On December 6, 2016 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer and Cellworks, a customized therapy design company that improves clinical outcomes and creates value for pharma, payers and physicians, reported the presentation of their collaborative effort to identify higher-risk MDS (HR-MDS) patients that are likely to respond to rigosertib at the 2016 ASH (Free ASH Whitepaper) Annual Meeting in San Diego California, taking place December 3-6, 2016 (Press release, Onconova, DEC 6, 2016, View Source [SID1234516960]).

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The presentation by Dr. Guillermo Garcia-Manero from the MD Anderson Cancer Center, lead investigator from the ONTME trial, used Cellworks’ proprietary bio-simulation platform to retrospectively correlate clinical benefit to IV rigosertib treatment in the Phase 3 ONTIME study in HR-MDS patients with molecular and cytogenetic data. This computer simulation led to the characterization of certain biological pathways that predict response to IV rigosertib in HR-MDS patients. Notably, patients with these predictive biological pathways also shared common cytogenetic abnormalities — trisomy of chromosomes 8 and 21 — that correlated with positive clinical outcome in ONTIME.

"This retrospective analysis of ONTIME has helped identify biological factors related to clinical outcomes to treatment with IV rigosertib," stated Guillermo Garcia-Manero, MD, Chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center, and lead author of the study. "These results confirm prior studies where patients with certain cytogenetic abnormalities were sensitive to IV rigosertib. These data also reinforce the clinical strategy of the ongoing Phase 3 INSPIRE trial to target only the highest-risk MDS patients with rigosertib."

"We are excited by this use of our proprietary bio-simulation platform to predict response to novel therapeutics in a heterogeneous disease like HR-MDS," commented Yatin Mundkur, CEO of Cellworks. "Among other applications, the Cellworks platform is intended to inform the design of Phase 2 and 3 clinical trials by establishing and validating inclusion criteria. In this case, we are pleased that this analysis has validated enrollment criteria for Onconova’s Phase 3 INSPIRE trial."

The poster entitled "Computational Analysis of Genomic Abnormalities from a Phase 3 Trial of Rigosertib in Higher-Risk MDS: Simulation of a Predictive Signature for Clinical Response," was presented on December 5, 2016 at the ASH (Free ASH Whitepaper) Annual Meeting in San Diego, California. A copy of the poster is available by visiting the Scientific Presentations section under the Investors & Media tab of Onconova’s website.

About Onconova Therapeutics, Inc.

Onconova Therapeutics is a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer. Onconova’s clinical and pre-clinical stage drug development candidates are derived from its extensive chemical library and are designed to work against specific cellular pathways that are important in cancer cells, while causing minimal damage to normal cells. The Company’s most advanced product candidate, rigosertib, is a small molecule inhibitor of cellular signaling and acts as a RAS mimetic. These effects of rigosertib appear to be mediated by direct binding of the compound to the RAS-binding domain (RBD) found in many RAS effector proteins, including the Raf and PI3 kinases. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan. In addition to rigosertib, two other candidates are in the clinical stage, and several candidates are in pre-clinical stages. For more information, please visit View Source

About IV Rigosertib

The intravenous form of rigosertib has been employed in Phase 1, 2, and 3 clinical trial involving more than 800 patients, and is currently being evaluated in the randomized Phase 3 global INSPIRE trial as 2nd-line treatment for patients with higher-risk MDS, after failure of hypomethylating agent, or HMA, therapy. This formulation is suited for patients with advanced disease and provides long duration of exposure and ensures adequate dosing under a controlled setting.

About INSPIRE

The INternational Study of Phase III IV RigosErtib, or INSPIRE, is based on guidance received from the U.S. Food and Drug Administration and European Medicines Agency and derives from the findings of the ONTIME Phase 3 trial. INSPIRE is a multi-center, randomized controlled study to assess the efficacy and safety of IV rigosertib in HR-MDS patients who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first nine months of initiation of HMA treatment. This time frame optimizes the opportunity to respond to treatment with an HMA prior to declaring treatment failure, as per NCCN Guidelines. The trial will enroll approximately 225 patients randomized at a 2:1 ratio into two treatment arms: IV rigosertib plus Best Supportive Care versus Physician’s Choice plus Best Supportive Care. The primary endpoint of INSPIRE is overall survival and an interim analysis is anticipated. Full details of the INSPIRE trial, such as inclusion and exclusion criteria, as well as secondary endpoints, can be found on clinicaltrials.gov (NCT02562443).

