On December 9, 2019 Menarini Ricerche reported is progressing with the clinical development of SEL24/MEN1703, and will be presenting the design of the ongoing First In Human clinical trial DIAMOND-01 (NCT03008187) at the 61st ASH (Free ASH Whitepaper) Congress, with a poster entitled: "First in Human Study of SEL24/MEN1703, First in Class, Orally Available Dual PIM/FLT3 Kinase Inhibitor, in Patients with Acute Myeloid Leukemia (Press release, Menarini, DEC 9, 2019, View Source [SID1234552165])." The poster, which will be disclosed today during the "Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation" session, describes the ongoing adjustment to the dose escalation design, with the objective to obtain more robust data on the recommended phase 2 dose.

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CLI24-001 (DIAMOND-01) trial is testing SEL24/MEN1703, a first in class, oral dual PIM/FLT3 inhibitor in-licensed from Ryvu Therapeutics. The primary objective of the study, currently carried out in newly diagnosed, relapsed or refractory AML (excluding acute promyelocytic leukemia) patients who are unsuitable for intensive chemotherapy, is to identify the recommended phase 2 dose of SEL24/MEN1703 given as single agent.

Furthermore, a second abstract reporting the identification of a pharmacodynamic biomarker for SEL24/MEN1703 and its implementation in the DIAMOND-01 trial, has been disclosed by ASH (Free ASH Whitepaper) as e-publication and is available in a special online-only issue of ASH (Free ASH Whitepaper)’s official Journal -Blood (2019) 134 (Supplement 1): 5087-.

Menarini strongly believes in innovation and is investing in the research and development of new treatment options for oncology patients, focusing on targeted therapies and precision medicine approaches. The contribution of Menarini Ricerche to ASH (Free ASH Whitepaper) with these data confirms such commitment to the development of innovative drugs that meet the needs of patients with difficult to treat cancers and poor prognosis.

On December 9, 2019 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium")reported that highlighted new data from a Phase 1 trial studying Actimab-A in combination with the salvage chemotherapy regimen CLAG-M that was presented in a poster presentation at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Actinium Pharmaceuticals, DEC 9, 2019, View Source [SID1234552095]). The poster reported results from the ongoing Phase 1 combination trial that is being conducted at the Medical College of Wisconsin (MCW). Patients receiving Actimab-A at a dose of 0.50 uCi/kg in the second dose cohort in addition to CLAG-M had an 86% overall response rate (ORR), which is a 56% higher response rate and is substantially greater than what has been observed with CLAG-M and MEC and more than double that of CLAG in a similar patient population that was treated at MCW. Notably, 71% of patients (5/7) achieved negative minimal residual disease (MRD) status in the second dose cohort. In addition to response rates, the poster reported that three patients on the study proceeded to a bone marrow transplant after receiving Actimab-A and CLAG-M. The addition of Actimab-A to CLAG-M appears to have a clinically acceptable safety profile with no patient deaths reported. A table below compares the ORR of patients receiving Actimab-A and CLAG-M to that of the CLAG-M, MEC and CLAG salvage regimens. The full poster can be accessed HERE.

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(PRNewsfoto/Actinium Pharmaceuticals, Inc.)

Regimen

Overall Response Rate

Actimab-A + CLAG-M

86% (6/7)

CLAG-M

55% (41/74)

MEC

44% (25/57)

CLAG

40% (6/15)

Sameem Abedin, M.D., Assistant Professor of Medicine at the Medical College of Wisconsin and Principal Investigator of the study, stated, "CLAG-M has become our preferred salvage regimen for patients with relapsed or refractory AML, as it demonstrated a higher overall response rate than other salvage regimens such as CLAG and MEC. We are pleased by the significantly higher response rate of eighty-six percent that was observed when adding Actimab-A to CLAG-M compared to the fifty-five percent response rate we observed with CLAG-M in prior studies. This efficacy is highly encouraging particularly as the combination appears to have a clinically acceptable safety profile. We look forward to completing this Phase 1 trial and hope to advance to a Phase 2 trial that we believe can serve as a pivotal trial for this promising combination given the high unmet need of patients with relapsed or refractory AML."

