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IMBRUVICA® (ibrutinib) Combination Regimen Significantly Improved Survival Versus the Chemoimmunotherapy FCR (Fludarabine, Cyclophosphamide and Rituximab) in Previously Untreated and Younger Chronic Lymphocytic Leukemia (CLL) Patients; Late-Breaking Phase 3 Data at ASH 2018

On December 4, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported its results from the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN), National Cancer Institute (NCI)-sponsored, Phase 3 study (E1912) evaluating IMBRUVICA (ibrutinib) plus rituximab versus the current National Comprehensive Cancer Network (NCCN) guidelines Category 1 treatment of fludarabine, cyclophosphamide and rituximab (FCR) in previously untreated younger patients (70 years old or younger) with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) (Press release, AbbVie, DEC 4, 2018, View Source [SID1234531879]).1,2 This interim analysis showed that IMBRUVICA plus rituximab significantly prolonged progression-free survival (PFS), the primary endpoint of the study, compared to FCR, with a 65 percent reduction in risk of progression or death. Furthermore, IMBRUVICA plus rituximab significantly improved overall survival (OS) compared to FCR. The findings were presented today during the Late-Breaker abstract oral session at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, CA (abstract #LBA-4).

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This study evaluated 529 patients in the United States from centers spanning four cooperative groups. The study was led by ECOG-ACRIN with additional study site participation by SWOG, ALLIANCE and NRG Oncology, and was sponsored by the NCI in collaboration with Pharmacyclics LLC, an AbbVie company, through the existing Cooperative Research and Development Agreement with NCI. IMBRUVICA is a once-daily, first-in-class BTK inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"We have been eagerly awaiting a new treatment regimen that could help younger chronic lymphocytic leukemia patients. These findings further support IMBRUVICA-based therapy as an efficacious first-line treatment for many patients with CLL," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "We are proud to participate and collaborate with the National Cancer Institute and the Division of Cancer Treatment."

At a median follow-up of 33.4 months, IMBRUVICA plus rituximab showed superior PFS compared to FCR in younger and previously untreated CLL patients (HR: 0.35; 95% confidence interval [CI]: 0.22-0.56; p<0.0001). The study also demonstrated an improved OS for the IMBRUVICA plus rituximab treatment arm versus FCR (HR: 0.17; 95% CI: 0.05-0.54; p=0.0003).

CLL is one of the two most common forms of leukemia in adults and is a type of cancer that can develop from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes).3 While these cancer cells start in the bone marrow, they then later spread into the blood. The prevalence of CLL is approximately 115,000 patients in the U.S. with approximately 20,000 newly diagnosed patients every year.4,5 CLL is predominately a disease of the elderly, with a median age at diagnosis ranging from 65-70 years.6

About Abstract #LBA-4: A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912)

Late-Breaker Oral Presentation: Tuesday, December 4 at 7:30am PT

The Phase 3 study (E1912) evaluated previously untreated CLL patients age 70 or younger, who were randomly assigned to receive IMBRUVICA (420 mg/day until disease progression) and rituximab (50 mg/m2 on day 1 of cycle 2; 325 mg/m2 on day 2 of cycle 2; 500 mg/m2 on day 1 of cycles 3-7) (n=354) or six courses of intravenous fludarabine (25 mg/m2) and cyclophosphamide (250 mg/m2) days 1-3 with rituximab (50 mg/m2 on day 1 of cycle 1; 325 mg/m2 on day 2 of cycle 1; 500 mg/m2 on day 1 of cycles 2-6) every 28-days (n=175). The primary endpoint was PFS with a secondary endpoint of OS.

With a median follow-up of 33.4 months, the pre-determined, interim analysis observed 77 PFS events and 14 deaths. IMBRUVICA plus rituximab significantly improved PFS compared to FCR (HR: 0.35; 95% CI: 0.22-0.56; p<0.0001), which crossed the pre-specified boundary. The IMBRUVICA plus rituximab treatment arm also significantly improved OS compared to FCR (HR: 0.17; 95% CI: 0.05-0.54; p=0.0003, pre-specified boundary for superiority p=0.0005).

FCR was more frequently associated with Grade 3 and 4 neutropenia (FCR: 44 percent vs. IMBRUVICA plus rituximab: 23 percent; p<0.0001) and infectious complications (FCR: 18 percent vs. IMBRUVICA plus rituximab: 7 percent; p<0.0001). Grade 3 and 4 treatment-related adverse events were observed in 58 percent of IMBRUVICA plus rituximab treated patients and 72 percent of FCR treated patients (p=0.0042).

