On December 6, 2020 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported a patient case study from the Company’s Phase 1 clinical trial of FT596, its universal, off-the-shelf, CD19-targeted chimeric antigen receptor (CAR) natural killer (NK) cell product candidate, at the 62nd Annual Society of Hematology Annual Meeting and Exposition (Press release, Fate Therapeutics, DEC 6, 2020, View Source [SID1234572226]).

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The case study described a heavily pre-treated patient with diffuse large B-cell lymphoma (DLBCL) who achieved a partial response following administration of a single-dose treatment cycle of FT596 as a monotherapy in the first dose cohort of 30 million cells. The patient subsequently received a second single-dose treatment cycle of FT596, which resulted in a deepening response as evidenced by further decrease in both tumor size and metabolic activity. No dose-limiting toxicities, no FT596-related serious adverse events, and no events of any grade of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or graft-versus-host disease were reported by the investigator. The patient had previously received seven prior treatment regimens, including five rituximab-containing regimens as well as autologous stem cell transplantation, and was most recently refractory to an experimental cellular therapy.

"The safety, pharmacokinetics and clinical activity observed following both the first and second single-dose treatment cycles of FT596 are compelling, especially when considering that the administered cell dose was significantly lower than the recommended cell dose of FDA-approved autologous CD19-targeted CAR T-cell therapies and that the heavily pre-treated patient was refractory to last prior therapy," said Dr. Wayne Chu, Senior Vice President, Clinical Development of Fate Therapeutics. "We are excited the CAR component of FT596 has shown clinical activity at this low dose level, and we continue to enroll patients in dose escalation with FT596 as a monotherapy and in combination with rituximab. Our recent Phase 1 clinical data with FT516 in combination with rituximab, which demonstrate the potential of our novel hnCD16 Fc receptor to potentiate ADCC and drive complete responses, support our belief that the multi-antigen targeting functionality of FT596 may offer best-in-class potential for patients with B-cell malignancies."

FT596 is derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three anti-tumor modalities: a proprietary CAR optimized for NK cell biology that targets CD19; a novel high-affinity, non-cleavable CD16 (hnCD16) Fc receptor that enhances antibody-dependent cellular cytotoxicity (ADCC), a potent anti-tumor mechanism by which NK cells recognize, bind and kill antibody-coated cancer cells; and an IL-15 receptor fusion that augments NK cell activity. The open-label, multi-center Phase 1 clinical trial is designed to assess the safety and activity of a single-dose treatment cycle of FT596 in up to four dose cohorts (30 million cells; 90 million cells; 300 million cells and 900 million cells) as a monotherapy and in combination with CD20-targeted monoclonal antibody therapy for the treatment of relapsed / refractory B-cell malignancies. Under the clinical protocol, the Company may seek consent of the U.S. Food and Drug Administration (FDA) for administration of a second single-dose treatment cycle.

Patient History
The patient, a 76 year old woman with refractory DLBCL, had received seven prior lines of therapy, which included five rituximab-containing regimens, autologous stem cell transplantation, and two experimental cellular therapies. Of note, the patient was most recently refractory to an experimental NK cell therapy regimen comprised of fludarabine and cyclophosphamide lympho-conditioning followed by ex vivo expanded, donor-derived NK cells (≥1 billion cells), IL-2, and rituximab. Approximately 3.5 months from last prior therapy, the patient enrolled into the first dose cohort of FT596 as a monotherapy at 30 million cells.

Safety
The patient underwent fludarabine and cyclophosphamide lympho-conditioning and was administered a single dose of FT596 as a monotherapy at 30 million cells (Study Day 1). Following FDA consent for continued treatment based on review of the clinical data from the first FT596 treatment cycle, the patient underwent another round of lympho-conditioning and was administered a second dose of FT596 as a monotherapy at 30 million cells (Study Day 47). No dose-limiting toxicities, and no cases of any grade of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or graft-versus-host disease, were observed. No FT596-related serious adverse events (SAEs) were reported, and the only Grade ≥3 adverse events deemed possibly related to FT596 were neutrophil count decreased, white blood cell count decreased, and lymphocyte count decreased. All other Grade ≥3 adverse events were consistent with lympho-conditioning chemotherapy and prior treatment regimens. No evidence of anti-product T- or B-cell mediated host-versus-product alloreactivity was detected.

