present "Anti-CD19 Chimeric Antigen Receptor-Modified T Cell Therapy for B Cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Fludarabine and Cyclophosphamide Lymphodepletion Improves In Vivo Expansion and Persistence of CAR T Cells and Clinical Outcomes." Dr. Turtle will be updating results on a total of 41 patients treated with JCAR014 against B-cell malignancies.

Key Takeaways include:

JCAR014 (CD19-specific CAR T cells of defined subset composition) demonstrated potent anti-tumor activity and an acceptable toxicity profile in r/r adult B-cell NHL patients and CLL patients previously treated with ibrutinib.
A meaningful percentage of patients achieved a complete response in both r/r NHL and r/r CLL.

While longer follow-up is necessary to define full durability, there have been no relapses in NHL and CLL patients that achieved a complete response in this study with follow-up ranging from 2 to 14 months.

The addition of fludarabine and cyclophosphamide (flu/cy) lymphodepletion improved CAR T cell peak expansion, persistence and clinical outcomes in NHL.

Severe cytokine release syndrome and severe neurotoxicity were observed in some patients; lower doses of this defined cell product candidate appeared to correlate with lower rates of these toxicities.

In a poster presentation on Saturday, December 5, 2015, Terry J. Fry, M.D. of the Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, presented "Clinical Activity and Persistence of Anti-CD22 Chimeric Antigen Receptor in Children and Young Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)." Dr. Fry reported on a first-in-human anti-CD22 CAR T cell therapy (JCAR018) in pediatric and young adult r/r B-cell ALL. Key takeaways include:
JCAR018 provides a potential treatment alternative to patients with CD19 epitope loss variants, particularly relevant in pediatric ALL.

In this Phase I dose-escalation trial, nine patients have enrolled and seven patients have been assessed to date.
Six patients were treated with the lowest dose (3 x 105 cells/kg), with one patient reaching MRD-negative CR, two patients having stable disease, and three patients having disease progression.

Three patients have enrolled at the next dose (1 x 106 cells/kg), which is in the dose range of CD19-directed CAR T programs. One patient achieved an MRD-negative CR, and two patients are too early to assess for response.

One patient at the lowest dose had Grade 3 diarrhea, and the maximum cytokine release syndrome was Grade 2.

ASH Investor and Analyst Event and Webcast
The Juno ASH (Free ASH Whitepaper) Investor and Analyst Event and webcast will be held Monday, December 7, 2015 at 8:30p.m. Eastern Time. The webcast can be accessed live on the Investor Relations page of Juno’s website, www.JunoTherapeutics.com, and will be available for replay for 30 days following the event.