On December 07, 2015 MorphoSys AG (FSE: MOR; Prime Standard Segment, TecDAX; OTC: MPSYY) reported that it has published safety and efficacy data on its proprietary drug candidate MOR202, a fully human HuCAL antibody targeting CD38, a highly expressed and validated target in multiple myeloma (MM) (Press release, MorphoSys, DEC 6, 2015, View Source [SID:1234508443]). The data are from a phase 1/2a clinical study in 52 heavily pretreated patients with relapsed/refractory multiple myeloma. The data, which were presented on Sunday, December 6, 2015, at the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (ASH) (Free ASH Whitepaper), show that MOR202 was safe and well tolerated with a 2-hour infusion time. The incidence of infusion-related reactions (IRR) was very low and mainly limited to the first infusion. In this heavily pre-treated patient population, MOR202 demonstrated encouraging responses with a best-in-class tolerability profile.

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"We are very pleased with the updated clinical results for MOR202. The clinically relevant dose regimens show encouraging clinical efficacy combined with a very good safety profile," commented Dr. Arndt Schottelius, Chief Development Officer of MorphoSys AG. "The clinical study will continue as planned, focusing on combination cohorts, as we see the highest potential for MOR202 in combination therapy."

The ongoing phase 1/2a, open-label, multi-center, dose-escalation study is being conducted in several centers in Germany and Austria. The study is evaluating the safety and preliminary efficacy of MOR202 as monotherapy and in combination with the immunomodulatory drugs (IMiDs) pomalidomide (POM) and lenalidomide (LEN) plus dexamethasone (Dex) in patients with relapsed/refractory multiple myeloma. The primary endpoints of the trial are the safety, tolerability and recommended dose of MOR202 alone and in combination with the IMiDs. Secondary outcome measures are pharmacokinetics and preliminary efficacy based on overall response rate, duration of response, time-to-progression, and progression-free survival.

The data presented at ASH (Free ASH Whitepaper) show that MOR202 can be safely administered as a 2-hour infusion and is well tolerated. Infusion-related reactions occurred in only 1 patient (6%) in the cohorts treated with the clinically relevant dose regimens. Patients received a median of 4 prior therapies. The maximum tolerated dose (MTD) has not been reached. In the monotherapy group, comprising patients treated with the clinically relevant dose regimens, 3 out of 9 patients (33%) achieved an objective response rate, with the other 6 patients showing stable disease. In the early combination cohorts at 8 mg/kg MOR202 with IMiDs (n=6), 1 very good partial response (VGPR; to be confirmed in next response assessment), 2 partial responses (PR) and 1 minimal response (MR) were reported. In upcoming cohorts, patients will receive 16 mg/kg MOR202 in combination with pomalidomide (POM) and lenalidomide (LEN) plus dexamethasone. In addition, confirmatory cohorts are planned to validate the recommended dose of MOR202 as monotherapy and in combination with POM/Dex and LEN/Dex.

MorphoSys also presented promising preclinical data demonstrating synergy of MOR202 in combination with different compounds representative of drug classes commonly used in the treatment of multiple myeloma. Another set of pre-clinical data focused on MOR202’s ability to kill targeted cells via ADCC. While MOR202 showed a level of killing of multiple myeloma cells equivalent to that of surrogates of daratumumab and isatuximab, it exhibited significantly reduced killing of NK cells. These results suggest that MOR202 may show a more durable clinical response than other compounds of its class, by sparing the NK cells needed for ADCC.

MorphoSys will hold today, December 7, 2015, at 8:00pm EST (December 8, 2015: 1:00am GMT, 2:00am MEZ) an Investor & Analyst Event at the 2015 ASH (Free ASH Whitepaper) Annual Meeting. Two KOLs will present the new clinical data for MOR208 and MOR202.