Clinical Response & Pharmacokinetics
The patient achieved a partial response as of the Day 29 protocol-defined response assessment (Study Day 29), with a greater than 50% reduction in tumor size and a substantial reduction in metabolic activity as assessed by PET-CT scan per Lugano 2014 criteria. The protocol-defined response assessment following the second FT596 treatment cycle (Study Day 75) showed a deepening response, with an additional 33% reduction in tumor size and further reduction in metabolic activity. The duration of response, which was not aided by further therapeutic intervention, was 3.8 months and is comparable to that of FDA-approved autologous CD19 CAR-T cell therapy among patients who achieve partial response as best overall response (2.1-3.4 months; Yescarta USPI; Kymriah USPI). The pharmacokinetic profile of both FT596 treatment cycles was consistent and indicative of cell expansion, with peak peripheral blood exposure observed on the eighth day following administration of FT596 (1732 and 1150 vector transgene copies per µg of genomic DNA, respectively), which further validates that retreatment with FT596 conferred additional clinical benefit.

Dose escalation in the FT596 Phase 1 study is currently ongoing in the second dose cohort of 90 million cells as monotherapy and in combination with CD20-targeted monoclonal antibody therapy for patients with relapsed / refractory B-cell lymphoma. In addition, for patients with relapsed / refractory chronic lymphocytic leukemia, the Company has initiated enrollment in the first dose cohort of 30 million cells as monotherapy and plans to begin enrollment in combination with obinutuzumab upon dose-limiting toxicity clearance of monotherapy in the first dose cohort.

FT596 is also currently being evaluated in an investigator-initiated Phase 1 clinical trial sponsored by investigators from the Masonic Cancer Center, University of Minnesota for patients with B-cell lymphoma who have undergone autologous hematopoietic stem cell transplant and are considered high risk for early relapse (NCT04555811). Up to three dose cohorts of FT596, beginning at 90 million cells per dose, in combination with CD20-targeted monoclonal antibody will be assessed.

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Company’s platform is uniquely capable of overcoming numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 300 issued patents and 150 pending patent applications.

About FT596
FT596 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three anti-tumor functional modalities: a proprietary chimeric antigen receptor (CAR) optimized for NK cell biology that targets B-cell antigen CD19; a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies; and an IL-15 receptor fusion (IL-15RF) that augments NK cell activity. In preclinical studies of FT596, the Company has demonstrated that dual activation of the CAR19 and hnCD16 targeting receptors enhances cytotoxic activity, indicating that multi-antigen engagement may elicit a deeper and more durable response. Additionally, in a humanized mouse model of lymphoma, FT596 in combination with the anti-CD20 monoclonal antibody rituximab showed enhanced killing of tumor cells in vivo as compared to rituximab alone. FT596 is being investigated in an open-label, multi-center Phase 1 clinical trial for the treatment of relapsed / refractory B-cell lymphoma as a monotherapy and in combination with rituximab, and for the treatment of relapsed / refractory chronic lymphocytic leukemia (CLL) as a monotherapy and in combination with obinutuzumab (NCT04245722).

On December 6, 2020 Arch Oncology, Inc., a clinical-stage immuno-oncology company focused on the discovery and development of anti-CD47 antibody therapies, reported the presentation of new preclinical data on AO-176 at the ASH (Free ASH Whitepaper) Annual Meeting 2020 (Press release, Arch Oncology, DEC 6, 2020, View Source;utm_medium=rss&utm_campaign=arch-oncology-presents-new-preclinical-data-on-highly-differentiated-anti-cd47-antibody-ao-176-at-ash-2020 [SID1234572225]). AO-176 is an anti-CD47 antibody with a potential best-in-class profile that works by blocking the "don’t eat me" signal and also by directly killing tumor cells, with preferential binding to tumor versus normal cells. Currently, AO-176 is being evaluated in Phase 1/2 clinical trials for the treatment of patients with select solid tumors and multiple myeloma, both as monotherapy and in combination with standard therapies.

