On December 2, 2018 MEI Pharma, Inc. (NASDAQ: MEIP), a late-stage pharmaceutical company focused on advancing new therapies for cancer, reported that results from an ongoing Phase 1b study support the complementary potential of intermittent and continuous dosing schedules of ME-401, a selective phosphatidylinositol 3-kinase ("PI3K") delta inhibitor, to optimize the clinical risk-benefit ratio in patients with relapsed/refractory follicular lymphoma (Press release, MEI Pharma, DEC 2, 2018, View Source [SID1234531809]). The data demonstrate that ME-401, as both a single agent and in combination with rituximab, continues to be associated with overall high objective response rates. In addition, low rates of Grade 3 immune-related adverse events (irAEs) were observed in patients on the intermittent dosing schedule while maintaining a high level of clinical response. These data are being presented today at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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The data announced today continue to support the rationale for MEI’s planned Phase 2 study that evaluates both a continuous (CS) and intermittent (IS) dosing schedule of ME-401 as a means to enhance the drug candidate’s clinical profile and thus potentially deliver improved benefits to patients. The Phase 2 study is expected to start around year-end and is intended to support MEI’s accelerated approval registration strategy if successful.

Patients in the Phase 1b study received ME-401 as a single agent (dosed on the CS or IS) and in combination with rituximab (dosed on the IS only) to explore treatment options for patients with B-cell malignancies. The IS dosing regimen consists of 60 mg given continuously, once-daily, for the first 2 cycles followed by 60 mg given on days 1-7 of a 28-day cycle and results showed:

As a single agent, 76% objective response rate in patients with relapsed or refractory follicular lymphoma (FL), and 100% in all patients with chronic lymphocytic lymphoma (CLL) and small lymphocytic lymphoma (SLL).
In combination with rituximab, 78% objective response rate in patients with FL.
Median duration of response has not been reached. The lead patient has a duration of response of approximately 20 months and the median follow-up is 9.3 months.
Low rate of irAEs; 4 irAEs were reported in 36 patients administered the IS, with all cases occurring in the first 2 cycles following the switch to IS.
89% of patients switched to IS remain on therapy.
Disease control was maintained in 72% of these patients.
70% of patients who resumed on the continuous daily dosing schedule (CS) recaptured a response after progressing on IS.
The ME-401 ASH (Free ASH Whitepaper) 2018 poster can be accessed on the MEI Pharma website.

"The data presented today are very supportive of our rationale to investigate both a continuous and intermittent dosing regimen as part of our Phase 2 study evaluating ME-401 in follicular lymphoma and may also help advance its complementary potential to deliver improved benefits to patients in combination with other modalities," said Daniel P. Gold, Ph.D., president and chief executive officer of MEI Pharma. "While advances have been made in the treatment of B-cell malignancies, there remains a significant need for innovative therapies across a range of indications and patient populations not addressed by current therapeutic options; we believe the emerging clinical profile of ME-401, as both a single agent or in combination, holds the potential to deliver improved clinical benefit to patients with B-cell diseases."

ME-401 Phase 1b ASH (Free ASH Whitepaper) 2018 Data
ME-401 is being evaluated in an ongoing Phase 1b dose escalation study in patients with relapsed or refractory B-cell malignancies. Through October 2018, 60 patients were enrolled across three groups:

Group 1 included 31 patients with relapsed FL (n = 22) or CLL/SLL (n = 9) who received ME-401 CS at doses ≥60 mg per day in the dose escalation phase of the study. Beginning in December 2017 a total of 17 patients from Group 1 (FL=9, CLL/SLL=8) advanced to the IS after in cycle 4 or later cycles.
Group 2 included 16 patients with relapsed FL (n = 9), diffuse large B-cell lymphoma (n = 5), marginal zone lymphoma (MZL, n = 1), and CLL (n = 1) who received rituximab 375 mg/m2 x 8 doses over 6 months and ME-401 dosed under the IS regimen after receiving ME-401 60 mg daily for the first two cycles.
Group 3 may enroll up to 30 patients with relapsed FL/CLL/SLL in an expansion cohort of ME-401 using the IS regimen after receiving ME-401 60 mg daily for the first two cycles. In this group, 13 patients were enrolled to date with one FL patient reaching the Cycle 6 disease assessment as data cut off.
The median number of prior therapies of patients in the study is two and 50% of patients enrolled were ≥ 3rd line of therapy. Responses are assessed after 2 cycles (58 days) and 6 cycles, and then every 6 cycles. Ninety-two percent of all patients were previously treated with an anti-CD20 antibody.

