On December 12, 2017 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and Puma Biotechnology, Inc. (Nasdaq: PBYI) reported a preclinical research collaboration with Memorial Sloan Kettering Cancer Center (MSK) to explore the combination of Daiichi Sankyo’s investigational antibody drug conjugate DS-8201 and Puma Biotechnology’s irreversible pan-HER tyrosine kinase inhibitor neratinib (NERLYNX) in HER2-mutated or HER2-positive solid tumors (Press release, Puma Biotechnology, DEC 12, 2017, http://investor.pumabiotechnology.com/press-release/daiichi-sankyo-and-puma-biotechnology-announce-research-collaboration-major-cancer-cen [SID1234522597]).

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A team of scientists led by Maurizio Scaltriti, PhD, and in collaboration with a team of clinical investigators led by Bob Li, MD, will use isogenic models and established patient-derived xenograft models to assess the susceptibility of HER2-mutated or HER2-positive cancers to DS-8201, neratinib and other HER2-targeting therapies, elucidate mechanisms of action and resistance of these various tumor types, and evaluate the potential for synergistic combinations. Daiichi Sankyo and Puma Biotechnology will co-sponsor the research.

"Since early clinical data suggest that DS-8201 may have activity beyond breast and gastric cancers, the archetype HER2-driven tumors, we are interested in studying this asset on a molecular level as well as in combination with other HER2-targeting agents," said Tom Held, Vice President, Global Head, Antibody Drug Conjugate Task Force, Daiichi Sankyo. "In this collaboration, we are examining whether combining DS-8201 and neratinib, with its specific covalent binding to the HER2 receptor and associated increased internalization, is a rational combination therapy strategy to pursue. We are excited to join forces with Memorial Sloan Kettering and Puma to advance the understanding of combining HER2-targeted therapies to potentially treat various forms of HER2-mutated cancer."

"We are pleased to enter into this research collaboration with Memorial Sloan Kettering and Daiichi Sankyo to explore the combination of neratinib and DS-8201," said Alan Auerbach, Puma’s Chief Executive Officer and President. "Combination therapy with agents that address different and complementary pathways, with neratinib targeting the HER2 kinase and DS-8201 providing an innovative targeted delivery of a potent cytotoxic, represents an intriguing approach to the treatment of HER2 mutated tumors and helps to maximize the potential for both agents in treating cancers with a HER2 mutation."

About DS-8201

DS-8201 is the lead product in the ADC Franchise of the Daiichi Sankyo Cancer Enterprise. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary ADC technology, DS-8201 is a smart chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

DS-8201 is currently in phase 2 clinical development for HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to T-DM1 (DESTINY-Breast01), phase 2 development for HER2-positive advanced gastric resistent or refractory to trastuzumab (DESTINY-Gastric01) and phase 1 development for other HER2-expressing advanced/unresectable or metastatic solid tumors.

DS-8201 has been granted Breakthrough Therapy designation for the treatment of patients with HER2-positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after ado-trastuzumab emtansine (T-DM1), and Fast Track designation for the treatment of HER2-positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2-targeted therapies including T-DM1 by the U.S. Food and Drug Administration (FDA). DS-8201 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

About NERLYNX (neratinib)

Neratinib was approved by the FDA in July 2017 for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX (neratinib) tablets.

Important Safety Information (ISI)
NERLYNX (neratinib) tablets, for oral use

INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor indicated for the extended adjuvant treatment of adult patients with early-stage HER2 overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.

CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS:

Diarrhea: Aggressively manage diarrhea occurring despite recommended prophylaxis with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥ 2 diarrhea that occurs after maximal dose reduction.
Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities.
Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.
ADVERSE REACTIONS: The most common adverse reactions (≥ 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased and urinary tract infection.

To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) and www.NERLYNX.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

DRUG INTERACTIONS:

Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors (PPI) and H2-receptor antagonists. Separate NERLYNX by 3 hours after antacid dosing.
Strong or moderate CYP3A4 inhibitors: Avoid concomitant use.
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
P-glycoprotein (P-gp) substrates: Monitor for adverse reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with NERLYNX.
USE IN SPECIFIC POPULATIONS:

Lactation: Advise women not to breastfeed.
Please see Full Prescribing Information for additional safety information.

