Olutasidenib for Myeloid Leukemia

Overseen By Jeremy Ramdial, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anti-leukemic agents

Disqualifiers: Active HIV, Hepatitis B, Hepatitis C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 1 year

31 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical research study is to learn about the safety and tolerability of giving olutasidenib to patients with IDH1-mutated myeloid malignancies as maintenance therapy after they receive a stem cell transplant.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot use certain anti-leukemic agents after transplantation and before starting the study therapy. If you are on medications like prednisone, tacrolimus, sirolimus, or ruxolitinib, you may still be eligible.

What data supports the effectiveness of the drug Olutasidenib for Myeloid Leukemia?

The research does not provide direct evidence for Olutasidenib, but it discusses the effectiveness of farnesyltransferase inhibitors (FTIs) like tipifarnib in treating myeloid leukemia. FTIs target proteins involved in cell growth and survival, which may suggest potential benefits for similar drugs like Olutasidenib. ^{1 2 3 4 5}

Is Olutasidenib safe for human use?

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), and thrombocytopenia (low platelet count). Some patients experienced differentiation syndrome, a potentially serious condition, but overall, the side effects were manageable. ^{2 6 7 8 9}

What makes the drug olutasidenib unique for treating myeloid 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 involved in certain types of myeloid 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, offering a novel option compared to traditional chemotherapy. ^{6 7 8 10 11}

Research Team

Jeremy Ramdial, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for patients with IDH1-mutated myeloid malignancies who have undergone a stem cell transplant. The study aims to understand the safety of using Olutasidenib as a maintenance therapy post-transplant.

Inclusion Criteria

My cancer was IDH1 mutation positive at diagnosis.

Serum bilirubin </= 1.5 x upper limit of normal (ULN) except in subjects with Gilbert's Syndrome in whom total bilirubin must be </= 3.0 mg/dl. Aspartate transaminase (AST) or alanine transaminase (ALT) </= 2.5 x ULN. Alkaline phosphatase </=2.5 x ULN

Negative serum or urine pregnancy test for women with reproductive potential at screening

Exclusion Criteria

I have used specific medications after a transplant and before starting this study.

I had grade II-IV acute GVHD but now have no symptoms or mild symptoms only.

I have moderate or severe chronic graft-versus-host disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive olutasidenib as maintenance therapy after stem cell transplant

1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Olutasidenib

Trial Overview The intervention being studied is Olutasidenib, given as maintenance therapy after stem cell transplantation in patients with certain types of blood cancer (myeloid leukemia). This phase II trial focuses on its safety and how well patients tolerate it.

Participant Groups

Group I: Olutasidenib Maintenance Therapy Experimental Treatment 1 Intervention

Participants will be given screening tests to determine eligibility to study

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

In a phase 2 study involving 82 patients with poor-risk myelodysplastic syndrome (MDS), tipifarnib demonstrated significant efficacy, with a 32% overall response rate, including 15% achieving complete responses and 17% showing hematologic improvements.

The treatment was associated with manageable side effects, primarily grade 3-4 neutropenia (18%) and thrombocytopenia (32%), while severe nonhematologic adverse events were rare, indicating that tipifarnib is a promising option for patients with intermediate- to high-risk MDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome. Fenaux, P., Raza, A., Mufti, GJ., et al.[2021]

The combination of tipifarnib and bortezomib was well tolerated in 11 patients with untreated high-risk myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML), with no maximum tolerated dose reached during the study.

Clinical activity was observed, with three patients achieving a complete response and a median overall survival of 449 days, suggesting that this treatment combination may be effective and warrants further investigation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I clinical trial to study the safety of treatment with tipifarnib combined with bortezomib in patients with advanced stages of myelodysplastic syndrome and oligoblastic acute myeloid leukemia. Muus, P., Langemeijer, S., van Bijnen, S., et al.[2021]

In a phase 1 trial involving 84 elderly patients with acute myelogenous leukemia, the combination of tipifarnib and etoposide showed promising results, achieving complete remission in 30% of patients receiving a 14-day regimen.

The combination therapy was well-tolerated, with dose-limiting toxicities noted primarily in the longer 21-day treatment, suggesting that a shorter duration may be more effective and safer for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide. Karp, JE., Flatten, K., Feldman, EJ., et al.[2021]

A study analyzing gene expression in 58 bone marrow samples from AML patients identified eight markers that can predict response to the drug tipifarnib, with the AKAP13 gene being the most significant.

