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Novartis presents results from first global registration trial of CTL019 in pediatric and young adult patients with r/r B-ALL

On December 4, 2016 Novartis reported that findings from a Novartis clinical trial (ELIANA) evaluating efficacy and safety of CTL019, an investigational chimeric antigen receptor T cell (CAR T) therapy, in relapsed/refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL) will be presented today during an oral session at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting (Abstract #221, December 3, 4:00-5:30 p.m.) (Press release, Novartis, DEC 3, 2016, View Source [SID1234516884]). The global Phase II study found that 82% (41 of 50) of infused patients achieved complete remission or complete remission with incomplete blood count recovery at three months post CTL019 infusion. For all patients with complete remission, no minimal residual disease was detected. In addition, the estimated relapse-free rate among responders was 60% (95% CI: 36, 78) six months after infusion with CTL019.[1] The results set the stage for filing CTL019 with the US Food and Drug Administration (FDA) in early 2017 for pediatric and young adult patients with r/r B-cell ALL.

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ELIANA is the first pediatric global CAR T cell registration trial with study enrollment having occurred across 25 centers in the US, EU, Canada, Australia and Japan. Forty-eight percent of patients in ELIANA experienced grade 3 or 4 cytokine release syndrome (CRS), a known complication of the investigational therapy that may occur when the engineered cells become activated in the patient’s body. CRS was managed on a global scale using prior site education with implementation of the CRS treatment algorithm. There were no deaths due to CRS. Fifteen percent of patients experienced grade 3 neurological and psychiatric events including encephalopathy and delirium, with no grade 4 events seen.[1]

"These global multicenter trial data build on earlier encouraging research conducted at a single trial site, and advance the case for CTL019 as a potential treatment for children and young adults with relapsed or refractory B-cell ALL," said lead investigator Stephan Grupp, MD, PhD, the Yetta Deitch Novotny Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania (Penn), and Director of the Cancer Immunotherapy Frontier Program at the Children’s Hospital of Philadelphia (CHOP).

In addition to filing CTL019 for approval with the FDA in early 2017, Novartis plans to file with the European Medicines Agency (EMA) later in 2017. The investigational therapy received PRIME (PRIority MEdicines) designation from the EMA earlier this year.

"This first-of-its-kind trial represents exciting progress toward our goal of helping children and young adults with relapsed or refractory B-cell ALL, a patient population with an urgent need for new treatment options," said Bruno Strigini, CEO, Novartis Oncology. "We are committed to advancing CTL019 and look forward to working closely with the FDA and EMA in the coming months."

Dr. Shannon Maude from CHOP will give a poster presentation highlighting data from ENSIGN, the first US multicenter Phase II trial for CTL019 in pediatric and young adults with B-cell ALL (Abstract #2801, December 4, 6:00-8:00 p.m.).[2] A separate poster presentation will also highlight an ongoing Phase IIa study led by Penn which investigated the efficacy and safety of CTL019 in poor prognostic groups of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients (Abstract #3026, December 4, 6:00-8:00 p.m.).[3]

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.

Juno Therapeutics Announces Complete Response and Corresponding Early Survival Data for JCAR014 in Patients with Ibrutinib-Refractory CLL

On December 3, 2016 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company developing innovative cellular immunotherapies for the treatment of cancer, reported a presentation at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting encouraging early data for JCAR014 in patients with chronic lymphocytic leukemia (CLL) who failed treatment with ibrutinib (Press release, Juno, DEC 3, 2016, View Source [SID1234516883]). Insights from studies of the translational product, JCAR014, are being applied to the development of JCAR017 for the treatment of B-cell malignancies. Both JCAR014 and JCAR017 use a 4-1BB co-stimulatory domain and defined 1:1 cell ratio of CD4:CD8 T cells.

