CPX-351 + Ivosidenib for Acute Myeloid Leukemia/Myelodysplastic Syndrome

Overseen By Courtney DiNardo, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Strong CYP3A4 inducers

Disqualifiers: Uncontrolled medical condition, Congestive heart failure, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs, CPX-351 and ivosidenib, to determine their effectiveness in treating acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) with a specific genetic change called the IDH1 mutation. CPX-351 (also known as Vyxeos or liposome-encapsulated daunorubicin-cytarabine) is a chemotherapy drug that stops cancer cells from growing or spreading. Ivosidenib (also known as Tibsovo) blocks enzymes needed for cancer cell growth. The trial aims to assess whether these drugs together can control the disease and evaluate their safety. It seeks participants diagnosed with AML or high-risk MDS with the IDH1 mutation who have not previously received CPX-351. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not allow the use of other chemotherapeutic or anti-leukemic agents during the study, except for specific cases like intrathecal chemotherapy or hydroxyurea for rapidly growing disease. If you are taking strong CYP3A4 inducers, you must switch to other medications at least 5 half-lives before starting the trial.

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

Research has shown that both CPX-351 and ivosidenib are safe for treating blood cancers. The FDA has already approved CPX-351 for treating newly diagnosed acute myeloid leukemia (AML), indicating thorough study and general tolerability. Studies also indicate that when combined with other drugs, CPX-351 usually results in manageable side effects. Similarly, trials have tested ivosidenib, showing it to be safe with manageable side effects. These findings suggest that using CPX-351 and ivosidenib together should be safe for most people. However, individual experiences can differ, so discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for acute myeloid leukemia?

Unlike the standard treatments for acute myeloid leukemia (AML) and myelodysplastic syndrome, which often include intensive chemotherapy regimens, the combination of CPX-351 and ivosidenib offers a novel approach. CPX-351 is a liposome-encapsulated formulation of daunorubicin and cytarabine, designed to improve delivery and effectiveness while reducing toxicity. Ivosidenib, on the other hand, specifically targets and inhibits the IDH1 mutation, which is present in some AML patients, aiming to disrupt cancer cell metabolism. Researchers are excited about this combination because it merges targeted therapy with advanced drug delivery, potentially leading to more effective and safer treatments for patients.

What evidence suggests that CPX-351 and ivosidenib could be effective for acute myeloid leukemia or high-risk myelodysplastic syndrome?

Research shows that CPX-351 effectively treats certain types of acute myeloid leukemia (AML). It combines two chemotherapy drugs, cytarabine and daunorubicin, delivered in tiny fat bubbles. CPX-351 has improved overall survival rates compared to traditional treatments. Studies have found that ivosidenib can help individuals with the IDH1 mutation achieve complete remission, meaning no signs of cancer are detected. Specifically, one study found that 51% of patients taking ivosidenib with another drug achieved complete remission. This trial tests the combination of CPX-351 and ivosidenib to better control IDH1-mutated AML and high-risk myelodysplastic syndrome. ^{6 7 8 9 10}

Who Is on the Research Team?

Courtney DiNardo, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with acute myeloid leukemia or high-risk myelodysplastic syndrome that have an IDH1 mutation. Participants can be new to treatment or have relapsed and must be fit enough for intensive chemotherapy (ECOG <=2). They should not have severe heart issues, a history of certain brain infections, or excessive prior anthracycline exposure. Women must avoid pregnancy and men must refrain from donating sperm during the trial.

Inclusion Criteria

Direct bilirubin =< 2 x upper limit of normal (ULN) unless deemed to be related to underlying leukemia

I can take care of myself but might not be able to do heavy physical work.

Willing and able to provide informed consent

Exclusion Criteria

Corrected QT (QTc) interval using Fridericia's formula (QTcF) >= 470 msec. A prolonged QTc interval in the setting of right bundle branch block is permitted after discussion with the PI

I do not have severe stomach or metabolic issues affecting medication absorption.

I have previously been treated with ivosidenib or CPX-351.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and ivosidenib PO QD on days 1-28. Patients who do not achieve complete remission may receive a second cycle of induction therapy.

4 weeks

Consolidation

Patients receive CPX-351 IV over 90 minutes on days 1 and 3, and ivosidenib PO QD on days 1-28. Treatment repeats every 28 days for up to 2 cycles.

8 weeks

Maintenance

Patients receive ivosidenib PO QD for up to 2 years in the absence of disease progression or unacceptable toxicity.

