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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.


May 2, 2019—Ivosidenib (Tibsovo, Agios Pharmaceuticals, Inc.) for newly-diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation, as detected by an FDA-approved test, in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. (With Pharmacist's Applications to Practice)

July 20, 2018—Ivosidenib (Tibsovo, Agios Pharmaceuticals, Inc.) for adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. (With Pharmacist's Applications to Practice)


May 2, 2019, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211192s001lbl.pdf

On May 2, 2019, the Food and Drug Administration approved ivosidenib (TIBSOVO, Agios Pharmaceuticals, Inc.) for newly-diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation, as detected by an FDA-approved test, in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy.

Approval was based on an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) of single-agent ivosidenib for newly-diagnosed AML with an IDH1 mutation detected by the Abbott RealTimeTM IDH1 Assay. Patients enrolled were at least 75 years old or met at least one of the following criteria: baseline Eastern Cooperative Oncology Group performance status of ≥ 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin > 1.5 times the upper limit of normal, or creatinine clearance < 45 mL/min. The 28 patients treated had a median age of 77 years (range, 64-87 years), and 22 (79%) had therapy-related AML or AML with myelodysplasia-related changes. Ivosidenib was administered orally at a dose of 500 mg daily until disease progression, development of unacceptable toxicity, or hematopoietic stem cell transplantation. Two of the 28 patients underwent stem cell transplantation following ivosidenib.

Efficacy was based on the rate of complete remission (CR) or complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, and the conversion rate from transfusion dependence to transfusion independence. Twelve (42.9%) of the 28 achieved CR+CRh (95% CI: 24.5, 62.8), and 7 (41.2%) of the 17 transfusion-dependent patients achieved transfusion independence lasting at least 8 weeks.

The adverse reactions that occurred in at least 25% of patients were diarrhea, fatigue, edema, decreased appetite, leukocytosis, nausea, arthralgia, abdominal pain, dyspnea, differentiation syndrome and myalgia. Prescribing information contains a Boxed Warning alerting health care professionals and patients about the risk of differentiation syndrome which may be life-threatening or fatal.

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.

View full prescribing information for TIBSOVO.

This application used the Real-Time Oncology Review pilot program. FDA granted this application priority review and orphan product designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

FDA granted this application priority review, fast track, and orphan product designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.


Pharmacist’s Applications to Practice

Ivosidenib for the Treatment of Newly Diagnosed Acute Myeloid Leukemia with a Susceptible Isocitrate Dehydrogenase 1 (IDH1) Mutation in Patients Who Are at Least 75 Years Old or Who Have Comorbidities That Preclude the Use of Intensive Induction Chemotherapy

Author: Brittany Jensen, PharmD BCOP
Clinical Oncology Pharmacist
Advocate Aurora Health—Aurora Cancer Care
Milwaukee, WI

What is the potential role for ivosidenib in the treatment of acute myeloid leukemia (AML)?

  • Ivosidenib is the first approved targeted oral single-agent therapy for patients with newly diagnosed AML and a susceptible IDH1 mutation who would otherwise not be able to tolerate alternative treatment options available. The supplemental New Drug Application was granted priority review and accepted under the Real-Time Oncology Review pilot program of the U.S. Food and Drug Administration (FDA) on May 2, 2019, based on results from the AG120-C-001 trial (NCT02074839).1
    • AG120-C-001 was an open-label single-arm multicenter trial (N = 28).2
      • Patients enrolled were at least 75 years old (median age = 77) or had comorbidities precluding the use of intensive induction chemotherapy (i.e., baseline Eastern Cooperative Oncology Group [ECOG] performance status of ≥2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin >1.5 times the upper limit of normal, or creatinine clearance <45 mL/min).
    • The primary endpoint was combined complete remission (CR) and complete remission with partial hematologic improvement (CRh) rate.2
      • CR+CRh rate = 42.9% (CR rate = 28.6%; CRh rate = 14.3%).
      • Median durations of CR and CR+CRh were not estimable (5 patients achieved CR or CRh remaining on treatment as of the data cutoff).
      • Median time to best response of CR or CRh: 2.8 months (range, 1.9 to 12.9 months)
      • Seven of the 17 patients dependent on red blood cell (RBC) and/or platelet transfusions at baseline became independent of transfusions during any 56-day postbaseline period.
      • Six of the 11 patients who were independent of RBC and platelet transfusions at baseline remained transfusion independent during any 56-day postbaseline period.
  • Ivosidenib is included in the National Comprehensive Cancer Network Clinical Practice Guidelines for acute myeloid leukemia for treatment of newly diagnosed AML patients with a susceptible IDH1 mutation who are not candidates for intensive remission induction therapy or who declined it. Alternatively, patients could consider the following treatments:3
    • low-intensity therapy (azacitidine, decitabine)
    • venetoclax-based therapy (in combination with azacitidine, decitabine, or low-dose cytarabine)

What role can the pharmacist play in the management of patients on ivosidenib?

