AG-120 or AG-221 Combination Therapy for Acute Myeloid Leukemia

Not currently recruiting at 16 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Institut de Recherches Internationales Servier

Must not be taking: CYP3A4 inducers, QT prolongers

Disqualifiers: Pregnancy, Active infection, 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 examines a new combination of treatments for acute myeloid leukemia (AML), a type of blood cancer. It aims to assess the safety of two drugs, AG-120 (Ivosidenib or Tibsovo) and AG-221 (Enasidenib or Idhifa), when combined with standard chemotherapy treatments. Participants will receive varying doses of these new drugs alongside traditional therapies to determine the optimal and safest combination. This trial may suit individuals with untreated AML who have an IDH1 or IDH2 mutation and are beginning induction therapy. 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 combination therapy.

Will I have to stop taking my current medications?

The trial may require you to stop taking certain medications, especially those with narrow therapeutic windows or those that interact with the trial drugs. You might need to switch to alternative medications before enrolling, particularly if you are taking strong CYP3A4 inducers or medications affecting specific transporters. It's best to discuss your current medications with the study team to see if any changes are needed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that both AG-120 and AG-221 have been safe in past studies. AG-120, also called TIBSOVO®, is FDA-approved for treating adults with a specific type of acute myeloid leukemia (AML) that has the IDH1 mutation. Earlier studies reported common side effects such as tiredness and nausea, but many patients tolerated it well.

AG-221, known as IDHIFA®, is also FDA-approved for certain AML cases with the IDH2 mutation. Research suggests it is generally well tolerated. Common side effects include nausea and reduced appetite, while serious side effects are rare.

Both drugs are being tested with standard AML treatments. Although this trial is in an early stage, the existing approval of these drugs for other conditions provides some confidence in their safety. However, as with any treatment, individual experiences can differ, and ongoing trials aim to gather more detailed safety information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for acute myeloid leukemia (AML) because they combine novel agents, AG-120 and AG-221, with standard chemotherapy drugs like cytarabine and anthracyclines (daunorubicin and idarubicin). Unlike standard treatments that primarily target DNA synthesis, AG-120 and AG-221 work by inhibiting specific enzymes (IDH1 and IDH2, respectively), which play a role in cancer cell metabolism. This unique mechanism of action aims to disrupt cancer cell growth and survival differently than traditional chemotherapy. By targeting these enzymes, the treatments offer a promising new approach that could potentially enhance the effectiveness of existing therapies and improve patient outcomes.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

This trial will evaluate the effectiveness of AG-120 and AG-221 in combination therapies for Acute Myeloid Leukemia (AML). Research has shown that AG-120, also known as ivosidenib, benefits patients with a specific type of AML that has an IDH1 mutation. In one study, 51% of patients experienced either complete remission or partial recovery with this treatment, and patients lived for a median of 29.3 months, suggesting long-term benefits.

AG-221, or enasidenib, is another treatment option in this trial. Research has found improved survival rates for patients with IDH2 mutations using AG-221. In one study, patients lived for a median of 9.26 months, surpassing the standard treatment, and this treatment also led to a higher rate of complete remission. Both AG-120 and AG-221 have shown promise in improving outcomes for people with specific AML mutations. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

Adults with newly diagnosed Acute Myeloid Leukemia (AML) having specific mutations (IDH1/IDH2), who haven't had AML treatment but may have been treated for related conditions. They should be in a stable health condition, not pregnant or breastfeeding, and willing to use effective contraception.

Inclusion Criteria

I have AML with an IDH mutation and haven't started treatment yet.

My kidney function is within normal ranges.

I am eligible for initial and follow-up cancer treatments.

Exclusion Criteria

I am not on strong CYP3A4 inducers, or it can be managed.

I have had chemotherapy for AML, but hydroxyurea might be an exception.

I do not have any uncontrolled infections or fungal infections.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Participants receive AG-120 or AG-221 in combination with standard AML induction therapies (cytarabine with either daunorubicin or idarubicin)

Up to 8 weeks

Consolidation Therapy

Participants receive consolidation therapy (mitoxantrone/etoposide or up to 4 cycles of cytarabine) in combination with AG-120 or AG-221

Up to 18 weeks

Maintenance Therapy

Participants who complete consolidation therapy and are in CR or CRi may continue on maintenance therapy with daily treatment of AG-120 or AG-221

Until relapse or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• AG-120
• AG-221
• Cytarabine
• Daunorubicin
• Etoposide
• Idarubicin
• Mitoxantrone

Trial Overview The trial is testing AG-120 or AG-221 combined with standard AML therapies during different phases of treatment. It aims to find the safest doses of these drugs when used with induction and consolidation therapy, followed by maintenance until relapse or unacceptable toxicity.

How Is the Trial Designed?