AKAP13 overexpression was linked to resistance against tipifarnib, indicating that measuring this gene could help identify which patients are less likely to benefit from the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of molecular predictors of response in a study of tipifarnib treatment in relapsed and refractory acute myelogenous leukemia. Raponi, M., Harousseau, JL., Lancet, JE., et al.[2016]

Farnesyltransferase inhibitors (FTIs) are a promising new class of anticancer agents that target the farnesylation process of proteins involved in cancer cell growth and survival, particularly in myeloid leukemia.

FTIs have shown potential in clinical trials for myeloid leukemias, addressing the need for new therapies due to high treatment failure rates and toxicities associated with current treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic efficacy of prenylation inhibitors in the treatment of myeloid leukemia. Morgan, MA., Ganser, A., Reuter, CW.[2013]

Olutasidenib, a selective inhibitor of mutant IDH1, was well tolerated in patients with acute myeloid leukaemia or myelodysplastic syndrome, with no dose-limiting toxicities reported during the study, and a recommended phase 2 dose of 150 mg twice daily established based on safety and efficacy.

The study showed promising clinical activity, with 41% of patients with relapsed or refractory acute myeloid leukaemia responding to olutasidenib monotherapy, and an even higher response rate of 77% in treatment-naive patients receiving olutasidenib in combination with azacitidine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial. Watts, JM., Baer, MR., Yang, J., et al.[2022]

Olutasidenib (REZLIDHIATM) is an IDH1 inhibitor that has been approved in the USA for treating adults with relapsed or refractory acute myeloid leukaemia (AML) who have a specific IDH1 mutation.

The approval of olutasidenib marks a significant milestone in targeted cancer therapy, as it provides a new treatment option for patients with R/R AML based on genetic testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olutasidenib: First Approval. Kang, C.[2023]

In a study involving 153 patients with relapsed/refractory acute myeloid leukemia (AML) who had the mIDH1 mutation, olutasidenib showed a 35% rate of complete remission and an overall response rate of 48%, indicating its efficacy as a treatment option.

Olutasidenib was associated with manageable side effects, with significant adverse events including febrile neutropenia and anemia occurring in 20% of patients, while also achieving transfusion independence in 34% of transfusion-dependent patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. de Botton, S., Fenaux, P., Yee, K., et al.[2023]

Glasdegib, a small-molecule inhibitor targeting the hedgehog pathway, was approved by the FDA for treating newly diagnosed acute myeloid leukemia (AML) in patients over 75 or those unable to undergo intensive chemotherapy, showing significant promise in improving patient outcomes.

In a phase II trial, the combination of glasdegib with low-dose cytarabine (LDAC) nearly doubled the median overall survival of patients compared to LDAC alone, highlighting its efficacy in a vulnerable patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Goldsmith, SR., Lovell, AR., Schroeder, MA.[2019]

In a phase Ib/II trial involving 26 patients with relapsed/refractory gliomas carrying the IDH1R132X mutation, olutasidenib (150 mg twice daily) was well tolerated with no dose-limiting toxicities observed, indicating a favorable safety profile.

The treatment showed preliminary clinical activity, with a disease control rate of 48%, including 8% of patients achieving a partial response and 32% maintaining stable disease for at least 4 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: A multicenter, open-label, phase Ib/II trial. de la Fuente, MI., Colman, H., Rosenthal, M., et al.[2023]

Olutasidenib, an oral IDH1mut inhibitor, received regular approval for treating relapsed/refractory IDH1mut acute myeloid leukemia (AML) on December 1, 2022, following its rapid development since 2016.

In clinical trials, olutasidenib showed high rates of durable remission and significant benefits like transfusion independence in patients with R/R IDH1mut AML, highlighting its efficacy as a targeted therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olutasidenib: from bench to bedside. Venugopal, S., Watts, J.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome. [2021]

2. England pubmed.ncbi.nlm.nih.gov

A phase I clinical trial to study the safety of treatment with tipifarnib combined with bortezomib in patients with advanced stages of myelodysplastic syndrome and oligoblastic acute myeloid leukemia. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Identification of molecular predictors of response in a study of tipifarnib treatment in relapsed and refractory acute myelogenous leukemia. [2016]

5. England pubmed.ncbi.nlm.nih.gov

Therapeutic efficacy of prenylation inhibitors in the treatment of myeloid leukemia. [2013]

6. England pubmed.ncbi.nlm.nih.gov

Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Olutasidenib: First Approval. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. [2023]

9. Spain pubmed.ncbi.nlm.nih.gov

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]

10. England pubmed.ncbi.nlm.nih.gov

Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: A multicenter, open-label, phase Ib/II trial. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Olutasidenib: from bench to bedside. [2023]