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH (Free ASH Whitepaper) 2018, please visit: View Source

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by inhibiting a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.7 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host disease (cGVHD).8

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was initially approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for adult patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with CLL/SLL.
In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.
In August 2018, IMBRUVICA plus rituximab was approved for adult patients with WM.
Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases.9 IMBRUVICA was one of the first medicines to receive FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. To date, more than 135,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in 3% of patients, with fatalities occurring in 0.3% of 1,011 patients exposed to IMBRUVICA in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 24% of 1,011 patients exposed to IMBRUVICA in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,011 patients exposed to IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension has occurred in 12% of 1,011 patients treated with IMBRUVICA in clinical trials with a median time to onset of 5 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (9%) including non-skin carcinomas (2%) have occurred in 1,011 patients treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, neutropenia (58%)*, diarrhea (42%), anemia (39%)*, rash (31%), musculoskeletal pain (31%), bruising (31%), nausea (28%), fatigue (27%), hemorrhage (23%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (36%)*, thrombocytopenia (15%)*, and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%)*, pneumonia (10%), sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements and adverse reactions.

DRUG INTERACTIONS

CYP3A Inhibitors: Dose adjustments may be recommended.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.

GlycoMimetics Posters at 60th ASH Annual Meeting Highlight Preclinical Data on Two New Proprietary Drug Candidates

On December 4, 2018 GlycoMimetics, Inc. (NASDAQ: GLYC) reported at the 60thAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting yesterday two posters with preclinical data presentations: on GMI-1687, the company’s highly potent E-selectin antagonist that is bioavailable via subcutaneous administration, and GMI-1757, the company’s dual-function E-selectin/galectin-3 antagonist (Press release, GlycoMimetics, DEC 4, 2018, View Source [SID1234531877]).

"The new preclinical data presented at ASH (Free ASH Whitepaper) underscore GlycoMimetics’ commitment to pioneering advances in the field of glycobiology and to rationally designing innovative drug candidates that address areas of significant unmet medical need," said John Magnani, Ph.D., Senior Vice President and Chief Scientific Officer. "The two compounds, debuted in posters, are currently in preclinical testing. The GMI-1687 poster points to the potential for a life-cycle extension for uproleselan, which is more highly-potent and is subcutaneously bioavailable in animal models. The poster on GMI-1757, a novel galectin-3/E-selectin antagonist, suggests the compound may be able to play a role in the treatment of a variety of cancers and fibrotic conditions."

Details for the two poster presentations on GlycoMimetics’ wholly owned drug candidates follow:

Publication Number: 4678
TITLE: A Novel and Potent Inhibitor of E-Selectin, GMI-1687, Attenuates Thrombus Formation and Augments Chemotherapeutic Intervention of AML in Preclinical Models Following Subcutaneous Administration
Publication Number: 2211
TITLE: A Novel Glycomimetic Compound (GMI-1757) with Dual Functional Antagonism to E-Selectin and Galectin-3 Demonstrates Inhibition of Thrombus Formation in an Inferior Vena Cava Model

Fate Therapeutics Presents Off-the-Shelf CAR T and NK Cell Cancer Immunotherapy Pipeline at ASH Annual Meeting

On December 4, 2018 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported new preclinical data on the Company’s induced pluripotent stem cell (iPSC) product platform and its iPSC-derived, off-the-shelf cell-based cancer immunotherapy pipeline at the 60thAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Fate Therapeutics, DEC 4, 2018, View Source [SID1234531876]). Last week, the Company announced that the U.S. Food and Drug Administration (FDA) allowed its Investigational New Drug (IND) Application for FT500, the Company’s universal, off-the-shelf natural killer (NK) cell product candidate derived from a clonal master iPSC line. The clinical trial of FT500 is expected to be the first-ever clinical investigation in the U.S. of an iPSC-derived cell product.