  • The starting dose is 500 mg by mouth once daily with or without food (avoiding a high-fat meal), continued for a minimum of 6 months (to allow time for clinical response) and then until disease progression or unacceptable toxicity occurs.2
  • There are no dose adjustments recommended for renal or hepatic impairment.2
    • Ivosidenib has not been studied in patients with estimated glomerular filtration rate <30 mL/min/1.73m2 or Child-Pugh class C.
  • Ivosidenib is a major substrate of CYP3A4.2
    • Avoid strong or moderate CYP3A4 inhibitors. If co-administration is unavoidable, reduce dose to 250 mg once daily. After the strong CYP3A4 inhibitor has been discontinued, increase the dose (after at least 5 half-lives of the CYP3A4 inhibitor) to the recommended dose of 500 mg once daily.
    • Avoid co-administration of strong CYP3A4 inducers.
  • Use caution with co-administration of QTc-prolonging drugs. If co-administration is unavoidable, monitor patients at high risk for QTc prolongation.2
  • Monitoring should include the following:2
    • complete blood count (CBC) with differential, comprehensive metabolic panel (CMP), magnesium at baseline and at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy
    • creatine phosphokinase (CPK) weekly for the first month
    • electrocardiogram (ECG) at least weekly for the first 3 weeks and then at least monthly for the duration of therapy.
  • In patients with newly diagnosed AML, the most frequently reported grade ≥3 adverse reactions (≥5%) were fatigue (7%) and leukocytosis (7%). Serious adverse reactions (≥5%) were differentiation syndrome (18%), electrocardiogram QT prolongation (7%), and fatigue (7%). One case of posterior reversible encephalopathy syndrome (PRES) was seen.2
  • Counseling points: fatigue, arthralgia, diarrhea, edema, nausea, mucositis, decreased appetite, constipation.

Clinical Pearls

  • Differentiation syndrome was reported in 7 of the 28 patients (25%), which can be fatal if not treated. Six of the 7 patients (86%) who experienced differentiation syndrome recovered. Differentiation syndrome occurred as early as 1 day and up to 3 months after initiation.2
    • If differentiation syndrome is suspected, initiate corticosteroid therapy (intravenous [IV] dexamethasone 10 mg every 12 hours or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until symptom resolution.
    • If noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated.
  • Ivosidenib is available in 250-mg tablets supplied in bottles of 60 tablets to be stored at room temperature.2
  • Ivosidenib is approved for use in IDH1-mutant patients confirmed by Abbott RealTime IDH1 assay.4
  • Ivosidenib is currently under investigation in newly diagnosed AML patients with mutant IDH1 in combination with induction and consolidation therapy and in combination with subcutaneous azacitidine.5,6

References

  1. U.S. Food and Drug Administration. FDA approves ivosidenib as first-line treatment for AML with IDH1 mutation. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-first-line-treatment-aml-idh1-mutation. Accessed September 4, 2019.
  2. Tibsovo (ivosidenib) [prescribing information]. Cambridge, MA: Agios Pharmaceuticals, Inc.; May 2019.
  3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. Version 2.2020 (September 3, 2019). Available at https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed September 4, 2019.
  4. U.S. Food and Drug Administration. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). Available at https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-vitro-and-imaging-tools. Accessed September 5, 2019.
  5. ClinicalTrials.gov. A Study of Ivosidenib or Enasidenib in Combination With Induction Therapy and Consolidation Therapy, Followed by Maintenance Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia or Myedysplastic Syndrome EB2, With an IDH1 or IDH2 Mutation, Respectively, Eligible for Intensive Chemotherapy (HOVON150AML). Updated July 18, 2019. Available at https://clinicaltrials.gov/ct2/show/NCT03839771?term=ivosidenib&cond=newly+diagnosed+AML&rank=2. NLM identifier: NCT03839771.
  6. ClinicalTrials.gov. A Safety and Efficacy Study of Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus Subcutaneous Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia (AML). Updated May 24, 2019. Available at https://clinicaltrials.gov/ct2/show/NCT02677922?term=ivosidenib&cond=newly+diagnosed+AML&rank=3. NLM identifier: NCT02677922.

July 20, 2018, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211192s000lbl.pdf

On July 20, 2018, the Food and Drug Administration approved ivosidenib (Tibsovo, Agios Pharmaceuticals, Inc.) for adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test.

Approval was based on an open-label, single-arm, multicenter clinical trial (AG120-C-001, NCT02074839) that included 174 adult patients with relapsed or refractory AML with an IDH1 mutation confirmed using the Abbott RealTime IDH1 Assay, the FDA-approved test for selection of patients with AML for treatment with ivosidenib. 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 (range, 0.1 to 39.5 months). Twenty-one of the 174 patients (12%) received a stem cell transplant following ivosidenib treatment.