Group I: AG-221 with cytarabine and idarubicin Experimental Treatment 5 Interventions

Daily AG-221 administered orally in combination with standard Induction therapy and consolidation therapy. After 1 cycle of induction therapy, participants may undergo a second induction cycle given as per institutional practice. Participants who achieve an adequate response at the end of induction therapy will go on to receive consolidation therapy (mitoxantrone/etoposide or up to 4 cycles of cytarabine) in combination with AG-221. Participants who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-221.

Group II: AG-221 with cytarabine and daunorubicin Experimental Treatment 5 Interventions

Daily AG-221 administered orally in combination with standard Induction therapy and consolidation therapy. After 1 cycle of induction therapy, participants may undergo a second induction cycle given as per institutional practice. Participants who achieve an adequate response at the end of induction therapy will go on to receive consolidation therapy (mitoxantrone/etoposide or up to 4 cycles of cytarabine) in combination with AG-221. Participants who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-221.

Group III: AG-221 (starting on Day 8) with cytarabine and idarubicin Experimental Treatment 5 Interventions

Daily AG-221 administered orally starting on Day 8 of induction cycle 1 in combination with standard Induction therapy and consolidation therapy. After 1 cycle of induction therapy, participants may undergo a second induction cycle given as per institutional practice. Participants who achieve an adequate response at the end of induction therapy will go on to receive consolidation therapy (mitoxantrone/etoposide or up to 4 cycles of cytarabine) in combination with AG-221. Participants who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-221.

Group IV: AG-221 (starting on Day 8) with cytarabine and daunorubicin Experimental Treatment 5 Interventions

Daily AG-221 administered orally starting on Day 8 of induction cycle 1 in combination with standard Induction therapy and consolidation therapy. After 1 cycle of induction therapy, participants may undergo a second induction cycle given as per institutional practice. Participants who achieve an adequate response at the end of induction therapy will go on to receive consolidation therapy (mitoxantrone/etoposide or up to 4 cycles of cytarabine) in combination with AG-221. Participants who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-221.

Group V: AG-120 with cytarabine and idarubicin Experimental Treatment 5 Interventions

Daily AG-120 administered orally in combination with standard Induction therapy and consolidation therapy. After 1 cycle of induction therapy, participants may undergo a second induction cycle given as per institutional practice. Participants who achieve an adequate response at the end of induction therapy will go on to receive consolidation therapy (mitoxantrone/etoposide or up to 4 cycles of cytarabine) in combination with AG-120. Participants who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-120.

Group VI: AG-120 with cytarabine and daunorubicin Experimental Treatment 5 Interventions

Daily AG-120 administered orally in combination with standard Induction therapy and consolidation therapy. After 1 cycle of induction therapy, participants may undergo a second induction cycle given as per institutional practice. Participants who achieve an adequate response at the end of induction therapy will go on to receive consolidation therapy (mitoxantrone/etoposide or up to 4 cycles of cytarabine) in combination with AG-120. Participants who complete consolidation therapy and are in complete response (CR) or complete remission with incomplete hematologic recovery (CRi) (including CR with incomplete platelet recovery \[CRp\]) may continue on maintenance therapy and receive daily treatment with AG-120.

AG-120 is already approved in United States for the following indications:

Approved in United States as Tibsovo for:

• Acute myeloid leukemia (AML) with a susceptible IDH1 mutation

Who Is Running the Clinical Trial?

Institut de Recherches Internationales Servier

Lead Sponsor

Trials

91

Recruited

67,100+

Celgene Corporation

Industry Sponsor

Trials

446

Recruited

58,500+

Mark Alles

Celgene Corporation

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Sol J. Barer

Celgene Corporation

Chief Medical Officer since 2006

PhD in Organic and Physical Chemistry from Rutgers University

Published Research Related to This Trial

In a phase 1/2 study involving 95 patients with untreated acute myeloid leukemia (AML), the combination of tipifarnib with idarubicin and cytarabine resulted in a 64% complete remission rate, indicating its efficacy in treating this aggressive cancer.

The treatment was found to be safe, with the most common severe side effects being gastrointestinal issues, liver dysfunction, and skin rash, while also showing improved remission duration compared to historical data for idarubicin and cytarabine alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1-2 study of a farnesyltransferase inhibitor, tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome. Jabbour, E., Kantarjian, H., Ravandi, F., 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]

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 study of 43 patients under 60 years old with untreated acute myeloid leukemia, the combination of idarubicin, etoposide, and carboplatin achieved a remission rate of 67% with a median leukemia-free survival of 15.4 months.

The treatment was associated with significant mucosal toxicity, including severe gastrointestinal side effects in a substantial number of patients, indicating that while effective, the regimen's tolerability may need improvement through adjustments in postremission therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remission induction therapy of untreated acute myeloid leukemia using a non-cytarabine-containing regimen of idarubicin, etoposide, and carboplatin. Bow, EJ., Gallant, G., Williams, GJ., et al.[2015]

Current frontline treatments for acute myeloid leukemia (AML) using ara-C and topoisomerase II agents achieve complete response rates of 70%, but long-term survival remains low at 25%.

