On December 11, 2017 Astellas Pharma Inc. (TSE: 4503, President and CEO: Yoshihiko Hatanaka, "Astellas") reported the first data of the investigational agent gilteritinib from the ongoing, open-label, dose escalation/expansion Phase 1 study (NCT02236013) in newly diagnosed patients with acute myeloid leukemia (AML) (Press release, Astellas Pharma US, DEC 11, 2017, View Source [SID1234522546]). The data are being presented today in an oral presentation at the 2017 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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"These initial data shed encouraging light on the safety and tolerability of gilteritinib when combined with intensive chemotherapy for newly diagnosed AML patients," said Keith W. Pratz, M.D., of John Hopkins Sidney Kimmel Comprehensive Cancer Center, who is the principal investigator for the study. "In addition, while evaluating antitumor effects is an exploratory goal, the response rates in FLT3mut+ patients are promising and warrant expanded investigation of gilteritinib in this upfront treatment setting. Continuing research to evaluate the potential role for a FLT3 inhibitor in newly diagnosed patients and other stages of AML should continue to be a priority in our collective efforts to improve outcomes for patients."

The primary objective of this Phase 1 study is to assess the safety/tolerability profile, including dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD), of gilteritinib when combined with 7+3 induction (cytarabine and idarubicin) and high-dose cytarabine (HiDAC) consolidation chemotherapy, followed by single agent maintenance therapy in patients 18 years of age and older who have been newly diagnosed with AML. Assessment of antitumor effects of this combination therapy is an exploratory objective.

The two-part trial first enrolled patients to successive cohorts to determine the MTD. Successive cohorts received gilteritinib doses of 40, 80 or 120 mg/day. Dose escalation decisions were made based on DLTs that occurred following the first dose of gilteritinib during induction. Patients in the dose expansion cohort received gilteritinib at the recommended expansion dose established during dose escalation. Patients also received gilteritinib during consolidation, and then received maintenance therapy with once-daily gilteritinib over a 28-day cycle for up to 26 cycles.

"We are very encouraged by this initial data from our ongoing study of gilteritinib in combination with intensive chemotherapy in newly diagnosed AML patients, and pleased that it earned selection for oral presentation at ASH (Free ASH Whitepaper)," said Steven Benner, M.D., senior vice president and global therapeutic area head, Oncology Development, Astellas. "Mutations of FLT3 in AML are associated with a poor prognosis across the course of disease treatment and, through our comprehensive clinical development program, Astellas is committed to understanding how selective inhibition by gilteritinib might be beneficial to as many patients as possible."

As of July 9, 2017, 50 patients (n=17, dose escalation cohort; n=33, dose expansion cohort) had been enrolled in this ongoing study and 49 had received at least one dose of gilteritinib. Of the 48 patients with documented FLT3 mutation status, 23 (47.9%) were FLT3mut+, of whom 13 (56.5%) had internal tandem duplications (ITD).

Additional key findings include:

During dose escalation, two subjects in the 40 mg/day cohort who had received gilteritinib on days 1-14 experienced DLTs (neutropenia, thrombocytopenia and decreased ejection fraction). After gilteritinib induction schedule modification, no additional DLTs were observed.
The maximum tolerated dose was not reached; gilteritinib 120 mg/day was chosen as the recommended expansion dose.
Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurring in ≥ 10% of subjects were febrile neutropenia (36.7%), thrombocytopenia (18.4%), neutropenia (16.3%) and decreased platelet count (12.2%).
Serious drug-related TEAEs occurring in >1 subject were febrile neutropenia (n=8), sepsis (n=2), small intestinal obstruction (n=2), lung infection (n=2), and decreased ejection fraction (n=2).
In FLT3mut+ and FLT3 wild type subjects, end-of-treatment CRc rates were 100% and 60.9%, respectively.
About Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) is a cancer that impacts the blood and bone marrow, and its incidence increases with age. The American Cancer Society estimates that in 2017, approximately 21,000 new patients will be diagnosed with AML in the United States and about 10,000 cases will result in death.