"The responses and durability we’ve seen in this study are notable and demonstrate the potential for further investigation of JCAR017 for patients with relapsed/refractory high-risk CLL," said Mark J. Gilbert, M.D., Juno’s Chief Medical Officer. "This is especially important, given recent data that show these patients, who progress early on ibrutinib, have poor clinical outcomes with a median survival of approximately three months. In addition, emerging response criteria, such as undetectable disease in the bone marrow at the molecular level by deep sequencing, appear to correlate with long-term response duration."

The Phase I study (ASH Abstract #56), conducted by Cameron Turtle, MBBS, Ph.D., of the Fred Hutchinson Cancer Research Center, evaluated 24 heavily pre-treated patients, all of whom had failed ibrutinib, the standard-of-care treatment for CLL. Patients had received a median of five previous therapies, including three who failed prior allogeneic stem cell transplants. Patients received lymphodepletion with either fludarabine/cyclophosphamide (flu/cy) (N=21) or non-flu/cy (N=3) prior to infusion of JCAR014.

Key data for the flu/cy cohort include:
Two of 24 (8%) patients developed grade 3-5 severe cytokine release syndrome (sCRS) and 6/24 (25%) patients developed grade 3-5 severe neurotoxicity. The most frequent severe Treatment Emergent Adverse Events were febrile neutropenia (75%), CRS (29%), fever (17%), lung infection (13%), encephalopathy (13%), and hypotension (13%). There was one treatment-related mortality (4%) in the trial in a patient who received flu/cy lymphodepletion, with both grade 5 CRS and cerebral edema.

Of 17 efficacy-evaluable patients with bone marrow disease at the start of the trial and treated with flu/cy and the two lowest doses of JCAR014, 15/17 (88%) had a complete marrow response by flow cytometry. Fourteen of the complete bone marrow response patients had a response assessment by the more sensitive method of IgH deep sequencing, with 7/14 (50%) having no detectable disease. All seven of these patients are alive and progression free with follow-up ranging from 3 to 26 months. The complete marrow response by flow cytometry was similar in patients documented to be ibrutinib-refractory at 86% (12/14).

In patients with PET-avid disease at baseline and treated with flu/cy and the two lowest doses of JCAR014, 8/11 (73%) had a partial response (PR) or complete response (CR) at four weeks, with 7/11 (64%) having a CR.

In patients evaluated for efficacy at four weeks using IWCLL criteria and treated with flu/cy and the two lowest doses of JCAR014, 14/19 (74%) had a PR or CR, with 4/19 (21%) being a CR. All patients with either a CR or PR remain alive, with follow-up ranging from 3 to 26 months. There is no obvious early difference in time to progression between a CR and PR by IWCLL criteria. The response data were similar in patients documented to be ibrutinib-refractory, with overall response rate of 69% (11/16) and a CR rate of 25% (4/16).

Plans to study JCAR014 in combination with ibrutinib in CLL are underway, with a cohort expected to begin enrollment in early 2017. Juno is evaluating the use of this data with JCAR014 as a monotherapy and in combination with ibrutinib in support of a potential Juno-sponsored trial with JCAR017 in CLL.

Celgene Corporation, Dana-Farber Cancer Institute and University of Arkansas for Medical Sciences Establish the Myeloma Genome Project

On December 3, 2016 Celgene Corporation (NASDAQ:CELG), Dana-Farber Cancer Institute and the University of Arkansas for Medical Sciences reported the creation of the Myeloma Genome Project, a collaborative initiative aimed at compiling the largest dataset of high-quality genomic and clinical data to identify distinct molecular disease segments within multiple myeloma to advance diagnosis, prognosis and treatment of multiple myeloma patients (Press release, Celgene, DEC 3, 2016, View Source [SID1234516882]). The initiative seeks to develop clinically relevant tests. Details of the project and initial characterization and preliminary analyses of newly diagnosed myeloma patient data were presented today by Brian Walker, Ph.D., of the University of Arkansas for Medical Sciences at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, Calif.

"The Myeloma Genome Project is a really exciting initiative that may change the way we manage myeloma patients," said Gareth Morgan, M.D., Ph.D., Director of the Myeloma Institute at the University of Arkansas for Medical Sciences.

