On December 6, 2015 Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) reported the outcomes of two Phase 3 cancer studies (MAESTRO and TH-CR-406/SARC021) of evofosfamide (previously known as TH-302), an investigational hypoxia-activated prodrug, which is being evaluated for first-line treatment of advanced pancreatic adenocarcinoma and advanced soft tissue sarcoma, in combination with chemotherapy (Filing, 8-K, Threshold Pharmaceuticals, DEC 7, 2015, View Source [SID:1234508460]).

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The Phase 3 studies are being conducted under Threshold’s collaboration with Merck KGaA, Darmstadt, Germany.

In the Phase 3 MAESTRO study, patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma treated with evofosfamide in combination with gemcitabine did not demonstrate a statistically significant improvement in overall survival (OS) compared with gemcitabine plus placebo (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.71 – 1.01; p=0.0589).

In the Phase 3 TH-CR-406/SARC021 study being conducted in collaboration with the Sarcoma Alliance for Research through Collaboration (SARC), patients with locally advanced unresectable or metastatic soft tissue sarcoma treated with evofosfamide in combination with doxorubicin did not demonstrate a statistically significant improvement in OS compared with doxorubicin alone (HR: 1.06; 95% CI: 0.88 – 1.29).

Patient safety was monitored in MAESTRO and TH-CR-406/SARC021 by independent data monitoring committees throughout the conduct of each study. No new clinically significant safety findings were observed.

Detailed results from both studies will be submitted for presentation at upcoming international scientific meetings and for publication in peer-reviewed journals. Threshold will not be pursing further development of evofosfamide in soft tissue sarcoma and pancreatic cancer.

"We are surprised and disappointed that these studies did not show that evofosfamide could extend the lives of patients with these two difficult-to-treat diseases," said Barry Selick, Ph.D., Chief Executive Officer at Threshold. "Threshold has been pursuing evofosfamide for over ten years in collaboration with world-class scientists and investigators throughout the world. While we believe there remains substantial data to support the role of hypoxia in cancer treatment resistance, we are deeply frustrated with our inability in these trials to impact that in a meaningful way. I would like to thank all of the patients and their families, and the physicians, nurses, and support staff who participated in these studies."

Conference Call and Webcast
At 8:30 a.m. Eastern Time on Monday December 7, 2015, Threshold’s management will host a conference call and a simultaneous webcast. The webcast can be accessed on the company’s website in the Investors/Webcasts section View Source Alternatively, please call 1- (888) 767-9745 (U.S) or (440) 996-5547 (international). The conference ID number is 99761325. The webcast will be archived on Threshold’s website for at least 30 days.

About TH-CR-406/SARC021
TH-CR-406/SARC021 is a randomized, open-label, global, multicenter Phase 3 study, that was designed to assess the efficacy and safety of evofosfamide (300 mg/m2) in combination with doxorubicin (75 mg/m2) compared with doxorubicin alone, in patients with locally advanced unresectable or metastatic soft tissue sarcoma previously untreated with chemotherapy. A total of 640 patients were randomized in the study. The primary endpoint of the study is OS. Secondary endpoints include progression-free survival (PFS), response rate, safety and pharmacokinetics.

About MAESTRO
MAESTRO (MetAstatic or unrESectable pancreaTic adenocaRcinOma) is a randomized, placebo-controlled, international, multicenter, double-blind Phase 3 study, that was designed to assess the efficacy and safety of evofosfamide (340 mg/m2) in combination with gemcitabine (1000 mg/m2), compared with gemcitabine and placebo, in patients with previously untreated, locally advanced, unresectable or metastatic pancreatic adenocarcinoma. A total of 693 patients were randomized in the study. The primary endpoint of the study is OS. Secondary endpoints include PFS, overall response rate, disease control rate, quality of life based on patient-reported outcomes, safety and tolerability, pharmacokinetics and biomarkers.

