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Actinium Pharmaceuticals Highlights Analysis of Pivotal Iomab-B Phase 3 SIERRA Trial Presented in Oral Session at ASH Annual Meeting

On December 4, 2018 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) reported that additional data from an updated analysis of the pivotal Iomab-B Phase 3 SIERRA trial were highlighted last night in an oral presentation at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Actinium Pharmaceuticals, DEC 4, 2018, View Source [SID1234531873]). The SIERRA trial is the only ongoing Phase 3 trial offering a bone marrow transplant (BMT) to patients 55 years of age or older with active, relapsed or refractory acute myeloid leukemia (AML). Data in the table below were presented in the oral session and are updated from those at the time of abstract submission. Preliminary data strongly support the feasibility and safety of re-induction and targeted conditioning with Iomab-B prior to a BMT.

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Preliminary Feasibility and Safety Data

Randomized to
Iomab-B Study Arm
(N=19)

Randomized to
Conventional Care
(N=19)

Randomized to
Conventional Care,
No Remission, and
Crossed Over (N=10)

Number of Patients
Receiving BMT after
receiving therapy

100% (18/18)

(1 patient did not
receive therapeutic
Iomab-B dose)

21% (4/19)

100% (10/10)

Blast % at
Randomization

Median: 30%

Range: 4* -74

Median: 26%

Range: 6-97

At Randomization
24% (6-70)
At Crossover 45%
(10-70)

Days to BMT

(post-randomization)

Median: 28

Range: 23-38

Median: 67

Range: 66-86

Median: 66

Range: 57-161

Days to Absolute
Neutrophil
Engraftment

Median:13

Range: 9 – 22

Not entered

Median:13

Range: 9 – 20

Days to Platelet
Engraftment

Median: 16

Range: 13 – 26

Not entered

Median:17

Range: 10 – 20

100-Day Non-
Relapse Mortality

0% (0/18)

25% (1/4 – septic
shock)

10% (1/10 – diffuse
alveolar hemorrhage)

*1 patient with 4% blasts in the marrow had circulating AML blasts

Other Key Highlights:

15 of 19 (79%) patients in the control arm failed to achieve a complete response
67% (10/15) of patients eligible for crossover successfully transplanted with Iomab-B
All patients receiving Iomab-B engrafted despite active disease with high blast count (median 30%, or median 45% for crossover patients)
Patients receiving Iomab-B received a BMT more quickly post-randomization (28 days) than patients receiving conventional care (67 days)
In the conventional care arm, there was no difference in time to BMT for patients that crossed over to Iomab-B (66 days) compared to those achieving complete remission with conventional care (67 days)
No Grade 3 or 4 Iomab-B infusion related reactions with all Iomab-B infusions completed
No non-relapse mortality in patients randomized to Iomab-B arm
Abstract #1017: Targeted Conditioning of Iomab-B (131I-anti-CD45) Prior to Allogeneic Hematopoietic Cell Transplantation Versus Conventional Care in Relapsed or Refractory Acute Myeloid Leukemia (AML): Preliminary Feasibility and Safety Results from the Prospective, Randomized Phase 3 Sierra Trial

Dr. Edward Agura, Medical Director of Bone Marrow Transplantation at Baylor University Medical Center said, "Given that more than two thirds of patients who are diagnosed with AML are 55 years of age or older, there exists a significant unmet medical need to broaden transplant access and improve outcomes for these patients. The data from the SIERRA trial thus far are highly encouraging as they demonstrate that Iomab-B can enable a potentially curative transplant in patients with active disease, including those patients with progressing disease who did not achieve a response on conventional care. The nearly universal and rapid engraftment of patients receiving Iomab-B, together with no 100-day non-relapse mortality, is particularly compelling as these results have not been achieved with conventional care."

The 150 patient SIERRA study is a multi-center randomized trial that will compare outcomes of patients who receive Iomab-B and a BMT to those patients receiving physician’s choice of salvage chemotherapy, defined as conventional care, as no standard of care exists for this patient population. AML patients with active, relapsed or refractory AML have dismal prognoses and are typically not offered curative transplant as an option. This is largely because salvage treatments have a limited ability to produce a complete remission, which is necessary prior to BMT if conventional BMT is to be successful. However, with Iomab-B targeted conditioning, a complete remission prior to starting the Iomab-B conditioning is not necessary for a successful transplant.