Current technologies have discovered five major translocation groups within myeloma patients and these mutations have demonstrated varying effects on prognosis. The Myeloma Genome Project is also looking at minor translocation and mutational groups that are often poorly described due to small sample numbers in limited data sets. The group has established a set of 2,161 patients for which whole exome sequencing (WES; n=1,436), whole genome sequencing (WGS; n=708), targeted panel sequencing (n=993) and expression data from RNA-sequencing and gene expression arrays (n=1,497) were available. The data were collected from the Myeloma XI trial (UK), Intergroupe Francophone du Myeloma/Dana-Farber Cancer Institute, Myeloma Institute at the University of Arkansas for Medical Sciences and the Multiple Myeloma Research Foundation.

"Understanding the various subgroups within multiple myeloma that exhibit distinct pathogenesis and clinical behavior is critical when looking to advance new therapies, particularly when considering a targeted approach," said Rob Hershberg, M.D., Ph.D., Executive Vice President and Chief Scientific Officer at Celgene. "We look forward to the insights that this collaboration will provide for research and for patients."

"The Myeloma Genome Project expects to lead the way towards developing personalized and targeted therapy to improve patient outcomes in myeloma," said Nikhil Munshi, M.D., Director of Basic and Correlative Science at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.

The Myeloma Genome Project has begun to integrate these diverse, large genomic data sets and is identifying genetic information that may inform clinical targets for therapy. While analyses are not completed, the current efforts clearly demonstrate the feasibility of this approach and the project leaders plan to expand collaboration to include additional investigators and institutions and present updates at future medical and scientific meetings including publications in peer-reviewed journals.

Seattle Genetics Presents Phase 1b Data from Vadastuximab Talirine (SGN-CD33A; 33A) in Combination with Standard of Care in Frontline Acute Myeloid Leukemia at ASH Annual Meeting

On December 3, 2016 Seattle Genetics, Inc. (NASDAQ: SGEN), a global biotechnology company, reported phase 1b data evaluating vadastuximab talirine (SGN-CD33A; 33A) in combination with the frontline standard of care regimen for induction (cytarabine and daunorubicin, also known as 7+3) for younger patients with newly diagnosed acute myeloid leukemia (AML) in an oral presentation at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in San Diego, California, December 3-6, 2016 (Press release, Seattle Genetics, DEC 3, 2016, View Source [SID1234516877]). The data were also featured in an ASH (Free ASH Whitepaper) press program and selected to be included in the 2017 Highlights of ASH (Free ASH Whitepaper) post-meeting program. 33A is an investigational antibody-drug conjugate (ADC) targeted to CD33, a protein which is expressed on leukemic cells in nearly all AML patients.

"Our clinical trial data reported at ASH (Free ASH Whitepaper) demonstrate that adding vadastuximab talirine, also known as 33A, to standard of care treatment results in a rapid, high rate of remissions in frontline, younger AML patients with poor prognosis. Notably, seventy-eight percent of patients who achieved remissions in this trial tested negative for minimal residual disease, which means no cancer could be detected with a sensitive test," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "In this trial, 33A in combination with 7+3 was well-tolerated, with a low early mortality rate. Based on these promising, early data, we plan to initiate a randomized phase 2 clinical trial in 2017 in younger newly diagnosed AML patients to further evaluate the potential benefit of adding 33A to standard of care."

"People with acute myeloid leukemia die of infections or bleeding within weeks or a few months of diagnosis without effective, aggressive chemotherapy. Even with current treatment regimens, fewer than 50% of younger adults are successfully treated. The phase 1 results of 33A in combination with standard of care show a high rate of remissions in younger newly diagnosed AML patients without significantly adding to the toxicity of the treatment. Notably, 94 percent of remissions occur with only one cycle of treatment," said Harry P. Erba, M.D., Ph.D., University of Alabama-Birmingham and presenter of the phase 1 data at ASH (Free ASH Whitepaper). "Furthermore, the majority of these patients have no evidence of disease following the 33A combination even using a very sensitive test for residual leukemia (minimal residual disease negative). The rate at which patients become minimal residual disease negative following 33A combination treatment offers encouraging preliminary evidence that 33A in combination with 7+3 could reduce relapse rates and improve long-term outcomes for these patients."