"Fate Therapeutics is at the forefront in developing off-the-shelf, cell-based cancer immunotherapies, and is rapidly progressing multiple iPSC-derived CAR T- and NK cell product candidates that have the potential to disrupt autologous and allogeneic approaches to cell therapy," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "The clearance of our FT500 IND by the FDA is a landmark achievement and serves as a roadmap for advancement of our iPSC-derived cell product pipeline into clinical development. We believe the use of clonal master iPSC lines uniquely enables the production of multi-functional, cell-based cancer immunotherapies that are uniformly engineered, are available for off-the-shelf administration to patients and can be effectively combined in multi-dose, multi-cycle regimens with well-established immune-oncology agents, such as checkpoint inhibitor blockade and monoclonal antibody therapy, including in earlier lines of therapy."

Several of the Company’s iPSC-derived cell product candidates undergoing development were discussed during an investor event at ASH (Free ASH Whitepaper) by its collaborating experts in the field of cell-based cancer immunotherapy including:

Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering & Gene Transfer and Gene Expression Laboratory, Memorial Sloan Kettering Cancer Center;

Jeffrey S. Miller, M.D., Deputy Director, Masonic Cancer Center, University of Minnesota; and

Dan S. Kaufman, M.D., Ph.D., Professor of Medicine, Division of Regenerative Medicine, Director of Cell Therapy, University of California – San Diego.
FT500
The clinical trial of FT500 is intended to evaluate the safety and tolerability of multiple doses of FT500, in multiple dosing cycles with nivolumab, pembrolizumab or atezolizumab, in subjects that have progressed or failed on immune checkpoint blockade (CPB) therapy. Although CPB therapy can lead to prolonged responses, refractory disease and progression after initial response remain major causes of mortality. In patients receiving CPB therapy, mutations in beta-2-microglobulin (B2M), an essential component for the stable presentation of antigens by tumor cells, have been identified in approximately 30% of patients with progressing disease and are associated with poor overall survival. Investigators have demonstrated in various tumor model systems that NK cells have the potential to rescue CPB therapy by recognizing and killing B2M-deficient target cells. An oral presentation at ASH (Free ASH Whitepaper) by Dr. Miller showed that FT500 synergizes with T cells and anti-PD1 antibody to produce pro-inflammatory cytokines and completely clear target cancer cells in an in vitro three-dimensional tumor spheroid model.

FT516
FT516 is a universal, off-the-shelf NK cell product candidate manufactured from a clonal master iPSC line engineered to uniformly express a high-affinity, non-cleavable CD16 (hnCD16) Fc receptor. Since CD16 binds the Fc region of tumor-bound antibodies, FT516 can be combined with FDA-approved monoclonal antibody therapies to target a broad spectrum of tumor-associated antigens. In preclinical studies, FT516 exhibits potent and persistent anti-tumor activity in vitro and in vivo against multiple tumor types, including in combination with monoclonal antibody therapies that target CD20, HER2 and EGFR. The Company plans to submit an IND to the FDA by the end of 2018 to evaluate the safety and tolerability of multiple doses of FT516 in multiple dosing cycles in combination with FDA-approved monoclonal antibody therapy.

FT596
FT596 is a universal, off-the-shelf chimeric antigen receptor (CAR) NK cell product candidate that expresses a proprietary CAR targeting CD19, a novel IL-15 receptor fusion for cytokine-independent persistence, and a hnCD16 Fc receptor for augmented antibody-dependent cellular-cytotoxicity (ADCC). A poster presentation at ASH (Free ASH Whitepaper) by scientists from the Company and the University of California – San Diego highlighted new in vivo data demonstrating that FT596 displays long-term persistence without systemic cytokine support. Additionally, FT596 prevents tumor progression and promotes sustained long-term survival in a B-cell leukemia xenograft model. Moreover, as proof-of-concept for the mitigation of antigen escape, FT596 in combination with rituximab completely eliminates CD19+ and CD19- B-cell tumor cells in a co-culture cytotoxicity assay.

FT538
FT538 is a universal, off-the-shelf NK cell product candidate that expresses both a novel IL-15 receptor fusion for cytokine-independent persistence and a hnCD16 Fc receptor for augmented ADCC, and additionally lacks CD38 expression to eliminate fratricide when combined with CD38-targeting monoclonal antibody therapy. A poster presentation at ASH (Free ASH Whitepaper) by scientists from the Company and the University of Minnesota highlighted new in vitro data showing that FT538 in combination with daratumumab is resistant to fratricide and eliminates multiple myeloma cancer cells in a serial re-challenge assay. The Company is investigating the additional therapeutic benefit of including a novel humanized CAR targeting B-cell Maturation Antigen (BCMA) as a dual-targeting mechanism to address multiple myeloma and other BCMA-positive malignancies.

