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                Resources for Information | Approved Drugs

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                        Oncology (Cancer) / Hematologic Malignancies Approval Notifications
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          FDA D.I.S.C.O.: A new drug approval for IDH1 positive relapsed or refractory Acute Myeloid LeukemiaResources for Information | Approved Drugs FDA D.I.S.C.O.: A new drug approval for IDH1 positive relapsed or refractory Acute Myeloid Leukemia
  
  	
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*FDA medical oncologists discuss the July 2018 approval of ivosidenib for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test.*

Dr. Abhi Nair: Welcome back to the DISCO, the FDA’s Soundcast in Clinical Oncology from the Oncology Center of Excellence. We are located in Silver Spring, Maryland, and during our soundcasts, we discuss recent FDA approvals of cancer drugs and therapies. We hope this information will help you in better understanding these approvals and how new drugs and therapies are benefitting cancer patients.



I’m Dr. Abhi Nair, a medical oncologist at the Oncology Center of Excellence, and I’m joined by my colleague Dr. Sanjeeve Bala, also a medical oncologist and a clinical team leader at FDA.

SB: Hi everyone. Thanks for joining us.

AN: Today we will discuss the approval of ivosidenib marketed as Tibsovo for adult patients with relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation as detected by an FDA-approved test. Sanjeeve will now start off by giving us a background for relapsed or refractory AML treatment in general, and specifically IDH1 positive AML.

SB: Thanks, Abhi. Traditionally, patients with relapsed or refractory AML will undergo intensive salvage chemotherapy, and if a complete remission is achieved, this is followed by allogeneic hematopoietic stem cell transplantation. For younger adult patients without prior stem cell transplantation, about half in first relapse will achieve a second complete remission; and if they proceed to stem cell transplantation, 5-year survival is about 40%. However, many patients with relapsed AML cannot tolerate intensive salvage chemotherapy and older, refractory, or multiply relapsed patients have much poorer outcomes. Complete remission rates in studies of relapsed or refractory AML, including intensive and nonintensive treatment options, were as low as 12 to 18% with median overall survival of only 3 to 6 months. So obviously, there is a need for newer treatments for patients with relapsed or refractory AML.

Abhi: The mechanism of action of this newly approved agent takes us back to our biochemistry classes. The isocitrate dehydrogenases are enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) during cellular metabolism. Mutations of the IDH1 isoform are found in 6-16% of patients with AML. These mutations are associated with AML occurring in patients with older age, higher platelet levels, and normal cytogenetics, as well as with NPM1 and FLT3-ITD mutations.

Sanjeeve: Patients with relapsed or refractory AML that harbor IDH1 mutations also have a devastating prognosis. Although no prospective studies have addressed survival in this specific group, most retrospective data point towards poorer survival in these patients when compared to their wild-type counterparts. Abhi, let’s dig into the data. Let’s hear about the trial that led to approval.

AN: Ivosidenib was approved based on an open-label, single-arm, multicenter clinical trial that included 174 adult patients with relapsed or refractory AML. These patients had the IDH1 mutation confirmed using the Abbott RealTime IDH1 Assay. Ivosidenib was given orally at a starting dose of 500 mg daily until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. The median treatment duration was 4.1 months with a range of 0.1 to 39.5 months. 12% of patients received a stem cell transplant following ivosidenib treatment.

SB: What were the endpoints for this single-arm trial, Abhi?

AN: Sanjeeve, the endpoints were the rate of complete remission or CR plus complete remission with partial hematologic recovery or CRh, the CR+CRh duration, and the rate of conversion from transfusion dependence to independence.

SB: I think we’re ready to hear those trial results.

AN: Sanjeeve, those were encouraging as well. Among the 110 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 41 patients or 37%, became independent of RBC and platelet transfusions during any 56-day post-baseline period.

SB: Abhi, I know you mentioned that patients were selected for the IDH1 mutation using a specific test. Was that test also approved by the FDA and is it commercially available for practicing oncologists?