Actimab-A is an Antibody Radiation-Conjugate (ARC) that delivers the potent alpha-emitting radioisotope Actinium-225 (Ac-225) via the antibody lintuzumab to cells that express CD33. CD33 is an antigen that is expressed on the vast majority of cancer cells in patients with acute myeloid leukemia (AML). CLAG-M is a salvage chemotherapy comprised of cytarabine, cladribine, G-CSF (granulocyte-colony stimulating factor) and mitoxantrone. The Phase 1 Actimab-A CLAG-M combination study is enrolling patients age 18 and older who have relapsed or refractory AML and are medically fit. The median age of patients enrolled in the trial to date is 62 and all patients had either intermediate risk or poor risk cytogenetics. Three patients had received three or more prior therapies and three patients had received a prior allogeneic bone marrow transplant. This patient population is similar to the study conducted at MCW that enrolled 146 patients, of which, 74 received CLAG-M, 57 received MEC and 15 received CLAG. MRD status was not reported in that study, however 71% of patients receiving 0.50 uCi/kg of Actimab-A and CLAG-M achieved MRD negative status1.

"These results further our excitement for the combination of Actimab-A and CLAG-M as well as other ARC combinations that we have ongoing like that with the Bcl-2 inhibitor venetoclax," commented Dr. Mark Berger, Actinium’s Chief Medical Officer. "The emergence of several recently approved agents, including targeted therapies, for patients with AML is exciting but their use can be limited to patients with a specific mutation and the lack of curative outcomes with these therapies points to a need for continued innovation. Our targeted Antibody Radiation-Conjugates can be a solution to the unmet need of many patients as radiation is a validated modality, hematologic cancers are sensitive and susceptible to radiation and patients with hematologic cancers are typically not exposed to external radiation given the diffuse nature of their disease. Because radiation is agnostic to genetic and cytogenetic abnormalities and there is no known resistance mechanism to alpha particles like actinium-225, we see great potential for additional combinations with other chemotherapy regimens like 7+3, targeted agents like FLT3 and IDH inhibitors and immunotherapies. Finally, these results increase our excitement for the Actimab-A venetoclax combination trial, and our Company looks forward to the clinical results next year that we believe can confirm the synergy we observed in our preclinical research."

The overall response rates observed with the Actimab-A CLAG-M combination compare favorably to response rates reported with recently approved therapies in patients with relapsed or refractory AML that are shown in the table below.

Agent or Regimen

Response Rate

Actimab-A + CLAG-M

83%

Gilteritinib (FLT3 inhibitor)2

68%

Venetoclax + HMA3

64%

Enasidenib (IDH2 inhibitor)4

40%

Venetoclax5

19%

Azacytidine (HMA)6

17%

The Actimab-A CLAG-M Phase 1 trial is expected to be completed in mid-2020. Actinium is also conducting a Phase 1 clinical trial studying Actimab-A in combination with the Bcl-2 inhibitor venetoclax in patients with relapsed or refractory AML to evaluate the safety of the combination and determine if the addition of Actimab-A to venetoclax can increase patient responses and outcomes. In preclinical studies, it was observed that Actimab-A can deplete Mcl-1, a protein that has been implicated in mediating resistance to Bcl-2 inhibitors like Venetoclax and provides a potentiating effect.

Sources:

1) MRD data from a subsequent analysis

2) Perl et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-1740.

3) Aldoss et al. Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia. Haematologica. 2018 Sep;103(9):e404-e407.

4) Stein et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017 Aug 10;130(6):722-731.

5) Konopleva et al. Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia. Cancer Discov. 2016 Oct;6(10):1106-1117.

6) Itzykson et al. Azacitidine for the treatment of relapsed and refractory AML in older patients. Leuk Res. 2015 Feb;39(2):124-30.

On December 9, 2019 Zentalis Pharmaceuticals (the "Company" or "Zentalis"), a clinical-stage biopharmaceutical company focused on developing clinically differentiated, novel small molecule therapeutics that target fundamental pathways in cancer, reported the completion of an $85 million Series C financing (Press release, Zentalis Pharmaceuticals, DEC 9, 2019, View Source [SID1234552116]). The Company has raised a total of $147 million in gross proceeds from private financings since its founding in December 2014.