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"At ASH (Free ASH Whitepaper) this year, we are pleased to highlight the growing body of preclinical data on AO-176, demonstrating a breadth of efficacy data in models of lymphoma, AML, and multiple myeloma," said Daniel Pereira, Ph.D., Chief Scientific Officer of Arch Oncology. "In our multiple myeloma preclinical studies, AO-176 shows potent tumor inhibition and complete durable responses as a monotherapy, as well as in combination with several standard therapies, including proteasome inhibitors, IMIDs, and anti-CD38 antibodies."

Poster Presentations at ASH (Free ASH Whitepaper) Annual Meeting & Exposition 2020

Date: December 5, 2020 7:00 am – 3:30 pm PT
Abstract Title: Pre-clinical Combination of AO-176, a Highly Differentiated Clinical Stage CD47 Antibody, with Either Azacitidine or Venetoclax Significantly Enhances DAMP Induction and Phagocytosis of Acute Myeloid Leukemia

Date: December 6, 2020 7:00 am – 3:30 pm PT
Abstract Title: AO-176, a Highly Differentiated Clinical Stage Anti-CD47 Antibody, Exerts Potent Anti-Tumor Activity in Preclinical Models of Multiple Myeloma as a Single Agent and in Combination With Approved Therapeutics

A copy of these poster presentations will be available at the beginning of each session at View Source

About AO-176

AO-176 is a humanized anti-CD47 IgG2 antibody with a potential best-in-class profile. AO-176 is highly differentiated, with the potential to improve upon the safety and efficacy profile relative to other agents in this class of innate checkpoint inhibitors. AO-176 works by blocking the "don’t eat me" signal, the standard mechanism of anti-CD47 antibodies. Beyond blocking this signal, AO-176 has additional mechanisms, including directly killing tumor cells and inducing DAMPs (Damage Associated Molecular Patterns), resulting in Immunogenic Cell Death. Importantly, AO-176 binds preferentially to tumor cells, instead of to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Publications and presentations on AO-176 can be found at View Source

AO-176 is being evaluated in Phase 1/2 clinical trials for the treatment of patients with select solid tumors and multiple myeloma, both as monotherapy and in combination with standard therapies. In a Phase 1 trial in solid tumors, AO-176 demonstrated encouraging safety and evidence of anti-tumor activity when administered as a single agent. Additional information about these trials may be found at www.clinicaltrials.gov using the trial identification number NCT03834948 (solid tumors) or NCT04445701 (multiple myeloma).

On December 6, 2020 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST) reported that two oral presentations and three posters relating to the Phase 2 MANIFEST and the Phase 3 MANIFEST-2 clinical trials of CPI-0610 in myelofibrosis (MF) were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Constellation Pharmaceuticals, DEC 6, 2020, View Source [SID1234572224]). The preliminary data in these presentations are based on a data cutoff of September 29, 2020, and reflect an analysis of clinical activity in 63 first-line (1L) and 94 second-line (2L) or later patients.

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"We are pleased both with the response rates and consistency of the results we are seeing in MANIFEST," said Jigar Raythatha, president and chief executive officer of Constellation Pharmaceuticals. "In addition, we are excited by results from our translational studies that suggest that CPI-0610 may potentially be a disease modifying therapy that affects all four hallmarks of myelofibrosis. We are pleased to have initiated MANIFEST-2, our global registrational study of CPI-0610, in JAK-inhibitor-naïve MF patients."