On December 6, 2015 bluebird bio, Inc. (NASDAQ:BLUE), a clinical-stage company committed to developing potentially transformative gene therapies for severe genetic diseases and T cell-based immunotherapies for cancer, reported that pre-clinical data from its anti-BCMA oncology program were presented by bluebird bio scientists at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, bluebird bio, DEC 6, 2015, View Source;p=RssLanding&cat=news&id=2120416 [SID:1234508424]).

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"We believe the unique science and translational gene therapy platforms we have built differentiate bluebird bio in the oncology field and have the potential to yield important new therapies for patients living with cancer. Our three oncology posters at ASH (Free ASH Whitepaper) this year, covering critical basic research, translational and manufacturing aspects of our T cell oncology pipeline, demonstrate the strength of our T cell immunotherapy translational science," said Rob Ross, M.D., head of oncology, bluebird bio. "We are also excited to see the first anti-BCMA clinical data from Dr. Jim Kochenderfer of the National Cancer Institute, which was highlighted in yesterday’s press release from ASH (Free ASH Whitepaper). We believe these data provide excellent proof of concept for bb2121 and are pleased that Jim will serve as one of the principal investigators for our Phase 1 study of bb2121."

Abstract #1893: Manufacturing an Enhanced CAR T Cell Product by Inhibition of the PI3K/Akt Pathway During T Cell Expansion Results in Improved In Vivo Efficacy of Anti-BCMA CAR T Cells

Overview and results, presented by Molly Perkins, D.Phil., bluebird bio, include:

bluebird bio explored the potential for culture modifications to improve the therapeutic potential of CAR T cells without adding complexity to manufacturing. The company tested this hypothesis using CAR T cells specific to B cell maturation antigen (BCMA) manufactured using standard IL-2 culture with an inhibitor of PI3K added to the media, or with IL-7 and IL-15, in place of IL-2.
In an in vivo aggressive lymphoma model, mice treated with anti-BCMA CAR T cells cultured only with IL-2 experienced no effect on tumor growth and succumbed to the tumors within two weeks after treatment; anti-BCMA CAR T cells grown in IL-7 and IL-15 also did not affect tumor growth. In contrast, mice treated with anti-BCMA CAR T cells cultured with IL-2 and an inhibitor of PI3K experienced complete and long-term tumor regression.

In an in vivo multiple myeloma model, mice received a single administration of anti-BCMA CAR T cells cultured under various conditions; all treatment groups demonstrated tumor regression regardless of culture conditions. In a model of tumor relapse, two weeks after tumor clearance, surviving mice were re-challenged with the same multiple myeloma tumors on the opposite flank; only animals that had been treated with anti-BCMA CAR T cells cultured with the PI3K inhibitor were able to resist subsequent tumor challenge.

These data suggest that inhibition of PI3K during ex vivo expansion may generate a superior anti-BCMA CAR T cell product for clinical use; this approach could potentially apply to the manufacture of CAR T cell therapies against other oncology targets.
Abstract #3094: A Novel and Highly Potent CAR T Cell Drug Product for Treatment of BCMA-Expressing Hematological Malignancies

Overview and results, presented by Alena Chekmasova, Ph.D., bluebird bio, include:

bluebird bio has developed a CAR targeting BCMA (bb2121) that consists of an extracellular single chain variable fragment scFv antigen recognition domain derived from antibodies to BCMA linked to CD137 (4-1BB) co-stimulatory and CD3zeta chain signaling domains.

Based on receptor density quantification, bb2121 can recognize tumor cells expressing less than 1,000 BCMA molecules per cell.
In a preclinical BCMA+ multiple myeloma xenograft model, a single IV administration of bb2121 anti-BCMA CAR T cells resulted in rapid and sustained elimination of the tumors with 100 percent survival, while a month-long course of anti-myeloma therapy Velcade (bortezomib) only delayed tumor growth.

