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Calithera Biosciences Reports Phase I Data for CB-839 in Patients With Hematological Malignancies at the 57th American Society of Hematology Annual Meeting

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

bluebird bio Presents Pre-Clinical and Manufacturing Data from CAR T Oncology Programs at ASH Annual Meeting

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]).

"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.

Agios Announces Data from Ongoing Phase 1/2 Trial of AG-221 Showing Durable Responses in Patients with Advanced Hematologic Malignancies

On December 6, 2015 Agios Pharmaceuticals, Inc. (Nasdaq:AGIO), a leader in the fields of cancer metabolism and rare genetic metabolic disorders, reported new data from the dose-escalation phase and expansion cohorts from the ongoing Phase 1/2 study evaluating single agent AG-221, a first-in-class, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-2 (IDH2), in advanced hematologic malignancies (Press release, Agios Pharmaceuticals, DEC 6, 2015, View Source;p=RssLanding&cat=news&id=2120425 [SID:1234508423]). The data are being presented at the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (ASH) (Free ASH Whitepaper) taking place December 5-8, 2015 in Orlando. AG-221 is being developed in collaboration with Celgene.

Data as of September 1, 2015 from 209 patients with IDH2 mutant positive advanced hematologic malignancies treated with single agent AG-221 showed durable clinical activity and a favorable safety profile. More than 50 patients were added as of the last analysis, and 66 patients remain on treatment. In patients with relapsed or refractory AML, the study had an overall response rate of 37 percent (59 of 159 response-evaluable patients) and a complete remission rate of 18 percent (29 of 159 response-evaluable patients). Responding relapsed or refractory AML patients were on study treatment for up to 18 months with a 6.9-month median response duration (not reported at previous data presentations). The overall safety profile observed was consistent with previously reported data.

"With data from more than 200 patients, it is clear that single agent AG-221 has a favorable safety profile and durable response rate in IDH2 mutant hematologic malignancies," said Eytan Stein, M.D., lead investigator and attending physician in the leukemia service at Memorial Sloan Kettering Cancer Center. "In addition, a subset of patients with stable disease had improvements in neutrophil and platelet counts, which may have important clinical implications for reductions in infections and bleeding. We look forward to developing these data further to describe the overall clinical profile for AG-221 in patients with advanced cancers."

"The consistency of the overall response rate and complete remission rate in this study over time is encouraging," said Chris Bowden, M.D., chief medical officer of Agios. "We continue to believe that AG-221 can make a meaningful difference for patients with IDH2 mutant positive cancers and are focused on executing our strategy of speed and breadth with our partner Celgene. We are making rapid progress in the relapsed/refractory and frontline AML settings, with the Phase 3 IDHENTIFY study open for enrollment and plans to initiate the first of two frontline combination studies by the end of the year."

About the Ongoing Phase 1/2 Trial for AG-221 in Advanced Hematologic Malignancies

AG-221 is currently being evaluated in an ongoing Phase 1/2 trial that includes a dose-escalation phase and five expansion cohorts. The first four expansion cohorts have completed enrollment.

Arm 1: 25 patients with IDH2 mutant positive relapsed or refractory AML age ≥60 years, or any patient with AML regardless of age who has relapsed following a bone marrow transplant (BMT)

Arm 2: 25 patients with IDH2 mutant positive relapsed or refractory AML age <60 years, excluding patients with AML who have relapsed following a BMT

Arm 3: 25 patients with IDH2 mutant positive untreated AML age ≥60 years who decline standard of care chemotherapy
Arm 4: 25 patients with IDH2 mutant positive advanced hematologic malignancies not eligible for arms 1 to 3

Arm 5: The Phase 2 portion of the trial includes 125 patients with IDH2 mutant positive AML who are in second or later relapse, refractory to second-line induction or reinduction treatment, or have relapsed after allogeneic transplantation

Data reported here are from patients receiving AG-221 administered from 50 mg to 650 mg total daily doses in the dose escalation arm and 100 mg once daily in the first four expansion arms, as of September 1, 2015. The median age of these patients is 69 (ranging from 19-100). Patients with relapsed or refractory AML received a median of two prior lines of therapy (ranging from one to six). These new data reflect responses in the evaluable population, which include all patients with a day 28 or later response assessment or discontinued before assessment.

Safety Data

A safety analysis was conducted for all 231 treated patients.

The majority of adverse events reported by investigators were mild to moderate, with the most common being nausea, diarrhea, fatigue and febrile neutropenia.