The recommended dose of NERLYNX is 240 mg (six 40 mg tablets) given orally once daily with food, continuously for one year. Antidiarrheal prophylaxis should be initiated with the first dose of NERLYNX and continued during the first 2 months (56 days) of treatment and as needed thereafter.

To help ensure patients have access to NERLYNX, Puma has implemented the Puma Patient Lynx support program to assist patients and healthcare providers with reimbursement support and referrals to resources that can help with financial assistance. More information on the Puma Patient Lynx program can be found at www.NERLYNX.com or 1-855-816-5421.

About Puma Biotechnology

Puma Biotechnology, Inc. is a biopharmaceutical company with a focus on the development and commercialization of innovative products to enhance cancer care. Puma in-licenses the global development and commercialization rights to three drug candidates — PB272 (neratinib (oral)), PB272 (neratinib (intravenous)) and PB357. NERLYNX (neratinib) is approved for commercial use by prescription in the United States as extended adjuvant therapy for early stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy and is marketed as NERLYNX. Neratinib is a potent irreversible tyrosine kinase inhibitor that blocks signal transduction through the epidermal growth factor receptors, HER1, HER2 and HER4. Currently, Puma is primarily focused on the commercialization of NERLYNX and the continued development of its other advanced drug candidates directed at the treatment of HER2-positive breast cancer. Puma believes that NERLYNX has clinical application in the potential treatment of several other cancers that over-express or have a mutation in HER2. Further information about Puma Biotechnology can be found at www.pumabiotechnology.com

About Daiichi Sankyo Cancer Enterprise

The vision of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking in order to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by our Antibody Drug Conjugate (ADC) and Acute Myeloid Leukemia (AML) Franchises, our cancer pipeline includes more than 20 small molecules, monoclonal antibodies and ADCs stemming from our powerful research engines: our two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. Compounds in development include: quizartinib, an oral FLT3 inhibitor, for newly-diagnosed and relapsed or refractory AML with FLT3-ITD mutations; DS-8201, an ADC for HER2-expressing breast and gastric cancer, and other HER2-expressing solid tumors; and pexidartinib, an oral CSF-1R inhibitor, for tenosynovial giant cell tumor (TGCT), which is also being explored in a range of solid tumors in combination with the anti-PD1 immunotherapy pembrolizumab. For more information, please visit: www.DSCancerEnterprise.com.

On December 12, 2017 Servier, Pfizer Inc. (NYSE: PFE) and Cellectis (Paris:ALCLS) (NASDAQ:CLLS) (Euronext Growth: ALCLS – Nasdaq: CLLS) presented at the the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in Atlanta reported preliminary results from two phase 1 studies of UCART19, an investigational allogeneic anti-CD19 CAR T-cell product, in adult and pediatric patients with relapsed or refractory (R/R) CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) (Press release, Cellectis, DEC 12, 2017, View Source [SID1234522628]). These first-in-human data demonstrated the safety and tolerability of UCART19, resulting in an 83% complete remission rate across the adult and pediatric patient population.

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Results from the CALM (UCART19 in Advanced Lymphoid Malignancies) Trial

The CALM study (UCART19 in Advanced Lymphoid Malignancies) is an open label, dose-escalation study designed to evaluate the safety, tolerability and anti-leukemic activity of UCART19 in adult patients with R/R B-ALL. Five out seven patients treated achieved molecular remission at Day 28 post UCAR19. Molecular remission is defined by negative minimal residual disease (MRD). MRD is a measurement of the number of residual leukemic cells that remain after treatment.

"These early results for UCART19 are very encouraging both in terms of manageable safety and the impressive complete molecular remission rate in these hard-to-treat adult patients with R/R B-ALL," said Reuben Benjamin, Principal Investigator of the CALM Study and Consultant Hematologist at King’s College Hospital, United Kingdom. "This first cohort explored a lower dose of UCART19 that is approximately one tenth of that used in most autologous CAR-T trials. These results support additional evaluation of UCART19 at varying doses."

Only one Grade 1 cutaneous acute graft versus host disease (GvHD) occurred. No severe neurotoxicity was observed. Cytokine release syndromes (CRS) were mild and manageable except in one patient treated with UCART19 at the first dose level, who developed CRS Grade 4 and neutropenic sepsis leading to death at Day 15.

