Ivosidenib + Chemotherapy for Acute Myeloid Leukemia

Overseen By Study Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Northwestern University

Must not be taking: Strong CYP3A4 inducers

Disqualifiers: Acute promyelocytic leukemia, Cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and assess the side effects of ivosidenib when combined with chemotherapy for treating a specific type of acute myeloid leukemia (AML) that has returned or is unresponsive to treatment. Ivosidenib blocks a mutation that promotes cancer cell growth, while the chemotherapy drugs target cancer cells in various ways. Participants should have AML with an IDH1 mutation that has relapsed or is not responding to treatment. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications, but there are specific requirements. You must have a 7-day washout from prior therapy or 5 half-lives, whichever is shorter. If you are taking sensitive CYP substrate medications with a narrow therapeutic range, you must switch to other medications at least 5 half-lives or 14 days before starting the trial. If you are on strong CYP3A4 inducers or sensitive CYP3A4 substrates, you must switch to other medications within 5 half-lives before dosing or ensure they can be monitored during the study.

Will I have to stop taking my current medications?

The trial requires a 7-day washout period (time without taking certain medications) from prior therapy or 5 half-lives, whichever is shorter. Additionally, if you are taking certain medications that interact with the trial drugs, you may need to switch to other medications before starting the trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that ivosidenib, when combined with other treatments, can be effective but may cause side effects. In one study, almost all patients experienced at least one negative reaction to the drug, a common occurrence with cancer treatments.

Cytarabine, another drug in the trial, is generally safe for most patients. It is used safely in older adults at lower doses to prevent side effects like nerve damage.

Fludarabine carries some risks, such as affecting liver function, but it is usually safe when combined with other cancer drugs.

Lastly, filgrastim is a safe supportive drug. It helps reduce the risk of infection by increasing white blood cells during cancer treatments.

Overall, these treatments are generally well-tolerated, but side effects can occur. Prospective trial participants should discuss these with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of ivosidenib with chemotherapy for acute myeloid leukemia (AML) because it offers a novel approach to treatment. Unlike standard AML treatments that primarily rely on chemotherapy drugs like cytarabine and fludarabine, ivosidenib targets a specific genetic mutation, IDH1, found in some leukemia cells. This targeted approach could potentially improve treatment outcomes by specifically attacking cancer cells with this mutation, while sparing healthy cells. Additionally, ivosidenib is taken orally, which could provide more convenience compared to traditional intravenous chemotherapy methods.

What evidence suggests that this treatment might be an effective treatment for acute myeloid leukemia?

Research has shown that ivosidenib may effectively treat acute myeloid leukemia (AML) with an IDH1 mutation. In studies, 51% of patients using ivosidenib with azacitidine achieved complete remission, with no signs of cancer detected. Ivosidenib also enabled faster and more reliable recovery of blood counts, reducing the need for blood transfusions. In this trial, participants will receive a combination of ivosidenib with chemotherapy, including cytarabine and fludarabine. Cytarabine has achieved remission rates of 60% to 80% in AML treatment. Researchers are studying fludarabine with cytarabine to determine if it can improve remission rates. Overall, combining ivosidenib with chemotherapy shows promising results for this specific type of leukemia. ^{1 3 6 7 8}

Who Is on the Research Team?

Shira Dinner, MD

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

This trial is for adults with acute myeloid leukemia (AML) that has returned or isn't responding to treatment. They must have an IDH1 mutation, functioning kidneys and liver, no severe heart issues, and not be pregnant or nursing. Participants need to agree to use effective contraception during the study and for 4 months after.

Inclusion Criteria

My high bilirubin levels are due to a specific condition, not liver issues.

I have had previous treatments for my condition, regardless of how many.

I agree to use two effective birth control methods if I can have children.

Exclusion Criteria

I do not have an ongoing serious infection that isn't getting better with treatment.

I do not have conditions like short-gut syndrome that affect drug absorption.

My heart's electrical cycle is within a normal range, not affected by medications.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive filgrastim, fludarabine phosphate, cytarabine, and ivosidenib. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.

4 weeks

Daily visits for treatment administration

Consolidation

Patients receive filgrastim, fludarabine phosphate, cytarabine, and ivosidenib. Treatment continues for 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity.

4 weeks

Daily visits for treatment administration

Maintenance

Patients receive ivosidenib. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

Up to 24 months

Monthly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Monthly visits

What Are the Treatments Tested in This Trial?