The serious adverse events (SAE) were mainly disease related. Twenty-three percent of patients had treatment-related SAEs, notably differentiation syndrome (4 percent), leukocytosis (4 percent) and nausea (2 percent). Drug-related Grade 5 SAEs include atrial flutter (one patient), cardiac tamponade (one patient), pericardial effusion (one patient) and respiratory failure (one patient).
A maximum tolerated dose (MTD) has not been reached.

Efficacy Data

Seventy-nine out of 209 total response-evaluable patients achieved investigator-assessed objective responses for an overall response rate of 38 percent.

Of the 79 patients who achieved an objective response, there were 37 (18 percent) complete remissions (CR), three CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), three CRs with incomplete hematologic recovery (CRi) and 22 partial remissions (PR).

Of the 159 patients with relapsed or refractory AML, 59 (37 percent) achieved an objective response, including 29 (18 percent) CRs, one CRp, nine mCRs, three CRis and 17 PRs.

Of the 24 patients with AML who declined standard of care chemotherapy, 10 achieved an objective response, including four CRs, one CRp, one mCR and four PRs.

Of the 14 patients with myelodysplastic syndrome (MDS), seven achieved an objective response, including three CRs, one CRp and three mCRs.

Responding relapsed or refractory AML patients were on study treatment for up to 18 months with a median duration of treatment of 6.8 months (ranging from 1.8 to 18 months).

Responses were durable, with a median response duration of 6.9 months in patients with relapsed or refractory AML.
Neutrophil and platelet improvements were observed in some patients with stable disease.
2015 Milestones for AG-221 in Hematologic Malignancies

Remaining milestones for AG-221 in 2015 include:

Enroll patients in the Phase 3 IDHENTIFY study of AG-221, an international, multi-center, open-label, randomized clinical trial designed to compare the efficacy and safety of AG-221 versus conventional care regimens in patients age ≥60 with IDH2 mutant-positive AML that is refractory to or relapsed after second- or third-line therapy. This study is being conducted by Celgene.
Continue to enroll patients into the Phase 2 portion of 125 patients with IDH2 mutant-positive AML who are in second or later relapse, refractory to second-line induction or re-induction treatment, or have relapsed after allogeneic transplantation.
Initiate a Phase 1b combination study of either AG-221 or AG-120 with standard induction (7+3, Ara-C and idarubicin/daunorubicin) and consolidation (Ara-C, or mitoxantrone with etoposide) chemotherapy in newly diagnosed AML patients eligible for intensive chemotherapy by the end of 2015.

Investor Event and Webcast Information

Agios will host an investor event on Monday, December 7, 2015 beginning at 12:00 p.m. ET in Orlando to review data presented at ASH (Free ASH Whitepaper), including new data from the ongoing studies of AG-221 and AG-120. The event will be webcast live and can be accessed under "Events & Presentations" in the Investors and Media section of the company’s website at www.agios.com.

About Acute Myelogenous Leukemia (AML)

AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. AML incidence significantly increases with age, and according to the American Cancer Society, the median age of onset is 66. Less than 10 percent of U.S. AML patients are eligible for bone marrow transplant and the vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 20 to 25 percent. IDH1 and IDH2 mutations are present in about 15 to 23 percent of AML cases.

About Myelodysplastic Syndrome (MDS)

MDS comprises a diverse group of bone marrow disorders in which immature blood cells in the bone marrow do not mature or become healthy blood cells. The National Cancer Institute estimates that more than 10,000 people are diagnosed with MDS in the U.S. each year. Failure of the bone marrow to produce mature healthy cells is a gradual process, and reduced blood cell and/or reduced platelet counts may be accompanied by the loss of the body’s ability to fight infections and control bleeding. For roughly 30 percent of the patients diagnosed with MDS, this bone marrow failure will progress to AML. Chemotherapy and supportive blood products are used to treat MDS.

Spectrum Pharmaceuticals and Onxeo Announce Complete Response in 67% of Patients with Peripheral T-Cell Lymphoma in Combination of Belinostat (Beleodaq®) and Standard CHOP

On December 6, 2015 Spectrum Pharmaceuticals (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations and a primary focus in Hematology and Oncology, and Onxeo S.A. (Euronext Paris, NASDAQ Copenhagen: ONXEO), an innovative company specializing in the development of orphan oncology drugs, reported the results from their Phase 1 combination trial of belinostat (Beleodaq) with the CHOP (Cyclophosphamide, Hydroxyl-doxorubicin; Vincristine, and Prednisone) chemotherapy regimen as first-line treatment for newly diagnosed peripheral T-cell lymphoma (PTCL) (Press release, Spectrum Pharmaceuticals, DEC 6, 2015, View Source [SID:1234508432]).

