Celgene International Sàrl, a subsidiary of Celgene Corporation (Nasdaq:CELG) announced data from a sub-analysis of a Phase II, multicenter, international, open-label study of ISTODAX (romidepsin) in refractory or relapsed PTCL following prior systemic therapy were presented by Professor Bertrand Coiffier, Hospices Civils de Lyon and Université Lyon1, Lyon, France at the 53rd American Society of Hematology Annual Meeting.
In the study, 131 patients received 14 mg/m2 of ISTODAX as a 4-hour intravenous infusion on days 1, 8 and 15 of a 28-day cycle for up to six cycles. Treatment could be extended beyond six cycles in patients who achieved response or had stable disease. Efficacy assessments were made by an Independent Review Committee (IRC) and consisted of an initial radiographic review of images using computed tomography (CT) or magnetic resonance imaging (MRI) followed by an overall clinical assessment based on radiologic evaluations, photographs, and relevant clinical parameters.
The sub-analysis assessed the efficacy and safety of romidepsin in the most common subtypes of PTCL: PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic lymphoma kinase-1"´negative anaplastic large cell lymphoma (ALK-1"´negative ALCL). Of the 130 patients with histologically-confirmed PTCL by central review, 117 had a more common subtype, including PTCL-NOS (n=69), AITL (n=27) and ALK-1"´negative ALCL (n=21).
Overall response rates (ORR) consisting of confirmed and unconfirmed complete responses and partial responses (CR+CRu+ PR) were similar across the three most common subtypes: 29% (20/69) of patients with PTCL-NOS, 30% (8/27) of patients with AITL and 24% (5/21) of patients with ALK-1"´negative ALCL. Similar rates of complete response (CR/CRu), the primary study endpoint, were also observed across the three most common subtypes: 14% (10/69), 19% (5/27) and 19% (4/21) for PTCL-NOS, AITL and ALK-1-negative ALCL, respectively. Disease control (defined as ORR + stable disease [SD] of 90 days or longer) was noted in 46% (54/117) of patients with the most common PTCL subtypes with 49% (34/69), 44% (12/27), and 38% (8/21) for PTCL-NOS, AITL, and ALK-1-negative ALCL, respectively.
With a median follow-up of 21 months, the median duration of response (DOR) for all responders (CR+CRu+PR) was 17 months. For patients with PTCL-NOS and ALK-1"´negative ALCL the median DOR was 17 months and 12 months, respectively. Median DOR was not yet evaluable for patients with AITL, who had the longest DOR ongoing at 34 months.
The most common (? 10%) grade 3 or higher adverse events among patients with PTCL-NOS, AITL and ALK-1-negative ALCL subtypes included: thrombocytopenia (22% [15/69], 30% [8/27], 29% [6/21]), neutropenia (17% [12/69], 22% [6/27], 14% [3/21]), infections (13% [9/69], 22% [6/27], 14% [3/21]) and anemia (6% [4/69], 15% [4/27], 10% [2/21]). Romidepsin was discontinued due to infection in 1 patient with PTCL-NOS and 3 patients with ALK-1"´negative ALCL.
About ISTODAX
ISTODAX® (romidepsin) is a member of a class of cancer drugs known as histone deacetylase (HDAC) inhibitors. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate non-histone proteins, such as transcription factors. HDAC inhibitors can be divided into four main classes: cyclic tetrapeptides (I), short-chain fatty acids (II), hydroxamic acids (III), and benzamides (IV). The cyclic peptide structure of ISTODAX is novel among the cyclic tetrapeptides. In vitro, ISTODAX causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of some cancer cell lines. For full prescribing information, visit www.ISTODAX.com.
Important U.S. Safety Information
ISTODAX(R) (romidepsin) for injection is indicated for treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.
ISTODAX(R) (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.
These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.
Important Safety Information
WARNINGS AND PRECAUTIONS:
- Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary
- Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy.
- Electrocardiographic (ECG) changes have been observed with ISTODAX
- In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment
- Due to the risk of QT prolongation, ensure that potassium and magnesium are within the normal range before administration
- Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate
- Based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D)
- ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives
ADVERSE REACTIONS:
Peripheral T-Cell Lymphoma
- The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (n=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (n=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%).
- Infections were the most common type of serious adverse event reported in Study 3 (n=131) and Study 4 (n=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections.
- The most common adverse reactions regardless of causality in Study 3 (n=131) were nausea (59%), asthenia/fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (n=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).
Cutaneous T-Cell Lymphoma
- The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (n=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (n=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%).
- Infections were the most common type of serious adverse event reported in both Study 1 (n=102) and Study 2 (n=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection.
- The most common adverse reactions regardless of causality in Study 1 (n=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (n=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%).
DRUG INTERACTIONS:
- ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible
- Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors
- Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives
USE IN SPECIFIC POPULATIONS:
- Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
- Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution.
Please see full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.
ISTODAX(R) (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.
About PTCL
Peripheral T-cell lymphoma is a term that encompasses a number of different malignancies of T-cell origin that account for about 10-15% of all cases of non-Hodgkin´s lymphoma. PTCL can occur at any age from young adulthood to old age and is slightly more common in men than in women. It is a particularly aggressive form of lymphoma with a short median duration of life expectancy (approximately two years) from diagnosis.
About Celgene International Sàrl
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.
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