Results from the PALL (Pediatric Acute Lymphoblastic Leukemia) Trial

The PALL (Pediatric Acute Lymphoblastic Leukemia) study is a phase 1, open label study designed to evaluate the safety and ability of UCART19 to induce molecular remission defined by MRD negativity at Day 28 to enable allogeneic stem cell transplantation in pediatric patients with high-risk R/R B-ALL. Results showed all five children achieved MRD negativity, enabling them to proceed to allogeneic stem cell transplant. Only one Grade 1 cutaneous acute GvHD occurred. No severe neurotoxicity was observed. Cytokine release syndromes were mild in the majority of cases and were all manageable.

Servier is the sponsor of both studies that are active in Europe and the United States.

"We are proud to present the first clinical trial data with UCART19 in patients with heavily pretreated R/R ALL," said Patrick Therasse, MD, PhD, Head of Research and Development-Oncology for Servier. "We believe this innovative, allogeneic CAR T-cell approach could be disruptive to the patient community."

About UCART19

UCART19 is an allogeneic CAR T-cell product candidate being developed for treatment of CD19-expressing hematological malignancies, gene edited with TALEN. UCART19 is initially being developed in adult and pediatric ALL and is currently in Phase I. UCART19 has the potential to overcome the limitation of the current autologous approach by providing an allogeneic, frozen, "off-the-shelf" T cell based medicinal product.

In November 2015, Servier acquired the exclusive rights to UCART19 from Cellectis. Following further agreements, Servier and Pfizer began collaborating on a joint clinical development program for this cancer immunotherapy. Pfizer has been granted exclusive rights by Servier to develop and commercialize UCART19 in the United States, while Servier retains exclusive rights for all other countries.

About Servier

Servier is an international pharmaceutical company governed by a non-profit foundation, with its headquarters in France (Suresnes). With a strong international presence in 148 countries and a turnover of 4 billion euros in 2016, Servier employs 21 000 people worldwide. Entirely independent, the Group reinvests 25% of its turnover (excluding generic drugs) in research and development and uses all its profits for development. Corporate growth is driven by Servier’s constant search for innovation in five areas of excellence: cardiovascular, immune-inflammatory and neuropsychiatric diseases, cancers and diabetes, as well as by its activities in high-quality generic drugs.

Becoming a key player in oncology is part of Servier’s long-term strategy. Currently, there are nine molecular entities in clinical development in this area, targeting gastric and lung cancers and other solid tumors, as well as various leukemias and lymphomas. This portfolio of innovative cancer treatments is being developed with partners worldwide, and covers different cancer hallmarks and modalities, including cytotoxics, proapoptotics, targeted, immune and cellular therapies, to deliver life-changing medicines to patients. More information: View Source

Pfizer Inc.: Working together for a healthier world

At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world’s best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.pfizer.com. In addition, to learn more, please visit us on www.pfizer.com and follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn, YouTube, and like us on Facebook at Facebook.com/Pfizer.

PFIZER DISCLOSURE NOTICE

The information contained in this release is as of December 12, 2017. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.

This release contains forward-looking information about a product candidate, UCART19, including its potential benefits, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical study commencement and completion dates as well as the possibility of unfavorable study results, including unfavorable new clinical data and additional analyses of existing clinical data; risks associated with preliminary data; the risk that clinical trial data are subject to differing interpretations, and, even when we view data as sufficient to support the safety and/or effectiveness of a product candidate, regulatory authorities may not share our views and may require additional data or may deny approval altogether; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when drug applications may be filed for UCART19 in any jurisdiction; whether and when any such applications may be approved by regulatory authorities, which will depend on the assessment by such regulatory authorities of the benefit-risk profile suggested by the totality of the efficacy and safety information submitted, and, if approved, whether UCART19 will be commercially successful; decisions by regulatory authorities regarding labeling and other matters that could affect the availability or commercial potential of UCART19; and competitive developments.

A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2016 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned "Risk Factors" and "Forward-Looking Information and Factors That May Affect Future Results", as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at www.sec.gov and www.pfizer.com.

On December 12, 2017 Servier, Pfizer Inc. (NYSE: PFE) and Cellectis (Euronext Growth: ALCLS – Nasdaq: CLLS) presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in Atlanta preliminary results from two phase 1 studies of UCART19, an investigational allogeneic anti-CD19 CAR T-cell product, in adult and pediatric patients with relapsed or refractory (R/R) CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) (Press release, Cellectis, DEC 12, 2017, View Source;utm_medium=feed&utm_campaign=Feed%3A+cellectis+%28Cellectis+RSS+Feed%29#When:23:42:00Z [SID1234522594]). These first-in-human data demonstrated the safety and tolerability of UCART19, resulting in an 83% complete remission rate across the adult and pediatric patient population.