The following interim results from the ongoing phase 1 study evaluating 33A in combination with 7+3 in frontline AML will be presented by Dr. Harry P. Erba, University of Alabama-Birmingham, in an oral session on Saturday, December 3, 2016:

A Phase 1b Study of Vadastuximab Talirine in Combination with 7+3 Induction Therapy for Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) (Abstract #211, oral presentation on Saturday, December 3, 2016 at 4:00 p.m. PT)

Data were reported from 42 newly diagnosed AML patients with a median age of 46 years and intermediate or adverse cytogenetic risk of 50 percent and 36 percent, respectively. Seventeen percent of patients had secondary AML. Key findings include:

Of 42 patients evaluable for response, 32 patients (76 percent) achieved a complete remission (CR) or complete remission with incomplete platelet or neutrophil recovery (CRi). Ninety-four percent of the remissions (CR or CRi) occurred with one cycle of therapy.
Twenty-five of the 32 patients (78 percent) who achieved remission were negative for minimal residual disease (MRD). MRD-negative remission post-induction is generally correlated with reduced rates of relapse and improved overall survival.
Remissions were observed in higher-risk patients, including 18 of 21 (86 percent) and nine of 15 (60 percent) patients with intermediate or adverse cytogenetics, respectively.
Overall survival (OS) is still evolving and median OS has not yet been reached. The 30-day mortality rate was two percent. Twenty-one of 42 patients (50 percent) went on to receive an allogenic stem cell transplant.
The most common Grade 3 or 4 treatment-emergent adverse events occurring in 20 percent or more of patients were febrile neutropenia, thrombocytopenia, anemia and neutropenia. No non-hematologic treatment-emergent adverse events of Grade 3 or higher were reported in 15 percent or more of patients. No veno-occlusive disease/sinusoidal obstruction syndrome or significant hepatotoxicity was observed on treatment.
The most common Grade 1 and 2 treatment-emergent adverse events occurring in 20 percent or more of patients were nausea, diarrhea, constipation, hypokalemia and decreased appetite. No infusion-related reactions occurred.
This phase 1 study continues to enroll patients. A randomized phase 2 trial of 33A plus 7+3 versus 7+3 alone is planned.
Seattle Genetics is broadly evaluating 33A across multiple lines of therapy in patients with myeloid malignancies. The ongoing global phase 3 CASCADE study is a randomized, double-blind, multi-center trial designed to evaluate 33A in combination with hypomethylating agents (HMAs) in approximately 500 previously untreated AML patients. Further, phase 1 and 2 clinical trials for relapsed AML and for previously untreated myelodysplastic syndrome (MDS) are currently underway. More information about 33A and ongoing clinical trials can be found at www.ADC-CD33.com.

About Acute Myeloid Leukemia

Acute myeloid leukemia, also called acute myelocytic leukemia or AML, is an aggressive cancer of the bone marrow and blood that progresses rapidly without treatment. Cancerous cells called leukemic blasts multiply and crowd out normal cells in the bone marrow and interfere with normal blood cell production leading to anemia, infection, and bleeding. According to the SEER database and Kantar Health Sciences, in 2016 approximately 33,000 new cases of AML (mostly in adults) will be diagnosed in the U.S. and Europe. In the U.S. alone, nearly 10,500 deaths will occur from AML this year. Treatment options for AML have remained virtually unchanged for nearly 40 years and frontline treatment consists primarily of chemotherapy. A subset of patients (typically those over 60 years of age) cannot tolerate such therapy and are typically given lower intensity agents, supportive care, or are recommended for clinical trials.

About Vadastuximab Talirine (SGN-CD33A)

Vadastuximab talirine (SGN-CD33A; 33A) is a novel investigational ADC targeted to CD33 utilizing Seattle Genetics’ proprietary ADC technology. CD33 is expressed on most AML and MDS blast cells. The CD33 engineered cysteine antibody is stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer via site-specific conjugation technology (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its potent cell-killing PBD agent upon internalization into CD33-expressing cells.