On December 6, 2016 Celgene Corporation (NASDAQ:CELG), reported results from two studies (Abstracts #1143, LBA-1) evaluating the investigational use of REVLIMID (lenalidomide) maintenance therapy in patients with multiple myeloma (Press release, Celgene, DEC 6, 2016, View Source [SID1234516959]). These studies were presented at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, Calif.

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Myeloma XI Study

The Myeloma XI trial is a UK-based, large, randomized, open-label phase III study that included a comparison of investigational lenalidomide maintenance treatment versus no maintenance for patients with newly diagnosed multiple myeloma. The study included both transplant-eligible (TE) and transplant non-eligible (TNE) patients. Patients received induction treatment in both segments with lenalidomide or thalidomide plus cyclophosphamide and dexamethasone. TE patients proceeded to a standard melphalan 200mg/m2 autologous stem cell transplant (ASCT). Patients were then randomized to either maintenance lenalidomide or observation after achieving maximum response (TNE) or at 100 days after transplant (TE). Lenalidomide maintenance was administered at a dose of 10mg daily in 21/28 day cycles until disease progression.

Overall, the primary endpoint of progression-free survival (PFS) was 36 months for patients receiving lenalidomide (n=857) and 18 months for observation (n=694) (HR:0.45 95% CI [0.39, 0.52] P < 0.0001) in the maintenance phase of the study.

For TE patients, median PFS was 50 months for lenalidomide (n=451) and 28 months for observation (n=377) (HR:0.48 95% CI [0.38, 0.60] P < 0.0001).
For TNE patients, median PFS was 24 months for lenalidomide (n=406) and 11 months for observation (n=317) (HR:0.42 95% CI [0.35, 0.60] P < 0.0001).
Grade 3-4 adverse events for patients receiving lenalidomide (n=864) included neutropenia (34%), thrombocytopenia (7%) and anemia (4%). The incidence of deep-vein thrombosis/pulmonary embolism was 1% in all grades. Second primary malignancies (SPM) were observed in 72 patients in the study (24 in the observation arm and 48 in the lenalidomide arm (HR 1.78 95% CI [1.02, 3.10]))
"The Myeloma XI study provides important insights for the continued investigation of lenalidomide as a maintenance treatment for people living with multiple myeloma," said Gareth Morgan, M.D., Ph.D., Director of the Myeloma Institute at the University of Arkansas for Medical Sciences. "Building on previous studies, lenalidomide maintenance in this study delayed relapse in patients compared to no maintenance."

StaMINA Study

In the phase III BMT CTN 0702 StaMINA trial, TE patients were randomized following transplant between three arms to receive either 4 cycles of lenalidomide-bortezomib-dexamethasone (RVD) consolidation (ACM) (n=254), tandem melphalan 200mg/m2 autologous stem cell transplant (TAM) consolidation (n=247), or no consolidation (AM) (n=257). All arms included lenalidomide maintenance (at a starting dose of 10 mg daily in 28/28 day cycles until disease progression.

At a median follow-up of 38 months, all three arms demonstrated comparable PFS and OS. The addition of RVD consolidation or a second ASCT was not superior to a single ASCT followed by lenalidomide maintenance. The estimated PFS rates were 57% (95% CI: 50-63%), 56% (95% CI: 49-63%) and 52% (95% CI: 45-59%) for ACM, TAM and AM arms, respectively (ACM vs TAM p=0.75, ACM vs AM p=0.21, TAM vs AM p=0.37). The estimated overall survival (OS) rates were 86% (95% CI: 80-90%), 82% (95% CI: 76-87%) and 83% (95% CI: 78-88%). Median OS had not been reached.

There were 39 cases of SPM reported in 36 patients and the cumulative incidences for first SPM were 6.0% (95% CI: 3.4-9.6%), 5.9% (95% CI: 3.3-9.6%) and 4.0% (95% CI: 1.9-7.2%) for the ACM, TAM and AM arms, respectively.

