2013-12-10 14:33:01 -
Celgene International Sàrl, a wholly-owned subsidiary of Celgene Corporation (NASDAQ:CELG) today announced that updated analyses from MM-003, the company’s phase III study of pomalidomide plus low-dose dexamethasone compared with high-dose dexamethasone in patients with refractory multiple myeloma who have failed therapy with both bortezomib and lenalidomide, administered either alone or in combination were presented at the American Society of Hematology Annual Meeting in New Orleans, La. Pomalidomide is marketed as POMALYST® in the United States and IMNOVID® in the European Union.
It was previously reported that with a median follow-up of 10 months, pomalidomide plus low-dose dexamethasone significantly extended progression-free survival (PFS) (4.0 months vs 1.9 months, HR= 0.48, p<0.001) and overall survival (OS) (12.7 months vs 8.1 months, HR= 0.74,
p<0.028) compared with high-dose dexamethasone. The OS benefit was observed despite 50% of the patients in the high-dose dexamethasone arm receiving subsequent pomalidomide. The overall response rate (ORR) for the pomalidomide plus low-dose dexamethasone arm and high-dose dexamethasone arm was 31% vs. 10% (P < 0.001), respectively. The results were published in The Lancet Oncology in September 2013.
In a retrospective analysis, the increases in ORR and median PFS were maintained for pomalidomide plus low-dose dexamethasone compared with high-dose dexamethasone regardless of modified high-risk cytogenetics (del (17p) or t(4;14)) (ORR: 25% vs. 9%, P=0.071; PFS: 3.8 vs. 1.1 months, HR=0.44, P<0.001) or standard-risk cytogenetics (ORR: 35% vs.
10%, P<0.001; PFS: 4.2 vs. 2.3 months, HR=0.55, P<0.001). Numerical increases in median OS were observed regardless of cytogenetics (modified high risk: 9.9 vs. 4.9 months, HR=0.67, P=0.092; standard risk: 14.1 vs 9 months, HR=0.85, P=0.38). Of note, 46% of patients receiving high-dose dexamethasone with high-risk and 64% of patients receiving high-dose dexamethasone with standard-risk cytogenetics received subsequent pomalidomide.
In another retrospective analysis of MM-003 the effect of prior therapies on study outcomes was evaluated. The median number of prior therapies was 5 (range, 2-17). Most patients (75%) were refractory to both bortezomib and lenalidomide. In patients who received pomalidomide plus low-dose dexamethasone, the overall response rate for patients who had at least three prior therapies (n=70) was 26% with 4% of those patients achieving at least a very good partial response. For patients who received pomalidomide plus low-dose dexamethasone and had less than three prior therapies (n=232), the overall response rate was 34% with 8% of patients achieving at least a very good partial response. The hazard ratio for risk of disease progression for pomalidomide plus low-dose dexamethasone compared with high-dose dexamethasone was HR=0.63 (0.40-1.00) for patients with up to three prior therapies and HR=0.45 (0.35-0.57) for patients with more than three prior therapies. The hazard ratio for risk of death for pomalidomide plus low-dose dexamethasone compared with high-dose dexamethasone was HR=0.56 (0.33-0.96) for patients with at least three prior therapies and HR=0.76 (0.58-1.00) for patients with up to three prior therapies.
In the primary analysis, the most frequent grade 3/4 adverse events (AEs) for pomalidomide plus low-dose dexamethasone compared with high-dose dexamethasone were neutropenia (48% vs. 16%), anemia (33% vs.
37%), and infections (30% vs. 24%). Grade 3/4 deep-vein thrombosis/pulmonary embolism was infrequent (1% vs. 0%). Only 1% of patients in each arm experienced grade 3/4 peripheral neuropathy.
Discontinuation due to AEs was 9% vs 10%.
In the MM-003 study, 455 patients who were refractory to their last prior therapy (progressive disease during therapy or within 60 days) and exhausted bortezomib and lenalidomide alone or in combination were randomized 2:1 to receive 28-day cycles of pomalidomide 4 mg on days 1-21 + dexamethasone 40 mg (20 mg for patients older than 75 years) weekly or dexamethasone 40 mg (20 mg for pts older than 75 years) on days 1-4, 9-12, and 17-20. The primary endpoint of the study was progression-free survival and secondary endpoints included overall survival, response rate and safety.
About POMALYST ®
POMALYST ® oral therapy comprises pomalidomide, an IMiDs ® compound.
POMALYST and other IMiDs compounds continue to be evaluated in over 100 clinical trials.
POMALYST ® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.
Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.
U.S. Regulatory Information for Pomalyst
Important Safety Information
WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM
- 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 TM .
- Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors
- POMALYST can cause fetal harm 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 a fetus
- Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis.
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 the drug 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 distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists 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 [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.
Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%.
Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.
Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia.
Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.
Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.
Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.
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.
In the clinical trial MM-002 of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction.
- In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%,22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%)
- 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction
- In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion
- 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction
- In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%),urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)
No formal drug interaction studies have been conducted with POMALYST.
Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. 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 greater than or equal to 65 years of age were more likely than patients less than or equal to 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 U.S. Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.
POMALYST (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate in the MM-002 clinical trial. Clinical benefit, such as improvement in survival or symptoms, has not been verified.
Celgene International Sàrl, located in Boudry, in the Canton of Neuchâtel, Switzerland, is a wholly-owned subsidiary and international headquarters of Celgene Corporation. Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global pharmaceutical 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 the Company's website at www.celgene.com : cts.businesswire.com/ct/CT?id=smartlink&url=http%3A%2F%2Fwww ..
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