About Gilteritinib

Gilteritinib is an investigational compound that has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) as well as FLT3 tyrosine kinase domain (TKD), two common types of FLT3 mutations that are seen in approximately one-third of patients with AML. Further, gilteritinib has also demonstrated inhibition of the AXL receptor in AML cell lines, which has been reported to be associated with therapeutic resistance. Astellas is currently investigating gilteritinib in various AML patient populations through several additional Phase 3 trials. Visit d to learn more about ongoing gilteritinib clinical trials.

Gilteritinib was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global rights to develop, manufacture and potentially commercialize gilteritinib. Gilteritinib has been granted Orphan Drug designation and Fast Track designation by the U.S. FDA, and SAKIGAKE designation by the Japan Ministry of Health, Labor and Welfare.

The safety and efficacy of the agent discussed herein are under investigation and have not been established. There is no guarantee that the agent will receive regulatory approval and become commercially available for the uses being investigated. Information about pharmaceutical products (including products currently in development), which is included in this press release are not intended to constitute an advertisement or medical advice.

On December 11, 2017 Amgen (NASDAQ: AMGN) reported new results showing the positive overall survival (OS) findings from the final analysis of the Phase 3 ASPIRE trial. The study met the key secondary endpoint of OS, demonstrating that the addition of KYPROLIS (carfilzomib) to lenalidomide and dexamethasone (KRd) reduced the risk of death by 21 percent versus lenalidomide and dexamethasone alone (Rd) and extended survival by 7.9 months in patients with relapsed or refractory multiple myeloma (median OS 48.3 months for KRd versus 40.4 months for Rd, HR = 0.79, 95 percent CI, 0.67 – 0.95; p = 0.0045) (Press release, Amgen, DEC 11, 2017, View Source;p=RssLanding&cat=news&id=2322144 [SID1234522543]). These results were presented today during an oral presentation at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in Atlanta (ASH abstract #743).

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"While significant advances have recently been made in treating relapsed or refractory multiple myeloma, most reported clinical trials have focused on how long a new treatment helps prevent recurrence of disease rather than on survival," said Keith Stewart, M.B., Ch.B., Mayo Clinic in Arizona and principal investigator of the ASPIRE trial. "Results from the ASPIRE trial are among the first to show a significant overall survival advantage resulting from adding carfilzomib to lenalidomide and dexamethasone treatment in patients with relapsed or refractory multiple myeloma. The data support the early use of carfilzomib as an effective therapy at first relapse, regardless of prior treatment with Velcade or transplant."

"KYPROLIS-based regimens are the first and only to demonstrate superior overall survival versus today’s standard of care in two Phase 3 studies and are resetting survival expectations for relapsed or refractory multiple myeloma patients," said David Reese, M.D., senior vice president of Translational Sciences and Oncology at Amgen. "We are pleased with the KYPROLIS overall survival data presented at ASH (Free ASH Whitepaper) this year as the results underscore our commitment to developing innovative treatment options to help cancer patients live longer."

The final analysis of ASPIRE included subgroup analyses by prior lines of therapy, prior Velcade exposure at first relapse, and prior transplant at first relapse. Among these three groups, there was an 18 to 29 percent reduction in the risk of death for KRd versus Rd, consistent with findings in the overall population. Median OS was 11.4 months longer for KRd versus Rd in patients who had received one prior line of therapy (47.3 versus 35.9 months [HR = 0.81, 95 percent CI, 0.62 – 1.06]) and 6.5 months longer for patients with two or more prior lines (48.8 versus 42.3 months [HR = 0.79, 95 percent CI, 0.62 – 0.99]).

Notably the maximum OS improvement of 11 months was observed for patients at first relapse. This OS analysis supports the early use of KYPROLIS as effective therapy at first relapse, regardless of prior Velcade exposure or transplant. Patients treated with KRd reported improved global health status, with higher Global Health Status/Quality of Life (QoL) scores compared with Rd over 18 cycles of treatment (1‑sided p‑value = 0.0001) measured with the EORTC QLQ‑C30, an instrument validated in multiple myeloma.