Objective Response Rates

The objective response rate of patients across all groups with FL is 76% (29/38) and for CLL/SLL is 100% (11/11).
As a single agent, 76% (22/29) objective response rate in patients with FL and 100% (10/10) in patients with CLL and SLL.
In combination with rituximab, 78% (7/9) objective response rate in patients with FL.
Duration of Response

In FL and CLL/SLL patients, the median follow-up is 9.3 months (range, approximately 2.1 to 19.5 months) with no median yet reached.
Across all groups, failure-free survival (i.e. no disease progression on the continuous dosing schedule) in FL and CLL/SLL has not reached a median yet; median follow-up is 6.9 months (range 0.4 to 21.1 months).
72% of patients across all groups on the IS regimen have not experienced disease progression with a median follow-up of 7.9 months (range, 0.8 to 10.5 months).
Of the 10 patients that progressed on the IS regimen, 70% of patients retreated with daily dosing recaptured disease response.
Rates of irAEs

Of the 36 patients who switched to IS, only 11% (4/36) experienced an irAE after the switch. All 4 reported cases of irAEs occurred in the first 2 cycles after the switch to the IS regimen.
About ME-401
ME-401 is an investigational oral phosphatidylinositol 3-kinase ("PI3K") delta inhibitor; PI3K delta is often overexpressed in cancer cells and plays a key role in the proliferation and survival of hematologic cancer cells. ME-401 displays high selectivity for the PI3K delta isoform and has distinct pharmaceutical properties from other PI3K delta inhibitors. It is being clinically evaluated in patients with various B-cell malignancies. MEI is initiating a Phase 2 study to evaluate the efficacy, safety, and tolerability of ME-401 as a single agent in patients with follicular lymphoma after failure of at least two prior systemic therapies including chemotherapy and an anti-CD20 antibody. The Phase 2 study is intended to support an accelerated approval marketing application with the U.S. Food and Drug Administration.

On December 2, 2018 MorphoSys reported its Updated Data from L-MIND Study of MOR208 in combination with Lenalidomide in r/r DLBCL at ASH (Free ASH Whitepaper) 2018 (Press release, MorphoSys, DEC 2, 2018, View Source [SID1234531777])

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MorphoSys AG (FSE: MOR; Prime Standard Segment; MDAX & TecDAX; Nasdaq: MOR) presented data from the ongoing single-arm phase 2 clinical trial known as L-MIND in an oral presentation at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2018 in San Diego, USA. L-MIND is designed to investigate the antibody MOR208 in combination with lenalidomide in patients with relapsed or refractory diffuse large B cell lymphoma (r/r DLBCL) who are not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). MOR208 is an investigational humanized Fc-enhanced monoclonal antibody directed against CD19 and is currently in clinical development in blood cancer indications.

The L-MIND study enrolled patients with r/r DLBCL, who are ineligible for HDC and ASCT, after up to three prior lines of therapy, with at least one prior therapy including an anti-CD20 targeting therapy, such as rituximab. The updated interim data reported today (cut-off date June 5, 2018) included all 81 patients enrolled in the L-MIND trial, with a median observation time of 12 months. Efficacy results in this update are based on assessment by the investigators for all 81 patients. Patients enrolled had a median age of 72 years and had received a median of two prior treatment lines.

The data showed a response in 47 out of 81 patients (overall response rate, or ORR, 58%), with complete responses (CR) in 27 (33%) and partial responses (PR) in 20 (25%) patients. The median progression-free survival (mPFS) was 16.2 months (95% confidence interval (CI) 6.3 months – not reached). Responses were durable with the median duration of response (DoR) not reached (95% CI: NR – NR) and 70% of responding patients were without progression at 12 months (12-month DoR rate: 70%, Kaplan-Meier estimate). A significant proportion of patients (37/81; 46%) were still on study treatment, with 19 having been treated for over 12 months. Median overall survival (OS) was not reached (95% CI: 18.6 months – NR); the 12-month OS rate was 73% (95% CI: 63% – 85%).

Efficacy parameters, such as response rates and median PFS showed comparable results in most patient subgroups of interest, including low/low-intermediate versus intermediate-high/high IPI score, rituximab refractory versus not refractory and primary refractory versus not refractory, amongst others.