Beleodaq is a histone deacetylase (HDAC) inhibitor that received accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed or refractory PTCL in July 2014.

The results were presented today in an oral presentation at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition by Dr. Patrick Johnston, MD, PhD, Assistant Professor of Medicine at the Mayo Clinic, Rochester, MN, USA.

Abstract #253: Safe and Effective Treatment of Patients with Peripheral T-cell Lymphoma (PTCL) with the Novel HDAC Inhibitor, Belinostat, in Combination with CHOP: Results of the Bel-CHOP Phase 1 Trial

This open-label, two-part trial enrolled a total of 23 patients. Eleven were enrolled in Part A, the dose-escalation phase, to determine the study’s primary endpoint, the maximum tolerated dose (MTD). Part B of the study, the Expansion Phase, enrolled 12 additional patients at this dose level. The MTD of belinostat was established at 1,000 mg/m2 IV infusion on Days 1-5 (the recommended single agent dose) when combined with the CHOP regimen, with each component given at its full recommended dose. Secondary endpoints included safety, tolerability, Objective Response Rate (ORR: Complete Response + Partial Response), and pharmacokinetics.

Results outlined in the oral presentation showed an ORR of 86% with the belinostat and CHOP combination, based on 21 evaluable patients (18/21), with the vast majority, 67%, achieving a Complete Response (14/21), and 19% achieving a Partial Response (4/21). In addition, the belinostat and CHOP combination was shown to have an acceptable safety profile with no new or unexpected toxicities. The most common ( > 10%) Grade 3-4 hematologic adverse events (AEs) reported with Bel-CHOP were as expected: neutrophil count decreased (30%), anemia (22%), neutropenia (22%), white blood cell (WBC) count decreased (22%), febrile neutropenia (17%) and lymphocyte count decreased (17%). No Grade 3-4 non-hematologic AEs > 10% were reported. No patient discontinued therapy due to AEs. One patient died as a result of disease progression during the study.

Dr. Patrick Johnston, MD, PhD, Assistant Professor of Medicine at the Mayo Clinic and investigator on the trial, commented, "PTCL is a very difficult lymphoma to treat due to its heterogeneous nature, and its association with multiple recurrence and poor prognosis; only approximately 37% of patients achieve 5-year overall survival. New combination treatment strategies are undeniably needed to improve efficacy without compromising tolerability, and we are encouraged by these Phase 1 study results indicating that the combination of belinostat and CHOP is a potentially viable treatment option. A good safety profile combined with an Objective Response Rate of 86%, and 67% of patients achieving complete response, are unusual in an early trial of this cancer type. We look forward to further evaluating the combination in a planned Phase 3 trial."

"We are proud to have had several presentations on our products at the ASH (Free ASH Whitepaper) meeting, and are optimistic about the new combination data with belinostat," said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals. "Beleodaq was approved for the treatment of patients with relapsed or refractory PTCL based on an Objective Response Rate in the pivotal Phase 2 BELIEF study of 25.8%. The results of this Phase 1 study indicate encouraging safety and efficacy for the combination of belinostat and CHOP in newly diagnosed patients. The clinical activity suggests that earlier treatment with belinostat could be beneficial for the treatment of this devastating disease. Spectrum has a unique PTCL franchise with two FDA approved drugs; we are very proud to be able to offer patients and clinicians additional treatment options for a disease which had no FDA-approved treatments until a few years ago."

Graham Dixon, PhD, Chief Scientific Officer of Onxeo, added, "We are very excited to have these results discussed in an oral presentation at the ASH (Free ASH Whitepaper) Annual Meeting. Collectively, the efficacy and safety findings demonstrate the potential value of belinostat plus CHOP, and Onxeo is thrilled to continue the development of belinostat to more broadly assess this promising therapy in PTCL and beyond."