Interventions

• Cytarabine
• Filgrastim
• Fludarabine
• Fludarabine Phosphate
• Ivosidenib

Trial Overview The trial tests ivosidenib combined with chemotherapy drugs cytarabine, filgrastim, and fludarabine in patients with AML. It aims to find the safest dose of ivosidenib when used with these chemotherapies and see if this combination is more effective than chemotherapy alone.

How Is the Trial Designed?

Group I: Treatment (combination chemotherapy, ivosidenib) Experimental Treatment 5 Interventions

INDUCTION: Patients receive filgrastim SC QD on days 0-6, fludarabine phosphate IV QD over 30 minutes on days 1-5, cytarabine IV QD over 4 hours on days 1-5, and ivosidenib PO QD on days 7-28. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive filgrastim SC QD on days 0-5, fludarabine phosphate IV QD over 30 minutes on days 1-4, cytarabine IV QD over 4 hours on days 1-4, and ivosidenib PO QD on days 1-28. Treatment continues for 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive ivosidenib PO QD on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

Cytarabine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia
• Meningeal leukemia

Approved in European Union as Depocyt for:

• Lymphomatous meningitis

Approved in Canada as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

Agios Pharmaceuticals

Collaborator

Trials

1

Recruited

2+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a pilot study involving 17 patients with acute myeloid leukemia (AML), the combination of fludarabine, topotecan, and cytarabine (FTA) resulted in a 35% complete remission rate, indicating its potential efficacy in treating this condition.

However, the treatment was associated with significant side effects, as 41% of patients experienced severe diarrhea, highlighting the need for careful monitoring and further investigation of FTA's safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fludarabine, topotecan, and cytarabine regimen is active in patients with refractory acute myelogenous leukemia. Giles, FJ., Cortes, JE., Kantarjian, HM., et al.[2013]

In a study of 39 patients with refractory or relapsed acute myeloid leukemia (AML), the fludarabine and cytarabine (FA) regimen demonstrated a higher clinical efficacy, achieving complete remission in 47% and partial remission in 42% of patients, outperforming other salvage chemotherapy regimens.

While the FA regimen was effective, it was associated with significant myelosuppression, with all patients experiencing Grade IV hematologic toxicity, though nonhematologic side effects were generally mild to moderate and manageable with supportive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical study on fludarabine combined with cytarabine regimen in the treatment of patients with refractory and relapsed acute myeloid leukemia]. Yao, YY., Zhu, Q., Zou, LF., et al.[2016]

Adding the MDR-1 modulator PSC 833 to chemotherapy did not improve complete remission rates or overall survival in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS).

G-CSF treatment during induction chemotherapy significantly reduced relapse rates in patients achieving complete remission, particularly benefiting those with intermediate-risk AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Current and new therapeutic strategies in acute myeloid leukemia]. Naito, K., Ohnishi, K.[2021]

Fludarabine phosphate (2-F-ara-AMP) shows significant cytotoxic effects against various leukemia cell lines, particularly when combined with cytarabine, which produced synergistic effects in several cell lines, suggesting a strong potential for combination therapy.

The study indicates that combining fludarabine phosphate with methotrexate or vincristine is not effective and may be inappropriate, highlighting the importance of selecting the right combinations for chemotherapy in treating leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro cytotoxic effects of fludarabine (2-F-ara-A) in combination with commonly used antileukemic agents by isobologram analysis. Kano, Y., Akutsu, M., Tsunoda, S., et al.[2019]

Ivosidenib has been approved by the FDA for treating patients with IDH1-mutant relapsed/refractory acute myeloid leukemia, highlighting its significance in targeted cancer therapy.

In a phase I trial, 32.8% of patients achieved either a complete remission or a complete remission with partial hematologic recovery, demonstrating the drug's efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivosidenib Gets Go-Ahead for AML. [2019]

A phase III study demonstrated that combining azacitidine with the IDH1 inhibitor ivosidenib significantly improves treatment outcomes for patients with acute myeloid leukemia who cannot undergo intensive chemotherapy.

The combination therapy tripled overall survival rates and enhanced complete remission and event-free survival compared to azacitidine alone, indicating a substantial efficacy boost from this drug pairing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivosidenib Boosts OS with Azacitidine in AML. [2022]

In a phase III trial involving 112 newly diagnosed AML patients under 60 years, the FLAI regimen (fludarabine, cytarabine, and idarubicin) resulted in a significantly higher complete remission (CR) rate of 74% compared to 51% for the ICE regimen (idarubicin, Ara-C, and etoposide).