"The StaMINA trial demonstrated that the addition of RVD consolidation or a second autologous stem cell transplant did not provide a superior outcome, on average, to a single autologous stem cell transplant followed immediately by lenalidomide maintenance," said Edward Stadtmauer, M.D., Section Chief, Hematologic Malignancies at the University of Pennsylvania School of Medicine. "As transplants continue to be an option for many myeloma patients, these are important insights for determining the path to subsequent maintenance therapy."

Health-Related Quality of Life Analysis

An additional analysis presented at ASH (Free ASH Whitepaper) (Abstract #537) examined health related quality of life in post-transplant maintenance in patients from Celgene’s CONNECT MM registry.

The analysis evaluated data from patients newly-diagnosed with multiple myeloma (n=1493) registered between September 2009 and December 2011.

Quality of life was measured for those who received ASCT (n=540) using the EQ-5D quality of life index, Fact-MM total score and brief pain inventory (BPI), assessed at a median follow-up of 39.5 months. Patients who received any maintenance therapy (n=238) were compared with those receiving no maintenance therapy (n=138). Another analysis compared those receiving any maintenance therapy versus those who received lenalidomide maintenance (n=167).

In the analysis, patients on average did not report a decrease in quality of life measures with the use of maintenance therapy. The EQ-5D overall index score was 0.79 (0.14) across all patient groups. The Fact-MM total score was 117.7 for any maintenance, compared with 118.9 for lenalidomide maintenance and 114.8 for no maintenance. BPI was 4.0 for any maintenance and 3.9 for both lenalidomide maintenance and no maintenance.

REVLIMID is not approved as a maintenance treatment for post ASCT patients with multiple myeloma.

Celgene filed a supplemental New Drug Application (sNDA) with the U.S. Food and Drug Administration (FDA) for the expanded indication of REVLIMID as maintenance treatment in newly diagnosed multiple myeloma patients after receiving an ASCT based on separate studies. The sNDA was granted Priority Review and the Prescription Drug User Fee Act date of February 24, 2017.

In June, an application was submitted to the European Medicines Agency (EMA) for the review of REVLIMID as maintenance treatment in NDMM patients after receiving an ASCT. A decision on the European Union (EU) application is expected in the first half of 2017.

About REVLIMID

REVLIMID (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM)

REVLIMID is indicated for the treatment of patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities

REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib

REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity

Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS program (formerly known as the "RevAssist" program).

Information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)

REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism

REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus

Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: See Boxed WARNINGS

Females of Reproductive Potential: See Boxed WARNINGS
Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm
Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID
REVLIMID REMS Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the REVLIMID REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements

Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. MDS: Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or dose reduction. Please see the Black Box WARNINGS for further information. MCL: Patients taking REVLIMID for MCL should have their CBCs monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction

Venous and Arterial Thromboembolism: See Boxed WARNINGS: Venous thromboembolic events (DVT and PE) and arterial thromboses (MI and CVA) are increased in patients treated with REVLIMID. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended and regimen is based on patients underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision

Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving REVLIMID, an increase of invasive SPM notably AML and MDS have been observed. Monitor patients for the development of SPMs. Take into account both the potential benefit of REVLIMID and risk of SPMs when considering treatment

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID/dex. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered

Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose; risk-benefit of treatment should be evaluated in patients with lactose intolerance

Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken

Tumor Flare Reaction (TFR): TFR has occurred during investigational use of lenalidomide for CLL and lymphoma. Monitoring and evaluation of TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤ Grade 1. REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment ( > 4 cycles) with REVLIMID has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection

ADVERSE REACTIONS

Multiple Myeloma

In newly diagnosed: The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or RD18
The most common adverse reactions reported in ≥20% (Arm Rd Continuous): diarrhea (46%), anemia (44%), neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash, (26%), decreased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%), abdominal pain (21%), muscle spasms (20%), and thrombocytopenia (20%)
After at least one prior therapy the most common adverse reactions reported in ≥20% (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), and weight decreased (20% vs 15%)
Myelodysplastic Syndromes