FT819
FT819 is an off-the-shelf, TCR-less CD19 CAR T-cell product candidate manufactured from a clonal master iPSC line that is undergoing preclinical development under a collaboration with Memorial Sloan Kettering Cancer Center (MSK) led by Dr. Sadelain. FT819 is engineered to completely eliminate expression of the T-cell receptor and to insert a next-generation CAR receptor into the T-cell receptor alpha locus, a strategy which is intended to convey enhanced safety and efficacy while eliminating the possibility of graft-versus-host disease. A poster presentation at ASH (Free ASH Whitepaper) by scientists from the Company and MSK showcased new in vivo data demonstrating that FT819, when thawed and directly infused, effectively controls tumor progression comparable to peripheral blood CAR T cells in a preclinical mouse model of acute lymphoblastic leukemia.

A copy of the Company’s presentation from its ASH (Free ASH Whitepaper) investor event can be accessed under "Events & Presentations" in the Investors & Media section of the Company’s website at www.fatetherapeutics.com.

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary iPSC product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered in repeat doses to mediate more effective pharmacologic activity, including in combination with cycles of other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event, and selecting a single iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf to treat many patients. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 100 issued patents and 100 pending patent applications.

Updated Interim Results from Ongoing Phase 2a Study of Portola Pharmaceuticals’ Oral Syk/JAK Inhibitor Cerdulatinib Continues to Demonstrate Clinical Responses in Heavily Pre-Treated T-Cell Malignancies

On December 4, 2018 Portola Pharmaceuticals, Inc. (Nasdaq: PTLA) reported updated interim results from the Company’s ongoing Phase 2a study of cerdulatinib, an investigational, oral Syk/JAK inhibitor, in patients with specific subtypes of T-cell Non-Hodgkin Lymphoma, including relapsed/refractory peripheral T-cell lymphoma (PTCL); angioimmunoblastic T-cell lymphoma (AITL), a subset of PTCL; and cutaneous T-cell lymphoma (CTCL) (Press release, Portola Pharmaceuticals, DEC 4, 2018, View Source;p=RssLanding&cat=news&id=2379193 [SID1234531875]). The data will be presented today during an oral session at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego (December 1-4).

As of the November 1, 2018 cut-off date, 41 PTCL patients and 27 CTCL patients were evaluable for response. The objective response rate (ORR) was 34 percent in the PTCL cohort and 26 percent in the CTCL cohort. Among the subset of patients in the PTCL cohort with AITL, the ORR was 57 percent.

PTCL Cohort Data

Eleven of 41 patients (27 percent) achieved a complete response (CR), and three patients (7 percent) achieved a partial response (PR).
In the subgroup of 14 patients with AITL, seven patients (50 percent) achieved a CR and one patient (7 percent) achieved a PR.
One patient who achieved a CR went on to transplant.
Eight responding patients have remained on drug for three to more than 12 months and five patients have had a duration of response of six months or greater. Follow-up is ongoing.
CTCL Cohort Data

In the CTCL cohort, two patients (7 percent) achieved a CR and five patients (19 percent) achieved a PR. Responses have been seen in patients with Mycosis Fungoides and Sezary Syndrome.
Eleven of 23 patients (48 percent) achieved a ≥ 50 percent reduction in skin lesions, based on the Modified Severity Weighted Assessment Tool (mSWAT).
Rapid improvements in pruritus, or severe itching – a common and often serious condition associated with CTCL – have been observed, as measured by the Likert scale.
The CTCL cohort continues to enroll and data analysis is ongoing.
Cerdulatinib has demonstrated tolerability in both PTCL and CTCL. The most common grade 3 or greater adverse events across the PTCL and CTCL cohorts with a frequency > 5 percent were lipase increase (23 percent), amylase increase (18 percent), sepsis/bacteremia (8 percent), and neutropenia, pneumonia/lung infection and diarrhea (7 percent each). These events are manageable and further accrual is ongoing.

"The ongoing Phase 2a cerdulatinib data continue to demonstrate meaningful clinical activity, with particularly compelling complete response rates among AITL patients and the potential for durable response among patients with PTCL and CTCL," said Steven M. Horwitz, M.D., Memorial Sloan Kettering Center, and study investigator. "Like many others with T-cell malignancies, the patients in this study have failed prior therapies and are in need of additional treatment options. It is encouraging to see such a strong early signal in both disease response and quality-of-life measures, such as itching."