Using flow cytometry and immunohistochemistry, bb2121 T cells were shown to rapidly target and infiltrate tumors, and T cell expansion was correlated with tumor regression.

bb2121 anti-BCMA CAR T cells also induced xenograft regression and enhanced survival in a preclinical model of advanced Burkitt’s lymphoma.

Taken together, these studies support the potential clinical application of bb2121 for the treatment of patients with tumors expressing BCMA.

Abstract #3243: Characterization of Lentiviral Vector Derived Anti-BCMA CAR T Cells Reveals Key Parameters for Robust Manufacturing of Cell-Based Gene Therapies for Multiple Myeloma

Overview and results, presented by Graham W.J. Lilley, M.Sc., bluebird bio, include:

Successful personalized medicine will require robust and reproducible drug product manufacturing. A series of experiments were conducted to determine whether variations in anti-BCMA CAR surface expression resulted in changes in the activity of CAR T cells.
T cells transduced with varying amounts of virus to yield different amounts of CAR surface expression were diluted with donor-matched untransduced cells to achieve a uniform population of T cells containing 26 ± 4 percent anti-BCMA CAR T cells. When exposed to tumor, these CAR T cell populations exhibited no difference in cytotoxicity against BCMA-expressing cells.

All T cell productions easily achieved a level of anti-BCMA CAR expression that resulted in potent anti-BCMA activity, thus potency of the final drug product was shown to be independent of total anti-BCMA CAR expression on the cell surface.

These data show that the bluebird bio T cell manufacturing process has the potential to overcome significant challenges associated with personalized medicine by reducing the effects of variability while maintaining potency in autologous cellular drug product manufacturing.

On December 07, 2015 MorphoSys AG (FSE: MOR; Prime Standard Segment, TecDAX; OTC: MPSYY) reported clinical data on its proprietary drug candidate MOR208 (Press release, MorphoSys, DEC 6, 2015, View Source [SID:1234508444]). MOR208 is a potent anti-CD19 antibody with a proprietary modification to the Fc portion that is being developed to treat B cell malignancies. The data, which were presented at the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, are from a phase 2a monotherapy study of patients with different subtypes of relapsed or refractory Non-Hodgkin’s Lymphoma (NHL) and another phase 2 study where MOR208 is tested in chronic lymphocytic leukemia (CLL) in combination with lenalidomide. Clinical trials of the combination of MOR208 with other anti-lymphoma therapies (e.g. lenalidomide and bendamustine) will commence shortly.

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"The MOR208 data presented at ASH (Free ASH Whitepaper) provide further confirmation for the potential of MOR208 to become an important treatment option in a field with significant unmet need," commented Dr. Arndt Schottelius, Chief Development Officer of MorphoSys AG. "Encouraging single-agent activity together with a long duration of response as a single agent in patients with relapsed/refractory NHL bodes well for additional combination trials in DLBCL and CLL."

The open-label, phase 2a, multicenter study was designed to assess the activity and safety of single-agent MOR208 in patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and other indolent NHL (iNHL), who had received at least one prior rituximab-containing therapy. Patients were initially treated with a total of eight weekly doses of 12 mg/kg MOR208. Those with at least stable disease stayed on MOR208 treatment for an additional four weeks. After completion of these twelve weekly doses of treatment, those patients who demonstrated at least a partial response received maintenance therapy until disease progression or unacceptable toxicity.

The data for the NHL phase 2a monotherapy study presented at ASH (Free ASH Whitepaper) 2015 summarize efficacy and safety results for 92 heavily pre-treated patients. The clinical data show that MOR208 is well tolerated with a low level of infusion reactions and demonstrates encouraging single-agent activity. The overall response rate was 28% across all four subtypes of NHL and reached 36% in the DLBCL subgroup (both based on evaluable patients). At the time of the analysis, several responders – 9 out of 21 – had an ongoing response to the single agent treatment. Median progression-free survival for all subtypes of NHL tested in the study amounted to 6 months. The longest response duration observed so far exceeded 20 months in both DLBCL and FL.