Grade 3 and 4 adverse events reported in ≥ 5% of patients with del 5q MDS were neutropenia (53%), thrombocytopenia (50%), pneumonia (7%), rash (7%), anemia (6%), leukopenia (5%), fatigue (5%), dyspnea (5%), and back pain (5%)
Adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): thrombocytopenia (61.5%), neutropenia (58.8%), diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)
Mantle Cell Lymphoma

Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%)
Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%)
DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels is recommended due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin

NURSING MOTHERS

Discontinue drug or nursing taking into consideration the importance of the drug to the mother

PEDIATRIC USE

Safety and effectiveness in patients below the age of 18 have not been established

RENAL IMPAIRMENT

REVLIMID is primarily excreted unchanged by the kidneys; adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis

Please see full Prescribing Information, including Boxed WARNINGS.

On December 6, 2016 Kite Pharma, Inc. (Nasdaq:KITE) reported results from the ZUMA-1 trial of axicabtagene ciloleucel (KTE-C19) in patients with chemorefractory aggressive non-Hodgkin lymphoma (NHL) in two oral presentations at the American Society of Hematology (ASH) (Free ASH Whitepaper) 58th Annual Meeting in San Diego, California (Press release, Kite Pharma, DEC 6, 2016, View Source [SID1234516957]).

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ZUMA-1 enrolled 111 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL). Patients were required to have chemorefractory disease, defined as progressive or stable disease as best response to last line of therapy, or disease progression ≤12 months after autologous stem cell transplant. Manufacturing was successful for 110 patients, and 101 patients were treated. The pre-specified interim analysis was triggered when 51 patients with DLBCL had a minimum of three months of follow-up. At the time of interim analysis, 11 patients with PMBCL/TFL had been followed for three months. An additional 31 patients with one month of follow-up were included in the late breaker presentation.

"The vast majority of patients enrolled in ZUMA-1 are unable to undergo autologous stem cell transplant due to chemorefractory disease. This group has a dire need for more effective therapies," said Jeff Wiezorek, M.D., Senior Vice President of Clinical Development. "We are encouraged by the high rate of complete remissions in this group and look forward to presenting longer follow-up at the primary analysis in the first quarter 2017. We are grateful to the patients and investigators who have made this important study possible."

ZUMA-1 met the primary endpoint of objective response rate (ORR), p < 0.0001. Response rates by disease subtype are shown in the table below. Responses were observed across key subgroups, including 75 percent CR in patients who relapsed in ≤12 months after autologous stem cell transplant and 47 percent CR in patients refractory to second line or later chemotherapy. At the month three assessment, 39 percent of patients were in CR.

Best Overall Response in Patients with ≥3 Month Follow-up
Subgroup
N ORR CR
DLBCL
51 76% 47%
TFL / PMBCL 11 91% 73%
Total 62 79% 52%
In 93 patients with a minimum one month follow-up, the most common grade 3 or higher adverse events included neutropenia (63 percent), anemia (42 percent), leukopenia (40 percent), febrile neutropenia (29 percent), thrombocytopenia (26 percent), encephalopathy (19 percent), hypophosphatemia (17 percent), and decreased lymphocyte count (17 percent). Grade 3 or higher CRS and NE were observed in 13 percent and 29 percent of patients, respectively. Three patients died from treatment-emergent adverse events (hemophagocytic lymphohistiocytosis, cardiac arrest in the setting of CRS and pulmonary embolism). There were no cases of cerebral edema.

The primary analysis of ZUMA-1 will include a minimum of 6 months of follow-up. Kite intends to seek regulatory approval of axicabtagene ciloleucel in refractory aggressive NHL and plans to complete its rolling submission of the Biologics License Application (BLA) in the first quarter of 2017.

The late-breaker abstract (LBA-6), "KTE-C19 (anti-CD19 CAR T Cells) Induces Complete Remissions in Patients with Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Results from the Pivotal Phase 2 ZUMA-1," was presented by Sattva S. Neelapu, M.D., Associate Professor, Deputy Department Chair ad interim, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. View Source

About axicabtagene ciloleucel

Kite Pharma’s lead product candidate, axicabtagene ciloleucel, is an investigational therapy in which a patient’s T cells are engineered to express a chimeric antigen receptor (CAR) to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias, and redirect the T cells to kill cancer cells. Axicabtagene ciloleucel has been granted Breakthrough Therapy Designation status for diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL) by the U.S. Food and Drug Administration (FDA) and Priority Medicines (PRIME) regulatory support for DLBCL in the EU.

