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MacroGenics Presents Flotetuzumab Data in Patients with Primary Induction Failure and Early Relapsed Acute Myeloid Leukemia at the 2019 ASH Annual Meeting

On December 9, 2019 MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported updated results from a Phase 1/2 dose expansion study of flotetuzumab, an investigational, bispecific CD123 x CD3 DART molecule in patients with primary induction failure and early relapsed acute myeloid leukemia (AML) (Press release, MacroGenics, DEC 9, 2019, View Source [SID1234553172]). The data were presented in an oral session at the 61st Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Orlando, FL, taking place December 7-10, 2019.

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"Patients with AML who have failed primary induction therapy or relapsed early after an initial response represent a significant unmet medical need. A remission rate of 32% observed in the ongoing study of flotetuzumab in this extremely challenging patient population is noteworthy," said Geoffrey Uy, M.D., Associate Professor, Department of Medicine, Division of Oncology at the Washington University School of Medicine in St. Louis. "Importantly, by implementing a lead-in dosing schedule for flotetuzumab, as well as early intervention with tocilizumab in this study, we were able to mitigate cytokine release syndrome, known to be associated with T-cell engagers."

In the Phase 1/2 (NCT02152956) open-label, dose expansion study, 30 patients classified as primary induction failure or early relapsed AML who had received a median of four prior therapies were treated with flotetuzumab at the recommended phase 2 dose (RP2D) of 500 ng/kg/day by continuous infusion. Data were reported as of the cut-off date of November 1, 2019. The study is currently ongoing, with additional patients being enrolled.

Responses, including complete remission (CR), CRh (CR with partial hematological recovery) and CRi (CR with incomplete hematological improvement) per a modified International Working Group (IWG) Response Criteria for AML, are summarized in the table below. Four responders received allogeneic hematopoietic stem cell transplantation as consolidation therapy and remain in remission after 6 to 21 months.

The most common treatment-related adverse event (TRAE) was infusion-related reaction/cytokine release syndrome (IRR/CRS) that occurred in all (30/30) patients. However, most CRS events observed were of short duration and mild to moderate (grade 1 or 2) in severity, with only one grade 3 event reported in one patient.

"Based on the encouraging data from this study, and pending anticipated discussions with the FDA in the first half of 2020, we are planning for a potential registration-enabling study of flotetuzumab in this high unmet need population of patients with refractory AML, who have limited treatment options," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics.

A separate oral presentation described translational research that showed an inflammatory (IFN-γ-related) gene expression signature in a subset of patients with AML that correlated with a lack of response to induction chemotherapy. Furthermore, the same gene signature was associated with patients more likely to respond to flotetuzumab, supporting the mechanism being exploited by this molecule. In addition, AML patients with an immune-infiltrated tumor micro-environment show high expression of immune checkpoint molecules, including PD-L1, which provides a scientific rationale for combining flotetuzumab with checkpoint blockade as a potential mechanism for enhanced anti-leukemic activity. MacroGenics has initiated a study combining flotetuzumab with MGA012, an anti-PD-1 antibody, given the strong preclinical and translational data that indicate the combination may enhance CD123-directed T cell killing.

Flotetuzumab Presentations at ASH (Free ASH Whitepaper)

Oral Presentations

Abstract #733: Uy, et al. "Flotetuzumab, an Investigational CD123 x CD3 Bispecific DART Protein, in Salvage Therapy for Primary Refractory and Early Relapsed Acute Myeloid Leukemia (AML) Patients"
Abstract #460: Vadakekolathu, et al. "Immune Landscapes Predict Chemotherapy Resistance and Anti-Leukemic Activity of Flotetuzumab, an Investigational CD123 × CD3 Bispecific DART Molecule, in Patients with Relapsed/Refractory Acute Myeloid Leukemia"
Poster Presentations

Abstract #1410: Goodwin, et al. "Flotetuzumab (FLZ), an Investigational CD123 x CD3 Bispecific DART Protein-Induced Clustering of CD3+ T Cells and CD123+ AML Cells in Bone Marrow Biopsies Is Associated with Response to Treatment in Primary Refractory AML Patients"
Abstract #1387: Gopalakrishnapillai, et al. "Effect of Ara-C on T-Cell Function and Flotetuzumab Activity in Pediatric Acute Myeloid Leukemia"
Abstract #2662: Wei, et al: "A Phase 1 Study of Flotetuzumab, a CD123 x CD3 DART Protein, Combined with MGA012, an Anti-PD-1 Antibody, in Patients with Relapsed or Refractory Acute Myeloid Leukemia"
These slide and poster presentations are available on the Events & Presentations page on MacroGenics’ website at View Source

Conference Call & Webcast

MacroGenics management and external guest speakers will host a conference call and audio webcast today at 8:00 p.m. ET to review the flotetuzumab data presented at the ASH (Free ASH Whitepaper) Annual Meeting and discuss ongoing clinical development plans.