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Ivosidenib
• Liposome-encapsulated Daunorubicin-Cytarabine

Trial Overview The study is testing CPX-351 (a chemo drug combo) alongside Ivosidenib in patients with specific genetic changes in their cancer cells. The goal is to see if this combination helps control the growth of cancer cells better than current treatments by blocking enzymes needed for cell growth.

How Is the Trial Designed?

Group I: Treatment (CPX-351, ivosidenib) Experimental Treatment 2 Interventions

INDUCTION: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and ivosidenib PO QD on days 1-28. Patients who do not achieve complete remission may receive a second cycle of induction therapy in the absence of disease progression or unacceptable toxicity. Patients achieving complete remission proceed to consolidation. CONSOLIDATION: Patients receive CPX-351 IV over 90 minutes on days 1 and 3, and ivosidenib PO QD on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive ivosidenib PO QD for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients who are experiencing clinical benefit and who have not experienced excessive toxicity after completion of 2 years of maintenance may be eligible to continue therapy after discussion with the principal investigator.

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

Approved in United States as Tibsovo for:

• Acute myeloid leukemia (AML) with IDH1 mutation

Approved in European Union as Tibsovo for:

• Acute myeloid leukemia (AML) with IDH1 mutation

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In a phase 3 study, CPX-351 significantly improved remission rates and overall survival in older adults with high-risk acute myeloid leukemia (AML) compared to the standard treatment (7+3), with higher remission frequencies of 41% versus 26% for adverse-risk patients.

The safety profile of CPX-351 was consistent with the overall study population, showing lower early mortality and shorter hospital stays, indicating it is a safe and effective treatment option for patients with adverse or intermediate-risk AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of CPX-351 versus 7 + 3 chemotherapy by European LeukemiaNet 2017 risk subgroups in older adults with newly diagnosed, high-risk/secondary AML: post hoc analysis of a randomized, phase 3 trial. Cortes, JE., Lin, TL., Asubonteng, K., et al.[2023]

CPX-351, a liposomal formulation of cytarabine and daunorubicin, shows improved safety and efficacy in treating acute myeloid leukemia by providing prolonged tissue exposure and altered distribution compared to traditional non-liposomal combinations.

Preclinical studies indicate that CPX-351 maintains similar drug release and metabolism patterns as the standard treatment but results in lower unbound plasma concentrations, which may contribute to its enhanced therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, drug metabolism, and tissue distribution of CPX-351 in animals. Wang, Q., Tardi, P., Sadowski, N., et al.[2021]

In a phase III trial involving 309 patients aged 60 to 75 with newly diagnosed high-risk secondary acute myeloid leukemia (sAML), CPX-351 significantly improved median overall survival compared to the standard 7+3 chemotherapy regimen, with a median survival of 9.56 months versus 5.95 months.

The overall remission rate was also higher with CPX-351 (47.7%) compared to 7+3 (33.3%), while the safety profile was comparable between the two treatments, indicating that CPX-351 is both more effective and similarly safe for older adults with sAML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. Lancet, JE., Uy, GL., Cortes, JE., et al.[2022]

CPX-351, a combination of daunorubicin and cytarabine, has been shown to improve survival and remission rates in adults with newly diagnosed therapy-related acute myeloid leukemia (AML) compared to standard chemotherapy, with comparable safety profiles.

Real-world studies have expanded the understanding of CPX-351's effectiveness in diverse patient populations, including younger adults and those with specific genetic mutations, helping healthcare providers make better-informed treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with CPX-351 in high-risk acute myeloid leukemia. Lemoli, RM., Montesinos, P., Jain, A.[2023]

VYXEOS™, a liposomal formulation of daunorubicin and cytarabine, has been shown to significantly improve overall survival and event-free survival in older patients with newly diagnosed high-risk acute myeloid leukaemia (AML) compared to conventional chemotherapy (7+3).

The treatment also resulted in higher rates of complete remission and was well-tolerated, with a safety profile similar to that of the standard chemotherapy regimen, making it a valuable option for patients with therapy-related AML or AML with myelodysplasia-related changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daunorubicin/Cytarabine Liposome: A Review in Acute Myeloid Leukaemia. Blair, HA.[2020]

CPX-351, a liposomal-encapsulated combination of daunorubicin and cytarabine, has been approved for treating therapy-related acute myeloid leukemia (tAML) and AML with myelodysplasia-related changes (AML-MRCs), showing improved overall survival and remission rates in older patients compared to the traditional '7 + 3' treatment.