On December 6, 2016 Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical stage biotechnology company focused on the development of novel cancer therapeutics, reported that clinical data from its lead product candidate CB-839, a first-in-class glutaminase inhibitor, will be presented at the 2016 San Antonio Breast Cancer Symposium, December 6-10, 2016 in San Antonio, Texas (Press release, Calithera Biosciences, DEC 6, 2016, View Source;p=RssLanding&cat=news&id=2227919 [SID1234516955]). The data demonstrate the clinical activity, tolerability and unique mechanism of action of CB-839 in patients with advanced/metastatic triple negative breast cancer (TNBC).

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"Triple negative breast cancer in the advanced and metastatic population remains a significant unmet need. We are particularly pleased to observe responses with CB-839 plus paclitaxel in taxane-refractory patients," said Susan Molineaux, PhD, President and Chief Executive Officer of Calithera.

Dr. Angela DeMichele from the University of Pennsylvania will present in a poster session, "Phase I study of CB-839, a small molecule inhibitor of glutaminase, in combination with paclitaxel in patients with triple negative breast cancer," (Abstract P6-11-05). The abstract was selected for presentation on Saturday, December 10, 2016. Eligible patients must have locally advanced/metastatic TNBC, with prior paclitaxel treatment allowed. As of November 25, 2016, 28 triple negative breast cancer patients had been treated with doses of CB-839 of 400, 600 or 800 mg bid in combination with 80 mg/m2 IV paclitaxel, weekly, three weeks out of four; 23 were evaluable for response. The majority of patients had received at least three prior lines of therapy, with 43% of patients treated with five or more prior therapies in the advanced/metastatic setting. Most patients had received prior taxane therapy in either the neo-adjuvant or metastatic setting. Among evaluable patients treated with CB-839 doses of at least 600 mg bid (n=16), there are 5 partial responses (31%) and disease control (response or stable disease) in 11 patients (69%). In addition, the combination overcomes resistance to paclitaxel in heavily pretreated TNBC patients. There is a 38% response rate and 50% disease control rate in patients who received prior taxanes in the metastatic setting. There is a 50% response rate among taxane-refractory African American patients, consistent with higher glutamine utilization observed in tumors from this population.1

The combination of CB-839 and paclitaxel has been well tolerated to date, with adverse events that have been easily manageable and reversible, including several paclitaxel related toxicities. There was one case of dose-limiting, recurrent grade 3 neutropenia at the 400 mg dose level, which led to a reduction in the dose of paclitaxel for that patient. The most frequent adverse event ≥ Grade 3 is neutropenia (n=6).

On December 6, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that updated findings from the phase 1b KEYNOTE-028 study investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in previously treated patients with advanced small cell lung cancer (SCLC) and malignant pleural mesothelioma, showed clinical activity and durable responses in some patients (Press release, Merck & Co, DEC 6, 2016, View Source [SID1234516954]). These data were featured in oral presentations at the 17th World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer.

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"As data from our initial trials exploring KEYTRUDA mature, we are encouraged to see durable clinical activity in difficult-to-treat cancers such as small cell lung cancer and malignant pleural mesothelioma, where new treatments are clearly needed," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "With our extensive immuno-oncology research program, we are developing KEYTRUDA across a range of thoracic malignancies, and we have additional studies underway in these two cancer types."

KEYNOTE-028 is an ongoing multi-cohort, non-randomized Phase 1b basket trial evaluating the safety, tolerability, and anti-tumor activity of KEYTRUDA monotherapy (10 mg/kg dosed every two weeks) in more than 450 patients with PD-L1 positive tumors across 20 different types of cancer. PD-L1 positivity was defined as expression in one percent or more of tumor and associated inflammatory cells or positive staining in stroma. The primary outcome measure is overall response rate (ORR), with secondary outcome measures of progression-free survival (PFS), overall survival (OS), and duration of response.