AN: Yes. At the time of this approval, the FDA also simultaneously approved the Abbott RealTime IDH1 Assay for use in selecting patients for treatment with ivosidenib, making it commercially available for oncologists to order in their offices.

SB: And what about the safety of ivosidenib?

AN: The approved label contains a boxed warning for an adverse reaction called differentiation syndrome. Differentiation syndrome is due to the rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. The FDA label has more details on the management of this adverse reaction. Other labelled warnings for ivosidenib include QT prolongation and Guillain-Barré Syndrome.

SB: What are the most common adverse reactions of ivosidenib?

AN: The most common adverse reactions (≥20%) were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, QT prolongation, rash, pyrexia, cough, and constipation.

SB: Abhi, what is the recommended dose and regimen for ivosidenib?

AN: Sanjeeve, the recommended ivosidenib dose is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treatment is recommended for a minimum of 6 months to allow time for clinical response.

SB: Abhi, can you summarize the three main take away points from this DISCO?

AN: Sure, the three main take away points are: One, ivosidenib is FDA approved for patients with relapsed or refractory acute myeloid leukemia who harbor the IDH1 mutation as detected by the FDA approcved test. Two, the test to detect the IDH1 mutation was also simultaneously FDA approved making it commercially available to oncologists; and three, the recommended ivosidenib dose is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity.

AN: You can find more details in the prescribing information, which is also online at Drugs@FDA. For a transcript with a link to the prescribing information and the multidisciplinary team of FDA experts who conducted the review, visit the FDA Oncology Center of Excellence DISCO website at fda.gov/DISCO.

SB: And so, to our listeners, are there other FDA oncology drug approvals that you want to hear about? Leave us your questions and comments on Twitter @FDAOncologya>. Or, send us an email. Our email address is FDAoncology@fda.hhs.gov. I’m Sanjeeve Bala, thanks for joining us at the DISCO.

AN: And until next time at the DISCO, I’m Abhi Nair.

Acknowledgements

This Drug Information Soundcast in Clinical Oncology was developed by Abhilasha Nair, Sanjeeve Bala, Kelly Norsworthy, Kirsten B. Goldberg, and Richard Pazdur, of the Oncology Center of Excellence and the Office of Hematology and Oncology Products. Steven Jackson of the Division of Drug Information was the sound producer.

Members of the Multidisciplinary Review and Evaluation team for this New Drug Application were:

Nonclinical Reviewer: Ramadevi Gudi, PhD
Nonclinical Team Leader: Christopher Sheth, PhD
Office of Clinical Pharmacology Reviewers: Vicky Hsu, PhD; Justin Earp, PhD; Xiling Jiang, PhD; Sarah Dorff, PhD
Office of Clinical Pharmacology Team Leaders: Gene Williams, PhD; Lian Ma, PhD; Yuching Yang, PhD; Rosane Orbach Charlab, PhD
Clinical Reviewer: Kelly Norsworthy, MD
Clinical Team Leader: Donna Przepiorka, MD, PhD
Statistical Reviewer: Lola Luo, PhD
Statistical Team Leader: Yuan-Li Shen, DrPH
Cross‐Disciplinary Team Leader: Donna Przepiorka, MD, PhD
Division Director (DHOT) John K. Leighton, PhD
Division Director (OCP) Nam Atiqur Rahman, PhD
Deputy Division Director (OB) Thomas E. Gwise, PhD
Supervisory Associate Division Director (DHP) Albert Deisseroth, MD, PhD
Office Director Richard Pazdur, MD

Further Information:

Drug Approval Package: TIBSOVO (ivosidenib)

                                                                                  Content current as of:
      11/15/2018
              
              
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						  OncologyResources for Information | Approved Drugs

          
                        Oncology (Cancer) / Hematologic Malignancies Approval Notifications
          Ongoing | Cancer Accelerated Approvals
          Verified Clinical Benefit | Cancer Accelerated Approvals
          Withdrawn | Cancer Accelerated Approvals
          Other | Cancer Accelerated Approvals


                        Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description
 
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