No unexpected toxicities were observed for the treatment combination and no infusion-related reactions (IRRs) were reported for MOR208. The most frequent treatment-emergent adverse events (TEAEs) with a toxicity grading of 3 or higher were neutropenia in 35 (43%), thrombocytopenia in 14 (17%), and anemia in 7 (9%) patients each. Treatment-related serious adverse events (SAEs) occurred in 16 (19.8%) patients, the majority of which were infections or neutropenic fever. 41 (50.6%) patients required dose reduction with lenalidomide, 58 patients (72%) could stay on a daily lenalidomide dose of 20 mg or higher.

The results reported today confirm data from earlier interim analyses reported from this trial in March 2018, when 68 patients had been eligible for investigators’ efficacy assessment at the Dec 12, 2017 cut-off date.

"Patients with relapsed or refractory DLBCL who, after having failed initial therapies, are ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT), need more treatment options," commented Dr. Malte Peters, Chief Development Officer of MorphoSys AG. "We are encouraged by our most recent clinical data from the ongoing L-MIND trial. These support our plan to develop MOR208 in combination with lenalidomide, based on our current FDA breakthrough therapy designation, as a potential chemo-free treatment option for this patient population."

Details about the presentation on L-MIND data at ASH (Free ASH Whitepaper) 2018:

Abstract publication number: 227
Session name: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)-Results from Prospective Clinical Trials"
Session date and time: Saturday, December 1, 2018, 4:00pm-5:30pm PST
Presentation time: 5:00pm PST
Room: Marriot Marquis San Diego Marina, Pacific Ballroom 20, San Diego, California.

MorphoSys will hold an investor & analyst event after the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2018 on December 5, 2018, 10:00am EST (3:00pm GMT, 4:00pm CET) in New York. The presentation, a live webcast and a replay of the webcast will be made available at View Source

About DLBCL
Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of malignant lymphoma worldwide and accounts for approximately 30% of all non-Hodgkin lymphomas. Between 30% and 40% of all patients with DLBCL either fail to respond to or show a relapse to initial therapy. Patients who failed frontline therapy and are not eligible to high dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) are reported to have a poor outcome and require more therapeutic options.

About CD19 and MOR208
CD19 is broadly and homogeneously expressed across different B cell malignancies including DLBCL and CLL. CD19 has been reported to enhance B cell receptor (BCR) signaling, which is assumed important for B cell survival, making CD19 a potential target in B cell malignancies.
MOR208 is an investigational humanized Fc-engineered monoclonal antibody directed against CD19. Fc-modification of MOR208 is intended to lead to a significant potentiation of antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), thus aiming to improve a key mechanism of tumor cell killing. MOR208 has been observed in preclinical models to induce direct apoptosis by binding to CD19, which is assumed to be involved in B cell receptor (BCR) signaling.
MorphoSys is clinically investigating MOR208 as a therapeutic option in B cell malignancies in a number of ongoing combination trials. An open-label phase 2 combination trial (L-MIND study) is investigating the safety and efficacy of MOR208 in combination with lenalidomide in patients with relapsed/refractory DLBCL who are not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). Based on interim data from L-MIND, in October 2017 the U.S. FDA granted Breakthrough Therapy Designation for MOR208 plus lenalidomide in this patient population. The pivotal phase 2/3 B-MIND study is designed to investigate MOR208 in combination with the chemotherapeutic agent bendamustine in patients with relapsed/refractory DLBCL who are not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) in comparison to the combination of the anti-CD20 antibody rituximab plus bendamustine. In addition, MOR208 is currently being investigated in patients with relapsed/refractory CLL/SLL after discontinuation of a prior Bruton tyrosine kinase (BTK) inhibitor therapy (e.g. ibrutinib) in combination with idelalisib or venetoclax.

On December 2, 2018 Harpoon Therapeutics, Inc. ("Harpoon"), a clinical-stage immunotherapy company developing a novel class of T cell engagers that harness the power of the body’s immune system to treat patients with cancer and other diseases, reported its preclinical data supporting the development of HPN217, a new compound targeting B cell maturation antigen (BCMA) (Press release, Harpoon Therapeutics, DEC 2, 2018, View Source [SID1234531793]). Generated from Harpoon’s Tri-specific T cell Activating Construct ("TriTAC") platform, HPN217 is engineered to re-direct a patient’s own T cells to kill BCMA-positive cancer cells. HPN217 is Harpoon’s first TriTAC designed for the treatment of hematologic cancers, such as multiple myeloma. Data were presented at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, held December 1-4.