Dr. Mark Berger, Actinium’s Chief Medical Officer said, "We believe that Iomab-B represents a potentially disruptive modality for targeted conditioning. The preliminary data from the SIERRA trial presented at ASH (Free ASH Whitepaper) exceeded our expectations regarding feasibility and safety, which adds to the already extensive body of research and data demonstrating the utility of Iomab-B for targeted conditioning in multiple hematologic indications. With this data in hand we are highly motivated to complete the SIERRA trial, which will serve as the beachhead for our multi-target, multi-disease pipeline for targeted conditioning, where we are committed to expanding our leadership position."

Moleculin Announces Breakthrough Discovery for its WP1066

On December 4, 2018 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a clinical stage pharmaceutical company focused on the development of oncology drug candidates, all of which are based on license agreements with The University of Texas System on behalf of the M.D. Anderson Cancer Center, reported that its own sponsored research has now confirmed a recent published study demonstrating the ability of its clinical-stage immuno-stimulating STAT3 inhibitor, WP1066, to inhibit a key immune checkpoint target known as PD-L1 (Press release, Moleculin, DEC 4, 2018, View Source [SID1234531871]).

"We have known for some time that WP1066 had the potential to stimulate a natural immune response," commented Dr. Donald Picker, Moleculin’s Chief Science Officer. "But, this data suggests that our drug may be capable of having a major impact on the field of checkpoint blockades. With this information combined with findings from other recently published studies demonstrating the impotant role of STAT3 in cancer immunology, we plan to run additional in vitro and in vivo studies, some of which are already underway, with WP1066 in combination with well-known checkpoint inhibitors to gather more data on this response."

Walter Klemp, Moleculin’s Chairman and CEO added, "This potential was initially reported in a 2017 Japanese study (Journal of clinical and experimental hematopathology, Vol. 57 No.1, 21-25, 2017), but we have now been able to confirm this activity with our own sponsored research at MD Anderson. Also, very recent independent research (Front Pharmacol. 2018 May 22;9:536. doi: 10.3389/fphar.2018.00536. eCollection 2018.) has linked STAT3, HIF1-a and c-Myc (all targets of WP1066) to the mechanism (a ligand known as PD-L1) believed to be largely responsible for resistance to current checkpoint blockade therapies. We believe this could put WP1066 center-stage in the field of immunotherapy. It’s potentially a tremendous breakthrough for our company."

Verastem Oncology Presents Duvelisib Development Program Data at the American Society of Hematology 2018 Annual Meeting

On December 4, 2018 Verastem, Inc. (Nasdaq:VSTM) (Verastem Oncology or the Company), focused on developing and commercializing medicines to improve the survival and quality of life of cancer patients, reported the presentation of seven posters highlighting new and updated clinical and preclinical data from its duvelisib development program at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2018 Annual Meeting, taking place December 1-4, 2018, in San Diego (Press release, Verastem, DEC 4, 2018, View Source;p=RssLanding&cat=news&id=2379420 [SID1234531868]). Duvelisib is an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma.

"The PI3K pathway is critical for the survival and proliferation of many types of cancer cells," said Robert Forrester, Verastem President and Chief Executive Officer. "At Verastem Oncology we are committed to progressing the scientific research and clinical development with our corporate, clinical and academic research partners worldwide to unlock the potential of PI3K inhibition and usher in new treatment strategies for patients in need."

"Research being presented at ASH (Free ASH Whitepaper) this year by Chen, et al used CLL patient samples to demonstrate critical points about dual PI3K-delta and PI3K-gamma inhibition," said Jonathan Pachter, PhD, Chief Scientific Officer at Verastem Oncology. "This research suggests that while PI3K-delta inhibition targets the malignant B cells directly, PI3K-gamma inhibition blocks the support of CLL growth by macrophages and T cells in the tumor microenvironment. Data presented show that when CLL cells from patients who progressed on ibrutinib were implanted in mice, dual PI3K-delta and PI3K-gamma inhibition effectively reduced the CLL burden thereby suggesting the potential value of the dual inhibition in tumors resistant to BTK inhibition. The importance of dual inhibition of PI3K-delta and PI3K-gamma, in this case in combination with BCL-2 inhibition, was also described by Ye, et al in an aggressive lymphoma model. This study highlights the synergistic activity of the combination in inhibiting ibrutinib resistance compensatory pathways and inducing apoptosis in preclinical models of Mantle Cell Lymphoma."

