On August 2, 2021 Celgene Corporation, now a wholly owned subsidiary of Bristol Myers Squibb, reported that it received accelerated approval by the U.S. Food & Drug Administration (FDA) for Istodax (romidepsin), a histone deacetylase (HDAC) inhibitor, as monotherapy for the treatment of peripheral T-cell lymphoma (PTCL) in adult patients who have received at least one prior therapy (Press release, Bristol-Myers Squibb, AUG 2, 2021, View Source [SID1234585528]). This accelerated approval was based upon results from two clinical studies, assessing the effect of Istodax on the surrogate endpoint of overall response rate. Bristol Myers Squibb conducted a subsequent confirmatory Phase 3 study evaluating romidepsin plus CHOP (Ro-CHOP) versus CHOP in first-line PTCL patients, but the trial did not meet the primary efficacy endpoint of progression free survival.

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Based on this outcome, Bristol Myers Squibb made the decision to withdraw the PTCL indication from the U.S. market. The company took this action in accordance with the FDA’s requirements for evaluating accelerated approvals that have not demonstrated sufficient clinical benefit.

Bristol Myers Squibb is notifying healthcare professionals about the withdrawal. Istodax remains on the market for treatment of patients with cutaneous T-cell lymphoma (CTCL) who have received at least one prior systemic therapy. Patients who are being treated with Istodax for PTCL should consult with their healthcare provider in all aspects of their medical care and may remain on treatment if deemed clinically appropriate by the treating physician. For patients who are currently being treated with Istodax for PTCL, and who have questions about access and reimbursement support, please contact BMS Access Support at 1-800-861-0048 or visit www.bmsaccesssupport.com.

"While the outcome of the confirmatory study in peripheral T-cell lymphoma is disappointing, Bristol Myers Squibb will continue to provide Istodax for patients with cutaneous T-cell lymphoma, where it remains an approved and important treatment option," said Noah Berkowitz, M.D., Ph.D., senior vice president, Hematology Development, Bristol Myers Squibb. "As always, our efforts across blood cancer research and development remain centered on delivering better outcomes for patients in need."

Since the initial approval of Istodax, nearly a decade ago, more options have been made available for patients, many of which have redefined treatment across PTCL and other hematologic conditions.

Bristol Myers Squibb continues to evaluate the potential of its therapies for people with blood cancers and disorders who may benefit, while pursuing the next breakthroughs for patients.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

About Istodax

Istodax (romidepsin) for injection is an epigenetic therapy and 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. In vitro, Istodax causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of some cancer cell lines. The mechanism of the antineoplastic effect of romidepsin observed in nonclinical and clinical studies has not been fully characterized. For full prescribing information, visit www.ISTODAX.com.

Indication

ISTODAX (romidepsin) for injection is indicated for treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

Important Safety Information

WARNINGS AND PRECAUTIONS

Myelosuppression: ISTODAX (romidepsin) for injection can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; monitor blood counts regularly during treatment with ISTODAX; interrupt and/or modify the dose as necessary
Infections: fatal and serious infections, including pneumonia, sepsis and viral reactivation, including reactivation of Epstein Barr and hepatitis B viruses, have been reported during and after treatment with ISTODAX in clinical trials. The risk of life-threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow. Reactivation of hepatitis B virus infection was reported in 1% of patients in clinical trials. Reactivation of Epstein Barr viral infection leading to liver failure has occurred, including after ganciclovir prophylaxis. Consider monitoring for reactivation and antiviral prophylaxis in patients with evidence of prior hepatitis B infection.
Electrocardiographic (ECG) changes: ECG changes have been observed with ISTODAX. In patients with congenital long QT syndrome, patients with a history taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment. Confirm that potassium and magnesium levels are within the normal range before administration of ISODAX
Tumor lysis syndrome (TLS): TLS has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden are at greater risk and should be closely monitored and managed as appropriate
Embryo-fetal toxicity: ISTODAX can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to a fetus and to use effective contraception.
ADVERSE REACTIONS

Cutaneous T-Cell Lymphoma

The most common adverse reactions (≥30%), excluding laboratory abnormalities, are nausea, fatigue, infections, vomiting, anorexia, electrocardiogram ST-T wave changes, dysgeusia, constipation and pruritis. Grade 3‐4 laboratory abnormalities (≥10%) include lymphopenia, neutropenia, anemia and thrombocytopenia.

DRUG INTERACTIONS

Monitor more frequently prothrombin time and international Normalized Ratio in patients concurrently administered ISTODAX and warfarin or coumarin derivatives
Romidepsin is metabolized by CYP3A4
>> Monitor patients for toxicity related to increased romidepsin exposure and follow dose modifications for toxicity when ISTODAX is initially co-administered with strong CYP3A4 inhibitors

>> Avoid co-administration of ISTODAX (romidepsin) with rifampin and other potent inducers of CYP3A4

Exercise caution with concomitant use of ISTODAX and P-glycoprotein (P-gp, ABCB1) inhibitors
USE IN SPECIFIC POPULATIONS

Pregnancy Category D:If this drug is used during pregnancy, of if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus
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 sever hepatic impairment and/or patients with the end-stage renal disease should be treated with caution