Data Highlights

Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients

42 of 63 evaluable patients (67%) achieved a ≥35% reduction in spleen volume (SVR35) at 24 weeks (the primary endpoint for Arm 3). The median spleen volume reduction was 50%
34 of 60 evaluable patients (57%) achieved a ≥50% reduction in Total Symptom Scores (TSS50) at 24 weeks. The median TSS reduction was 59%
Arm 1 (2L or later) – CPI-0610 monotherapy in JAK-inhibitor-experienced or -ineligible patients

7 of 23 (30%) evaluable patients that were not transfusion dependent at baseline (non-TD) achieved SVR35 at 24 weeks, the primary endpoint for cohort 1B. 10 of 21 (48%) evaluable non-TD patients achieved TSS50 at 24 weeks
10 of 20 (50%) evaluable non-TD patients who did not receive transfusions 12 weeks prior to treatment achieved a ≥1.5 g/dL increase in hemoglobin
3 of 14 (21%) evaluable transfusion-dependent (TD) patients converted to transfusion independence (TI), the primary endpoint for cohort 1A
Arm 2 (2L) – CPI-0610 + ruxolitinib in ruxolitinib-experienced patients

6 of 21 (29%) evaluable non-TD patients achieved SVR35 at 24 weeks, the primary endpoint for cohort 2B. 8 of 21 (38%) evaluable non-TD patients achieved TSS50 at 24 weeks
13 of 36 (36%) evaluable TD patients converted to transfusion independence, the primary endpoint for cohort 2A
Translational data

In samples from patients in Arm 3, 16 of 48 evaluable patients (33%) had at least one grade improvement in bone marrow fibrosis and in 88% (14/16) of these patients, improvements occurred within six months of starting treatment. Only 2 of 48 patients had worsening in bone marrow fibrosis
38 of 116 (33%) patients with evaluable samples across all three treatment arms had a one grade or greater improvement in bone marrow fibrosis. In 84% (32/38) of these patients, improvements occurred within six months of treatment. Only 7 of 116 patients had worsening in bone marrow fibrosis
Analysis of evaluable patient samples from MANIFEST suggests that CPI-0610 promotes normalization of megakaryocyte and erythroid differentiation and proliferation, which the Company believes may improve bone marrow function and hemoglobin levels, and may ultimately be disease-modifying in patients
Safety

CPI-0610 was generally well tolerated in MANIFEST, both as monotherapy and in combination with ruxolitinib, and in both JAK-inhibitor-naïve and -ineligible as well as JAK-inhibitor-experienced patients.

Among the most common treatment-emergent adverse events (TEAEs) for CPI-0610 monotherapy in 46 safety-evaluable patients in Arm 1, those that were Grade 3 were thrombocytopenia (15%), anemia (13%), diarrhea (4%), constipation (2%), respiratory tract infection (2%), and decreased weight (2%). Other Grade 3/4 TEAEs (≥ 5%) include hyperuricemia (9%), hyperkalemia (6%) and dyspnea (6%). Nine patients discontinued treatment because of TEAEs.

Among the most common TEAEs in 78 safety-evaluable patients in Arm 2, those that were Grade 3 were thrombocytopenia (23%), anemia (10%), respiratory tract infections (5%), diarrhea (4%), asthenic conditions (4%), and nausea (3%). Grade 4 TEAEs included thrombocytopenia (3%) and anemia (1%). Nine patients discontinued treatment due to TEAEs, including six Grade 5 TEAEs, which were acute kidney injury, traumatic subdural hematoma, brain stem hemorrhage (no concomitant thrombocytopenia), disease progression, congestive heart failure, and transformation to AML.

Among the most common TEAEs in 78 safety-evaluable patients in Arm 3, those that were Grade 3 were anemia (28%) and thrombocytopenia (5%). Grade 4 TEAEs included thrombocytopenia (3%), anemia (1%), and respiratory tract infection (1%). Two patients discontinued treatment due to TEAEs. In addition, there were two Grade 5 TEAEs, each resulting from multi-organ failure due to sepsis.

