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

2 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of ivosidenib when given together with combination chemotherapy for the treatment of 1DH1 mutant acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). Ivosidenib may stop the growth of cancer cells by blocking the IDH1 mutation and some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate, cytarabine, and filgrastim, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ivosidenib with combination chemotherapy may work better in treating patients with acute myeloid leukemia compared to chemotherapy alone.

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.

What data supports the idea that Ivosidenib + Chemotherapy for Acute Myeloid Leukemia is an effective treatment?

The available research does not provide specific data on the effectiveness of Ivosidenib combined with chemotherapy for Acute Myeloid Leukemia. Instead, it discusses other chemotherapy combinations, such as fludarabine with cytarabine, which have shown varying levels of success. For example, one study showed a 47% complete remission rate with a fludarabine and cytarabine regimen. However, without specific data on Ivosidenib, we cannot directly compare its effectiveness to these other treatments. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination Ivosidenib + Chemotherapy for Acute Myeloid Leukemia?

Research shows that combining fludarabine and cytarabine (Ara-C) is effective in treating acute myeloid leukemia (AML), with studies reporting complete remission rates of up to 69.2% in certain regimens. Additionally, the use of granulocyte colony-stimulating factor (G-CSF) alongside chemotherapy has been shown to reduce relapse rates in AML patients. ^{1 2 3 4 5}

What safety data exists for the treatment of Ivosidenib + Chemotherapy for Acute Myeloid Leukemia?

The safety data for the treatment involving Ivosidenib and chemotherapy agents like Cytarabine and Fludarabine includes several findings: Fludarabine combined with Cytarabine has been shown to be effective and well-tolerated in treating acute myeloid leukemia (AML), with myelosuppression being a major side effect. In a study combining Fludarabine, Topotecan, and Cytarabine, 41% of patients developed grade 3 or 4 diarrhea. Fludarabine has shown synergistic effects with Cytarabine in vitro, suggesting potential benefits in combination therapy. Overall, these studies indicate that while the combination therapies are effective, they can have significant side effects such as myelosuppression and diarrhea, warranting careful monitoring and further investigation. ^{1 4 6 7 8}

What safety data exists for the combination of Ivosidenib and chemotherapy in treating acute myeloid leukemia?

Fludarabine and cytarabine, components of the chemotherapy regimen, have been studied in various trials. Fludarabine is generally well-tolerated but can cause severe myelosuppression (a decrease in bone marrow activity leading to fewer blood cells). In one study, a combination of fludarabine, topotecan, and cytarabine caused severe diarrhea in some patients, indicating potential gastrointestinal side effects. ^{1 4 6 7 8}

Is the drug combination of Ivosidenib, Cytarabine, and Fludarabine promising for treating acute myeloid leukemia?

Yes, the drug combination is promising. Ivosidenib has shown to improve survival rates and remission in patients with acute myeloid leukemia, especially when combined with other drugs like azacitidine. Fludarabine and Cytarabine have also been effective in treating this type of leukemia, making the combination a strong option for treatment. ^{1 4 9 10 11}

What makes the drug combination of Ivosidenib and chemotherapy unique for treating acute myeloid leukemia?

This treatment is unique because it combines Ivosidenib, which targets a specific genetic mutation (IDH1) in acute myeloid leukemia, with chemotherapy drugs like Cytarabine and Fludarabine. This combination is particularly beneficial for patients with the IDH1 mutation, offering improved survival rates and remission compared to other treatments. ^{1 4 9 10 11}

Research Team

Shira Dinner, MD

Principal Investigator

Northwestern University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

A fludarabine, topotecan, and cytarabine regimen is active in patients with refractory acute myelogenous leukemia. [2013]

2. China 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]. [2016]

3. Japan pubmed.ncbi.nlm.nih.gov

[Current and new therapeutic strategies in acute myeloid leukemia]. [2021]

4. England 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. [2013]

5. England 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. [2013]

6. United States 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. [2021]

7. England 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. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Phase I study of fludarabine (2-fluoro-ara-AMP). [2019]

9. United States 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. [2023]

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

Ivosidenib Gets Go-Ahead for AML. [2019]

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

Ivosidenib Boosts OS with Azacitidine in AML. [2022]