Overall survival by Revised International Staging System (R-ISS) stage was also assessed. For R-ISS stage I (KRd, n = 42; Rd, n = 46), median OS was not reached for KRd and was 58 months for Rd (HR = 0.49, 95 percent CI, 0.26 – 0.92). For patients with R-ISS stage II (KRd, n = 194; Rd, n = 195), median OS was 45.4 months for KRd and 41.2 months for Rd (4.2 months; HR = 0.86, 95 percent CI, 0.68 – 1.10). For the small number of patients with R-ISS stage III (KRd, n = 37; Rd, n = 47), median OS was 23.3 months for KRd and 18.8 months for Rd (4.5 months; HR = 1.05, 95 percent CI, 0.66 – 1.68).

The safety data from ASPIRE was consistent with the known safety profile of KYPROLIS. The most common adverse events (greater than or equal to 20 percent) in the KYPROLIS arm were diarrhea, anemia, neutropenia, fatigue, upper respiratory tract infection, pyrexia, cough, hypokalemia, thrombocytopenia, muscle spasms, pneumonia, nasopharyngitis, nausea, constipation, insomnia and bronchitis.

Overall survival results from the Phase 3 ENDEAVOR head-to-head study of KYPROLIS plus dexamethasone (Kd) versus Velcade plus dexamethasone were also presented at ASH (Free ASH Whitepaper) and showed that Kd was superior in extending survival across a variety of sub-group analyses of relapsed or refractory multiple myeloma patients, including age, prior line of therapy and previous exposure to Velcade (ASH abstract #1885, ASH (Free ASH Whitepaper) abstract #1850).

The KRd and Kd regimens used in these trials are currently approved in the U.S., European Union and other countries based on primary analyses of progression-free survival (PFS) in the ASPIRE and ENDEAVOR studies, respectively. The KYPROLIS dosing used for ASPIRE (27 mg/m2; 10-minute infusion) and ENDEAVOR (56 mg/m2; 30-minute infusion) were optimized for each treatment regimen and are the currently approved doses for the KRd and Kd regimens, respectively.1

Based on the ASPIRE results, Amgen has submitted a supplemental New Drug Application to the U.S. Food and Drug Administration to include the OS data from ASPIRE in the product information for KYPROLIS.

On December 11, 2017 Aileron Therapeutics, the clinical-stage leader in the field of stapled peptides developing therapeutics for cancers and other diseases, reported two oral presentations of preclinical data from collaborators on ALRN-6924 in T-cell lymphomas (TCL) and acute myeloid leukemia (AML) (Press release, Aileron Therapeutics, DEC 11, 2017, View Source;p=RssLanding&cat=news&id=2322188 [SID1234522542]). ALRN-6924, a stapled peptide therapeutic, is believed to be the first product candidate undergoing clinical evaluations that has been shown to disrupt both MDMX- and MDM2-mediated inhibition of the wild type p53 tumor suppressor gene. The data were reviewed in separate oral presentations by researchers from the Dana-Farber Cancer Institute and the Albert Einstein College of Medicine during the 2017 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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"We are encouraged by these positive preclinical data from our collaborators, which demonstrate that dual inhibition by ALRN-6924 induces strong p53 activity that leads to anti-cancer effects," said Dr. Manuel C. Aivado, Chief Medical Officer. "These data support the clinical results we saw in our Phase 1 all-comers trial, and we look forward to continuing to evaluate ALRN-6924 in our ongoing PTCL and AML clinical trials."

TCL Study Highlights (Abstract #571)

In an in vitro and in vivo preclinical study, MDMX and MDM2 were evaluated as potential targets for treating wild type p53 T-cell lymphomas by using ALRN-6924 to inhibit their expression. The data showed that ALRN-6924 induced apoptotic cell death in TCL lines, and significantly reduced tumor burden compared to the vehicle in animal models. Furthermore, ALRN-6924 had a favorable safety profile and demonstrated superior efficacy across multiple TCL subtypes compared to the current standard-of-care.

