Program starting with four studies of durvalumab and combination therapies across multiple hematologic disorders
SUMMIT, N.J.--(BUSINESS WIRE)--Celgene Corporation (NASDAQ:CELG) and AstraZeneca (NYSE:AZN), today announced 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.
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 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.
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
POMALYST is only available through a restricted distribution program called POMALYST REMS®.
Venous and Arterial Thromboembolism
- 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
- 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.
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%).
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
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
- 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.
- 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 should be advised to discontinue nursing or the drug, taking into consideration the importance of the drug to the mother
- 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%)
Please see full Prescribing Information
Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global biopharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation. For more information, please visit www.celgene.com. Follow us on Twitter @Celgene, and on Facebook, Pinterest and LinkedIn.
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