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"We believe the characteristics of HPN217 – including its structure as a single flexible polypeptide, low molecular weight, and in vitro and in vivo stability with half-life extension – offer advantages over conventional bispecific antibodies targeting BCMA," said Che-Leung Law, PhD, Harpoon’s Vice President, Translational Medicine. "Supported by preclinical data showing tumor growth inhibition in models of multiple myeloma and mantle cell lymphoma, HPN217 is expected to enter a Phase 1 clinical trial for multiple myeloma in 2019."

"Recent clinical data has validated the importance of BCMA as a drug target for T cells in the treatment of multiple myeloma," said Gerald McMahon, PhD, President and Chief Executive Officer of Harpoon. "The introduction of our third TriTAC compound demonstrates the ability of our technology platform to generate new product candidates."

The poster entitled "Preclinical and Nonclinical Characterization of HPN217: A Tri-specific T cell Activating Construct (TriTAC) Targeting B Cell Maturation Antigen (BCMA) for the Treatment of Multiple Myeloma" can be found on the Publications page of Harpoon’s website.

Key information presented includes:

Design of HPN217 TriTAC

The design of HPN217 is based on Harpoon’s novel TriTAC platform. It is a single polypeptide consisting of three domains that recognize human BCMA for myeloma cell targeting, serum albumin for half-life extension, and CD3ε for T cell engagement.

Proof-of-concept In Vitro and In Vivo Preclinical Studies

HPN217 demonstrated BCMA- and T cell-dependent antitumor activity in tissue culture and in xenografts modeling multiple myeloma and lymphoma. Effective preclinical antitumor activities could be observed in models with BCMA receptor copy number as low as approximately 2,200 per cell.

Pharmacokinetics Properties and In Vivo Stability in Nonclinical Studies

In animal studies, HPN217 demonstrated a circulating terminal half-life of 70-84 hours. Importantly, HPN217 remained functionally intact after one week in circulation.

About Multiple Myeloma

Multiple myeloma is the second most prevalent blood cancer after Non-Hodgkin’s lymphoma. There are approximately 229,000 people living with myeloma worldwide, with 114,000 new cases diagnosed and 87,000 deaths each year. The American Cancer Society estimates that approximately 30,700 new cases will be diagnosed and approximately 12,770 deaths are expected to occur from multiple myeloma in the United States in 2018. Despite advances in the treatment of multiple myeloma over the past decade, there remains a significant unmet need.

On December 2, 2018 Unum Therapeutics Inc. (NASDAQ: UMRX), reported preliminary results from the ongoing, multicenter Phase 1 ATTCK-20-03 study of ACTR707 in combination with rituximab in patients with relapsed/refractory CD20+ B cell non-Hodgkin lymphoma (r/r NHL) at the American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in San Diego, CA (Press release, Unum Therapeutics, DEC 2, 2018, View Source [SID1234531811]).

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Unum presented updated data from all patients in the first two dose levels of ACTR707 in combination with rituximab. First-in-human dosing was well tolerated, with no dose-limiting toxicities observed and no serious or severe adverse events of cytokine release syndrome (CRS) or neurological events observed in any patients. Three of the six patients treated at dose level 1 achieved a complete response, two of which were ongoing with greater than 6 months follow up, as of the November 1, 2018 cutoff. One of the three patients in dose level 2 also achieved a complete response, which remained ongoing as of the November 1 cutoff. Based on these data, enrollment in dose level 3 is progressing as planned.

"These preliminary results demonstrate ACTR T cell activity with complete responses at both dose levels, dose-dependent ACTR707 expansion, and a well-tolerated safety profile, supporting further dose escalation," said Michael Vasconcelles, Chief Medical Officer of Unum. "We are encouraged by these data and the potential of ACTR707 plus rituximab to have a best-in-class profile relative to CD19-directed CAR-T therapies in this heavily pretreated patient population with aggressive non-Hodgkin lymphoma."

Pharmacodynamic evidence of activity of ACTR707 in combination with rituximab supporting the proof of mechanism includes dose-dependent peak ACTR707 expansion and ACTR707 persistence, detectable > 200 days in the peripheral blood post ACTR707 infusion. Additionally, no impact of ACTR707 on the pharmacokinetics of rituximab has been observed. ACTR707-related serious adverse events were febrile neutropenia in 2 patients and 1 case of pancytopenia.