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Results from the CALM (UCART19 in Advanced Lymphoid Malignancies) Trial

The CALM study (UCART19 in Advanced Lymphoid Malignancies) is an open label, dose-escalation study designed to evaluate the safety, tolerability and anti-leukemic activity of UCART19 in adult patients with R/R B-ALL. Five out seven patients treated achieved molecular remission at Day 28 post UCAR19. Molecular remission is defined by negative minimal residual disease (MRD). MRD is a measurement of the number of residual leukemic cells that remain after treatment.

"These early results for UCART19 are very encouraging both in terms of manageable safety and the impressive complete molecular remission rate in these hard-to-treat adult patients with R/R B-ALL," said Reuben Benjamin, Principal Investigator of the CALM Study and Consultant Hematologist at King’s College Hospital, United Kingdom. "This first cohort explored a lower dose of UCART19 that is approximately one tenth of that used in most autologous CAR-T trials. These results support additional evaluation of UCART19 at varying doses."

Only one Grade 1 cutaneous acute graft versus host disease (GvHD) occurred. No severe neurotoxicity was observed. Cytokine release syndromes (CRS) were mild and manageable except in one patient treated with UCART19 at the first dose level, who developed CRS Grade 4 and neutropenic sepsis leading to death at Day 15.

Results from the PALL (Pediatric Acute Lymphoblastic Leukemia) Trial

The PALL (Pediatric Acute Lymphoblastic Leukemia) study is a phase 1, open label study designed to evaluate the safety and ability of UCART19 to induce molecular remission defined by MRD negativity at Day 28 to enable allogeneic stem cell transplantation in pediatric patients with high-risk R/R B-ALL. Results showed all five children achieved MRD negativity, enabling them to proceed to allogeneic stem cell transplant. Only one Grade 1 cutaneous acute GvHD occurred. No severe neurotoxicity was observed. Cytokine release syndromes were mild in the majority of cases and were all manageable.

Servier is the sponsor of both studies that are active in Europe and the United States.

"We are proud to present the first clinical trial data with UCART19 in patients with heavily pretreated R/R ALL," said Patrick Therasse, MD, PhD, Head of Research and Development-Oncology for Servier. "We believe this innovative, allogeneic CAR T-cell approach could be disruptive to the patient community."

About UCART19

UCART19 is an allogeneic CAR T-cell product candidate being developed for treatment of CD19-expressing hematological malignancies, gene edited with TALEN. UCART19 is initially being developed in adult and pediatric ALL and is currently in Phase I. UCART19 has the potential to overcome the limitation of the current autologous approach by providing an allogeneic, frozen, "off-the-shelf" T cell based medicinal product.

In November 2015, Servier acquired the exclusive rights to UCART19 from Cellectis. Following further agreements, Servier and Pfizer began collaborating on a joint clinical development program for this cancer immunotherapy. Pfizer has been granted exclusive rights by Servier to develop and commercialize UCART19 in the United States, while Servier retains exclusive rights for all other countries.

On December 12, 2017 Cyclacel Pharmaceuticals, Inc. (NASDAQ: CYCC, NASDAQ: CYCCP; "Cyclacel" or the "Company"), a biopharmaceutical company developing oral therapies that target various phases of cell cycle control for the treatment of cancer and other serious disorders, reported results from the Company’s Phase 3 SEAMLESS study (Press release, Cyclacel, DEC 12, 2017, View Source [SID1234522595]). Cyclacel had previously announced top-line results from its Phase 3 SEAMLESS study in February 2017. The study enrolled elderly patients with newly diagnosed acute myeloid leukemia (AML) and compared alternating cycles of decitabine and sapacitabine versus decitabine. Data were reported at an oral presentation on Monday, December 11, at 6:45 PM EST at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta, Georgia.

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"Although the study did not reach its primary endpoint of superiority in survival, we are encouraged by the higher complete remission rate on the sapacitabine-decitabine arm, especially in the subgroup with low white blood cell count; additional analysis of the data should be pursued," said Hagop Kantarjian, M.D., Professor and Chair, Department of Leukemia, The University of Texas MD Anderson Cancer Center, and chair of the study.