"While still early, the continuing and durable response rates in PTCL and the encouraging responses in CTCL underscore the potential of cerdulatinib to control relapsed/refractory T-cell malignancies," said John Curnutte, M.D., Ph.D., executive vice president and head of research and development at Portola. "We will apply our learnings from this study to inform the design of a pivotal trial, and look forward to continuing discussions with the U.S. Food and Drug Administration about the potential for an accelerated approval pathway for cerdulatinib in PTCL."

ASH Oral Session Details – Monday, December 3, 2018 at 7:15 p.m. PST

Title: 1001. The Novel Syk/JAK Inhibitor Cerdulatinib Demonstrates Good Tolerability
and Clinical Response in a Phase 2a Study in Relapsed/Refractory Peripheral
T-Cell Lymphoma and Cutaneous T-Cell Lymphoma

Session: 624 (Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: T Cell
Lymphoma: Chemotherapy and Targeted Approaches)

Presenter: Steven M. Horwitz, M.D., Memorial Sloan-Kettering Cancer Center

Session Time: 6:15 – 7:45 p.m. PST; Room 6F

About Cerdulatinib
Cerdulatinib is an investigational oral, dual spleen tyrosine kinase (Syk) and janus kinase (JAK) inhibitor that uniquely inhibits two key cell signaling pathways implicated in certain hematologic malignancies and autoimmune diseases. There is a strong rationale for inhibiting both Syk (B-cell receptor pathway) and JAK (cytokine receptors) in B-cell malignancies where both targets have been shown to promote cancer cell growth and survival. In addition, pre-clinical data suggest an important role for Syk and JAK in PTCL tumor survival.

The U.S. Food and Drug Administration granted cerdulatinib Orphan Drug Designation for the treatment of PTCL in September 2018.

Autolus Therapeutics Presents Initial AUTO3 Clinical Data from Phase 1/2
Clinical Trials in B cell Malignancies at the 60th ASH Annual Meeting

On December 4, 2018 Autolus Therapeutics plc (Nasdaq: AUTL), a clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies, reported its updated results from its ongoing Phase 1/2 AMELIA clinical trial of AUTO3 in patients with relapsed/refractory pediatric acute lymphoblastic leukemia (pALL) and its ongoing Phase 1/2 ALEXANDER clinical trial in patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, San Diego, California (Press release, Autolus, DEC 4, 2018, View Source [SID1234531874]). AUTO3 is a dual-targeted therapy incorporating two separate chimeric antigen receptors (CARs). Observations from preclinical studies indicate that AUTO3 independently targets CD19 and CD22. AUTO3 is designed to reduce relapse driven by antigen loss, a key defense mechanism used by the tumor cells and the primary cause of relapse in pALL.

"The preliminary results of the AMELIA trial indicate that AUTO3, the first dual targeting CD19 and CD22 CAR T cell therapy under development for pediatric ALL, appears to have a manageable safety profile, with the potential to overcome target-negative relapse, a major limitation of current CD19-targeted therapies," said Professor Persis Amrolia, lead investigator and Consultant in Bone Marrow Transplant at Great Ormond Street Hospital (GOSH) and NIHR Research Professor of Transplantation Immunology at UCL Great Ormond Street Institute of Child Health (ICH).

"In the ALEXANDER trial, preliminary results indicate that AUTO3 followed by consolidation with a limited duration of anti-PD1 therapy appears to have a manageable safety profile at the doses evaluated. This is the first therapy that aims to address two emerging resistance mechanisms for non-Hodgkin lymphoma, target-negative relapse and checkpoint upregulation," said Dr. Anas Younes, Chief, Lymphoma Service at Memorial Sloan Kettering Cancer Center.

Simultaneous Targeting of CD19 and CD22: Phase 1 Trial of AUTO3, a Bicistronic Chimeric Antigen Receptor (CAR) T-cell Therapy, in Pediatric Patients with Relapse/Refractory B-cell Acute Lymphoblastic Leukemia (r/r B-ALL): AMELIA Trial (Abstract Number 279, oral presentation at 8:00AM on Sunday, December 2, 2018)