About the ATTCK-20-03 Trial

ATTCK-20-03 is a Phase I, multi-center, open label, single arm clinical trial evaluating ACTR707 in combination with rituximab in patients with r/r NHL. Eligible patients for enrollment must have, among other criteria, received adequate prior anti-lymphoma therapy, including anti-CD20 monoclonal antibody and chemotherapy, for their CD20+ r/r NHL. Key eligibility criteria include: pre-specified eligible NHL subtypes, including DLBCL, disease progression following immediate prior therapy, adequate organ function and performance status, and measurable disease. The trial design includes a dose escalation phase using an adaptive design, followed by a cohort expansion phase. Primary study objectives are to characterize the safety of ACTR707 in combination with rituximab and to determine the maximum tolerated dose and proposed recommended Phase 2 dose. Secondary study objectives include: assessment of the anti-lymphoma activity of the combination, ACTR707 persistence, rituximab pharmacokinetics, and inflammatory markers and cytokine levels. Following leukapheresis, each patient receives lymphodepletion followed by the first infusion of rituximab and then a single infusion of ACTR707. Rituximab infusions continue on a regular, pre-specified schedule.

About ACTR707
ACTR707 is an investigational drug that is being evaluated in adult patients with CD20+ r/r NHL in combination with rituximab as well as in adult patients with other cancer types in combination with other antibodies. ACTR707 was identified through a comprehensive high-throughput screening effort aimed at identifying receptors with improved functional characteristics across several dimensions. In preclinical testing, ACTR707 demonstrated potent activity against a wide range of hematologic and solid tumor cancers. Given the challenges of the immunosuppressive solid tumor microenvironment, Unum believes that ACTR707’s increased activity may be particularly important in addressing solid tumor cancers. ACTR707 is currently being tested in combination with rituximab in patients with r/r NHL in a Phase I multi-center open label clinical trial, ATTCK-20-03. Testing is expected to be initiated later in 2018 in ATTCK-34-01, a Phase I multi-center open label clinical trial exploring the combination of ACTR707 with trastuzumab in patients with HER2+ advanced cancers.

On December 2, 2018 Syros Pharmaceuticals (NASDAQ: SYRS), a leader in the development of medicines that control the expression of genes, reported initial clinical data from cohorts in its ongoing Phase 2 trial evaluating SY-1425, its first-in-class selective retinoic acid receptor alpha (RARα) agonist, in combination with azacitidine and with daratumumab in genomically defined patients with acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (MDS) (Press release, Syros Pharmaceuticals, DEC 2, 2018, View Source [SID1234531794]). These data are being presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

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"AML and MDS are complex diseases, and we need therapies that can be used in combination to help patients live longer and with a better quality of life," said Rachel J. Cook, M.D., M.S., Assistant Professor of Medicine and Site Director for Acute Leukemia at the Knight Cancer Institute, Oregon Health and Science University and a clinical investigator in the Phase 2 study of SY-1425. "These data provide early clinical evidence that SY-1425 may be a meaningful treatment option for defined subsets of AML and MDS patients that is generally well-tolerated in combination with other therapies. I look forward to continuing to investigate SY-1425 to fully understand its potential to benefit patients."

"These initial combination data from our ongoing Phase 2 trial of SY-1425 are promising," said David A. Roth, M.D., Syros Chief Medical Officer. "SY-1425 in combination with azacitidine showed both a high response rate and rapid onset of clinical responses in AML patients selected with our RARA or IRF8 biomarkers that we have not seen to date in the biomarker-negative cohort. The combination was generally well-tolerated with no evidence of increased toxicities beyond what would be expected with each agent alone, including myelosuppression that can sometimes be seen when combining drugs to treat leukemia. These data speak to the combination potential of SY-1425 as well as to the potential of our platform to identify patients most likely to respond to gene control medicines. We look forward to further characterizing the clinical activity of SY-1425 in combination with azacitidine as we continue to enroll and follow patients in the trial."

SY-1425 in Combination with Azacitidine
The ongoing Phase 2 trial cohort is evaluating the safety and efficacy of SY-1425 in combination with azacitidine, a standard-of-care hypomethylating agent, in RARA or IRF8 biomarker-positive patients with newly diagnosed AML who are not suitable candidates for standard chemotherapy. The trial also includes a cohort evaluating SY-1425 in combination with azacitidine in biomarker-negative newly diagnosed, unfit AML patients, with the aim of supporting the development of a commercial companion diagnostic. Patients in these cohorts were treated with azacitidine administered at standard daily doses of 75 mg/m2 intravenously or subcutaneously for seven days, followed by SY-1425 administered at 6 mg/m2 orally divided in two daily doses for the remainder of the 28-day cycle.