A second presentation, from investigators at The Ohio State University, reported on an investigator-initiated trial (IIT) of combinations of MOR208 with lenalidomide in relapsed/refractory or treatment-naive CLL patients. Patient accrual in both cohorts is ongoing; so far 16 patients have been enrolled and 11 patients have been evaluated. The combination of MOR208 with lenalidomide has been well tolerated. Three partial responses and two stable diseases were observed in the relapsed/refractory cohort and four partial responses in the treatment-naïve cohort so far. Responses have generally deepened over time, with five patients completing 12 cycles of therapy. This study has recently been amended to include patients with Richter’s transformation and to add MOR208 to ibrutinib in patients undergoing molecular relapse.

"There is a high unmet medical need for CLL patients, especially following discontinuation after ibrutinib therapy," said Dr. Jennifer Woyach, Assistant Professor of Internal Medicine at Ohio State University. "We just recently added additional cohorts to our ongoing CLL study to evaluate MOR208 in combination with ibrutinib as we see MOR208 as a promising combination partner in this setting."

MorphoSys will hold today, December 7, 2015, at 8:00pm EST (December 8, 2015: 1:00am GMT, 2:00am MEZ) an Investor & Analyst Event at the 2015 ASH (Free ASH Whitepaper) Annual Meeting. Two KOLs will present the new clinical data for MOR208 and MOR202.

A replay and the presentation will be made available at View Source

Live-Webcast: http://morphosys.equisolvewebcast.com/analyst-event-12-7-15

The ASH (Free ASH Whitepaper) presentations can be downloaded from the Company’s website:

Poster #1528
Jurczak et al: Phase 2a Study of Single-Agent MOR208 in Patients with Relapsed or Refractory B-cell Non-Hodgkin’s Lymphoma

Poster #2953
Woyach et al: A Phase II Study of the Fc Engineered CD19 Antibody MOR208 in Combination with Lenalidomide for Patients with Chronic Lymphocytic Leukemia (CLL)

On December 6, 2015 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported new, positive data from the Phase II M13-982 study of venetoclax, an investigational medicine being developed in partnership with AbbVie (Press release, Genentech, DEC 6, 2015, View Source [SID:1234508544]). Results of the study showed a clinically meaningful reduction in the number of cancer cells (overall response rate, OR) in 79.4 percent of people with previously treated (relapsed or refractory) chronic lymphocytic leukemia (CLL) with 17p deletion. No unexpected safety signals were reported for venetoclax.

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"The high response rates, including complete responses and duration of response, demonstrate the potential of venetoclax to help people with this hard-to-treat type of leukemia," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "This is a patient population that has very few treatment options, and we are working with AbbVie to bring this new option to people as quickly as possible."

These pivotal data from the Phase II M13-982 study were featured in the official press program of the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando on Sunday, December 6, and will be presented during the Late-Breaking Abstracts Session on Tuesday, December 8, at 7:30 A.M. EST by Dr. Stephan Stilgenbauer, University of Ulm, Germany (Abstract #LBA6). The results show:

· The study met its primary endpoint, with an ORR of 79.4 percent with venetoclax, as assessed by an independent review committee (IRC). In addition, 7.5 percent of people achieved a complete response with or without complete recovery (complete response without normal blood counts) in the bone marrow (CR/CRi).

· Forty-five people had an assessment for minimal residual disease (MRD) in the blood. Notably 18 people (17 percent of the total, 21 percent of responders) achieved MRD-negativity, meaning no cancer could be detected using a specific test. Ten of these 18 people also had bone marrow assessments and six were MRD-negative.

· At one year, 84.7 percent of all responses and 94.4 percent of MRD-negative responses were maintained. The one-year progression-free survival (PFS) and overall survival (OS) rates were 72 percent and 86.7 percent, respectively.