ASH Oral Presentations

Title: CPI-0610, a Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, in Combination with Ruxolitinib, in JAK-Inhibitor-Naïve Myelofibrosis Patients: Update of MANIFEST Phase 2 Study
Oral Session: 634. Myeloproliferative Syndromes: Clinical: New Therapies and JAKi-based Combinations for Myelofibrosis
Date and Time: December 5, 2020, 11:30 AM EST
Presenter: Dr. John Mascarenhas, Associate Professor of the Icahn School of Medicine at Mount Sinai

Title: CPI-0610, Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, As "Add-on" to Ruxolitinib, in Advanced Myelofibrosis Patients with Suboptimal Response: Update of MANIFEST Phase 2 Study
Oral Session: 634. Myeloproliferative Syndromes: Clinical: New Therapies and JAKi-based Combinations for Myelofibrosis
Date and Time: December 5, 2020, 11:45 AM EST
Presenter: Dr. Srdan Verstovsek, Medical Oncologist, MD Anderson Cancer Center

ASH Poster Presentations

Title: CPI-0610, a Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, As Monotherapy in Advanced Myelofibrosis Patients Refractory / Intolerant to JAK Inhibitor: Update from Phase 2 MANIFEST Study
Session: 634. Myeloproliferative Syndromes: Clinical: Poster II
Date and Time: Sunday, December 6, 2020, 10:00 AM-6:30 PM EST
Presenter: Dr. Moshe Talpaz, Professor of Leukemia Research and Professor of Internal Medicine, University of Michigan Medical School

Title: MANIFEST-2, a Global, Phase 3, Randomized, Double-Blind, Active-Control Study of CPI-0610 and Ruxolitinib vs. Placebo and Ruxolitinib in JAK-Inhibitor-Naïve Myelofibrosis Patients
Session: 634. Myeloproliferative Syndromes: Clinical: Poster III
Date and Time: Monday, December 7, 2020, 10:00 AM-6:30 PM EST
Presenter: Dr. John Mascarenhas, Associate Professor of the Icahn School of Medicine at Mount Sinai

Title: The BET Inhibitor, CPI-0610, Promotes Myeloid Differentiation in Myelofibrosis Patient Bone Marrow and Peripheral CD34+ Hematopoietic Stem Cells
Session: 634. Myeloproliferative Syndromes: Clinical: Poster III
Date and Time: Monday, December 7, 2020, 10:00 AM-6:30 PM EST
Presenter: Dr. Mohamed Salama, Professor of Pathology and Laboratory Medicine, Mayo Clinic School of Medicine and Chief Medical Officer at Mayo Clinic Laboratories

Title: LSD1 Inhibitor CPI-482 Shows Efficacy and Prolongs Survival in Mouse Models of AML and post-MPN AML in the context of constitutive JAK-STAT pathway activation
Session: 635. Myeloproliferative Syndromes: Basic Science: Poster III
Date and Time: Monday, December 7, 2020, 10:00 AM-6:30 PM EST
Presenter: Dr. Raajit Rampal, Clinical Director of Leukemia Service at Memorial Sloan Kettering Cancer Center

Conference Call

Constellation will host a virtual analyst/investor event and conference call on December 7, 2020 at 8:00 AM EDT to discuss the data relating to the MANIFEST clinical trial for CPI-0610 being presented at the ASH (Free ASH Whitepaper) meeting. The agenda of the event will include:

An overview of MF and the potential impact of Constellation’s BET inhibitor, CPI-0610, in treating MF
A review of the clinical and translational data from MANIFEST presented at ASH (Free ASH Whitepaper)
A physician panel discussion and question-and-answer session with Dr. John Mascarenhas, Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai – New York and Dr. Serge Verstovsek, Professor of Medicine at University of Texas MD Anderson Cancer Center
The event will be webcast live and can be accessed on the Investor Relations section of Constellation’s website at View Source To participate in the live question-and-answer session, please dial (877) 473-2077 (domestic) or (661) 378-9662 (international) and refer to conference ID 7164095.

