CPX-351 vs CLAG-M for Acute Myeloid Leukemia

Overseen By Roland Walter, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Fred Hutchinson Cancer Research Center

Must not be taking: Anti-leukemia agents

Disqualifiers: CML blast crisis, Infections, Pregnancy, 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

Compensation: Varies

Number of Visits: Unknown

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well CPX-351 or the CLAG-M regimen (consisting of the drugs cladribine, cytarabine, G-CSF, and mitoxantrone) works in treating medically less-fit patients with acute myeloid leukemia or other high-grade myeloid neoplasms. Drugs used in chemotherapy, such as CPX-351, cladribine, cytarabine, G-CSF, and mitoxantrone, 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 CPX-351 or the CLAG-M regimen at doses typically used for medically-fit patients with acute myeloid leukemia may work better than reduced doses of CPX-351 in treating medically less-fit patients with acute myeloid leukemia or other high-grade myeloid neoplasms.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must stop hydroxyurea before starting the study treatment. If you are on a FLT3-inhibitor for FLT3-mutated AML, you can continue that treatment.

What data supports the effectiveness of the drug CPX-351 for treating acute myeloid leukemia?

CPX-351, a combination of cytarabine and daunorubicin, has shown improved survival rates and higher remission rates in older patients with secondary acute myeloid leukemia compared to the traditional '7+3' regimen. It was approved by the FDA for its effectiveness in treating newly diagnosed therapy-related AML and AML with myelodysplasia-related changes. ^{1 2 3 4 5}

Is CPX-351 generally safe for humans?

CPX-351, a combination of cytarabine and daunorubicin, has been studied for safety in humans and animals. It was approved by the FDA for certain types of acute myeloid leukemia (AML) and has shown a favorable safety profile compared to traditional treatments, with lower unbound drug concentrations in the body, which may reduce side effects. ^{1 2 6 7 8}

What makes the drug CPX-351 unique for treating acute myeloid leukemia?

CPX-351 is unique because it combines two drugs, cytarabine and daunorubicin, in a special liposomal form that delivers them in a fixed 5:1 ratio directly to leukemia cells, improving survival rates compared to the traditional 7+3 regimen. This formulation allows for better targeting of leukemia cells while maintaining a similar safety profile. ^{1 6 9 10 11}

Research Team

Roland Walter, MD

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

This trial is for less-fit patients with untreated high-grade myeloid neoplasms or AML, excluding acute promyelocytic leukemia. Participants must have a specific risk score (TRM >= 13.1), agree to use contraception, and be able to consent. Prior low-intensity treatments are allowed; significant liver function and heart health are required.

Inclusion Criteria

My bilirubin levels are below 2.0 mg/mL, or higher for specific medical reasons.

Ability to understand and the willingness to sign a written informed consent document

I have used hydroxyurea but will stop before the study starts. I may have had treatments for high WBC or tumor complications.

Exclusion Criteria

I have a severe form of leukemia and cannot be treated with tyrosine kinase inhibitors.

You have a known allergy or extreme sensitivity to any of the drugs being used in this study.

I have an infection, but it is being treated or is under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Patients receive CPX-351 or CLAG-M regimen. CPX-351 is administered IV over 90 minutes on days 1, 3, and 5. CLAG-M includes cladribine, cytarabine, G-CSF, and mitoxantrone administered over several days.

1-2 weeks

Multiple visits for IV administration

Post-Remission Treatment

Patients achieving CR/CRi receive additional courses of reduced or intermediate doses of CPX-351 or cytarabine.

Up to 4 additional courses

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• Cladribine
• Cytarabine
• Liposome-encapsulated Daunorubicin-Cytarabine
• Mitoxantrone
• Recombinant Granulocyte Colony-Stimulating Factor

Trial Overview The study compares CPX-351 chemotherapy against the CLAG-M regimen in treating medically less-fit patients with certain types of blood cancer. It aims to determine if full doses used for fitter patients could be more effective than reduced doses in this population.

Participant Groups

Group I: Arm II (CLAG-M) Experimental Treatment 6 Interventions

INDUCTION: Patients receive cladribine IV over 2 hours on days 1-5, cytarabine IV over 2 hours on days 1-5, G-CSF SC on days 0-5, and mitoxantrone IV over 60 minutes on days 1-3 in the absence of disease progression or unacceptable toxicity. Patients who achieve a response other than an MRDneg CR receive a second course of cladribine IV over 2 hours on days 1-5, cytarabine IV over 2 hours on days 1-5, G-CSF SC on days 0-5, and mitoxantrone IV over 60 minutes on days 1-3 in the absence of disease progression or unacceptable toxicity. POST-REMISSION: Patients who achieve a CR/CRi receive an intermediate dose of cytarabine IV over 2 hours on days 1-6 for up to 4 additional courses in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (CPX-351) Experimental Treatment 3 Interventions

INDUCTION: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5 in the absence of disease progression or unacceptable toxicity. Patients who achieve a response other than an MRDneg CR receive a second course of CPX-351 intravenously IV over 90 minutes on days 1, 3, and 5 in the absence of disease progression or unacceptable toxicity. POST-REMISSION: Patients who achieve a CR/CRi receive a reduced dose of CPX-351 IV over 90 minutes on days 1, 3, and 5 for up to 4 additional courses in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as Leustatin for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma
• Multiple sclerosis

Approved in European Union as Litak for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Research Center

Lead Sponsor

Trials

444

Recruited

148,000+

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

Jazz Pharmaceuticals

Industry Sponsor

Trials

252

Recruited

35,100+

Bruce C. Cozadd

Jazz Pharmaceuticals

Chief Executive Officer since 2009

BA in Economics from Yale University, MBA from Stanford University

Dr. Austin

Jazz Pharmaceuticals

Chief Medical Officer since 2023

MD from the Royal College of Surgeons in Ireland

Findings from Research

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, 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]

In a study of 55 children with relapsed/refractory acute myeloid leukemia (R/R-AML), the CLAG-M treatment showed an overall response rate of 80%, significantly outperforming the MEC/IEC treatment, which had a response rate of 51%.