About Evofosfamide
Evofosfamide (previously known as TH-302) is an investigational hypoxia-activated prodrug of a
bis-alkylating agent that is preferentially activated under severe hypoxic tumor conditions, a feature of many solid tumors. Areas of low oxygen levels (hypoxia) in solid tumors are due to insufficient blood vessel supply. Similarly, the bone marrow of patients with hematological malignancies has also been shown, in some cases, to be severely hypoxic.

Evofosfamide is being studied in patients with locally advanced unresectable or metastatic soft tissue sarcoma and in patients with locally advanced unresectable or metastatic pancreatic cancer. Evofosfamide is also being investigated in a Phase 2 study designed to support registration for the treatment of non-squamous non-small cell lung cancer, and in earlier-stage clinical studies of other solid tumors and hematological malignancies.
Threshold has a global license and co-development agreement for evofosfamide with Merck KGaA, Darmstadt, Germany.

On December 7, 2015 Celgene Corporation (NASDAQ:CELG) and AstraZeneca (NYSE:AZN), reported the initiation of the FUSION clinical development program of durvalumab (MEDI4736), an investigational human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1) in hematologic disorders (Press release, Celgene, DEC 7, 2015, View Source [SID:1234508448]).

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The FUSION program is part of a strategic collaboration with AstraZeneca and its global biologics research and development arm MedImmune, to develop and commercialize durvalumab across a range of blood cancers including non-Hodgkin’s lymphoma, myelodysplastic syndromes and multiple myeloma.

The program will initially include four studies:

MM-001 – A phase 1b multicenter, open-label study to determine the recommended dose and regimen of durvalumab as a monotherapy or in combination with pomalidomide with or without low-dose dexamethasone in patients with relapsed/refractory multiple myeloma

CC-486-MDS-006 – A phase 2 international, multicenter, randomized, open-label, parallel-group study to evaluate the efficacy and safety of CC-486 alone or in combination with durvalumab in patients with MDS who fail to achieve an objective response to treatment with azacitidine for injection or decitabine

MEDI4736 -NHL-001 – A phase 1/2 open-label, multicenter study to assess the safety and tolerability of durvalumab as monotherapy and in combination therapy in patients with lymphoma or chronic lymphocytic leukemia

MEDI4736-MDS-001 – A randomized, multicenter, open-label phase 2 study evaluating the efficacy and safety of azacitidine subcutaneous in combination with durvalumab in previously untreated patients with higher-risk myelodysplastic syndromes or in elderly (≥ 65 years) acute myeloid leukemia subjects not eligible for hematopoietic stem cell transplantation

"The initiation of the FUSION program represents an important step forward in Celgene’s development of immuno-oncology approaches in hematologic disease," said Robert Hershberg, M.D., Ph.D., Celgene’s Senior Vice President, Immuno-Oncology. "Checkpoint inhibitors hold tremendous promise in the treatment of cancer and we believe Celgene’s deep experience in hematology allows us unique perspective on this growing area of clinical research."

"We’re pleased with the rapid start of the first clinical trials in the FUSION development program through our strategic partnership with Celgene," Robert Iannone, Senior Vice President, Head of Immuno-oncology, Global Medicines Development at AstraZeneca. "Durvalumab is a highly promising investigational immunotherapy for a range of tumour types and we look forward to exploring its potential as a PD-L1 inhibitor for patients with blood cancers, for whom current treatment choices are limited."

The Celgene partnership with AstraZeneca/MedImmune is part of a comprehensive commitment to immuno-oncology that includes not only clinical-stage checkpoint inhibitors and t-cell activators, but also earlier stage research efforts on the tumor microenvironment focused on tumor-associated macrophages, monocytes, natural killer cells and regulatory T cells.

For more information about the FUSION clinical program, visit booth #505 at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, FL.

About durvalumab (MEDI4736)

Durvalumab is an investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1). Signals from PD-L1 help tumours avoid detection by the immune system. Durvalumab blocks these signals, countering the tumour’s immune-evading tactics. Durvalumab is being investigated in an extensive clinical trial programme, as monotherapy or in combination in multiple cancer types.