· No unexpected safety signals were reported. The most common Grade 3-4 adverse events were low white blood cell count (40 percent), low red blood cell count (18 percent), and low platelet count (15 percent). Grade 3 or higher infection occurred in 20 percent of people. Laboratory tumor lysis syndrome was reported in five people; none had clinical consequences.

Data for venetoclax as a monotherapy or in combinations with other medicines across multiple blood cancers, including CLL, non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM) and acute myeloid leukemia (AML), will also be presented during the ASH (Free ASH Whitepaper) Annual Meeting.

Separately, positive results in people with CLL included in the Phase I M12-175 study of venetoclax were published online today in the New England Journal of Medicine. The findings support the potential of venetoclax monotherapy for people with relapsed or refractory CLL, including those with 17p deletion.

AbbVie has submitted a New Drug Application (NDA) for venetoclax to the U.S. Food and Drug Administration (FDA) under breakthrough therapy designation (BTD), based in part on results of the M13-982 study. Venetoclax received BTD from the FDA earlier this year for the treatment of people with relapsed or refractory CLL harboring the 17p deletion. AbbVie has also submitted a marketing authorization application (MAA) to the European Medicines Agency (EMA). Submissions to other regulatory authorities around the world are planned in 2016.

About Study M13-982

M13-982 (NCT01889186) is a Phase II, open-label, single arm, multicenter study evaluating the efficacy and safety of venetoclax in patients with relapsed, refractory or previously untreated chronic lymphocytic leukemia (CLL) harboring the 17p deletion. The main study cohort included 107 patients with relapsed or refractory disease (all patients except for one had 17p deletion) and approximately 50 patients with relapsed, refractory or previously untreated disease have been enrolled in the safety expansion cohort. The primary endpoint of the study is overall response rate (ORR) as determined by an independent review committee (IRC), and secondary endpoints include complete response (CR), partial response (PR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). The level of minimal residual disease (MRD) in peripheral blood and/or bone marrow was assessed in a subset of patients.

About Study M12-175

M12-175 (NCT01328626) is a Phase I, open-label, multicenter study of venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) or non-Hodgkin’s lymphoma (NHL). The study involved an initial dose-escalation phase, followed by an expanded safety phase. The study enrolled approximately 116 patients with relapsed or refractory CLL or SLL, and approximately 95 patients with relapsed or refractory NHL. The primary endpoints of the study included safety, maximum tolerated dose (MTD) and recommended Phase II dose (RPTD). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), overall survival (OS) and duration of response (DOR). The level of minimal residual disease (MRD) in peripheral blood and/or bone marrow was assessed in patients with CLL.

About Chronic Lymphocytic Leukemia (CLL)

CLL is one of the most common forms of blood cancer and in 2015, it is expected that there will be about 4,650 deaths from CLL in the United States. Most cases of CLL (95 percent) start in white blood cells called B-cells that have a protein called CD20 on their surface. In certain cases of CLL, a part of chromosome 17 is lost and along with it an important gene that controls apoptosis called p53. The 17p deletion is found in 3 to 10 percent of previously untreated cases and approximately 30 to 50 percent of relapsed or refractory cases.

About Venetoclax (RG7601, GDC-0199/ABT-199)

Venetoclax is an investigational small molecule designed to selectively bind and inhibit the BCL-2 protein, which plays an important role in a process called apoptosis (programmed cell death). It is believed that blocking BCL-2 may restore the signaling system that tells cancer cells to self-destruct. The BCL-2 protein is linked to the development of resistance in certain blood cancers and is expressed in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL). In collaboration with AbbVie, venetoclax is being evaluated in a robust development program as a single agent or in combination with other medicines. There are ongoing Phase II and III studies for venetoclax in CLL, and Phase I and II studies are also ongoing in several other blood cancers, including indolent NHL, diffuse large B-cell lymphoma (DLBCL), acute myeloid leukemia (AML) and multiple myeloma (MM).