"We are delighted to have presented a wide range of data from our ongoing duvelisib development programs, including updated long-term follow-up data from the Phase 3 DUO study as well as the DUO crossover extension study," said Hagop Youssoufian, MSc, MD, Head of Medical Strategy at Verastem Oncology. "Other key presentations include the Zinzani and Lehmberg data, which describe compelling new biomarker research being conducted relating to predictive factors for response to duvelisib in certain hematologic malignancies."

Details for the ASH (Free ASH Whitepaper) 2018 poster presentations are as follows:

Poster Presentations

Title: Clinical and Biological Indicators of Duvelisib Efficacy in CLL from the Phase 3 DUO Study
Presenter: Jennifer Brown, Harvard Medical School and Dana-Farber Cancer Institute
Abstract Number/Publication ID: 1856
Session: 642. CLL: Therapy, excluding Transplantation: Poster I

Title: The Efficacy and Safety of Duvelisib Following Disease Progression on Ofatumumab in Patients with Relapsed/Refractory CLL or SLL: Updated Results from the DUO Crossover Extension Study
Presenter: Matthew Davids, Dana-Farber Cancer Institute
Abstract Number/Publication ID: 3140
Session: 642. CLL: Therapy, excluding Transplantation: Poster II

Title: Characterization of the Long-Term Efficacy and Safety of Duvelisib Monotherapy in Patients with Relapsed/Refractory CLL/SLL on Treatment for > 2 Years across 4 Clinical Studies
Presenter: Ian Flinn, Sarah Cannon Research Institute
Abstract Number/Publication ID: 3146
Session: 642. CLL: Therapy, excluding Transplantation: Poster II

Title: Simultaneous inhibition of BCL-2 and PI3K signaling overcomes ibrutinib resistance in mantle cell lymphoma
Presenter: Haige Ye, MD Anderson Cancer Center
Abstract Number/Publication ID: 2950
Session: 625. Lymphoma: Pre-Clinical—Chemotherapy and Biologic Agents: Poster II

Title: Prognostic and Immune-Related Factors for Response to Duvelisib in the Phase 2 DYNAMO Clinical Trial in iNHL
Presenter: Pier Luigi Zinzani, University of Bologna Institute of Hematology
Abstract Number/Publication ID: 4167
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Poster III

Title: Dual Inhibition of PI3K-δ and PI3K-γ by Duvelisib Impairs CLL B Cells and CLL-Supporting Cells and Overcomes Ibrutinib Resistance in a Patient-Derived Xenograft Model
Presenter: Shih-Shih Chen, The Feinstein Institute for Medical Research, Northwell Health
Abstract Number/Publication ID: 4420
Session: 642. CLL: Therapy, excluding Transplantation: Poster III

Title: Dynamic BH3 Profiling Predicts Patient Response and MRD Status in Chronic Lymphocytic Leukemia (CLL) Patients Undergoing Frontline Treatment with Kinase Inhibitor Augmented (KIA) FCR
Presenter: Timothy Z. Lehmberg, Dana-Farber Cancer Institute
Abstract Number/Publication ID: 4395
Session: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster III

PDF copies of these poster presentations will be available here following the conclusion of the meeting.

Phio Pharmaceuticals to Present at the Tumor Targeted Lymphocytes Summit in Boston on December 13

On December 4, 2018 Phio Pharmaceuticals Corp. (NASDAQ: PHIO), a biotechnology company developing the next generation of immuno-oncology therapeutics based on its proprietary self-delivering RNAi (sd-rxRNA) therapeutic platform, reported that Dr. Gerrit Dispersyn, President and Chief Operating Officer, will give a presentation at the Tumor Targeted Lymphocytes Summit being held at the Hilton Boston Back Bay in Boston on December 11-13 (Press release, Phio Pharmaceuticals, DEC 4, 2018, View Source [SID1234531867]).