Durvalumab is an investigational product and has not been approved for any use.

About POMALYST

In the U.S., POMALYST (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

U.S. Regulatory Information for POMALYST

Important Safety Information
WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity

POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment.
Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment.
POMALYST is only available through a restricted distribution program called POMALYST REMS.

Venous and Arterial Thromboembolism

Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Prophylactic antithrombotic measures were employed in clinical trials. Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.

CONTRAINDICATIONS: Pregnancy

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

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity

Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy
Males: Pomalidomide 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 POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm
Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of POMALYST therapy because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST
POMALYST REMS Program
Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called "POMALYST REMS." Prescribers and pharmacies must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436.

Venous and Arterial Thromboembolism: Venous thromboembolic events (DVT and PE) and arterial thromboembolic events (ATE) (myocardial infarction and stroke) have been observed in patients treated with POMALYST. In Trial 2, where anticoagulant therapies were mandated, thromboembolic events occurred in 8.0% of patients treated with POMALYST and low dose-dexamethasone (Low-dose Dex) vs 3.3% treated with high-dose dexamethasone. Venous thromboembolic events (VTE) occurred in 4.7% of patients treated with POMALYST and Low-dose Dex vs 1.3% treated with high-dose dexamethasone. Arterial thromboembolic events include terms for arterial thromboembolic events, ischemic cerebrovascular conditions, and ischemic heart disease. Arterial thromboembolic events occurred in 3.0% of patients treated with POMALYST and Low-dose Dex vs 1.3% treated with high-dose dexamethasone. 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).

Hematologic Toxicity: In trials 1 and 2 in patients who received POMALYST + Low-dose Dex, neutropenia (46%) was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly therafter. Patients may require dose interruption and/or modification.

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with POMALYST. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST. Monitor liver function tests monthly. Stop POMALYST upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.

Hypersensitivity Reactions: Angioedema and severe dermatologic reactions have been reported. Discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe dermatologic reactions, and do not resume therapy.

Dizziness and Confusional State: In trials 1 and 2 in patients who received POMALYST + Low-dose Dex, 14% experienced dizziness and 7% a confusional state; 1% of patients experienced Grade 3 or 4 dizziness and 3% experienced a Grade 3 or 4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.

Neuropathy: In trials 1 and 2, patients who received POMALYST + Low-dose Dex experienced neuropathy (18%) and peripheral neuropathy (~12%). In trial 2, 2% of patients experienced Grade 3 neuropathy.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) may occur in patients treated with POMALYST. Patients at risk are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

ADVERSE REACTIONS

Nearly all patients treated with POMALYST + Low-dose Dex experienced at least one adverse reaction (99%). In trial 2, the most common adverse reactions included neutropenia (51.3%), fatigue and asthenia (46.7%), upper respiratory tract infection (31%), thrombocytopenia (29.7%), pyrexia (26.7%), dyspnea (25.3%), diarrhea (22%), constipation (21.7%), back pain (19.7%), cough (20%), pneumonia (19.3%), edema peripheral (17.3%), peripheral neuropathy (17.3%), bone pain (18%), nausea (15%), and muscle spasms (15.3%). Grade 3 or 4 adverse reactions included neutropenia (48.3%), thrombocytopenia (22%), and pneumonia (15.7%).

DRUG INTERACTIONS

Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Avoid the use of strong CYP1A2 inhibitors. If medically necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, reduce POMALYST dose by 50%. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS

Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established.

Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients > 65 years of age were more likely than patients ≤ 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine > 3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin > 2.0 mg/dL and AST/ALT > 3.0 x ULN.