"We are pleased to report detailed results of the SEAMLESS study, which as previously announced, did not reach its primary endpoint," said Spiro Rombotis, President and Chief Executive Officer of Cyclacel. "We believe that the subgroup results have defined a patient population for whom the decitabine-sapacitabine regimen may represent an improvement over low intensity treatment by decitabine alone. We plan to discuss the data, the statistical robustness of the subgroup results and the optimal baseline peripheral white blood cell (WBC) cutpoint with European and US regulatory authorities and will provide updates as appropriate. We are grateful to the patients, their families and the investigators for their contributions to this large study. In parallel, we are progressing our other clinical programs in transcriptional regulation with CYC065 and DNA damage response with sapacitabine-seliciclib in biomarker-selected patients with solid tumors, such as those with BRCA mutations or resistance to existing cancer therapies."

Study Design & Intent-to-Treat Results

The randomized, open label, Phase 3 SEAMLESS study enrolled 482 patients, aged 70 years or older, with newly diagnosed AML who were not candidates for or refused intensive therapy at 110 US and EU sites. Patients were stratified by WBC, antecedent hematologic disorder (AHD), and marrow blasts, and randomized 1:1 to receive either intravenous decitabine administered in alternating cycles with oral sapacitabine versus intravenous decitabine alone.

The trial did not meet its primary endpoint of demonstrating statistically significant improvement in overall survival. A higher complete remission (CR) rate, a secondary endpoint, was observed on the decitabine-sapacitabine arm (17% versus 11%). Other endpoints and safety were similar between the arms.

Prespecified Subgroup Analysis

Baseline WBC

In the less than 10,000 WBC subgroup (n=319) a trend towards improved overall survival (median 8.0 versus 5.8 months, HR=0.84 [0.66, 1.06], p=0.14) favoring decitabine-sapacitabine and a significantly higher CR rate (21.0% versus 8.6%, p=0.0017) was achieved on decitabine-sapacitabine.

In the 10,000 or more WBC subgroup (n=163) significantly better overall survival (median 3.8 versus 5.5 months, HR=1.57 [1.12, 2.19], p=0.007) was observed on decitabine. A trend in CR rate (8.3% versus 15.2%, p=0.18) favoring decitabine was observed but it did not reach statistical significance.

Prior AHD

In the subgroup with prior AHD (n=136) a significantly higher CR rate (16.7% versus 5.7%, p=0.0398) was achieved on decitabine-sapacitabine. There was a numerical difference in median survival (6.4 versus 5.0 months, HR=0.85 [0.59, 1.24], p=0.41) favoring decitabine-sapacitabine but overall survival did not reach statistical significance.

In the subgroup without prior AHD (n=346) there was a numerical difference in median survival (5.9 versus 6.7 months, HR=1.08 [0.86, 1.35], p=0.52) favoring decitabine and CR rate (16.6% versus 12.9%) favoring decitabine-sapacitabine but neither reached statistical significance.

Cytogenetics

In the subgroup with other than unfavorable cytogenetics (n=288) there was a numerical difference in median survival (8.2 versus 5.7 months, HR=0.89 [0.69, 1.15], p=0.38) and CR rate (19.9% versus 11.6%, p=0.16) favoring decitabine-sapacitabine but neither reached statistical significance.

In the subgroup with unfavorable cytogenetics (n=194) there was a numerical difference in median survival (3.8 months versus 5.7 months, HR=1.27 [0.94, 1.73], p=0.12) favoring decitabine but overall survival did not reach statistical significance. There was a numerical difference in CR rate favoring decitabine-sapacitabine (12.0% versus 9.6%) but it did not reach statistical significance.

In the subgroup of patients with below 50% and with 50% or higher bone marrow blasts there were no statistically significant differences in overall survival between the arms.

Presentation

The presentation (abstract 891), titled "Results of a Phase 3 Study of Elderly Patients with Newly Diagnosed AML Treated with Sapacitabine and Decitabine Administered in Alternating Cycles," is available on the Cyclacel website at www.cyclacel.com.