In a Phase III trial involving patients aged 60-75, CPX-351 demonstrated higher rates of complete remission and event-free survival, suggesting that its fixed 5:1 drug ratio may enhance efficacy in these challenging subgroups of AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reformulating acute myeloid leukemia: liposomal cytarabine and daunorubicin (CPX-351) as an emerging therapy for secondary AML. Chen, EC., Fathi, AT., Brunner, AM.[2020]

CPX-351 (Vyxeos®) is a dual-drug liposomal formulation of cytarabine and daunorubicin designed to improve efficacy in treating acute myeloid leukemia (AML) by maintaining a synergistic 5:1 drug ratio, which enhances its effectiveness compared to traditional chemotherapy regimens.

The liposomal encapsulation allows for controlled release and preferential uptake by malignant cells, which helps to protect the drugs from metabolism and reduces exposure to off-target tissues, contributing to a favorable safety profile while effectively targeting leukemia cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties. Mayer, LD., Tardi, P., Louie, AC.[2020]

In a phase 3 study involving 309 patients aged 60 to 75 with high-risk acute myeloid leukemia, CPX-351 significantly improved median overall survival compared to conventional 7+3 chemotherapy, while maintaining a similar safety profile.

The Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis showed that CPX-351 provided a relative gain of 53.6% in quality-adjusted survival compared to 7+3, indicating a substantial clinical benefit for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML. Cortes, JE., Lin, TL., Uy, GL., et al.[2021]

CPX-351, a liposomal formulation of cytarabine and daunorubicin, showed high efficacy in treating childhood acute lymphoblastic leukemia (ALL) xenograft models, achieving complete responses in four B-lineage models and a partial response in one T-lineage model.

The drug was administered at a dose that resulted in plasma drug exposures similar to those seen in patients with acute myeloid leukemia (AML), indicating its potential effectiveness and safety for use in pediatric leukemia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of CPX-351, (cytarabine:daunorubicin) liposome injection, against acute lymphoblastic leukemia (ALL) xenograft models of the Pediatric Preclinical Testing Program. Carol, H., Fan, MM., Harasym, TO., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12185649/

The Role of CPX-351 in the Acute Myeloid Leukemia ... CPX-351 is a chemotherapy treatment for acute myeloid leukemia (AML) that combines the two drugs cytarabine and daunorubicin in very small fat bubbles called ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6520

V-RULES: Real-world effectiveness and safety of CPX-351 ... These results highlight the effectiveness and safety of CPX-351 for the treatment of t-AML and AML-MRC in the US RW setting, consistent with the pivotal trial ...

3. vyxeospro.com vyxeospro.com/clinical-data/efficacy

The only choice for more than double the 5-year OS vs 7+3 1 VYXEOS is the only FDA-approved treatment for sAML demonstrating superior overall survival a in a Phase 3 study.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265022000659

Current Status of CPX-351 Therapy in Acute Myeloid ... In this review, we will summarize the current role of CPX-351 in treating this largely heterogeneous disease. Introduction. In Acute myeloid leukemia(AML) the ...

5. bloodcancerunited.org bloodcancerunited.org/resources/newsroom/publication-cpx-351-clinical-data-blood-advances-phase-3-post-hoc-analyses

Publication of CPX-351 Clinical Data in 'Blood Advances' These results suggest deeper remissions may be achieved with CPX-351, leading to improved OS. LLS funded both Phase 2 and Phase 3 clinical development of Vyxeos ...

6. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/4271/534141/Interim-Results-of-the-Phase-II-Study

Interim Results of the Phase II Study Investigating CPX-351 in ... Based on the data showing the safety and efficacy of 7+3 and ivosidenib and the superiority of CPX-351 to 7+3 in a randomized study, we designed ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9221356/

CPX-351: An Old Scheme with a New Formulation in the ... The FDA approved CPX-351, a liposomal formulation of cytarabine and daunorubicin at a fixed 5:1 molar ratio, for the treatment of adults with newly diagnosed t ...

8. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT04493164

NCT04493164 | CPX-351 and Ivosidenib for the Treatment ... This phase II trial investigates how well CPX-351 and ivosidenib work in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndrome ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124070290

Interim Results of the Phase II Study Investigating CPX-351 ... Based on the data showing the safety and efficacy of 7+3 and ivosidenib and the superiority of CPX-351 to 7+3 in a randomized study, we designed ...

10. ashpublications.org ashpublications.org/bloodneoplasia/article/2/4/100123/537598/V-FAST-a-phase-1b-master-trial-to-investigate-CPX

V-FAST: a phase 1b master trial to investigate CPX-351 ... CPX-351 combined with venetoclax or midostaurin demonstrated a manageable safety profile and promising remission rates. These results support further ...