About MANIFEST

MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Constellation is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume reduction from baseline (SVR35) after 24 weeks of treatment. Constellation is also evaluating CPI-0610, either as a monotherapy in patients who are resistant to, intolerant of, or ineligible for ruxolitinib and no longer on the drug (Arm 1), or as add-on therapy in combination with ruxolitinib in patients with a sub-optimal response to ruxolitinib or MF progression (Arm 2). Patients in Arms 1 and 2 are being stratified based on TD status. The primary endpoint for the patients in cohorts 1A and 2A, who were TD at baseline, is conversion to TI for 12 consecutive weeks. The primary endpoint for the patients in cohorts 1B and 2B, who were not TD at baseline, is the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment.

About MANIFEST-2

MANIFEST-2 is a global, double-blind, randomized Phase 3 clinical study with CPI-0610 in combination with ruxolitinib versus placebo plus ruxolitinib in JAK-inhibitor-naïve patients with primary myelofibrosis or post-ET or post-PV myelofibrosis who have splenomegaly and symptoms requiring therapy. It is designed to enroll approximately 310 patients, randomized 1:1 to the CPI-0610 + ruxolitinib arm or the placebo + ruxolitinib arm. The primary endpoint of the study is a ≥35% reduction in spleen volume (SVR35) from baseline at 24 weeks. A key secondary endpoint of the study is 50% or greater improvement in Total Symptom Score (TSS50) from baseline at 24 weeks. Other endpoints include bone marrow fibrosis grade improvements, duration of transfusion independence, rate of red-blood-cell transfusion for the first 24 weeks, and hemoglobin response.

On December 5, 2020 Sysmex Inostics, Inc., a global leader and pioneer in blood-based, high-sensitivity molecular testing for oncology, reported the poster "Ultrasensitive Measurable Residual Disease (MRD) Detection in Acute Myeloid Leukemia (AML) Using a Targeted Next Generation Sequencing (NGS) Panel" at the 62nd Annual American Society of Hematology (ASH) (Free ASH Whitepaper) Virtual Meeting on Saturday, December 5th (Press release, Sysmex Inostics, DEC 5, 2020, View Source [SID1234572506]). Viewing time is between 7:00 AM and 3:30 PM (Pacific Standard Time)."

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AML is one of the deadliest blood cancers that takes over 10,000 lives in the U.S. each year. If cancer relapses after treatment, the prognosis is typically poor. Therefore, after initial treatment, patients are tested for MRD as a prognostic indicator of therapeutic effectiveness and relapse risk.

Groundbreaking FDA-approved AML therapeutics, such as ivosidenib, have been developed to target IDH1 mutations, which are present in about 5-10% of AML patients and can increase risk of relapse. Both newly diagnosed and relapsed/refractory AML patients with mutant IDH1 can benefit from IDH-directed therapy. In several clinical trials, the Sysmex Inostics OncoBEAM enhanced digital PCR technology has been used to monitor the levels of IDH mutations present in AML patients receiving targeted therapies. OncoBEAM technology is widely considered a gold standard for high sensitivity molecular testing and continues to be one of the most sensitive digital PCR approaches, capable of detecting mutations reliably at 0.02% mutant allele frequency (MAF).

Current NGS pan-heme panels lack sufficient sensitivity for reliable detection of molecular MRD, as their limits of detection are between 1-5% mutant allele frequency. Sysmex Safe-SeqS technology (SafeSEQ) dramatically expands the breadth of mutation detection for targets with established and emerging clinical validity for AML MRD while delivering comparable sensitivity to OncoBEAM. This highly sensitive, error-corrected NGS-based method can reliably detect molecular MRD present at levels as low as five mutant molecules, which is similar to the limit of detection observed across other SafeSEQ platform configurations and corresponds to 0.025% MAF for 20,000 genomic copies (66 ng of DNA) input.