FLAI was associated with lower rates of both hematological and non-hematological toxicities, particularly gastrointestinal issues, making it a safer option for induction treatment in AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients. Russo, D., Malagola, M., de Vivo, A., et al.[2013]

Fludarabine phosphate, an antimetabolite derived from adenosine arabinoside, has been found to be safe at a dose of 20 mg/m2 administered every 12 hours for 6 doses in good-risk patients during a phase I trial.

The main side effect of fludarabine phosphate is myelosuppression, which can become severe at higher doses, highlighting the need for careful dose management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of fludarabine (2-fluoro-ara-AMP). Kavanagh, JJ., Krakoff, IH., Bodey, GP.[2019]

In a phase I/II trial involving 44 adults with acute myeloid leukemia, clofarabine combined with total body irradiation (TBI) resulted in a low 6-month relapse rate of 16%, meeting the study's primary efficacy goal while maintaining acceptable safety with minimal severe toxicities.

Patients treated with the clofarabine-TBI regimen experienced significantly lower overall mortality and disease progression compared to historical data from those treated with fludarabine, suggesting that clofarabine may offer a more effective treatment option for high-risk AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II multisite trial of optimally dosed clofarabine and low-dose TBI for hematopoietic cell transplantation in acute myeloid leukemia. Krakow, EF., Gyurkocza, B., Storer, BE., et al.[2021]

Ivosidenib, when combined with azacitidine, significantly improves event-free survival and overall survival in older adults or those with comorbidities suffering from IDH1-mutated acute myeloid leukemia, as shown in a phase 3 study with improved survival rates (HR 0.35 and HR 0.44).

The combination therapy also resulted in a higher complete remission rate (47% vs. 15% with placebo) and maintained a safety profile similar to ivosidenib alone, with notable adverse effects including differentiation syndrome and QT interval prolongation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Ivosidenib in Combination with Azacitidine for Treatment of Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutation. Woods, A., Norsworthy, KJ., Wang, X., et al.[2023]

In a study of 52 patients with relapsed or refractory acute myeloid leukemia (AML), the FLAIRG regimen (which includes fludarabine, arabinosylcytosine, idarubicin, G-CSF, and ATRA) achieved a high complete remission rate of 69.2%.

The FLAIRG regimen was not only effective but also tolerable, allowing 53% of patients who responded to proceed to a transplant, suggesting it could serve as a valuable 'bridge' to transplant in high-risk AML cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Twice daily fludarabine/Ara-C associated to idarubicin, G-CSF and ATRA is an effective salvage regimen in non-promyelocytic acute myeloid leukemia. Montillo, M., Ricci, F., Tedeschi, A., et al.[2013]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40348597/

The Clinical Safety and Efficacy of Cytarabine ... Results: CPX-351 exhibited an adverse event profile that was comparable to that of conventional chemotherapy. It resulted in complete remission rates of 18%-41% ...

2. ashpublications.org ashpublications.org/ashclinicalnews/news/8741/Intermediate-Dose-of-Cytarabine-as-Effective-as

Intermediate Dose of Cytarabine as Effective as Higher Dose ... Cytarabine-based induction therapy of AML results in remission rates of 60% to 80%; however, the remissions are short-lived. Intensification ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e18535

Real-world outcomes of cytarabine consolidation in older ... Conclusions: Cytarabine consolidation in patients ≥60 years with AML is safe and feasible. Neurotoxicity was rare, especially at reduced dose.

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa1010222

Cytarabine Dose for Acute Myeloid Leukemia High-dose cytarabine (2000 to 3000 mg per square meter of body-surface area) is toxic but results in higher rates of relapse-free survival than does the ...

5. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2835472

Cytarabine Pharmacogenomics and Outcomes of Children ... In this cohort study with 1086 patients, a low ACS10 score was associated with inferior event-free survival in pediatric, adolescent, and young adult patients.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12330780/

Outpatient cytarabine consolidation in acute myeloid leukemia ... Outpatient cytarabine consolidation for select patients is safe and cost‐effective without an increased risk of major treatment complications.

7. sciencedirect.com sciencedirect.com/science/article/pii/S253113792300161X

Toxicity and outcome of adults with acute myeloid leukemia ... In conclusion, our data suggest that high-dose of cytarabine (18 g/m2) is a safe option after induction of AML. Conflicts of interest. None. Recommended ...

8. ashpublications.org ashpublications.org/blood/article/145/17/1870/535523/Venetoclax-plus-daunorubicin-and-cytarabine-for

Venetoclax plus daunorubicin and cytarabine for newly ... In a phase 1b study, we assessed the safety and efficacy of Ven with daunorubicin and cytarabine in patients with newly diagnosed AML. A total ...