On February 25, 2019 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported updated data from a Phase 1 study evaluating ivosidenib (TIBSOVO; AG-120) in combination with azacitidine in newly diagnosed isocitrate dehydrogenase-1 (IDH1) mutant acute myeloid leukemia (AML) patients (Press release, Agios Pharmaceuticals, FEB 25, 2019, View Source [SID1234533625]). The data were featured at the 17th International Symposium on Acute Leukemias taking place in Munich.
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
"With longer follow up from the ongoing Phase 1 study, the ivosidenib and azacitidine combination data in newly diagnosed AML patients are striking, with a 65% CR+CRh rate, 57% CR rate and the majority of CR patients achieving IDH1 mutation clearance," said Courtney DiNardo, M.D., lead investigator and assistant professor, department of leukemia at the University of Texas MD Anderson Cancer Center. "The combination regimen showed a 12-month survival rate of 82%, which is impressive given the age and comorbidities associated with patients who are not eligible for intensive chemotherapy. From a safety perspective, results from the combination were consistent with the safety profiles of each drug used alone and cytopenias were in line with those seen for azacitidine alone and favorable compared with other emerging hypomethylating agent combinations."
"As the Phase 1 data have matured, we saw an increase in patients achieving deep and durable remissions, validating our belief that the combination of azacitidine and ivosidenib has the potential to be a compelling treatment option and the cornerstone of therapy for frontline AML patients with an IDH1 mutation who are ineligible for intensive chemotherapy," said Chris Bowden, M.D., chief medical officer at Agios. "We will further evaluate the clinical benefit of ivosidenib in this treatment combination as part of the ongoing Phase 3 AGILE trial."
About the Ongoing Phase 1/2 Study
The ongoing Phase 1/2 study is evaluating an investigational use of ivosidenib or enasidenib in combination with azacitidine in patients with newly diagnosed IDH mutant AML unable to receive intensive chemotherapy. Data presented are from the ivosidenib arm of the Phase 1b portion of the study, in which 23 patients received 500 mg of ivosidenib daily plus azacitidine. Enrollment in the ivosidenib arm is complete.
As of the August 1, 2018 data cutoff, 14 (61%) patients remained on study.
The median number of treatment cycles was 8 (range 1-22).
The median age was 76 years old, and 52% of patients were age 75 or older.
74% of patients had de novo AML and 26% had secondary AML.
Ivosidenib Safety
The most common all-grade adverse events (AEs) regardless of cause occurring in ≥50% of patients were nausea (61%), diarrhea (57%), anemia (52%) and thrombocytopenia (52%).
The most common Grade 3/4 AEs were thrombocytopenia (48%), anemia (44%) and febrile neutropenia (44%).
Investigator reported IDH differentiation syndrome (DS) was reported in four patients, of which three were serious AEs. All four cases resolved, including two who achieved a complete response (CR), one stable disease and one was not evaluable for response.
Mean neutrophil and platelet counts were maintained near or above thresholds for CR with partial hematologic recovery (CRh) while on study treatment with ivosidenib and azacitidine. CRh is defined as <5% of blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts (ANC >500/microliter and platelets >50,000/microliter).
Ivosidenib Efficacy
Overall, 78% (18/23) of patients had a response.
65% (15/23) of patients had a CR+CRh
57% (13/23) of patients had a CR.
The median duration of CR (95% CI 7.7, NE) as well as CR+CRh (95% CI 7.7, NE) had not been reached.
The median time to response was 1.8 months (range 0.7-3.8 months) and the median time to CR was 3.5 months (range 0.8-6 months).
The 12-month survival rate was 82%.
The median duration of follow-up was 9.5 months (range 1.3-24 months).
For patients who achieved a CR, IDH1 mutation clearance was observed in 9 of 13 patients with available bone marrow mononuclear cells (BMMCs) and 10 of 13 patients with available peripheral blood mononuclear cells (PBMCs) as quantified by a sensitive digital PCR assay with lower limit of sensitivity for mutant IDH1 of 0.02-0.04% (or 10-4).
Ivosidenib is not approved in any country for the treatment of patients with newly diagnosed AML or approved in combination with azacitidine.
About TIBSOVO (ivosidenib)
TIBSOVO (ivosidenib) is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. For more information, visit TIBSOVO.com.
IMPORTANT SAFETY INFORMATION
WARNING: DIFFERENTIATION SYNDROME
Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.
WARNINGS AND PRECAUTIONS
Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 34 patients who experienced differentiation syndrome, 27 (79%) recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.
If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe.
QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. One patient developed ventricular fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.
Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.
Guillain-Barré Syndrome: Guillain-Barré syndrome occurred in <1% (2/258) of patients treated with TIBSOVO in the clinical study. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.
ADVERSE REACTIONS
The most common adverse reactions (≥20%) of any grade were fatigue (39%), leukocytosis (38%), arthralgia (36%), diarrhea (34%), dyspnea (33%), edema (32%), nausea (31%), mucositis (28%), electrocardiogram QT prolonged (26%), rash (26%), pyrexia (23%), cough (22%), and constipation (20%).
The most frequently reported ≥Grade 3 adverse reactions (≥5%) were electrocardiogram QT prolonged (10%), dyspnea (9%), leukocytosis (8%), tumor lysis syndrome (6%), and differentiation syndrome (5%).
Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
DRUG INTERACTIONS
Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.
Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.
Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.
QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.
LACTATION
Many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.
Please see full Prescribing Information, including Boxed WARNING.
About Acute Myelogenous Leukemia (AML)
AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. AML incidence significantly increases with age, and the median age of diagnosis is 68. The vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 27 percent. IDH1 mutations are present in about 6 to 10 percent of AML cases.