In addition to demonstrating robust analytical performance, 100% overall agreement was observed between SafeSEQ and OncoBEAM for the detection of IDH1 mutations in clinical samples from AML patients. Furthermore, in almost all (94%) patients tested, at least one additional mutation outside of IDH1 was detected by the SafeSEQ AML MRD assay, which is consistent with previous observations that IDH mutations can co-occur with drivers in other genes such as NPM1 and may provide additive value for MRD detection.

"In order to deliver a powerful clinical tool for molecular MRD detection for AML patients, we developed the SafeSEQ AML MRD test to provide additional information across the most highly relevant genomic regions, with sensitivity comparable to the focused OncoBEAM method," said Matt Ryder, Director of Translational Science at Sysmex Inostics. "By offering reliable detection of molecular MRD with 50 to 100 times greater sensitivity versus ‘pan-heme’ NGS tests, the Plasma-SeqSensei AML MRD test will help accelerate clinical development of novel therapeutics and, ultimately, provide oncologists with more reliable information on which to base important decisions for their AML patients."

Poster number 1078, "Ultrasensitive Measurable Residual Disease (MRD) Detection in Acute Myeloid Leukemia (AML) Using a Targeted Next Generation Sequencing (NGS) Panel" presented by Hillary Sloane, Associate Director of Medical & Scientific Affairs at Sysmex Inostics, will be available Saturday, December 5th from 7:00 AM to 3:30 PM (Pacific Standard Time) at the 62nd ASH (Free ASH Whitepaper) Annual Meeting during the Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis poster session number 617.

On December 5, 2020 Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) therapies for cancer, reported positive initial results from the Phase 1 UNIVERSAL study of ALLO-715 in relapsed/refractory multiple myeloma (MM) (Press release, Allogene, DEC 5, 2020, View Source [SID1234572472]). Data were presented at an oral session of the American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting. This study utilizes ALLO-647, Allogene’s anti-CD52 monoclonal antibody (mAb), as a part of its differentiated lymphodepletion regimen.

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"We are excited to demonstrate for the first time that an allogeneic CAR T therapy directed at BCMA can achieve deep clinical responses. We believe these initial results support that we are on the right track to bring the benefits of an off-the-shelf therapy to patients with refractory multiple myeloma," said David Chang, M.D., Ph.D., President, Chief Executive Officer and Co-Founder of Allogene. "We look forward to optimizing multiple aspects of this therapy in the ongoing UNIVERSAL trial."

"These data highlight the potential for an off-the-shelf CAR T therapy to treat patients within a matter of days, which eliminates the need for bridging therapy, a significant benefit in this refractory myeloma population," said Sham Mailankody, MBBS, Assistant Attending Physician, Memorial Sloan Kettering Cancer Center in New York, New York. "I am encouraged by the initial data from this trial, including the feasibility, safety and the ability of ALLO-715 to produce MRD negative responses."

As of the October 30, 2020 data cutoff, 35 patients were enrolled with 31 patients evaluable for safety and 26 patients evaluable for efficacy. Patients were refractory to their last line of myeloma therapy, had a median of five prior lines of therapy, and 94% were penta-exposed. Four patients became ineligible for treatment due to rapidly progressing disease. The median time from enrollment to the start of therapy was five days.

In the initial dose escalation phase of the UNIVERSAL trial, patients received lymphodepletion (LD) followed by ALLO-715 at one of three dose levels (DL1 = 40M cells, DL2 = 160M cells, DL3 = 320M cells) in a 3+3 dose escalation design. DL4 (480M cells) was added in a subsequent cohort. Two LD regimens were evaluated, with the trial enrollment primarily focused on the FCA lymphodepletion regimen:

FCA: Fludarabine 90 mg/m2, Cyclophosphamide 900 mg/m2, and ALLO-647 from 39 to 90mg divided over three days; and
CA: Cyclophosphamide 900 mg/m2 and ALLO-647 39mg divided over three days.
Higher CAR T cell doses were associated with an increased response rate and greater AlloCAR T cell expansion. In the DL3 cohort (320M CAR T+ cells), the overall response rate (ORR) was 60% with 40% of patients achieving a very good partial response (VGPR) or better (VGPR+). VGPR+ is defined as a stringent complete response (sCR), complete response (CR) or VGPR. Across all cohorts and lymphodepletion regimens, six patients achieved VGPR+, five of whom were in the FCA lymphodepletion regimen. Minimal residual disease (MRD) assessment was completed in five of the six patients with a VGPR+ response and all achieved an MRD negative status.