About Sapacitabine

Sapacitabine (CYC682), an orally-available nucleoside analogue, is currently being studied in an ongoing, extension of a Phase 1 study evaluating a combination regimen of sapacitabine and seliciclib, a first generation CDK inhibitor. Parts 1 and 2 of the study evaluated approximately 90 patients with advanced cancers. Part 3 is ongoing in patients with BRCA positive, breast, ovarian and pancreatic cancer. Over 1,000 patients with hematological malignancies and solid tumors have received sapacitabine.

About AML

AML is a rapidly progressing cancer of the blood characterized by the uncontrolled proliferation of immature blast cells in the bone marrow. The American Cancer Society estimates there will be approximately 21,380 new cases of AML and approximately 10,590 deaths from AML in the U.S. in 2017. AML is generally a disease of older adults and the median age is about 67 years. Newly diagnosed elderly patients with poor prognostic risk factors typically die within one year.

On December 12, 2017 Janssen Research & Development, LLC reported data from the Phase 3 ALCYONE study, showing that DARZALEX (daratumumab) in combination with bortezomib, melphalan and prednisone (VMP) significantly improved clinical outcomes, including reducing the risk of disease progression or death by 50 percent, in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) (Press release, Johnson & Johnson, DEC 12, 2017, View Source [SID1234522596]). These data were presented as a late-breaking abstract today at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta (Abstract #LBA-4). Study findings were simultaneously published in the New England Journal of Medicine.

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"These Phase 3 results for DARZALEX demonstrated clinically meaningful improvements with a manageable safety profile," said Dr. Maria-Victoria Mateos, Ph.D., lead ALCYONE study investigator and Director of the Myeloma Unit at University Hospital of Salamanca-IBSAL, Salamanca, Spain. "Selecting the right treatment regimen is critical for patients who are newly diagnosed, especially if they are transplant ineligible, as these patients tend to be older and more frail. These findings strongly support this DARZALEX frontline regimen as a new standard of care for these patients."

At a median follow-up of 16.5 months, DARZALEX-VMP reduced the risk of disease progression or death by 50 percent, compared to treatment with VMP alone (Hazard Ratio [HR] = 0.50; 95 percent CI [0.38-0.65], p<0.0001).1 The median progression-free survival (PFS) for DARZALEX-VMP had not yet been reached, compared to an estimated median PFS of 18.1 months for patients who received VMP alone.1

In addition to reducing the risk of disease progression or death, DARZALEX significantly improved overall response rates (ORR) (91 percent vs. 74 percent) compared to VMP alone, including more than doubling rates of stringent complete response (sCR) (18 percent vs. 7 percent) and significantly improving rates of very good partial response (VGPR) or better (71 percent vs. 50 percent) and complete response (CR) or better (43 percent vs. 24 percent).1 Patients receiving DARZALEX also reported a more than three-fold increase in the minimal residual disease (MRD) negativity rate (22 percent vs. 6 percent) compared to those who received VMP alone.1

The most common (≥10 percent) Grade 3/4 treatment-emergent adverse events (TEAEs) for DARZALEX-VMP vs. VMP were neutropenia (40 percent vs. 39 percent), thrombocytopenia (34 percent vs. 38 percent), anemia (16 percent vs. 20 percent) and pneumonia (11 percent vs. 4 percent).1 One patient in each arm discontinued treatment due to pneumonia, and 0.9 percent of patients discontinued DARZALEX due to an infection.1 Twenty-eight percent of patients experienced infusion reactions (IRs) due to DARZALEX.1 In the DARZALEX-VMP arm, 42 percent of patients experienced a serious adverse event (SAE), compared to 33 percent in the VMP arm.1 The most common (≥2 percent) SAEs were pneumonia (10 percent vs. 3 percent), anemia (2 percent vs. 3 percent), bronchitis (2 percent vs. 1 percent), lower respiratory tract infection (2 percent vs. 1 percent), upper respiratory tract infection (2 percent vs. 1 percent), febrile neutropenia (1 percent vs. 2 percent) and cardiac failure (<1 percent vs. 2 percent) for DARZALEX-VMP vs. VMP, respectively.1

"DARZALEX offers compelling and consistent clinical benefit across all lines of therapy in multiple myeloma," said Sen Zhuang, M.D. Ph.D., Vice President, Oncology Clinical Research, Janssen Research & Development. "These latest results convey the promise of DARZALEX in newly diagnosed patients for whom the initial therapy is most critical for long-term survival."