Dr. Dispersyn’s presentation, titled "Therapeutic Enhancement of TILs with Self-Delivering RNAi through Targeted Gene Silencing," will take place at 12:10 p.m. ET on Thursday, December 13. He will present an overview on the use of RNAi to improve the immunobiology of tumor infiltrating lymphocytes (TILs) and other immune effector cells, how its use compares to other approaches in Adoptive Cell Therapies (ACT), and considerations for clinical and commercial applicability.

Dr. Dispersyn’s presentation will be available under the "Investors – Events and Presentations" section of the Company’s website, www.phiopharma.com, approximately one hour following the presentation.

The Tumor Targeted Lymphocytes Summit is focused on the topic of optimizing the clinical translation of TILs and endogenous T cells to improve the efficacy of ACT

Amgen Announces First-In-Human Data Evaluating Investigational Novel BiTE® Immunotherapies AMG 420 And AMG 330 At ASH 2018

On December 4, 2018 Amgen (NASDAQ:AMGN) reported the first clinical results from studies evaluating investigational novel bispecific T cell engager (BiTE) immunotherapies AMG 420 and AMG 330 (Press release, Amgen, DEC 4, 2018, View Source;p=RssLanding&cat=news&id=2379192 [SID1234531859]). In two separate Phase 1 dose escalation studies, AMG 420, which targets B-cell maturation antigen (BCMA), and AMG 330, which targets CD33, provided early evidence of tolerability and anti-tumor activity in patients with relapsed and/or refractory multiple myeloma and relapsed or refractory acute myeloid leukemia (AML), respectively. These data were highlighted during oral presentations at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in San Diego.

BiTE antibody construct technology, pioneered by Amgen, is an innovative treatment approach that helps the body’s immune system attack cancer cells without the removal of immune cells from the patient. Amgen is studying a number of "off-the-shelf" investigational BiTE immunotherapies, with distinct targets, across a range of hematologic and solid tumors.

"Building on our success with the only approved BiTE immunotherapy available for patients, Amgen is emphasizing our commitment to the potential of this platform by advancing the development of approximately a dozen novel molecules across hematologic and solid tumor targets in hopes of continuing to offer meaningful advances to patients in need," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "We’re encouraged by the early results of investigational BiTE immunotherapies AMG 420 and AMG 330, especially when considered in the context of these heavily pre-treated patients, many of whom have run out of available options. We look forward to sharing more results from our BiTE pipeline at future medical meetings."

ASH Abstract #1010: Treatment with AMG 420, an anti-B-Cell Maturation Antigen (BCMA) Bispecific T-cell Engager (BiTE) Antibody Construct, Induces Minimal Residual Disease (MRD) Negative Complete Responses in Relapsed and/or Refractory (R/R) Multiple Myeloma (MM) Patients: Results of a First-in-Human (FIH) Phase 1 Dose Escalation Study

The data shared at ASH (Free ASH Whitepaper) were the first presentation of all endpoints from this Phase 1 dose-escalation trial of AMG 420 in patients with relapsed and/or refractory multiple myeloma. The objectives of the study included assessment of safety, tolerability and anti-tumor activity of AMG 420 per International Myeloma Working Group 2006 Uniform Response Criteria for Multiple Myeloma.

In the study, 42 patients with relapsed and/or refractory multiple myeloma who had progression after at least two prior lines of treatment (including a proteasome inhibitor and an immunomodulatory imide drug) received AMG 420 at varying doses [0.2 to 800 µg/day (d)]. AMG 420 induced clinical responses in 13 patients, including complete responses (CR) in seven patients. Four patients treated at the 400 µg/d dose achieved minimal residual disease (MRD) negative complete responses, meaning that no cancer cells were detectable in the bone marrow. The objective response rate at 400 µg/d was 70 percent (seven of 10 patients), with six patients still responding up to 7.5 months. One dose-limiting toxicity was observed up to the 400 µg/d dose (peripheral polyneuropathy, which improved to baseline after intravenous immunoglobulin and corticosteroid treatment).