33A was granted Orphan Drug Designation by both the U.S. Food and Drug Administration (FDA) and the European Commission for the treatment of AML. FDA orphan drug designation is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States.

Regenacy Pharmaceuticals to be Launched by Acetylon Pharmaceuticals and Celgene Corporation Agrees to Complete Acquisition of Acetylon

On December 2, 2016 Acetylon Pharmaceuticals reported that it has entered into an agreement to be acquired by Celgene Corporation (Press release, Acetylon, DEC 2, 2016, View Source [SID1234556812]). Prior to the consummation of the acquisition, Acetylon will spin out a new company, Regenacy Pharmaceuticals, LLC, which will focus on the development of novel drug candidates that selectively regenerate intracellular transport and upregulate gene expression to modify the course of disease. Regenacy will receive exclusive worldwide rights to Acetylon’s Phase 2 selective histone deacetylase 6 (HDAC6) inhibitor, ricolinostat (ACY-1215), for the treatment of certain non-cancer disease indications including neuropathies, as well as Acetylon’s preclinical selective HDAC1,2 inhibitor candidates and patent families for development in all human disease indications including sickle cell disease and beta-thalassemia.

The acquisition will provide Celgene with, among other things, worldwide rights to Acetylon’s selective HDAC6 inhibitor programs and intellectual property in oncology, neurodegeneration, and autoimmune disease, including its lead drug candidates citarinostat (ACY-241) and ricolinostat (ACY-1215).

Financial terms of the acquisition are not being disclosed. The transaction is subject to customary closing conditions, including the expiration of the applicable waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976. BMO Capital Markets Corp. served as exclusive financial advisor to Acetylon in the transaction.

Key members of the Acetylon executive team will join Regenacy, which will operate out of Acetylon’s former headquarters in Boston’s Seaport District. Regenacy will be owned by Acetylon shareholders (excluding Celgene) and will receive net working capital in Acetylon to fund Regenacy operations.

"Since its founding in 2008, Acetylon has made substantial progress in the development of selective HDAC inhibitors for enhanced therapeutic outcomes," said Walter C. Ogier, President and Chief Executive Officer of Regenacy. "We are excited to continue Acetylon’s legacy through the receipt of rights to many of Acetylon’s most promising compounds and the continued advancement of these clinical and preclinical programs in disease indications outside of Celgene’s areas of strategic focus, where we believe patients may especially benefit from selective HDAC inhibition."

"Acetylon has had a longstanding partnership with Celgene, and their acquisition of our HDAC6 inhibitor programs is a positive event for patients and a favorable outcome for our shareholders and employees," said Marc A. Cohen, Chairman of Acetylon. "Celgene is the optimal partner to realize the fullest potential of Acetylon’s selective HDAC6 inhibitor programs in multiple myeloma and other oncology indications. Their intimate knowledge of citarinostat and extensive experience in oncology make them uniquely qualified to continue development of these exciting programs."

About Selective HDAC Inhibition

Histone deacetylases (HDACs) comprise a family of 18 related enzymes found in most human cells, 11 of which utilize zinc atoms to catalyze the removal of acetyl groups from intracellular proteins. By this function, HDACs can induce structural changes in the DNA-histone complex to result in altered gene expression and protein synthesis. Inappropriate deacetylation can disrupt these processes and contribute to a wide range of diseases, whereas regeneration of acetylation selectively causes apoptosis (cell death) in cancer cells and also induces favorable immunomodulatory effects. Currently available HDAC drugs non-selectively affect the expression of numerous other genes in normal cells as well as disease-causing cells, which can result in side effects such as gastrointestinal dysfunction, lowered blood platelet levels and risk of hemorrhage, and profound fatigue as well as potential for significant cardiac toxicity. Selective inhibition of HDACs is anticipated to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition and to enable the development of optimized treatment regimens, including maximally effective combination drug therapies.