Please see full Prescribing Information, including Boxed WARNINGS

About VIDAZA

VIDAZA (azacitidine for injection) is indicated for treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS:

VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol and in patients with advanced malignant hepatic tumors

WARNINGS AND PRECAUTIONS:

Anemia, Neutropenia and Thrombocytopenia:

Because treatment with VIDAZA causes anemia, neutropenia, and thrombocytopenia, monitor complete blood counts frequently for response and/or toxicity, at a minimum, prior to each dosing cycle

VIDAZA Toxicity in Patients with Severe Pre-existing Hepatic Impairment:

Because azacitidine is potentially hepatotoxic in patients with severe preexisting hepatic impairment, caution is needed in patients with liver disease.

Renal Toxicity:

Azacitidine and its metabolites are primarily excreted by the kidneys and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. These patients, including the elderly should be closely monitored for toxicity

Use in Pregnancy:

VIDAZA may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be apprised of the potential hazard to the fetus. Men should be advised not to father a child while receiving VIDAZA
USE IN SPECIFIC POPULATIONS:

Nursing Mothers:

Nursing mothers should be advised to discontinue nursing or the drug, taking into consideration the importance of the drug to the mother

ADVERSE REACTIONS:

In Studies 1 and 2, the most commonly occurring adverse reactions by SC route were nausea (70.5%), anemia (69.5%), thrombocytopenia (65.5%), vomiting (54.1%), pyrexia (51.8%), leukopenia (48.2%), diarrhea (36.4%), injection site erythema (35.0%), constipation (33.6%), neutropenia (32.3%), and ecchymosis (30.5%). Other adverse reactions included dizziness (18.6%), chest pain (16.4%), febrile neutropenia (16.4%), myalgia (15.9%), injection site reaction (13.6%), and malaise (10.9%). In Study 3, the most common adverse reactions by IV route also included petechiae (45.8%), weakness (35.4%), rigors (35.4%), and hypokalemia (31.3%)
In Study 4, the most commonly occurring adverse reactions were thrombocytopenia (69.7%), neutropenia (65.7%), anemia (51.4%), constipation (50.3%), nausea (48.0%), injection site erythema (42.9%), and pyrexia (30.3%). The most commonly occurring Grade 3/4 adverse reactions were neutropenia (61.1%), thrombocytopenia (58.3%), leukopenia (14.9%), anemia (13.7%), and febrile neutropenia (12.6%)

On December 7, 2015 Celgene Corporation (NASDAQ:CELG) and Acceleron Pharma Inc. (NASDAQ:XLRN) reported that the United States Food and Drug Administration (FDA) has granted Fast Track Designation to luspatercept for the treatment of anemia in patients with lower-risk myelodysplastic syndromes (MDS) (Press release, Acceleron Pharma, DEC 7, 2015, View Source [SID:1234508446]). The Fast Track program of the FDA is designed to facilitate the development, and expedite the review, of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

Celgene and Acceleron are developing luspatercept to treat patients with rare blood disorders, including MDS and beta-thalassemia. For people with MDS, a type of blood cancer, anemia is a challenging clinical complication of the disease. Patients receive chronic red blood cell transfusions as standard of care to manage the anemia. Luspatercept is designed to increase red blood cell levels in a way that is fundamentally distinct from existing therapies, and has the potential to treat anemia in patients whose disease is not adequately addressed by the treatments available today.

“The FDA’s Fast Track Designation for luspatercept recognizes the serious unmet medical needs of patients with MDS,” said Jacqualyn A. Fouse, President, Hematology/Oncology for Celgene. “Celgene and Acceleron are working to initiate a Phase 3 clinical program to investigate the treatment of patients with low- and intermediate- risk MDS before the end of the year.”

The Companies previously announced FDA Fast Track Designation for luspatercept to treat beta-thalassemia.

About Luspatercept

Luspatercept is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the Transforming Growth Factor-Beta (TGF-beta) superfamily involved in the late stages of erythropoiesis (red blood cell production). Luspatercept is thought to regulate late-stage erythrocyte (red blood cell) precursor cell differentiation and maturation. This mechanism of action is distinct from that of erythropoietin (EPO), which stimulates the proliferation of early-stage erythrocyte precursor cells. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. Acceleron and Celgene are initiating phase 3 clinical trials that are designed to evaluate the safety and efficacy of luspatercept in patients with myelodysplastic syndromes (the “MEDALIST” study) and in patients with beta-thalassemia (the “BELIEVE” study). For more information, please visit www.clinicaltrials.gov.