On November 21, 2017, Janssen submitted a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) for DARZALEX in combination with VMP for this patient population. Janssen requested Priority Review of this sBLA, which would shorten FDA review to six months, compared to 10 months for Standard Review. If approved, this would be the fifth indication for DARZALEX in the U.S. and its first in the frontline setting. On November 21, 2017, Janssen also submitted an application for this patient population to the European Medicines Agency.

About the ALCYONE Trial1
The randomized, open-label, multicenter Phase 3 ALCYONE (MMY3007) study enrolled 706 newly diagnosed patients with multiple myeloma who were ineligible for high-dose chemotherapy with ASCT. In the DARZALEX-VMP arm, the median age was 71 years (range: 40-93), 30 percent were ≥75 years and 46 percent were male. Patients were randomized to receive nine cycles of either DARZALEX combined with VMP, or VMP alone. In the DARZALEX-VMP arm, patients received 16 mg/kg of DARZALEX once weekly for six weeks (Cycle 1; 1 Cycle = 42 days), followed by once every three weeks (Cycles 2-9). Following the nine cycles, patients in the DARZALEX-VMP arm continued to receive 16 mg/kg of DARZALEX once every four weeks until disease progression.

About DARZALEX (daratumumab) Injection, for Intravenous Infusion
DARZALEX (daratumumab) injection for intravenous use is the first CD38-directed antibody approved anywhere in the world.2 CD38 is a surface protein that is highly expressed across multiple myeloma cells.3 DARZALEX is believed to induce tumor cell death through multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as well as through apoptosis, in which a series of molecular steps in a cell lead to its death.2 A subset of myeloid derived suppressor cells (MDSCs), CD38+ regulatory T cells (Tregs) and CD38+ B cells (Bregs) were decreased by DARZALEX.2 DARZALEX is being evaluated in a comprehensive clinical development program across a range of treatment settings in multiple myeloma, such as in frontline and relapsed settings.4,5,6,7,8 Additional studies are ongoing or planned to assess its potential for a solid tumor indication and in other malignant and pre-malignant diseases in which CD38 is expressed, such as smoldering myeloma.9,10,11 DARZALEX was the first CD38-directed antibody to receive regulatory approval to treat relapsed or refractory multiple myeloma.2

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize DARZALEX.12 DARZALEX is commercialized in the U.S. by Janssen Biotech, Inc.12 For more information, visit www.DARZALEX.com.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow.13,14 Refractory cancer occurs when a patient’s disease is resistant to treatment or in the case of multiple myeloma, patients progress within 60 days of their last therapy.15,16 Relapsed cancer means the disease has returned after a period of initial, partial or complete remission.17 It is estimated that 30,280 people will be diagnosed and 12,590 will die from the disease in the United States in 2017.18 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms, which can include bone fracture or pain, low red blood counts, fatigue, calcium elevation, kidney problems or infections.19

IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS – None
WARNINGS AND PRECAUTIONS
Infusion Reactions – DARZALEX can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Interference with Serological Testing – Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.

Neutropenia – DARZALEX may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX is recommended. Consider supportive care with growth factors.

Thrombocytopenia – DARZALEX may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions.

Interference with Determination of Complete Response – Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions – In patients who received DARZALEX in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: neutropenia (92%), thrombocytopenia (73%), upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%) and pyrexia (3%).

In patients who received DARZALEX in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: thrombocytopenia (90%), neutropenia (58%), peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%).

In patients who received DARZALEX as monotherapy, the most frequently reported adverse reactions (incidence ≥20%) were: neutropenia (60%), thrombocytopenia (48%), infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).

In patients who received DARZALEX in combination with pomalidomide and dexamethasone, the most frequent adverse reactions (>20%) were infusion reactions (50%), diarrhea (38%), constipation (33%), nausea (30%), vomiting (21%), fatigue (50%), pyrexia (25%), upper respiratory tract infection (50%), muscle spasms (26%), back pain (25%), arthralgia (22%), dizziness (21%), insomnia (23%), cough (43%) and dyspnea (33%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients included pneumonia (7%).

DRUG INTERACTIONS
Effect of Other Drugs on daratumumab: The coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX did not affect the pharmacokinetics of daratumumab.

Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX with bortezomib did not affect the pharmacokinetics of bortezomib.