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Leading investors participating in this Series C financing include Matrix Capital, Viking Global Investors, Redmile Group, Farallon Capital, Perceptive Advisors, Surveyor Capital (a Citadel company) and Eventide Asset Management.

The proceeds from the Series C financing will be used to advance the Company’s lead clinical candidates towards pivotal trials and to broaden the scope of Zentalis’ ongoing clinical programs. The Company’s product pipeline is being developed to address unmet medical needs in large patient populations in both solid and liquid tumors and to make potential significant clinical advances over standard of care therapies.

The Company’s lead clinical product candidate, ZN-c5, is currently in Phase 1/2 trials. ZN-c5 is a potential best-in-class oral Selective Estrogen Receptor Degrader (SERD) for estrogen receptor-positive, HER2-negative (ER+/ HER2-) breast cancer, which affects approximately 70% of all breast cancer patients. ZN-c5 is being developed for use as monotherapy or in combination therapy. In May 2018, Zentalis entered into a clinical development collaboration agreement with Pfizer Inc. to enable trials of its ZN-c5 in combination with Pfizer’s Ibrance (palbociclib), a CDK4/6 inhibitor which is approved for ER+/HER2- advanced breast cancer patients in combination with hormonal therapies. The Company recently initiated dosing ZN-c5 in combination with Ibrance in a Phase 1/2 clinical trial targeting safety, efficacy and pharmacokinetics readouts in 2020, in addition to its ongoing monotherapy cohort.

Zentalis is also developing ZN-c3, a next-generation DNA Damage Response (DDR) drug candidate targeting the WEE1 kinase for solid tumors. ZN-c3 is currently in a Phase 1 trial. The Company’s additional pipeline compounds target other fundamental cancer pathways.

"Zentalis is delighted to partner with its outstanding group of leading healthcare investors to drive forward best-in-class chemistry for cancer patients. In my career, I have never seen a company progress at this pace with three INDs accepted in the first five years since inception. I am very proud of our team for these remarkable accomplishments. This financing reflects strong support for our capabilities, people and pipeline," said Anthony Sun, M.D., Chief Executive Officer, Zentalis Pharmaceuticals. "The investment positions us to implement our clinical and partnering strategies around our current pipeline and to accelerate expansion of our team."

"We were attracted to Zentalis by the excellent science, integrated discovery engine, broad therapeutic applicability and market potential with a strong pipeline across a broad range of oncology indications. There are significant advantages with a small molecule approach in cancer, such as oral delivery and ease of manufacturing compared to biologics or immunotherapy, and the ability to reach a large number of potential intracellular targets. We see tremendous opportunity for Zentalis’ pipeline candidates to be potential best-in-class agents for use as monotherapy or in combination. Their approach to targeting fundamental cancer pathways has the potential to address major unmet medical needs in large patient populations," said Karan Takhar, Managing Director at Matrix Capital Management.

On December 9, 2019 Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing monoclonal antibodies for the treatment of cancer, autoimmune disease, asthma and allergic diseases, reported initial data from its ongoing Phase 1 dose-escalation study of XmAb13676, a CD20 x CD3 bispecific antibody, in patients with B-cell malignancies (Press release, Xencor, DEC 9, 2019, View Source [SID1234552133]). Data are being presented by Krish Patel, M.D., Director of the Lymphoma Program at Swedish Cancer Institute, in a poster session today from 6:00 p.m. to 8:00 p.m. EST at the 61stAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida.

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"XmAb13676 has been generally well tolerated and has demonstrated encouraging clinical activity in patients with advanced non-Hodgkin’s lymphoma as a monotherapy in initial dose escalation cohorts. This activity supports the potential of XmAb13676 in lymphoma treatment, and we are planning additional studies as a monotherapy and in combination with other agents," said Bassil Dahiyat, Ph.D., president and chief executive officer at Xencor. "Dose escalation and optimization of dosing schedule, using a priming dose and step-up regimen, are ongoing."