About Myelodysplastic Syndromes

MDS comprise a heterogeneous group of hematologic malignancies of the bone marrow commonly leading to severe and chronic anemia due to ineffective erythropoiesis. The National Cancer Institute estimates that more than 10,000 people are diagnosed with MDS in the United States each year. Patients with MDS often have a hypercellular bone marrow with various dysplastic changes of the cells that are also seen in peripheral blood, resulting in cytopenias (low blood cell counts) and an increased risk of progression to acute myeloid leukemia. Nearly all MDS patients suffer from anemia. The anemia in MDS is often characterized by high endogenous levels of EPO driving an abundance of early stage red blood cell precursors and an inability of these precursor cells to properly differentiate into healthy, functional red blood cells. Many patients are therefore unresponsive to the administration of erythropoietin to correct the resulting anemia and instead require red blood cell transfusions, which can increase the risk of infection and iron-overload related toxicities.

On December 7, 2015 Kite Pharma, Inc. (Nasdaq:KITE) reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation status to the Company’s lead product candidate, KTE-C19, for the treatment of patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B cell lymphoma (PMBCL), and transformed follicular lymphoma (TFL) (Press release, Kite Pharma, DEC 7, 2015, View Source [SID:1234508441]).

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KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a chimeric antigen receptor designed to target the antigen CD19, a protein expressed on the cell surface of B cell lymphomas and leukemias.

"The FDA’s designation of KTE-C19 as a breakthrough therapy recognizes the potential for KTE-C19 to address the unmet need for patients with refractory DLBCL, PMBCL, and TFL," noted Arie Belldegrun, M.D., FACS, Chairman, President, and Chief Executive Officer. "We are pleased to receive this designation and look forward to working more closely with the FDA as we continue to advance our program for KTE-C19."

Breakthrough Therapy Designation is granted by the FDA to expedite the development and review of new therapies to treat serious or life-threatening conditions. The criteria for Breakthrough Therapy Designation require preliminary clinical evidence that demonstrates the therapy may have substantial improvement on at least one clinically significant endpoint over available therapy. This designation conveys all fast track program features, as well as more intensive FDA guidance on an efficient drug development program and eligibility for rolling review and priority review.

On December 7, 2015 Roche (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, Hoffmann-La Roche , DEC 7, 2015, View Source [SID:1234508439]).

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Results of the study showed a clinically meaningful reduction in the number of cancer cells (overall response rate, ORR) in 79.4 percent of people with previously treated (relapsed or refractory) chronic lymphocytic leukaemia (CLL) with 17p deletion. No unexpected safety signals were reported for venetoclax.
"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 leukaemia," 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 tumour 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 leukaemia (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 chronic lymphocytic leukaemia harbouring 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, multi-centre study evaluating the efficacy and safety of venetoclax in patients with relapsed, refractory or previously untreated CLL harbouring 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 people.

About Study M12-175
M12-175 (NCT01328626) is a Phase I, open-label, multi-centre study of venetoclax in people with relapsed or refractory chronic lymphocytic leukaemia (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. The level of minimal residual disease (MRD) in peripheral blood and/or bone marrow was assessed in people with CLL.

About Chronic Lymphocytic Leukaemia (CLL)
CLL is a slow-growing cancer of the blood and bone marrow that is generally considered incurable and is one of the most common adult leukaemias worldwide.1,2 Most cases of CLL (95 percent) start in white blood cells called B-cells.1 In certain cases of CLL, a part of chromosome 17 is lost and along with it an important gene that controls apoptosis called p53.3 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.4

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 signalling 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 leukaemia (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 leukaemia (AML) and multiple myeloma (MM).