As of the data cutoff, the overall median follow-up for efficacy was 3.2 months and six out of the nine patients treated with DL3 or DL4 with a response remain in response. The longest response was ongoing at six months from the DL3 cohort with FCA lymphodepletion.

Cell Dose
and LD
regimen
FCA CA
DL1
40 x 106
CAR+ cells DL2
160 x 106
CAR+ cells DL3
320 x 106
CAR+ cells DL4
480 x 106
CAR+ cells DL2
160 x 106
CAR+ cells DL3
320 x 106
CAR+ cells
Low
ALLO-647
(N=3) Low
ALLO-647
(N=4) Low
ALLO-647
(N=6) High
ALLO-647
(N=4) ALL
ALLO-647
(N=10) Low
ALLO-647
(N=3) Low
ALLO-647
(N=3) Low
ALLO-647
(N=3)
ORR,
n (%) - 2 (50%) 3 (50%) 3 (75%) 6 (60%) 1 (33%) - 2 (67%)
VGPR+ Rate,
n (%) - 1 (25%) 3 (50%) 1 (25%) 4 (40%) - - 1 (33%)
Of the 31 patients evaluable for safety, there was no graft-vs-host disease (GvHD) or Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) observed. Grade 1 and Grade 2 cytokine release syndrome (CRS) was reported in 14 patients (45%) and was manageable with standard therapies. Infection events ≥ Grade 3 in the trial was similar to what has been reported in other advanced MM studies. Adverse events ≥ Grade 3 reported as serious adverse events occurred in 19% of patients. As previously reported, a single Grade 5 event related to progressive myeloma and conditioning regimen occurred in the CA cohort.

Adverse Events of Interest Grade 1
N (%) Grade 2
N (%) Grade 3
N (%) Grade 4
N (%) Grade 5
N (%) All Grades
N (%)
Cytokine Release Syndrome 5 (16%) 9 (29%) - - - 14 (45%)
ICANS - - - - - -
Graft-versus-Host Disease - - - - - -
Infection 2 (7%) 6 (19%) 4 (13%) - 1 (3%) 13 (42%)
Infusion Reaction to ALLO-647 4 (13%) 3 (10%) - - - 7 (23%)
As part of the Company’s three-pronged anti-BCMA strategy, the Phase 1 UNIVERSAL study continues to enroll patients at higher doses of ALLO-715 and ALLO-647 in an effort to optimize the therapy. The UNIVERSAL study is expected to begin enrolling patients in the first half of 2021 to evaluate ALLO-715 in combination with SpringWorks Therapeutics’ investigational gamma secretase inhibitor, nirogacestat. An investigational new drug application (IND) is expected to be submitted in the first half of 2021 for the Company’s first TurboCAR candidate, ALLO-605, an investigational BCMA-directed AlloCAR T therapy for MM. TurboCAR technology allows cytokine activation signaling to be engineered selectively into CAR T cells and has shown the ability to improve the potency and persistence of allogeneic cells in preclinical models.

Webinar
Allogene will be hosting a webinar to discuss the data from UNIVERSAL on December 5 at 11:00 a.m. PT/2:00 p.m. ET. Please register for the webinar on the Company’s website at www.allogene.com under the Investors tab in the News and Events section (View Source) or by clicking the following link directly.

The webinar will also be available in replay and the materials presented will be posted on the Allogene website prior to the start of the event.