Olutasidenib for Leukemia
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: City of Hope Medical Center
Must be taking:IDH1 inhibitors
Disqualifiers: Active GVHD, Uncontrolled infection, Active malignancy, others
No Placebo Group
Approved in 1 jurisdiction
Trial Summary
What is the purpose of this trial?This phase I trial tests the safety, side effects, and effectiveness of olutasidenib in preventing the return of disease (relapse) in patients who have undergone donor (allogeneic) hematopoietic cell transplant for acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia (CMML) carrying an IDH1 mutation. Olutasidenib is in a class of medications called IDH1 inhibitors. It works by slowing or stopping the growth of cancer cells. Giving olutasidenib may be safe, tolerable and/or effective in preventing relapse in patients with IDH1 mutated AML, MDS or CMML after an allogeneic hematopoietic cell transplant.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor to get a clear answer based on your specific situation.
What data supports the effectiveness of the drug Olutasidenib for treating leukemia?
Farnesyltransferase inhibitors (FTIs), which are similar to Olutasidenib, have shown promise in treating various blood cancers, including leukemias and myelodysplastic syndromes (MDS). In clinical trials, FTIs have demonstrated the ability to reduce cancerous cells in the bone marrow and improve patient outcomes.
12345What safety information is available for Olutasidenib in humans?
Olutasidenib has been studied for safety in patients with acute myeloid leukemia and myelodysplastic syndrome. Common serious side effects include febrile neutropenia (fever with low white blood cell count), anemia (low red blood cell count), thrombocytopenia (low platelet count), and neutropenia (low white blood cell count). Differentiation syndrome, a potentially serious condition, occurred in some patients, with a few severe cases and one fatality reported.
678910What makes the drug Olutasidenib unique for treating leukemia?
Olutasidenib is unique because it is an oral drug specifically designed to target and inhibit the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, which is often found in certain types of leukemia. This targeted approach can lead to durable remissions and transfusion independence in patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH1 mutation.
6781112Eligibility Criteria
This trial is for patients with IDH1 mutated AML, MDS, or CMML who have had a donor hematopoietic cell transplant. It's designed to see if the drug olutasidenib can prevent their disease from coming back.Inclusion Criteria
I am 18 years old or older.
I am mostly able to care for myself and remain up and about.
My leukemia diagnosis includes mIDH1.
I am scheduled for or have had a stem cell transplant from a donor.
My bone marrow test after transplant shows less than 5% cancer cells.
I have been treated with IDH1 inhibitors before.
Exclusion Criteria
I am not pregnant or breastfeeding.
I am currently experiencing severe diarrhea.
I have a serious illness that is not under control.
I have had more than one bone marrow transplant from a donor.
I do not have active hepatitis B, C, or HIV.
I have no active cancer except for non-melanoma skin cancer or cervical cancer in-situ.
I have a moderate to severe form of acute graft-versus-host disease.
I am currently on medication for an uncontrolled infection.
Participant Groups
The trial is testing the safety and effectiveness of olutasidenib, an IDH1 inhibitor that aims to slow down or stop cancer cells from growing. This phase I trial will determine if it's safe and tolerable for preventing relapse after transplant.
1Treatment groups
Experimental Treatment
Group I: Treatment (olutasidenib)Experimental Treatment2 Interventions
Starting 50-120 days after transplant, patients receive olutasidenib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection on study.
Olutasidenib is already approved in United States for the following indications:
🇺🇸 Approved in United States as Rezlidhia for:
- Acute Myeloid Leukemia (AML) with a susceptible IDH1 mutation
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
City of Hope Medical CenterDuarte, CA
Cleveland Clinic Cancer CenterCleveland, OH
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Who is running the clinical trial?
City of Hope Medical CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Phase I trial and pharmacokinetic study of raltitrexed in children with recurrent or refractory leukemia: a pediatric oncology group study. [2014]To evaluate the toxicity, antileukemic activity, and pharmacology of raltitrexed administered weekly for 3 weeks to patients with refractory or recurrent leukemia.
Identification of molecular predictors of response in a study of tipifarnib treatment in relapsed and refractory acute myelogenous leukemia. [2016]Microarray technology was used to identify gene expression markers that predict response to the orally available farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777) in acute myelogenous leukemia (AML).