The KEYTRUDA (pembrolizumab) clinical development program includes more than 30 tumor types in nearly 400 clinical trials, including more than 200 trials that combine KEYTRUDA with other cancer treatments. Merck has initiated a phase 2 trial, KEYNOTE-158, to further evaluate KEYTRUDA in advanced solid tumors including SCLC and malignant pleural mesothelioma.

Results from KEYNOTE-028 SCLC Cohort (Abstract #OA05.01)

Data from the SCLC cohort of the KEYNOTE-028 trial were presented in an oral presentation on Dec. 5 by Dr. Patrick Ott, Dana-Farber Cancer Institute.

Updated findings from 24 heavily pre-treated patients with advanced SCLC demonstrated a confirmed ORR of 33.3 percent (n=8/24) (95% CI, 15.6%-55.3%), including one complete response and seven partial responses. One patient had stable disease and 13 patients had progressive disease. Responses were durable, with a median duration of response of 19.4 months (95% CI, range: 3.6+ to 20.0+).

Additionally, the median PFS was 1.9 months (95% CI, 1.7-5.9), with a six-month PFS rate of 28.6 percent and 12-month PFS rate of 23.8 percent. The median OS was 9.7 months (95% CI, 4.1-NR), with a six-month OS rate of 66.0 percent and a 12-month OS rate of 37.7 percent.

The safety profile of KEYTRUDA was consistent with that observed in previously reported studies. Grade 3-5 treatment-related adverse events were asthenia, blood bilirubin increased, colitis and intestinal ischemia (n=1 for all). Some patients experienced adverse events of special interest, including autoimmune thyroiditis, infusion site reaction, cytokine release syndrome and colitis (n=1 for all).

"These long-term data, which show meaningful response rates and durable responses in certain patients with small cell lung cancer, are encouraging," said Dr. Ott. "With these findings, we are advancing understanding of the potential for immunotherapy to make a difference for these patients."

Results from KEYNOTE-028 Malignant Pleural Mesothelioma Cohort (Abstract #OA13.03)

Data from the malignant pleural mesothelioma cohort of the KEYNOTE-028 trial were presented in an oral presentation on Dec. 6 by Dr. Evan Alley, Abramson Cancer Center, University of Pennsylvania.

Results showed a confirmed ORR of 20.0 percent (n=5/25) (95% CI, 6.8-40.7). All responses were partial responses and 13 patients had stable disease. The median duration of response was 12.0 months (range, 3.7-20.5+). In total, 60.9 percent of evaluable patients experienced a decrease in tumor size.

Additionally, the median PFS was 5.4 months (95% CI, 3.4-7.5), with a six-month PFS rate of 45.8 percent and a 12-month PFS rate of 20.8 percent. Median OS was 18.0 months (95% CI, 9.4-NR), with a six-month OS rate of 83.5 percent and a 12-month OS rate of 62.6 percent.

The safety profile of KEYTRUDA (pembrolizumab) was consistent with that observed in previously reported studies. Grade 3 treatment-related adverse events were ALT increase, appetite decrease, dyspnea, iridocyclitis, neutrophil count decreased, pyrexia and thrombocytopenia (n=1 for all). Some patients experienced adverse events of special interest, including erythema/erythema multiforme, hypothyroidism, infusion-related reaction, iridocyclitis and rhabdomyolysis (n=1 for all). There were no Grade 4 or 5 treatment-related adverse events and no treatment-related deaths.

About KEYTRUDA (pembrolizumab)

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

KEYTRUDA is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single use vial.

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA (pembrolizumab) is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

KEYTRUDA (pembrolizumab) can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3 (0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA (pembrolizumab) and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

In KEYNOTE-002, KEYTRUDA was discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA (pembrolizumab) occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculopapular rash (1%). The most common adverse reactions with KEYTRUDA vs chemotherapy were fatigue (43% with KEYTRUDA), pruritus (28% vs 8%), rash (24% vs 8%), constipation (22% vs 20%), nausea (22% with KEYTRUDA), diarrhea (20% vs 20%), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

KEYTRUDA was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).

KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (reported in at least 20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3 or 4) and new or worsening hypothyroidism.

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes nearly 400 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.