Commented David Weinstock, M.D. of Dana-Farber Cancer Institute, "Given the need for new treatment approaches for T-cell lymphomas, we evaluated ALRN-6924 in animal models and found that the compound’s dual inhibition mechanism for restoring the function of p53 showed promising activity across multiple TCL subtypes, including PTCL. Animal models in our studies displayed key markers that demonstrated consistency with on-target p53 activation and apoptosis, supporting further clinical development of ALRN-6924 for PTCL." i

AML Study Highlights (Abstract #795)

The preclinical data presented showed that dual inhibition of MDMX and MDM2 by ALRN-6924 led to activation of p53-dependent pathways in AML cells. The disruption of MDMX/p53 and MDM2/p53 interactions resulted in strong anti-leukemic effects, and induced cell cycle arrest and apoptosis in cell lines and wild type p53 AML patients’ cells. The compound exhibited strong on-target activity in AML cell lines and primary cells in vitro, as well as in a patient who received ALRN-6924. The data further demonstrated that ALRN-6924 showed superiority over MDM2-only inhibition, and led to improved survival in in vivo AML models.

"These results support our understanding that in most patients with acute myeloid leukemia, a devastating disease with limited therapeutic options, p53 is circumvented by activation of its natural suppressor proteins, MDMX and MDM2," said Ulrich Steidl, Ph.D., M.D. of the Albert Einstein College of Medicine. "The ability to reactivate the p53 pathway by inhibiting both MDMX and MDM2 using a novel therapeutic modality such as stapled peptides is an exciting new chapter in p53 research. The studies presented today strengthen the rationale for the use of ALRN-6924 in acute myeloid leukemia and other wild type p53 cancers." ii

About ALRN-6924
ALRN-6924 is a first-in-class product candidate designed to reactivate wild type p53 tumor suppression by disrupting the interactions between the two primary p53 suppressor proteins, MDMX and MDM2. Aileron believes ALRN-6924 is the first and only product candidate in clinical development that can equipotently bind to and disrupt the interaction of MDMX and MDM2 with p53. Based on preclinical data and preliminary evidence of safety and anti-tumor activity in its ongoing clinical trials, there may be a significant opportunity to develop ALRN-6924 as a monotherapy or combination therapy for a wide variety of solid and liquid tumors. ALRN-6924 is currently being evaluated in multiple clinical trials for the treatment of acute myeloid leukemia (AML), advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL). For information about its clinical trials, please visit www.clinicaltrials.gov.

On December 11, 2017 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported updated data from its completed pilot study1 of NY‑ESO SPEAR T-cell therapy in multiple myeloma patients in the setting of autologous stem cell transplant (ASCT) presented by the main investigator at the annual ASH (Free ASH Whitepaper) meeting (Press release, Adaptimmune, DEC 11, 2017, View Source;p=RssLanding&cat=news&id=2322198 [SID1234522540]).

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"Mature data from this study in multiple myeloma continues to show promising efficacy and acceptable safety," said Rafael Amado, Adaptimmune’s Chief Medical Officer. "We have observed a high response rate, long response duration, and encouraging long‑term survival in this population of patients with poor prognosis, treatment refractory myeloma. In addition, NY-ESO SPEAR memory T-cells persist long-term and respond to antigen after more than three years post‑treatment. NY-ESO SPEAR T-cell therapy is currently being evaluated in a second study in multiple myeloma patients with or without KEYTRUDA, all without stem cell transplant."

Long-term follow up data from the pilot study of NY-ESO in multiple myeloma in the context of ASCT

During an oral presentation, Dr. Edward Stadtmauer, University of Pennsylvania Abramson Cancer Center, presented an update on all twenty-five multiple myeloma patients treated in Adaptimmune’s pilot study in the setting of ASCT. The data cut-off for this oral presentation was August 16, 2017.

Overall Conclusions

NY-ESO SPEAR T-cell therapy in the setting of ASCT has promising efficacy and acceptable safety in multiple myeloma patients
Durable responses and long-term survival demonstrated in this refractory population
NY-ESO SPEAR T-cells persisted long term (>1000 days), but were are not exhausted
The most common adverse events (summarized below) were generally not unexpected in this patient population
Persisting cells produced multiple cytokines in response to antigen
Persisting cells included highly differentiated effector subsets and a population of self-renewing stem cell memory cells
A follow up study is ongoing in combination with KEYTRUDA, which will transition to GSK
Efficacy Results

Of the twenty-five patients treated in this study, 11 were alive at data cut-off
Three patients remain disease-progression free at 3, 4.5, and 5 years post-treatment
Five of 18 subjects tested were minimal residual disease negative at day 100
The median duration of response was >12 months
The median predicted overall survival is approximately three years
Overall response rate (ORR) at 100 days and one year were 76% and 44%, respectively, using International Myeloma Working Group criteria
Safety Results