References

1. Johnston, P. "Safe and Effective Treatment of Patients with Peripheral T-cell Lymphoma (PTCL) with the Novel HDAC Inhibitor, Belinostat, in Combination with CHOP: Results of the BelCHOP Phase 1 Trial." Abstract #253 accepted for Oral Presentation at the 2015 ASH (Free ASH Whitepaper) Annual Meeting, Dec. 5-8, 2015. Abstract available online at: View Source

About BELEODAQ

Beleodaq (belinostat) is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. In vitro, belinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Belinostat shows preferential cytotoxicity towards tumor cells compared to normal cells. Belinostat inhibited the enzymatic activity of histone deacetylases at nanomolar concentrations ( < 250 nM).

Indications and Usage

Beleodaq is a histone deacetylase inhibitor indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

Important Beleodaq Safety Information

Warnings and Precautions

Beleodaq can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia; monitor blood counts weekly during treatment, and modify dosage as necessary.

Serious and sometimes fatal infections, including pneumonia and sepsis, have occurred with Beleodaq. Do not administer Beleodaq to patients with an active infection. Patients with a history of extensive or intensive chemotherapy may be at higher risk of life threatening infections.

Beleodaq can cause fatal hepatotoxicity and liver function test abnormalities. Monitor liver function tests before treatment and before the start of each cycle. Interrupt or adjust dosage until recovery, or permanently discontinue Beleodaq based on the severity of the hepatic toxicity.

Tumor lysis syndrome has occurred in Beleodaq-treated patients in the clinical trial of patients with relapsed or refractory PTCL.

Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions.

Nausea, vomiting and diarrhea occur with Beleodaq and may require the use of antiemetic and antidiarrheal medications.

Beleodaq can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid pregnancy while receiving Beleodaq. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazard to the fetus.

Adverse Reactions

The most common adverse reactions observed in the trial in patients with relapsed or refractory PTCL treated with Beleodaq were nausea (42%), fatigue (37%), pyrexia (35%), anemia (32%), and vomiting (29%).
Sixty-one patients (47.3%) experienced serious adverse reactions while taking Beleodaq or within 30 days after their last dose of Beleodaq.

Drug Interactions

Beleodaq is primarily metabolized by UGT1A1. Avoid concomitant administration of Beleodaq with strong inhibitors of UGT1A1.

Use in Specific Populations

It is not known whether belinostat is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Beleodaq, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother.

Novartis drug PKC412 (midostaurin) improves overall survival by 23% in global Phase III study of AML patients with FLT3 mutations

On December 6, 2015 Novartis reported positive results from the global Phase III RATIFY (CALGB 10603) clinical trial (Press release, Novartis, DEC 6, 2015, View Source [SID:1234508430]).

In the study, adult patients under 60 years of age with newly-diagnosed FLT3-mutated acute myeloid leukemia (AML) who received the investigational compound PKC412 (midostaurin) plus standard induction and consolidation chemotherapy experienced a 23% improvement in overall survival (OS) (hazard ratio [HR] = 0.77, P = 0.0074) compared to those treated with standard induction and consolidation chemotherapy alone[4]. The median OS for patients in the PKC412 (midostaurin) treatment group was 74.7 months (95% confidence interval [CI]: 31.7, not attained), versus 25.6 months (95% CI: 18.6, 42.9) for patients in the placebo group[4].

The trial evaluated the addition of either PKC412 (midostaurin) or placebo to daunorubicin/cytarabine in the induction phase, followed by high-dose cytarabine in the consolidation phase; patients who achieved complete remission after consolidation chemotherapy continued treatment with PKC412 (midostaurin) or placebo as a single agent for up to one year[4].

The data, collected and analyzed in partnership with the Alliance for Clinical Trials in Oncology, are from the largest clinical trial in FLT3-mutated AML to date, with 3,279 patients screened and 717 study participants from around the world[4]. Results will be presented today at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida, first during the official ASH (Free ASH Whitepaper) media briefing at 11:00 am EST and then during the plenary session at 2:00 pm EST.

"The overall survival results for midostaurin, plus standard chemotherapy, in treating FLT3-mutated AML is a long-awaited advancement for hematologists and the AML community," said Richard M. Stone, MD, Professor of Medicine at the Dana-Farber Cancer Institute and Alliance for Clinical Trials in Oncology study chair for the RATIFY trial. "FLT3 is a common genetic mutation in AML and is currently associated with poorer prognoses, underscoring the critical need for new treatment options."