Dr. Amrolia reported on 10 patients with relapsed or refractory ALL who received an AUTO3 infusion as a single dose or split dose dependent on their tumor burden. Key inclusion criteria included age 1-24 years old with relapsed or refractory B-lineage ALL at high risk in first relapse or in second or greater relapse. Prior targeted therapies to CD19 and CD22 were not excluded. The average age of the 10 evaluable patients was 8.5 years, the median number of prior lines of therapy was 3. Product was successfully manufactured for all patients. AUTO3 was generally well tolerated with no ³ Grade 3 CRS, no ICU admission, and no pressors or critical care support for CRS required. One case of Grade 3 neurotoxicity was observed which was considered unlikely related to AUTO3 and primarily attributed to prior intrathecal chemotherapy. Grade 3 or higher cytopenias lasting at least 30 days were noted in 4 out of 10 patients. Among the 10 evaluable patients at all dose levels, 8 out of 10 achieved MRD negative CR and higher response rates were observed at doses ³3 x106/kg dose levels with all patients achieving MRD-negative remission. In the higher dose group, 4 out of 6 (67%) patients have an ongoing molecular CR and importantly, no loss of CD19 or CD22 was noted among relapsed patients. Initial data indicates response rates and persistence are dose dependant. Dose escalation is ongoing.

For more information about this trial and the inclusion criteria, visit www.ClinicalTrials.gov (NCT03289455).

Trial of AUTO3, the First Bicistronic Chimeric Antigen Receptor (CAR) Targeting CD19 and CD22, Followed By Anti-PD1 Consolidation in Patients with Relapsed/Refractory (r/r) Diffuse Large B Cell Lymphoma (DLBCL): Alexander Trial (Abstract Number 1679, poster presentation from 6:15 PM – 8:15PM on Saturday, December 1, 2018)

Dr. Kirit Ardeshna, principal investigator at University College London, UK, reported preliminary clinical data on safety and efficacy from this open-label, multi-center trial in patients with DLBCL treated with a single dose of AUTO3 followed by consolidation with anti-PD-1 antibody (pembrolizumab). Key inclusion criteria included histologically confirmed DLBCL, chemotherapy-refractory disease or relapse after at least two lines of therapy or after ASCT, and no prior allogeneic stem cell transplant. There were 7 patients evaluable for safety with at least 28 day follow up post-treatment. The median number of prior lines of therapy in these 7 evaluable patients was 3 (range was 2 to 4). All patients were treated at the starting dose of 50×106 transformed CAR T cells. Three patients received a consolidation with pembrolizumab, and 4 patients did not receive treatment with pembrolizumab. None of the treated patients developed CRS grade 3 or higher and one patient had neurotoxicity grade 3, considered possibly related to AUTO3. No dose limiting toxicities were observed and dose escalation continues. Six patients were evaluable for response, two achieved a CR and two a PR; two patients did not respond. The two CRs were ongoing at six and three months, respectively.

For more information about this trial and the inclusion criteria, visit www.ClinicalTrials.gov (NCT03287817).

About AUTO3

AUTO3 is a programmed T cell therapy containing two independent chimeric antigen receptors targeting CD19 and CD22 that have each been independently optimized for single target activity. By simultaneously targeting two B cell antigens, AUTO3 is designed to minimize relapse due to single antigen loss in patients with B cell malignancies. AUTO3 is currently being tested in two clinical trials, referred to as the AMELIA and ALEXANDER trials.

The AMELIA trial is a single-arm, open label, multi-center Phase 1/2 clinical trial of AUTO3 in patients up to 24 years of age with high-risk relapsed or refractory B-lineage. The trial also is enrolling patients who previously received CD19 or CD22 targeting therapies including other CAR T cell therapy. The primary objective for Phase 1 is to assess the safety and tolerability of AUTO 3 administration as well as to identify the Phase 2 dose and schedule. The purpose of this trial is to test the safety and efficacy, including the complete remission rate or minimal residual disease (MRD) negative response, of AUTO3. Autolus expects to enroll up to 54 patients in this trial.

The ALEXANDER trial is a single-arm, open label, multi-center Phase 1/2 clinical trial of AUTO3 in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL). The primary objective for the Phase 1 portion is to assess the safety and tolerability of AUTO3 administration as well as to identify the recommended Phase 2 dose and maximum tolerated dose (MTD) of AUTO3. The purpose of this trial is to test the safety and efficacy, including the overall response rate as per Lugano criteria, of AUTO3 followed by limited duration of consolidation with anti-PD1 antibody. Autolus expects to enroll approximately 100 patients in this trial.

For more information about these trials and the inclusion criteria, visit www.ClinicalTrials.gov.