To participate in the MacroGenics ASH (Free ASH Whitepaper) 2019 Conference Call, please dial (877) 303-6253 (domestic) or (973) 409-9610 (international) five minutes prior to the start of the call and provide the Conference ID: 3625435. A listen-only slide and audio webcast of the conference call can be accessed under "Events & Presentations" in the Investor Relations section of the Company’s website at View Source A replay of the webcast will be available shortly after the conclusion of the call and archived on the Company’s website for 30 days.

About Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a hematopoietic stem cell malignancy characterized by differentiation arrest and uncontrolled clonal proliferation of neoplastic precursors that prevent normal bone marrow hematopoiesis. Nearly 20,000 new cases of AML are diagnosed in the U.S. each year, with a median age of 69 years at diagnosis. Approximately 40-50% of newly diagnosed patients fail to achieve a complete remission with intensive induction therapy (primary induction failure) or experience disease recurrence after a short remission duration (<6 months; early relapsed). A very small number of these patients are expected to respond to salvage therapy. In addition, although new targeted agents have been approved for the treatment of frontline or relapsed/refractory AML in recent years, approximately 50% of patients have no known targetable mutations.

About Flotetuzumab

Flotetuzumab (also known as MGD006) is a clinical-stage molecule that recognizes both CD123 and CD3. CD123, the interleukin-3 receptor alpha chain, has been reported to be over-expressed on cancer cells in AML and other hematologic malignancies. The primary mechanism of action of flotetuzumab is believed to be its ability to redirect T lymphocytes to kill CD123-expressing cells. To achieve this, the DART molecule combines a portion of an antibody recognizing CD3, an activating molecule expressed by T cells, with an arm that recognizes CD123 on the target cancer cells.

Flotetuzumab is currently being evaluated in the U.S. and Europe in a Phase 1/2 dose expansion study designed to assess the safety, tolerability, and initial anti-leukemic activity of the molecule in patients with relapsed/refractory AML. The U.S. Food and Drug Administration has granted orphan drug designation to flotetuzumab for the treatment of AML. A Phase 1/2 study in combination with MGA012, a proprietary anti-PD-1 monoclonal antibody, in patients with relapsed/refractory AML is being conducted ex-U.S. MGA012 (also known as INCMGA00012) was exclusively licensed to Incyte Corporation in 2017 under a global collaboration and license agreement; MacroGenics retains the right to develop its pipeline molecules with MGA012. MacroGenics retains global development and commercialization rights to flotetuzumab.

Seven and Eight BioPharmaceuticals, Inc. Announces Clinical Collaboration to Evaluate BDB001 in Combination with KEYTRUDA® (pembrolizumab) in Patients with Advanced Solid Tumors

On December 9, 2019 Seven and Eight BioPharmaceuticals Inc. reported that it has signed a clinical research collaboration agreement with Merck (known as MSD outside the US and Canada), through a subsidiary, to explore the combination of Seven and Eight’s BDB001, an immune modulator targeting toll-like receptors (TLR) 7 and 8, and Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab) in treating patients with advanced solid tumors (Press release, Seven and Eight Biopharmaceuticals, DEC 9, 2019, View Source [SID1234552201]).

"Seven and Eight is developing a clinical pipeline that aims to address unmet medical needs. This clinical collaboration with Merck represents yet another step in our efforts to help cancer patients who fail to derive desirable clinical benefits from existing therapies."

"We are pleased to enter into a clinical collaboration with Merck," says Dr. Walter Lau, CEO of Seven and Eight. "There has been increasing evidence to show toll-like receptor agonists as a class of immune modulators to stimulate innate immune responses and enhance adaptive anti-tumor immunity. We hope through our joint efforts with Merck, we can explore how to use our lead compound BDB001 together with KEYTRUDA, especially in treating those patients with advanced and difficult-to-treat tumor types."

Dr. Lau adds, "Seven and Eight is developing a clinical pipeline that aims to address unmet medical needs. This clinical collaboration with Merck represents yet another step in our efforts to help cancer patients who fail to derive desirable clinical benefits from existing therapies."