As of Oct. 29, 2018, 11 biomarker-positive and eight biomarker-negative patients had been enrolled in the trial. Of the biomarker-positive patients, 10 were evaluable for safety and eight were also evaluable for clinical responses. Of the biomarker-negative patients, seven were evaluable for safety and six were also evaluable for clinical responses. The median age of the biomarker-positive patients was 76 and the median age of the biomarker-negative patients was 78, with more than half the patients in both cohorts having poor risk cytogenetics. Target enrollment in both the biomarker-positive cohort and the biomarker-negative cohort is 25, and Syros continues to enroll and follow patients.

Initial Safety Data

SY-1425 in combination with azacitidine was generally well-tolerated with no evidence of increased toxicities.
Adverse events (AEs) were consistent with what has been previously seen with SY-1425 or azacitidine as single agents in AML:
Across all grades and causalities, the most commonly reported AEs were decreased appetite (41%), fatigue (35%) and hypertriglyceridemia (35%).
The most commonly reported Grade 3 or higher AEs (all causality) were febrile neutropenia (24%), thrombocytopenia (24%), neutropenia (12%) and fatigue (12%).
Initial Clinical Activity Data

The complete response (CR) and complete response with incomplete blood count recovery (CRi) rate, as defined by Revised International Working Group (IWG) criteria, was 50% in the biomarker-positive cohort.
The overall response rate (ORR), using IWG criteria, was 63%, consisting of:
Three CRs, including one molecular CR.
One CRi.
One morphologic leukemia-free state (MLFS).
Duration of these IWG responses ranged from 29 to 337 days, with four of the five responding patients remaining on treatment as of the data cutoff.
Most of the initial responses were seen at the end of the first treatment cycle.
These data compare favorably to single-agent azacitidine, which shows response rates of 18-29% in newly diagnosed unfit AML patients1 with initial responses generally occurring after four cycles of treatment in most patients who respond2.
In the cohort of biomarker-negative patients, the ORR was 17%, with one of the six response-evaluable patients achieving a cytogenetic CR. While data from this cohort are less mature, the difference in the observed ORR supports the potential predictive value of the RARA and IRF8 biomarkers for identifying patients most likely to respond to SY-1425.
SY-1425 in Combination with Daratumumab
The ongoing Phase 2 trial is characterizing CD38 induction with SY-1425 and evaluating the safety and efficacy of SY-1425 in combination with daratumumab in a pilot cohort of 12 RARA or IRF8 biomarker-positive patients with relapsed or refractory AML or higher-risk MDS. Daratumumab is an anti-CD38 targeted therapy that is approved to treat multiple myeloma. While CD38 is normally expressed at high levels on multiple myeloma cells, AML cells have low CD38 expression. In preclinical studies, SY-1425 induced CD38 expression in AML cells, sensitizing them to treatment with daratumumab. Patients in this cohort were treated with SY-1425 as a single agent administered at 6 mg/m2 orally, divided in two daily doses, for seven days, after which daratumumab was added and administered at 16 mg/kg intravenously weekly for eight doses, then biweekly for eight doses and every four weeks thereafter.

As of Oct. 29, 2018, nine patients had been enrolled in this cohort. All nine were evaluable for safety and CD38 induction, and six were also evaluable for clinical responses. The median age of these patients was 68, with more than half having poor risk cytogenetics. Syros continues to enroll patients to complete the pilot.

Initial Safety Data

SY-1425 in combination with daratumumab was generally well-tolerated with no evidence of increased toxicities.
AEs were consistent with what has been previously seen with single-agent SY-1425 in AML and MDS patients or single-agent daratumumab in multiple myeloma patients:
Across all grades and causalities, the most commonly reported AEs were febrile neutropenia (67%), anemia (44%), nausea (44%), vomiting (44%) and infusion-related reaction (44%).
The most commonly reported Grade 3 or higher AEs (all causality) were febrile neutropenia (67%) and anemia (44%).
Initial CD38 Induction and Clinical Activity Data

Eight of the nine patients had increased CD38 expression in myeloid blast cells, with a median 1.57-fold induction as measured by mean fluorescence intensity (MFI), after seven days of treatment with SY-1425.
CD38 expression increased in only two of these patients to levels exceeding those of a multiple myeloma cell line control:
One had an MLFS response.
The other progressed without a clinical response.
The initial clinical data on both combinations presented at the ASH (Free ASH Whitepaper) meeting is now available on the Publications and Abstracts section of the Syros website at www.syros.com.

Additional details about the Phase 2 trial of SY-1425 can be found using the identifier NCT02807558 at www.clinicaltrials.gov.