Efficacy was established on the basis of the rate of complete remission (CR) plus complete remission with partial hematologic recovery (CRh), CR+CRh duration, and the rate of conversion from transfusion dependence to independence. The CR+CRh rate was 32.8% (95% CI: 25.8%-40.3%). The median time-to-response was 2 months (range, 0.9-5.6 months), and the median response duration was 8.2 months (95% CI: 5.6 -12 months). The CR and CRh rates were 24.7% (95% CI: 18.5%, 31.8%) and 8.0% (95% CI: 4.5%, 13.1%), respectively.

Among the 110 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 41 (37.3%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 64 patients who were independent of both RBC and platelet transfusions at baseline, 38 (59.4%) remained transfusion independent during any 56-day post-baseline period.

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

The FDA today also approved the Abbott RealTime IDH1 Assay for use in selecting patients for treatment with ivosidenib.

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.

View full prescribing Information for Tibsovo.

FDA granted this application priority review, fast track, and orphan product designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Ivosidenib for Relapsed or Refractory Acute Myeloid Leukemia

Author: Matthew Chui, PharmD
PGY-2 Oncology Pharmacy Resident
University of Minnesota Health Cancer Center
Minneapolis, MN

What is the potential role for ivosidenib in the treatment of relapsed or refractory acute myeloid leukemia (AML)?

  • Ivosidenib is currently the only drug indicated for patients with relapsed or refractory AML (r-r AML) who have an isocitrate dehydrogenase 1 (IDH1) mutation.1
  • In a phase-1 trial of 179 patients with r-r AML and IDH1 mutation:
    • Complete remission (CR) or complete remission with partial hematologic recovery (CRh) was demonstrated in 30.4% of patients.1
    • In patients who achieved CR or CRh, median duration of response was 6.5 months.1
    • Median overall survival of the r-r AML group was 10.2 or 14.5 months, depending on clearance of the IDH1 mutation.
    • 177 out of 179 (98.9%) patients experienced an adverse event. The most commonly reported (>20%) were diarrhea (30.7%), leukocytosis (29.6%), febrile neutropenia (28.5%), nausea (27.9%), fatigue (25.7%), dyspnea (24.6%), QT prolongation (24.6%), peripheral edema (21.8%), anemia (21.8%), pyrexia (21.2%), and cough (20.7%).
  • Prior to the approval of ivosidenib, patients with relapsed or refractory IDH1 mutation–positive AML had limited therapeutic options and often had to rely on systemic chemotherapy, which had limited efficacy.2

What role can the pharmacist play in the management of patients on ivosidenib?

  • Pharmacists can ensure monitoring of appropriate laboratory values including, but not limited to, the following:3
    • Comprehensive metabolic panel and complete blood count: at baseline, weekly for the first month, every other week for the second month, and then monthly thereafter
    • Creatine phosphokinase: weekly for the first month of therapy
    • Electrocardiogram: weekly for the first 3 weeks and then once monthly thereafter
  • Pharmacists can screen for drug-drug interactions because ivosidenib is a major cytochrome P450 3A4 (CYP3A4) substrate.
  • Pharmacists can provide recommendations for dose adjustments or interruptions in therapy for patients who experience differentiation syndrome, leukocytosis, and treatment-related adverse events.3
  • A patient assistance program is available through myAgios patient support services at https://www.myagios.com/hcp/index.html. Eligible patients are able to receive the drug for no more than $25.

Clinical Pearls

  • Time to response was 1.9 months (0.8–4.7 months). It is recommended that patients without disease progression or unacceptable toxicity be treated for a minimum of 6 months to allow sufficient time for clinical response.
  • IDH differentiation syndrome was reported in 10.6% of patients and is potentially lethal.1 Management of IDH differentiation syndrome in the study protocol was as follows:
    • Ivosidenib should be temporarily withheld if clinical symptoms cannot be medically managed with one of the following:
      • Initiation of hydroxyurea 2–3 g by mouth twice or three times daily
      • Initiation of dexamethasone 10 mg IV every 12 hours until symptoms resolve and for a minimum of 3 days
      • Initiation of furosemide and leukapheresis if clinically indicated.
  • Although 24.6% of patients experienced QTc prolongation, it’s important to note that 59.2% of patients in this study were receiving concomitant mediations known to prolong the QT interval, which included fluoroquinolones, ondansetron, and azole antifungal agents.1

References

  1. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378:2386-2398.
  2. Dang L, Yen K, Attar EC. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol. 2016;27:599-608.
  3. Tibsovo (ivosidenib) [prescribing information]. Cambridge, MA: Agios Pharmaceuticals, Inc.; July 2018.
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