Under the terms of the agreement, Seven and Eight will sponsor and be responsible for the conduct of the clinical study.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

ImmunoGen Presents Updated Findings from Phase 1 Study of IMGN632 at ASH Annual Meeting

On December 9, 2019 ImmunoGen, Inc., (Nasdaq: IMGN) a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that new safety and efficacy findings from the dose escalation and expansion of the first-in-human trial of IMGN632 in patients with relapsed/refractory acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) were presented in an oral session at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida (Press release, ImmunoGen, DEC 9, 2019, View Source [SID1234552200]). Preclinical data related to IMGN632 in combination with Vidaza (azacitidine) and Venclexta (venetoclax), and two "trial in progress" posters were also presented at the conference.

"The data presented at ASH (Free ASH Whitepaper) demonstrate the potential of IMGN632 to offer a new treatment option for patients with AML and BPDCN," said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen. "With the benefit of a comprehensive assessment of IMGN632’s safety and efficacy across a wide range of doses and two schedules, we have selected a dose and schedule that demonstrate significant anti-tumor activity, favorable tolerability, and the convenience of a short infusion that can be administered in an outpatient setting. Together with the preclinical data on combining IMGN632 with azacitidine and venetoclax presented by our collaborators from MD Anderson, these updated clinical results provide a strong foundation for our ongoing expansion of IMGN632 monotherapy studies in BPDCN, AML, and ALL, and the recent initiation of our trial to evaluate IMGN632 combinations with azacitidine and venetoclax in relapsed and frontline AML, as well as IMGN632 as a monotherapy in minimal residual disease positive AML patients."

"We are particularly encouraged by the activity and tolerability of IMGN632 in heavily pre-treated patients, including a 40% ORR in relapsed and refractory de novo AML patients treated at the recommended phase 2 dose, and the responses in relapsed or refractory BPDCN patients previously treated with Elzonris (tagraxofusp-erzs) and intensive chemotherapy," said Naval Daver, MD, Associate Professor in the Department of Leukemia at MD Anderson Cancer Center. "We look forward to continuing to evaluate IMGN632 as a monotherapy and in combination with azacitidine and venetoclax in doublet and triplet regimens in relapsed/refractory AML and frontline older AML."

PHASE 1 DATA ON IMGN632 AS A MONOTHERAPY IN AML AND BPDCN
Oral Presentation, Abstract #734
Updated key findings from the Phase 1 study of IMGN632 include the following:

Safety

IMGN632 was administered to 95 patients over dose levels ranging from 0.015 to 0.45 mg/kg intravenously on the every 3 week schedule and 0.015 to 0.06 mg/kg on the fractionated day 1, 4, and 8 schedule every 3 weeks.
IMGN632 displays a well tolerated safety profile and activity at doses up to and including 0.09 mg/kg per cycle.
The most common treatment-related adverse event was infusion-related reactions (24% all grades, 8% grade 3); none required IMGN632 discontinuation.
Single dose-limiting toxicities were seen at the highest dose levels tested (0.18-0.45 mg/kg): three reversible cases of veno-occlusive disease and one prolonged neutropenia; no patterns of hepatotoxicity or cytopenias occurred with doses below 0.18 mg/kg.
Although no maximum tolerated dose was determined on either schedule, based on the efficacy, safety, and pharmacokinetic data generated, the dose and schedule of 0.045 mg/kg given on day 1 every 3 weeks has been selected as the monotherapy recommended Phase 2 dose.
AML Efficacy

Across all dose levels and both schedules, of the patients assessable for efficacy (n=71), 38 (54%) had a reduction in bone marrow blasts and 13 (18%) achieved an objective response, including 2 complete remissions (CR) and 10 with incomplete recovery (CRi) and one morphologic leukemia free state (MLFS) in heavily pretreated patients. The vast majority of these responders (92%) had failed prior intensive therapies, including 3 with prior transplant, 69% had failed 2-3 prior lines of therapy, and 54% had an adverse risk classification.
At the dose and schedule selected as the recommended Phase 2 dose (0.045 mg/kg Q3W), a 40% response rate was seen in relapsed and refractory patients with de novo AML, including 1 CR, 4 CRi, and 1 MLFS (with subsequent conversion to CRi).
BPDCN Efficacy

3 of 9 (33%) evaluable relapsed/refractory BPDCN patients achieved a response after a 1-2 doses of 0.045 mg/kg IMGN632 (1 CR, 1 CRi, and 1 partial remission); all three patients had received prior SL-401 (tagraxofusp-erzs), two had received intense multi-agent chemotherapy, and one had prior stem cell transplant.
PRECLINICAL DATA ON IMGN632 IN COMBINATION WITH AZACITIDINE AND VENETOCLAX
Poster Presentation, Abstract 1375
IMGN632 was evaluated in combination with azacitidine, and as a triplet with azacitidine and venetoclax in AML models, including patient derived xenografts (PDX). The addition of IMGN632 to azacitidine alone or to azacitidine plus venetoclax consistently led to reductions in tumor burden and to improved survival in these murine models. These data support clinical testing of the addition of IMGN632 to standard of care therapy including azacitidine, and azacitidine plus venetoclax in AML patients.