Clinical development of farnesyltransferase inhibitors in leukemias and myelodysplastic syndrome. [2007]Farnesyltransferase inhibitors (FTIs) target multiple pathways including the Ras pathway implicated in the pathogenesis of some hematologic malignancies. R115777 and BMS-214662, selective FTIs in clinical development, exhibit preclinical activity against cell lines and tumor xenografts with or without ras mutations. Phase I dose-escalating trials at M.D. Anderson Cancer Center have explored the potential of these agents as monotherapy for leukemias and myelodysplastic syndrome (MDS). In 20 patients with MDS, two cycles of oral R115777 for 3 consecutive weeks followed by a 1-week rest produced an overall response rate of 30%, consistent with 29% reported in poor-prognosis acute leukemia or blast-phase chronic myelogenous leukemia (CML). Administration of BMS-214662 as a weekly intravenous infusion produced a decrease in bone marrow blasts of greater than 50% in 23% of patients with acute leukemia or MDS; 18% achieved normalization of blast counts to less than 5%. In both studies, most responding patients did not have ras mutations. The most common side effects at maximum tolerated doses of R115777 (400 mg twice daily) and BMS-214662 (118 mg/m(2) weekly) were myelosuppression and nausea, respectively. Further evaluation of FTIs for hematologic malignancies clearly is warranted. Future research should address whether molecular techniques can identify patients most likely to respond to an FTI, optimal administration schedules for these agents, and the value of incorporating an FTI into combination regimens for difficult-to-treat hematologic malignancies.
Advancing the treatment of hematologic malignancies through the development of targeted interventions. [2021]Significant advances have been made in the development of targeted interventions for hematologic malignancies. Progress has been made in defining the molecular pathogenesis of human leukemias. Data indicate that nonrandom, somatically acquired translocations, inversions, and other abnormalities occur in many acute leukemias. In the treatment of acute promyelocytic leukemia (APL), targeted therapy with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy leads to dramatic improvements in disease-free survival. Imatinib mesylate, a signal transduction inhibitor that inhibits tyrosine kinase activity, the protein product of the ABL proto-oncogene, has remarkable activity in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL). Farnesyltransferase inhibitors (FTIs), a promising class of agents that target multiple pathways including Ras proteins, are potential anticancer therapy for a wide range of malignancies, including leukemias and myelodysplastic syndromes (MDS). There also is evidence that recombinant human erythropoietin therapy (r-HuEPO) can benefit patients with chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphomas. This supplement will discuss advances in our understanding of human leukemias, including the use of unconjugated monoclonal antibodies such as Campath-1H (Wellcome, Beckenham, UK, and Ilex Oncology, San Antonio, TX) and rituximab and immunoconjugates such as gemtuzumab ozogamicin and BL-22. Although these novel therapies are beginning to fulfill their promise, continued research efforts are needed to determine the optimal role of targeted therapy in acute and chronic leukemias.
Inhibitors of signaling in myelodysplastic syndrome. [2009]Treatment of myelodysplastic syndrome (MDS) has been hampered by the lack of understanding of the molecular and biological abnormalities associated with this disease. Biological abnormalities may lead to typical phenotypic changes in more differentiated cells. Recent developments in the natural history and underlying molecular mechanisms of MDS and acute myeloid leukemia (AML) have identified new molecular therapeutic targets. Several new classes of drugs have shown promise in early clinical trials and may alter the standard of care of these patients. Among these new drugs are farnesyltransferase inhibitors, receptor tyrosine kinase inhibitors, protein kinase C inhibitors, and VEGF inhibitors. These agents have been tested in patients with solid tumors and hematological malignancies such as AML and MDS. Most of the studies in MDS are in early stages of development, where doses are being determined based on the experience in refractory or relapsed AML or solid tumors. Future therapies in MDS will attempt to resolve cytopenias, eliminate malignant clones and allow differentiation by attacking specific mechanisms of the disease.
Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial. [2022]Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aims for phase 1 of this phase 1/2 study were to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of olutasidenib, as monotherapy or in combination with azacitidine, in patients with acute myeloid leukaemia or myelodysplastic syndrome, harbouring mutant IDH1.
Olutasidenib: First Approval. [2023]Olutasidenib (REZLIDHIATM), an isocitrate dehydrogenase-1 (IDH1) inhibitor, is being developed by Rigel Pharmaceuticals for the treatment of relapsed or refractory (R/R) acute myeloid leukaemia (AML). Olutasidenib was recently approved in the USA for the treatment of adults with R/R AML with a susceptible IDH1 mutation as detected by a US Food and Drug Administration-approved test. This article summarizes the milestones in the development of olutasidenib leading to this first approval for R/R AML.
Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. [2023]Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Overall, 153 IDH1 inhibitor-naive patients with mIDH1R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) received olutasidenib monotherapy 150 mg twice daily in the pivotal cohort of this study. The median age of participants was 71 years (range, 32-87 years) and the median number of prior regimens received by patients was 2 (1-7). The rate of complete remission (CR) plus CR with partial hematologic recovery (CRh) was 35%, and the overall response rate was 48%. Response rates were similar in patients who had, and who had not, received prior venetoclax. With 55% of patients censored at the time of data cut-off, the median duration of CR/CRh was 25.9 months. The median duration of overall response was 11.7 months, and the median overall survival was 11.6 months. Of 86 patients who were transfusion dependent at baseline, a 56-day transfusion independence was achieved in 29 (34%), which included patients in all response groups. Grade 3 or 4 treatment-emergent adverse events (≥10%) were febrile neutropenia and anemia (n = 31; 20% each), thrombocytopenia (n = 25; 16%), and neutropenia (n = 20; 13%). Differentiation syndrome adverse events of special interest occurred in 22 (14%) patients, with 14 (9%) grade ≥3 and 1 fatal case reported. Overall, olutasidenib induced durable remissions and transfusion independence with a well-characterized and manageable side effect profile. The observed efficacy represents a therapeutic advance in this molecularly defined, poor-prognostic population of patients with mIDH1 R/R AML. This trial was registered at www.clinicaltrials.gov as #NCT02719574.
Glasdegib for the treatment of adult patients with newly diagnosed acute myeloid leukemia or high-grade myelodysplastic syndrome who are elderly or otherwise unfit for standard induction chemotherapy. [2019]On November 21, 2018, the U.S. Food and Drug Administration (FDA) approved glasdegib in combination with low-dose cytarabine (LDAC), for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients > 75 years old or who have comorbidities that would be prohibitive of intensive induction chemotherapy. Glasdegib is a small-molecule inhibitor of a component of the hedgehog (HH) pathway, an upregulated pathway in leukemia and leukemia stem cells that is associated with relapse, drug resistance and poor survival. Preclinical studies suggested that glasdegib could sensitize AML cells to chemotherapy. FDA approval was based on a randomized, placebo-controlled, phase II trial in elderly or infirmed adults with new AML, unable to receive intensive induction chemotherapy, in whom the addition of glasdegib to LDAC nearly doubled the median overall survival compared with LDAC alone. In this report, we examine the preclinical development of glasdegib, its pharmacology and the clinical investigation that demonstrated its safety and efficacy, resulting in its approval. Additionally, we highlight ongoing investigation and future applications of this therapy.
Real-world clinical outcomes with enasidenib in relapsed or refractory acute myeloid leukemia. [2022]Enasidenib was approved by the Food and Drug Administration in 2017 for the treatment of patients with relapsed or refractory (RR) acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation. Given limited data in clinical practice, this study assessed real-world clinical outcomes and healthcare resource use in patients with RR AML. Physicians performed chart abstraction of patients with RR IDH2-mutated AML treated with enasidenib (between 1/2018 and 6/2019) or other first-line (1 L) RR therapy (between 1/2016 and 7/2017). Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and adjusted risk of progression and death were estimated by multivariable Cox proportional hazard models. Among 124 patients treated with enasidenib and 76 patients treated with other 1 L RR therapy, overall response rate was higher among patients treated with enasidenib vs. other 1 L RR therapies (77% vs. 52%, p < 0.01). After a median follow-up of 9 and 6 months, median PFS was 8 months in enasidenib-treated patients and 5 months in patients receiving other 1 L RR therapy, respectively (adjusted HR=0.36, 95% CI: 0.23-0.57, p < 0.01). Median OS was 11 and 6 months in enasidenib-treated patients and patients receiving other 1 L RR therapy, respectively (adjusted HR=0.37, 95% CI: 0.22-0.60, p < 0.01). Fewer enasidenib-treated patients were hospitalized during 1 L RR therapy vs. those receiving other therapies (14% vs. 46%, p < 0.01). Results from this real-world study confirm the effectiveness of enasidenib among patients with IDH2-mutated RR AML and demonstrate that hospitalizations were significantly lower vs. other 1 L RR treatment in clinical practice.
Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: A multicenter, open-label, phase Ib/II trial. [2023]Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation.
Olutasidenib: from bench to bedside. [2023]The discovery of isocitrate dehydrogenase 1 (IDH1) mutations in acute myeloid leukemia (AML) and the resounding success of molecularly targeted therapies in related myeloid malignancies swiftly prompted the development of IDH1mut inhibitors. Olutasidenib (formerly known as FT-2102) is an orally administered novel IDH1mut inhibitor that entered clinical development in 2016, proceeded briskly through the developmental process, and was granted regular approval to treat patients with R/R IDH1mut AML on 1 December 2022. Single agent olutasidenib, a potent and selective IDH1mut inhibitor, demonstrated highly durable remission rates along with meaningful outcomes, such as transfusion independence, in patients with R/R IDH1mut AML. This review will examine the preclinical and clinical development and the positioning of olutasidenib in the IDH1mut AML treatment landscape.