Newer agents like nucleoside analogs and hypomethylating agents show promise, with combination therapies yielding higher complete response rates, particularly when used alongside traditional treatments like ara-C.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New chemotherapeutic agents in acute myeloid leukemia. Kantarjian, HM., Estey, EH., Keating, MA.[2013]

Ivosidenib is an FDA-approved treatment for adults with relapsed or refractory acute myeloid leukemia (R/R AML) with an IDH1 mutation, showing a complete remission (CR) + partial hematologic recovery (CRh) rate of 33% in a study of 174 patients over an 8.3-month follow-up.

While ivosidenib demonstrated short-term efficacy, including a median duration of response of 8.2 months and a 37% conversion rate from transfusion dependence to independence, serious adverse reactions such as differentiation syndrome and QT interval prolongation were noted, highlighting the need for ongoing safety assessments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Ivosidenib for Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation. Norsworthy, KJ., Luo, L., Hsu, V., et al.[2020]

The FLAG-IDA chemotherapy regimen was administered to seven children with refractory acute myeloid leukemia (AML), and while it was tolerable with no early deaths, the efficacy remains uncertain due to high relapse rates and limited patient numbers.

Hematological toxicity was common among patients, with one case of severe non-hematological toxicity (bacterial meningitis), highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin for relapsed childhood acute myeloid leukemia. Nakayama, H., Tomizawa, D., Tanaka, S., et al.[2018]

In a study involving five patients with therapy-related acute myeloid leukemia, a combination of idarubicin, high-dose cytarabine, and etoposide achieved complete remission in all patients after just one course of treatment.

The treatment was well-tolerated, with low levels of toxicity and no deaths during the induction therapy, suggesting it is a promising option for inducing remission in secondary acute myeloid leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idarubicin, high-dose cytarabine and etoposide for remission induction in therapy-related acute myeloid leukemia. Philpott, N., Mehta, J., Treleaven, J., et al.[2019]

In a study of 52 patients under 55 with acute myeloid leukemia (AML), the chemotherapy regimen BF12 led to a high remission rate of 78.4%, demonstrating its efficacy in treating newly diagnosed AML.

The same regimen also showed effectiveness in relapsed acute leukemia, with 65% of patients achieving complete remission, although some patients experienced toxicity-related deaths, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idarubicin, high-dose cytarabine, and etoposide for induction of remission in acute leukemia. Mehta, J., Powles, R., Singhal, S., et al.[2013]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40706052/

Long-term results from the AGILE study of azacitidine plus ... Hematologic recovery was faster, more durable, and conversion to transfusion independence (53.8% vs 17.1%; P = .0004) was more common with ivosidenib than with ...

2. ashpublications.org ashpublications.org/bloodadvances/article/9/20/5177/546354/Long-term-results-from-the-AGILE-study-of

Long-term results from the AGILE study of azacitidine plus ... In long-term follow-up, ivosidenib-azacitidine, with a median OS of 29.3 months, sustained survival and hematologic benefits in mutant IDH1 AML.

3. tibsovo.com tibsovo.com/aml/results

AML Clinical Trial Results | TIBSOVO® (ivosidenib tablets) In the clinical study, 51% of people (37 out of 72) on TIBSOVO + azacitidine achieved complete remission (CR) or complete remission with partial hematologic ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2117344

Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid ... Ivosidenib and azacitidine showed significant clinical benefit as compared with placebo and azacitidine in this difficult-to-treat population.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03173248

NCT03173248 | Study of AG-120 (Ivosidenib) vs. Placebo ... Study AG120-C-009 is a global, Phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial to evaluate the efficacy and safety of ...

6. tibsovopro.com tibsovopro.com/aml/safety

TIBSOVO® safety profile in acute myeloid leukemia (AML) Review common adverse reactions to TIBSOVO® and other important safety information for patients with AML. See Full Prescribing Information & Boxed Warning.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/211192_s008lbl.pdf

TIBSOVO (ivosidenib tablets - accessdata.fda.gov TIBSOVO is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.7012

Updated efficacy and safety data from the AGILE study in ... Updated efficacy and safety data ... Changes in health-related quality of life in patients with newly diagnosed acute myeloid leukemia receiving ...

9. investor.agios.com investor.agios.com/news-releases/news-release-details/agios-presents-updated-data-ivosidenib-phase-1-dose-escalation

Press Release Details Single Agent Ivosidenib Demonstrated CR+CRh Rate of 42.4% and Overall Response Rate (ORR) of 57.6% in Newly Diagnosed AML Patients ...

10. tibsovo.com tibsovo.com/

TIBSOVO® (ivosidenib tablets) #1 Prescribed FDA-Approved · Acute myeloid leukemia (AML) · MYELODYSPLASTIC SYNDROMES (MDS) · Cholangiocarcinoma (bile duct cancer) · IMPORTANT SAFETY INFORMATION.