Additional information, including abstracts, can be found at www.hematology.org.

ABOUT IMGN632
IMGN632 is a CD123-targeting ADC in Phase I testing for hematological malignancies, including acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), and acute lymphocytic leukemia (ALL). IMGN632 uses one of ImmunoGen’s novel indolino-benzodiazepine (IGN) payloads, which alkylate DNA without crosslinking. IGNs have been designed to have high potency against AML blasts, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads.

ABOUT ACUTE MYELOID LEUKEMIA (AML)
AML is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems, and anemia. It is estimated that, in the U.S. alone, 21,380 patients will be diagnosed with AML this year and 10,590 patients will die from the disease.

ABOUT BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM (BPDCN)
BPDCN is a rare form of blood cancer that has features of both leukemia and lymphoma, with characteristic skin lesions, lymph node involvement, and frequent spread to the bone marrow. This aggressive cancer requires intense treatment often followed by stem cell transplant. Despite the recent approval of a CD123-targeting therapy, the unmet need remains high in the relapsed/refractory setting.

ABOUT CD123
CD123, the interleukin-3 alpha chain, is expressed on multiple myeloid and lymphoid cancers including AML, BPDCN, ALL, chronic myeloid leukemia, and myeloproliferative neoplasms. With limited expression on normal hematopoietic cells, rapid internalization, and expression on AML leukemia stem cells, CD123 is a validated therapeutic target, with the recent approval of a CD123-targeting therapy for BPDCN.

BJ Bioscience Announces First Patient Dosed in FIH Trial of BJ-001 in Patients with Locally Advanced/Metastatic Solid Tumors

On December 9, 2019 BJ Bioscience Inc. (the ‘company’) reported that the first patient was successfully dosed on December 4, 2019 in the first-in-human (FIH) trial of the company’s BJ-001 program at NEXT ONCOLOGY in San Antonio, Texas (Press release, BJ Bioscience, DEC 9, 2019, View Source [SID1234552188]).

"We were so excited to learn the successful dosing of the first patient for our BJ-001 program. It marked a significant milestone for BJ Bioscience and for the BJ-001 program. With its tumor targeting property, BJ -001 is expected to benefit many cancer patients with integrin overexpression. The successful dosing of the first patient is a small but key step of testing this promising investigational drug," said Joe Zhang, MD. Ph.D., DABT, the co-founder and CEO of BJ Bioscience. "With strong support from our investor, we will soon initiate trials in China to speed up the development of this drug candidate globally."

The ongoing first-in-human study is an open-label, Phase 1a trial in locally advanced/metastatic or relapsed/refractory solid tumors utilizes an accelerated dose escalation design followed by a traditional 3+3 dose escalation algorithm to assess the safety and tolerability of BJ-001, to identify the MTD, and/or and RP2D of BJ-001 as a single agent and in combination with an anti-PD-1 antibody.

"We achieved this milestone with approximately 3 months after we received the ‘green light’ from the FDA. More proudly, we achieved FPI milestone with 3 days after the site was activated. It is exceptional based on my past experience in multinational pharmaceutical companies," commented Grace Yu, MD., VP of Clinical Development at BJ Bioscience. "It is a great example of successful team work. The team had been working diligently for this milestone. Thanks go to our colleagues at Next Oncology as well as the patient. We cannot achieve this milestone without the hard work and collaboration of each of the members."

"As of 08 Dec 2019, the patient has been completed C1D5. No CRS and no other adverse events have been observed." said Dr. Raghad Abdul Karim, Medical Oncologist, Hematologist, Principle Investigator of BJ-001-01-001US study, NEXT Oncology.

About BJ-001

BJ-001 is the first tumor targeting IL-15 fusion protein in the world. It is designed to target cancer cells that overexpress integrins such as αvβ3, αvβ5, and αvβ6 by its tumor targeting motif and to stimulate anti-cancer immunity by its IL-15 motif. Such design has a potent to increase anti-cancer effects and reduce systemic toxicity by localizing IL-15’s effects in tumor microenvironment. Many cancer types such as NSCLC, stomach cancer, and pancreatic cancer have been shown to overexpress integrin.

Corporate Presentation furnished by SpringWorks Therapeutics, Inc.

On December 9, 2019 SpringWorks Therapeutics presented the corporate presentation (Presentation, SpringWorks Therapeutics, DEC 9, 2019, View Source [SID1234552182]).