There were no fatal adverse events (AEs), and cytokine release syndrome was not reported
Autologous graft versus host disease (GvHD) was reported in six patients; all resolved with corticosteroids and supportive therapy
Most common AEs (any grade AE occurring in >50% of patients) included diarrhea (100%), nausea (100%), anemia (96%), thrombocytopenia (92%), fatigue (88%), pyrexia (84%), rash (84%), hypokalemia (76%), febrile neutropenia (72%), vomiting (72%), neutropenia (68%), back pain (60%), leukopenia (60%), cough (56%), dyspnea (56%), hypocalcemia (56%), peripheral edema (56%), stomatitis (56%), and abdominal pain (52%).
Exploratory Endpoints

TCR-transduced NY-ESO SPEAR T-cells persisted long term (>1000 days) with minimal expression of exhaustion markers, and persisting cells:
Were functional, producing multiple cytokines in response to antigen in vitro
Included highly differentiated effector subsets and a population of self-renewing stem cell memory cells

On December 11, 2017 Actinium Pharmaceuticals, Inc. (NYSE American:ATNM) ("Actinium" or "the Company") reported results from an analysis performed on a large U.S. library of samples from 865 multiple myeloma patients which showed that twenty-five percent of patients had CD33 expression on their multiple myeloma cells (Press release, Actinium Pharmaceuticals, DEC 11, 2017, View Source [SID1234522539]). Actinium is currently conducting a Phase 1 clinical trial for its Actimab-M drug candidate in patients with refractory multiple myeloma. Actinium is the first and only company thus far to have a CD33 targeted therapy for multiple myeloma and the results from this analysis provide further rationale for the Company’s myeloma initiative.

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This analysis was the first of its kind to analyze such a large, U.S. based patient sample library as previous studies exploring CD33 expression in multiple myeloma looked at significantly smaller sample sizes from established multiple myeloma cell lines. Patient samples at initial diagnosis were assessed for CD33 expression and CD33 expression was stratified with CD33 expression greater than 40% considered high and greater than 60% very high. The analysis showed that 61.6% of patients in the dataset had high CD33 expression and 41% of patients had very high CD33 expression which translates to approximately fifteen percent of the overall multiple myeloma sample population.

The online abstract can accessed through the following link:
View Source

Dr. Mark Berger, Actinium’s Chief Medical Officer said, "It is generally believed that expression of CD33 on multiple myeloma plasmocytes is in line with the low levels of expression in cells of the lymphoid lineage. The results from this study confirm that CD33 is expressed in a significant sub-set of multiple myeloma patients. Given that CD33 expression levels have been found to be high or very high in a large percentage of patients that do express the antigen, we have great confidence that our Actimab-M drug candidate, which uses an anti-CD33 antibody, can have a beneficial impact on these patients. In a disease like multiple myeloma, which remains incurable, we believe it is important to explore new therapeutic modalities and use of our CD33 targeting ARC or Antibody Radio-Conjugate is supported by these results. Additionally, myeloma cells are sensitive to radiation and targeting them using an ARC like Actimab-M may provide further advantages."

Patients that relapsed were also assessed for CD33 expression and 27.1% of relapsed patients were found to have CD33 expression with 58.3% of these patients having very high expression at initial diagnosis and relapse.

About Actimab-M

Actimab-M is being investigated in patients with refractory multiple myeloma. Multiple myeloma is a currently incurable cancer of plasma cells, which are white blood cells that produce antibodies. Actimab-M is currently being studied in a Phase 1 dose escalation study in up to 12 patients that is designed to establish safety, maximum tolerable dose and proof of concept. Actimab-M is an ARC or Antibody Radio-Conjugate that consists of Actinium-225, an alpha-emitting radioisotope coupled to the anti-CD33 monoclonal antibody, lintuzumab. CD33 has been shown to be expressed on myeloma plasmocytes in 25% of multiple myeloma patients and up to 35% of multiple myeloma patients and has also shown to be correlated with poorer outcomes.