Key Highlights

At data cut off in November 2019, 45 patients with relapsed/refractory non-Hodgkin’s lymphoma (r/r NHL) had received doses of XmAb13676 ranging from 0.7 to 170 mcg/kg, and 8 patients with relapsed/refractory chronic lymphocytic leukemia (r/r CLL) had received doses ranging from 0.7 to 20 mcg/kg. The study was designed in two parts: Part A to establish an initial priming dose with flat dosing regimens and Part B to escalate dosing on subsequent administrations to the priming dose. Prophylactic treatment for cytokine release syndrome (CRS) was mandated prior to each dose of XmAb13676.

XmAb13676 was generally well tolerated, and a priming dose of 45 mcg/kg was chosen for continued dose escalation in Part B for patients with NHL.

Safety was evaluated in all 53 patients. The most common treatment-emergent adverse events (AEs) were pyrexia (55%), CRS (53%) and anemia (41%). CRS was more frequent and generally higher grade on the first dose. Three patients (6%) experienced Grade 3 or 4 CRS on the first dose, all prior to the implementation of step-up dosing. AEs consistent with the symptoms of CRS, but not reported as such, were observed in an additional 23% of patients and were mild to moderate in severity.

CRS Grades by NHL Dose Groups in Treatment Cycle 1

Nervous system disorders, which were observed in 49% of patients, were mild or moderate in severity, and the most common of these events were dizziness (17%), headache (17%), paresthesia (9%) and lethargy (6%). One patient experienced short-term encephalopathy during a CRS event (Grade 2), and one patient lost consciousness during a bowel movement. Grade 3 or 4 AEs experienced by more than 5% of patients, other than CRS, included anemia (23%), neutropenia (15%), thrombocytopenia (11%), lymphopenia (9%) and hypokalemia (6%).

Eighteen patients with diffuse large B-cell lymphoma (DLBCL) who received doses of 80 to 170 mcg/kg are included in the analysis to describe clinical activity. These patients had a median age of 63.5 years, a median of three prior systemic therapies and had been diagnosed a median of 21.5 months prior to treatment. The objective response rate was 39% (n=7), and the complete response rate was 28% (n=5). XmAb13676 demonstrated clinical activity in an apparent dose-dependent manner. At dose levels with clinical activity for patients with DLBCL, 80 to 170 mcg/kg, a complete response was observed in one patient (20%; n=1/5) with follicular lymphoma (FL). Additional complete responses have been observed in Waldenström macroglobulinemia (n=1) and Richter transformation of CLL (n=1), both at 20 mcg/kg, the highest dose administered in the ongoing Part A of the study for patients with CLL.

The poster will be made available under Archived Scientific Presentations on the Events & Presentations page in the Investors section of www.xencor.com.

Webcast Information

Xencor will provide an overview of these data in a live webcast presentation at 8:30 p.m. EST on Monday, December 9, 2019. The webcast can also be accessed on the Events & Presentations page in the Investors section of www.xencor.com, and it will remain archived for 30 days.

About XmAb13676

XmAb13676 is a tumor-targeted antibody that contains both a CD20 binding domain and a T-cell binding domain (CD3) in a Phase 1 clinical trial for the treatment of B-cell malignancies. An XmAb bispecific Fc domain serves as the scaffold for these two antigen binding domains and confers long circulating half-life, stability and ease of manufacture on XmAb13676. CD20 is highly expressed on B-cell tumors, including in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL). Engagement of CD3 by XmAb13676 activates T cells for highly potent and targeted killing of CD20-expressing tumor cells.

About XmAb Bispecific Fc Technology

XmAb bispecific Fc domains enable the rapid design and simplified development of bispecific antibodies, and other protein structures, that bind two or more different targets simultaneously using an engineered heterodimer Fc domain. Seven XmAb bispecific antibodies are being evaluated in Phase 1 clinical studies conducted by Xencor or its pharmaceutical partners.