The treatment strategy in AML has remained unchanged for more than 25 years[2],[3]. Of the approximately 350,000 people with leukemias worldwide[5], about 25% have AML[1]. One-third of AML patients also harbor a FLT3 gene mutation[6], which is associated with worse outcomes and shorter survival than in those without the mutation[7]. PKC412 (midostaurin) is the first drug to illustrate an overall survival benefit targeting FLT3 in AML – a hematological malignancy with no approved targeted treatments.

In addition to meeting the primary endpoint of OS, event free survival (EFS, defined as the earliest death, relapse or no complete response within 60 days of the start of induction therapy) was significantly higher in the PKC412 (midostaurin) treatment group versus the placebo group [HR = 0.79, P = 0.0025 and median of 8.0 months (95% CI: 5.14, 10.6) vs. 3.0 months (95% CI: 1.9, 5.9)] [4].

No statistically significant differences were observed in the overall rate of grade 3 or higher hematologic and non-hematologic adverse events (AEs) [4]. A total of 37 deaths were reported, with no difference in treatment-related deaths observed between groups[4].

"The RATIFY study, in partnership with the Alliance for Clinical Trials in Oncology, reflects our relentless pursuit to develop targeted therapies that can improve and extend people’s lives," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "Based on the results of this trial, we plan to move forward with global regulatory submissions for PKC412 (midostaurin) in the first half of 2016."

In order to help identify patients who may have a FLT3 mutation and potentially benefit from treatment with PKC412 (midostaurin), Novartis is collaborating with Invivoscribe Technologies, Inc. who will lead regulatory submissions for a companion diagnostic.

About the RATIFY trial
RATIFY (Randomized AML Trial In FLT3 in patients <60 Years old; also known as CALGB 10603) was a Phase III, international, randomized, placebo-controlled, double-blind group trial of newly-diagnosed AML patients aged 18 to less than 60 with a FLT3 mutation[4]. The study compared PKC412 (midostaurin) to placebo administered orally with up to two cycles of standard induction (daunorubicin/cytarabine) chemotherapy, and up to four cycles of consolidation (high-dose cytarabine) chemotherapy, followed by PKC412 (midostaurin) or placebo treatment as a single agent for up to one year in patients who continue in complete remission after consolidation chemotherapy[4]. The primary endpoint was OS and the key secondary endpoint was EFS[4].

The data were collected by the Alliance for Clinical Trials in Oncology ("Alliance") on behalf of 13 contributing international cooperative groups. The Alliance was the sponsor of the study in North America and Novartis was the sponsor in Europe and Australia. A total of 225 sites from 17 countries participated in this study, spanning North America, Europe and Australia. A total of 3,279 patients with AML were screened, and 717 patients with an activating FLT3 mutation aged 18 to less than 60 were enrolled[4].

Patients were stratified according to the following mutation subtypes: tyrosine kinase domain (TKD), internal tandem duplications (ITD) high allelic mutation fraction (>0.7) and ITD low allelic mutation fraction (0.05-0.7)[4]. All three subtypes treated with PKC412 (midostaurin) demonstrated improved OS versus placebo[4]. Allogeneic hematopoietic stem cell transplantation (SCT) was allowed[4]. PKC412 (midostaurin) benefited patients regardless of whether they went on to receive a SCT[4].

About acute myeloid leukemia (AML) and the FLT3 mutation
AML is an aggressive cancer of the blood and bone marrow[8]. It prevents white blood cells from maturing, causing an accumulation of "blasts" which do not allow room for the normal blood cells[8]. AML is the most common acute leukemia in adults, but also has the lowest survival rate[1]. AML accounts for approximately 25% of all adult leukemias worldwide, with the highest incidence rates occurring in the United States, Europe and Australia[1].

Mutations in specific genes are found in many cases of AML, and biomarker testing is considered standard of care for newly-diagnosed patients to help determine the best possible treatment option[6]. FLT3 is a receptor tyrosine kinase, a type of cell-surface receptor, which plays a role in the proliferation, or increase, in the number of certain blood cells[9].

About PKC412 (midostaurin)
PKC412 (midostaurin) is an investigational, oral, multi-targeted kinase inhibitor in development for the treatment of patients with AML with a FLT3 mutation. PKC412 (midostaurin) inhibits multiple kinases, or enzymes, including FLT3, that help regulate many essential cell processes, thereby interrupting cancer cells’ ability to grow and multiply[10].

PKC412 (midostaurin) is also being investigated for the treatment of aggressive systemic mastocytosis/mast cell leukemia[11].

PKC412 (midostaurin) is an investigational compound; the safety and efficacy profile have not been fully established.