On December 06, 2015 Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical stage biotechnology company focused on the development of novel cancer therapeutics, reported that clinical and preclinical data from its lead product candidate CB-839, a first-in-class glutaminase inhibitor was presented today at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (ASH) (Free ASH Whitepaper), in Orlando, Florida (Press release, Calithera Biosciences, DEC 6, 2015, View Source;p=RssLanding&cat=news&id=2120418 [SID:1234508425]). The data demonstrated the clinical activity, tolerability and unique mechanism of action of CB-839 in patients with acute myeloid leukemia (AML) and multiple myeloma.

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"We are encouraged by the promising clinical activity of CB-839 as a single agent in AML, and early tolerability and preliminary signals of efficacy in combination therapy in multiple myeloma," said Susan Molineaux, PhD, President and Chief Executive Officer of Calithera. "We are actively enrolling six combination expansion cohorts of CB-839 in solid and hematological malignancies and look forward to presenting additional combination data in 2016."

CB-839 in Multiple Myeloma

Dr. Dan Vogl from the University of Pennsylvania presented a poster titled, "Phase I study of CB-839, a first in class glutaminase inhibitor in patients with multiple myeloma and lymphoma," (Abstract #3059). As of November 9, 2015, 23 multiple myeloma patients had been treated, including 14 treated with CB-839 as a monotherapy, and nine patients treated in combination with either dexamethasone (n=5) or pomalidomide and dexamethasone (n=4). The majority of patients had received at least four prior lines of therapy. In the monotherapy cohort, the best response was stable disease, which was reported in seven patients, including one patient who has remained on study for over seven months. The first patient to receive the CB-839 plus pomalidomide and dexamethasone combination has had a clinically significant reduction in myeloma markers, including urine M-protein and serum free light chain. Three of 14 (21%) monotherapy patients experienced Grade 3 events suspected to be related to CB-839, and one dose limiting toxicity (DLT) of Grade 4 neutropenia deemed possibly related to CB-839 occurred in the pomalidomide and dexamethasone combination group. No patients discontinued due to adverse events.

CB-839 in Acute Myeloid Leukemia

Dr. Eunice Wang from Roswell Park Cancer Institute presented a poster titled, "Phase I study of CB-839, a first in class, orally administered small molecule inhibitor of glutaminase in patients with relapsed/refractory leukemia," (Abstract #2566). As of November 9, 2015, 26 acute leukemia patients had been treated including 24 with AML. This represents an update from the data presented June 11, 2015 at the European Hematology Association (EHA) (Free EHA Whitepaper). All patients were relapsed and/or refractory, with 61% of patients treated with two or more prior therapies, and 23% of patients treated with prior allogeneic transplant. The mean age of patients was 75 years. Oral CB-839 was administered continuously in 21-day treatment cycles from 100 to 1000 mg three times daily (n=16), or twice daily (n=10). The 24 AML patients included two IDH1 and three IDH2 mutant AML patients. One patient achieved a complete response in the bone marrow with incomplete recovery of peripheral counts (CRi) and remains on therapy over 16 months. Five of 26 efficacy-evaluable patients across dose levels remained on therapy for at least 4 cycles (12 weeks), and up to 23+ cycles (>16 months). There were no DLTs identified and no patients discontinued due to adverse events.

In addition, Calithera and their collaborators presented two preclinical posters that provide the rationale for use of biomarkers of CB-839 in multiple myeloma, and elucidate the role of glutamine in AML. Details for the presentations are as follows:

Metabolomic, Proteomic and Genomic Profiling Identifies Biomarkers of Sensitivity to Glutaminase

Abstract: #1802

Andrew L. MacKinnon, Ph.D., Calithera Biosciences

Role of Glutamine in Metabolic and Epigenetic Reprogramming in AML

Abstract: #2559

Juliana Velez Lujan, Ph.D., University of Texas MD Anderson Cancer Center