OnDecember 3, 2016 Pfizer Inc. (NYSE:PFE) reported new data from a randomized Phase 2 study of glasdegib (PF-04449913), an oral, smoothened (SMO) inhibitor, showing the addition of glasdegib to low-dose cytarabine (LDAC) significantly increased overall survival (OS) when compared to LDAC alone in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) who were ineligible for intensive chemotherapy (HR: 0.501, 80% CI: 0.384, 0.654, one-sided log rank p-value 0.0003) (Press release, Pfizer, DEC 3, 2016, View Source [SID1234516885]). Glasdegib is the first SMO inhibitor to show clinical benefit in this patient population. These data were presented today at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, CA.

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Glasdegib is an investigational oral therapy that inhibits the SMO receptor, thereby disrupting the hedgehog (Hh) pathway. The results presented are from a Phase 2, multicenter, randomized study that included 132 patients with previously untreated AML or high-risk MDS who were ineligible for intensive chemotherapy. Patients were treated with either LDAC 20mg subcutaneously twice daily for ten days plus oral glasdegib 100 mg daily or LDAC alone. The primary endpoint of this study was OS.

"The hedgehog pathway is a compelling target in cancer research because of the ability to target and disrupt the root of the cancer, that is the cancer-originating cell," said Jorge Cortes, University of Texas, MD Anderson Cancer Center. "As the first smoothened inhibitor to demonstrate clinical benefit in patients with AML and high-risk MDS who were ineligible for intensive chemotherapy, these results with glasdegib provide hope that interfering with this pathway may lead to potential new treatment options for blood cancers that may improve patient outcomes."

The results presented show that at the time of data cut-off, median OS for patients taking glasdegib plus LDAC (n=88) was 8.8 months (80% CI: 6.9, 9.9) compared to 4.9 months (80% CI: 3.5, 6.0) for patients taking LDAC only (n=44) (HR: 0.501, 80% CI: 0.384, 0.654, one-sided log rank p-value 0.0003). Low blood counts and gastrointestinal toxicities occurred more frequently among patients treated with glasdegib plus LDAC than those treated with LDAC alone. Blood infections were less among patients treated with glasdegib plus LDAC (3.6 %) compared to LDAC alone (12.2%). Patients in the glasdegib plus LDAC group experienced increased distortion of taste (23.8%), muscle spasms (20.2%) and thinning or loss of hair (10.2%). Serious AEs of febrile neutropenia were also more frequent in patients taking glasdegib plus LDAC (36.9%) compared to LDAC alone (26.8%). The most common cause of death in both arms was disease progression.

"Acute myeloid leukemia is a rapidly progressing blood cancer for which new treatment options are needed," said Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development. "Pfizer is excited about the promising data seen in AML patients treated with glasdegib and is working to explore further opportunities to evaluate glasdegib in the treatment of this disease."

For more information about glasdegib and other hematology products in development by Pfizer, please visit View Source

About Glasdegib

Glasdegib is an investigational oral therapy that inhibits the SMO receptor, thereby disrupting the hedgehog (Hh) pathway. SMO inhibition of Hh signaling impacts tumor biology by disrupting the regulation of cancer stem cell (CSC) survival. This may inhibit development of drug resistance and prevent relapse. Glasdegib is currently under investigation for select hematologic malignancies, including AML and MDS.

About Pfizer Hematology

Along with our marketed products for hematological conditions, Pfizer is advancing a broad range of therapies that leverage select pathways and mechanisms of action to address acute and chronic leukemias, myeloproliferative disorders and lymphoma. In the near-term, Pfizer is in discussions with global regulatory authorities about inotuzumab ozogamicin for the treatment of acute lymphoblastic leukemia (ALL) and Mylotarg (gemtuzumab ozogamicin) for the treatment of acute myeloid leukemia (AML).

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.

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.

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"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.

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.

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"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.