CLAG-M also resulted in better overall survival (66.8% vs. 40.4%) and progression-free survival (52.6% vs. 34.9%) at 3 years compared to MEC/IEC, particularly benefiting low-risk patients, while those with the FLT3-ITD mutation had poorer outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved outcome of children with relapsed/refractory acute myeloid leukemia by addition of cladribine to re-induction chemotherapy. Ruan, M., Liu, LP., Zhang, AL., et al.[2021]

In a study involving 53 AML patients, CPX-351 demonstrated significant cytotoxic activity, particularly in cases with the FLT3-ITD mutation, which were five times more sensitive to the treatment.

The effectiveness of CPX-351 was consistent across various leukemia types, with its cellular uptake correlating with its cytotoxic potency, suggesting that ex vivo testing could help identify AML patients who would benefit most from this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CPX-351 exhibits potent and direct ex vivo cytotoxicity against AML blasts with enhanced efficacy for cells harboring the FLT3-ITD mutation. Gordon, MJ., Tardi, P., Loriaux, MM., et al.[2018]

CPX-351, a new liposomal formulation of daunorubicin and cytarabine, has been approved for treating newly diagnosed therapy-related acute myeloid leukemia (tAML) and AML with myelodysplasia-related changes, showing improved overall survival compared to the traditional '7+3' regimen.

This new treatment delivers a fixed 5:1 ratio of the two drugs, which may enhance efficacy, particularly in older patients who typically have poorer outcomes with standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CPX-351 daunorubicin-cytarabine liposome: a novel formulation to treat patients with newly diagnosed secondary acute myeloid leukemia. Cafaro, A., Giannini, MB., Silimbani, P., et al.[2020]

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]

CPX-351, a liposomal formulation of cytarabine and daunorubicin, shows superior cytotoxicity compared to standard daunorubicin and cytarabine combinations in cytarabine-resistant leukemia cells, indicating its potential effectiveness in treating high-risk acute myeloid leukemia (AML).

In primary AML patient samples, CPX-351 demonstrated a rapid increase in intracellular ara-CTP levels, particularly in patients who later experienced treatment failure, suggesting that Flu-CPX may improve patient outcomes by enhancing drug activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CPX-351 exhibits hENT-independent uptake and can be potentiated by fludarabine in leukaemic cells lines and primary refractory AML. Anderson, E., Mehta, P., Heywood, J., et al.[2022]

The recommended phase II dose (RP2D) of CPX-351 for treating relapsed acute myeloid leukemia in children is 135 units/m2, with manageable toxicity and no toxic mortality reported during the study.

The treatment showed promising efficacy, with a 54% complete response rate and 84% of responders having no detectable residual disease, outperforming previous clinical trials for similar patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II Study of CPX-351 Followed by Fludarabine, Cytarabine, and Granulocyte-Colony Stimulating Factor for Children With Relapsed Acute Myeloid Leukemia: A Report From the Children's Oncology Group. Cooper, TM., Absalon, MJ., Alonzo, TA., et al.[2021]

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]

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 liposome formulation of cytarabine and daunorubicin, demonstrated potent anti-leukemic activity in a mouse model, effectively reducing leukemia cells in bone marrow to undetectable levels for weeks, unlike the free-drug cocktail which only provided temporary suppression.

The enhanced efficacy of CPX-351 is attributed to its ability to deliver higher concentrations of the drugs directly to leukemia cells, leading to prolonged exposure and selective killing of these cells, while causing similar levels of myelosuppression as the free-drug cocktail.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leukemia-selective uptake and cytotoxicity of CPX-351, a synergistic fixed-ratio cytarabine:daunorubicin formulation, in bone marrow xenografts. Lim, WS., Tardi, PG., Dos Santos, N., et al.[2022]

References

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

Reformulating acute myeloid leukemia: liposomal cytarabine and daunorubicin (CPX-351) as an emerging therapy for secondary AML. [2020]

2. United States 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. [2021]

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

Improved outcome of children with relapsed/refractory acute myeloid leukemia by addition of cladribine to re-induction chemotherapy. [2021]

4. England pubmed.ncbi.nlm.nih.gov

CPX-351 exhibits potent and direct ex vivo cytotoxicity against AML blasts with enhanced efficacy for cells harboring the FLT3-ITD mutation. [2018]

5. Italy pubmed.ncbi.nlm.nih.gov

CPX-351 daunorubicin-cytarabine liposome: a novel formulation to treat patients with newly diagnosed secondary acute myeloid leukemia. [2020]

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

Pharmacokinetics, drug metabolism, and tissue distribution of CPX-351 in animals. [2021]

7. England pubmed.ncbi.nlm.nih.gov

CPX-351 exhibits hENT-independent uptake and can be potentiated by fludarabine in leukaemic cells lines and primary refractory AML. [2022]

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

Phase I/II Study of CPX-351 Followed by Fludarabine, Cytarabine, and Granulocyte-Colony Stimulating Factor for Children With Relapsed Acute Myeloid Leukemia: A Report From the Children's Oncology Group. [2021]

9. England 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. [2021]

10. United States 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. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Leukemia-selective uptake and cytotoxicity of CPX-351, a synergistic fixed-ratio cytarabine:daunorubicin formulation, in bone marrow xenografts. [2022]