Of those patients with serious adverse events (AEs) (n=20, 48 percent), 17 required hospitalization and four had prolonged hospitalization. Serious AEs included infections (n=12), peripheral polyneuropathy (n=2), and one each of liver failure, cardiac failure, edema, biliary obstruction, spinal cord compression, renal failure and weight loss. Treatment-related serious AEs included polyneuropathy (n=2, both grade 3) and edema (n=1, grade 3). Cytokine release syndrome (CRS) was seen in 16 patients (grade 1, n=13; grade 2, n=2; grade 3, n=1). In this study, 800 µg/d was determined to not be tolerable, as two out of the three patients treated at this dose experienced dose-limiting toxicities.

Two patients died during the course of the study from AEs not considered treatment-related. One patient died after the first cycle of treatment from acute respiratory distress due to concurrent flu and aspergillosis. The second patient died from liver failure secondary to a viral infection during the course of treatment.

"These first-in-human data of a BCMA-targeting BiTE immunotherapy showed encouraging evidence of AMG 420 activity, with no major toxicities up to the 400 µg/d dose in patients with relapsed and/or refractory multiple myeloma who received a median of four prior therapies," said Max S. Topp, M.D., professor, Hospital of Wuerzburg, Germany and AMG 420 clinical study investigator. "Despite recent treatment advances, multiple myeloma continues to be a disease characterized by cycles of relapse and recurrence requiring additional therapies to help control the disease."

Additionally, AMG 420 was granted Fast Track Designation by the U.S. Food and Drug Administration (FDA). Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need. The purpose is to get important new drugs to the patient earlier. Fast Track addresses a broad range of serious conditions.

ASH Abstract #25: A Phase 1 First-in-Human Study of AMG 330, an Anti-CD33 Bispecific T-cell Engager (BiTE) Antibody Construct, in Relapsed/Refractory Acute Myeloid Leukemia (R/R AML)

In a separate first-in-human Phase 1 dose escalation study, 40 patients with relapsed or refractory AML were enrolled to receive AMG 330 in 12 dose cohorts with a target dose range of 0.5 to 480 µg/d. The study objectives were to evaluate the safety, pharmacokinetics and pharmacodynamics of AMG 330 and to estimate the maximum tolerated dose. Results showed that two patients in the trial achieved a CR at the 240 µg/d dose and two patients achieved a CR with incomplete blood count recovery, one at the 240 µg/d dose and one at the 120 μg/d dose. The CRs were not sustained beyond one cycle of treatment.

Patients in the trial received a median of one (range: 1-6) cycle with AMG 330; the majority of patients discontinued treatment for disease progression. Other reasons for study discontinuation included AEs (n=6, 2 treatment-related) and patient request (n=2).

Serious AEs were seen in 73 percent of patients (treatment-related in 17 patients). The most common serious AEs seen in more than one patient included CRS (n=11), febrile neutropenia (n=7), pneumonia (n=4), leukopenia (n=4), pyrexia (n=3), thrombocytopenia (n=3) and subdural hematoma (n=2). One patient died on study due to AML progression and one due to intracranial hemorrhage (neither treatment-related). There were dose-limiting toxicities of grade 2 CRS and grade 4 ventricular fibrillation with a target dose of 480 μg/d administered as a single-step regimen.

"The majority of adult AML patients will not be cured with standard chemotherapy, underscoring the need for innovative treatment options for those who have relapsed or are refractory to currently available treatments1," said Farhad Ravandi, M.D., Janiece and Stephen A. Lasher professor of medicine and chief of section of Developmental Therapeutics in the Department of Leukemia at the University of Texas – MD Anderson Cancer Center and AMG 330 clinical study investigator. "These early data are encouraging as they indicate AMG 330 may have anti-leukemic activity in heavily pretreated patients with relapsed or refractory AML, validating the need for continued evaluation of the BiTE platform in targeting CD33."

About BiTE Technology
Bispecific T cell engager (BiTE) antibody construct is an innovative technology that can be engineered to target any tumor antigen expressed by any type of cancer. The protein molecules are designed to kill malignant cells using the patient’s own immune system by bridging T cells to tumor cells. BiTE antibody construct helps connect the T cells to the targeted cell, with the intent of causing T cells to inject toxins which trigger cancer cell death (apoptosis). Amgen is developing BiTE antibody constructs to uniquely (or specifically) target numerous hematologic malignancies and solid tumors.