CD3 bispecific antibodies contain an anti-tumor associated antigen binding domain and a second binding domain targeted to CD3, an activating receptor on T cells, with the goal to recruit or activate T cells against the antigen target. Candidates in clinical development include XmAb14045 (CD123 x CD3), XmAb13676 (CD20 x CD3), XmAb18087 (SSTR2 x CD3) and Amgen’s AMG 424 (CD38 x CD3).
Tumor microenvironment (TME) activator bispecific antibodies promote tumor-selective T-cell activation by targeting multiple checkpoints or co-stimulating receptors. These candidates incorporate Xencor’s Xtend technology for longer half-life in their design. Candidates in clinical development include XmAb20717 (PD1 x CTLA4), XmAb22841 (CTLA4 x LAG3) and XmAb23104 (PD1 x ICOS).
Cytokine candidates are built on a heterodimeric Fc domain and have their potencies tuned to improve therapeutic index. These candidates incorporate Xtend technology for longer half-life.

On December 9, 2019 Amphivena Therapeutics, Inc., a private clinical stage immuno-oncology company developing T cell engager therapeutics for cancer, reported at the American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting data from a Phase 1 study of its bivalent T cell engager clinical candidate, AMV564 (Press release, Amphivena Therapeutics, DEC 9, 2019, View Source [SID1234552150]). In an oral presentation, Dr. Jorge E. Cortes, of the Georgia Cancer Center, Augusta University, Augusta, Georgia, said that the data provide early evidence of safety and clinical activity with evidence of T cell activation, increases in bone marrow T cells, and anti-leukemic blast activity. Of the 38 patients for whom response data was reported, five had Complete or Partial Responses as defined by the European LeukemiaNet (ELN) criteria.

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"AMV564 was shown to be safe and well-tolerated, with no dose-limiting toxicities and no Grade 3+ Cytokine Release Syndrome (CRS), at doses up to 450 mcg/day in heavily pre-treated relapsed/refractory AML patients when administered by continuous IV infusion with a 14-day dosing regimen," said Dr. Cortes. "These findings provide a differentiated product profile that we believe should be further advanced in clinical development."

"We are pleased with the early signs of efficacy and safety in this First in Human clinical trial, and we are exploring subcutaneous and chronic dosing of AMV564 in other clinical trials," said Curtis Ruegg, Ph.D., President and CEO of Amphivena. "AMV564’s excellent safety profile supports conduct of combination trials of AMV564 with other agents as we look ahead into the AMV564 development program."

As of the data cutoff, 41 patients had been dosed with AMV564 and 11 dose cohorts were explored in a 14-day continuous IV dosing regimen. The primary objectives of the Phase 1 dose escalation study are to characterize the safety of AMV564 as well as identify a maximum tolerated dose and a recommended Phase 2 dose.

The presentation was made at 5:45 PM EST in the Chapin Theater (W320), Orange County Convention Center, Orlando, FL.

About AMV564

AMV564 is a bivalent, bispecific (2:2) T cell engager that binds CD33 and CD3. To date, over 50 patients have received AMV564 in two Phase 1 clinical trials for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). It is currently being evaluated in a First-in-Human Phase 1 trial in patients with relapsed/refractory AML at Washington University School of Medicine, MD Anderson Cancer Center, New York-Presbyterian/Weill Cornell Medical Center and Weill Cornell Medicine, Fred Hutchinson Cancer Research Center, The Ohio State University Wexner Medical Center, University of Pennsylvania Medical Center, Northwestern Memorial Hospital, and The Johns Hopkins Hospital.

The safety, efficacy and selectivity of AMV564 was highlighted most recently at the Society for Immunotherapy in Cancer (SITC) (Free SITC Whitepaper) Annual Meeting on November 7 where it was reported that AMV564 selectively reduces MDSC in the bone marrow and periphery in acute myeloid leukemia and myelodysplastic syndrome patients. The company also observed at SITC (Free SITC Whitepaper) that T cell activation on therapy can lead to rapid increases in MDSC that can be modulated by AMV564 due to avid binding of activated CD33 on MDSC. Amphivena also presented data at the 24th European Hematology Association (EHA) (Free EHA Whitepaper) meeting in Amsterdam (Abstract S877). Amphivena believes that AMV564 has demonstrated novel clinical activity by rapidly and selectively eliminating leukemic blasts and rare immature, granulocytic and monocytic MDSCs while sparing normal CD33-expressing cells, including neutrophils and monocytes.