Combination Chemotherapy for Acute Myeloid Leukemia

Overseen By Musa Yilmaz

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Strong CYP3A4 inducers

Disqualifiers: Active infection, Active malignancies, GI impairment, Cardiac issues, others

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

Compensation: Varies

Number of Visits: 6

80 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial does not specify if you need to stop taking your current medications. However, if you are taking a strong CYP3A4 inducing medication, you may need to stop it, as it is listed in the exclusion criteria.

What data supports the effectiveness of the drug combination Cladribine, Cytarabine, and Idarubicin for treating Acute Myeloid Leukemia?

Research shows that the combination of Cladribine, Cytarabine, and Idarubicin has been used as a salvage treatment for relapsed Acute Myeloid Leukemia (AML) with some success, including a study where the overall response rate was 51% in children with AML at first relapse. Additionally, adding Cladribine to Idarubicin and Cytarabine during induction increased the overall efficacy rate in adult AML patients. ^{1 2 3 4 5}

What safety data exists for the combination chemotherapy treatment for acute myeloid leukemia?

The combination of cladribine, cytarabine, and idarubicin has been studied in various trials for acute myeloid leukemia, showing limited toxicity and manageable side effects. In one study, the early toxic death rate was 11%, and patients experienced fever and required antibiotics, but overall, the treatment was considered feasible and safe for use in older adults. ^{2 5 6 7 8}

What makes the combination chemotherapy with Cladribine, Cytarabine, Idarubicin, and Quizartinib unique for treating acute myeloid leukemia?

This treatment is unique because it combines Cladribine, Cytarabine, Idarubicin, and Quizartinib, which may offer a novel approach by integrating a targeted therapy (Quizartinib) with traditional chemotherapy agents, potentially enhancing effectiveness against acute myeloid leukemia. ^{1 3 9 10 11}

What is the purpose of this trial?

This phase I/II trial studies the side effects and how well cladribine, idarubicin, cytarabine, and quizartinib work in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndrome that is newly diagnosed, has come back (relapsed), or does not respond to treatment (refractory). Drugs used in chemotherapy, such as cladribine, idarubicin, and cytarabine, 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. Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving quizartinib with cladribine, idarubicin, and cytarabine may help to control acute myeloid leukemia or high-risk myelodysplastic syndrome.

Research Team

Musa Yilmaz

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with newly diagnosed, relapsed, or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Eligible participants are those aged 18-65 who haven't had certain chemotherapies, have a good performance status, functioning organs, and no serious concurrent illnesses. Women of childbearing potential must test negative for pregnancy and use contraception.

Inclusion Criteria

Transaminases (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x upper limit of normal (ULN)

My cancer is a type of leukemia affecting areas outside the bone marrow.

Creatinine < 1.5 mg/dl

Exclusion Criteria

- Left bundle branch block

I have had a fast heart rate that needed treatment.

I do not have a serious infection or fever over 101°F in the last 48 hours.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive idarubicin, cladribine, cytarabine, and quizartinib. Treatment repeats every 28 days for up to 2 cycles.

8 weeks

Multiple visits for IV administration

Consolidation

Patients achieving CR or CRp receive idarubicin, cladribine, cytarabine, and quizartinib. Treatment repeats every 28 days for up to 5 cycles.

20 weeks

Multiple visits for IV administration

Maintenance

Patients achieving CR or CRi/CRh receive quizartinib. Treatment repeats every 28 days for up to 12 cycles.

48 weeks

Monthly visits for oral administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

6-12 months

Follow-up visits every 6-12 months

Treatment Details

Interventions

• Cladribine
• Cytarabine
• Idarubicin
• Quizartinib

Trial Overview The trial tests the effectiveness and side effects of combining chemotherapy drugs cladribine, idarubicin, cytarabine with quizartinib in patients with AML or MDS. It aims to see if this combination can help control these diseases by killing cancer cells or stopping their growth.

Participant Groups

Group I: Treatment (idarubicin, cladribine, cytarabine, quizartinib) Experimental Treatment 4 Interventions

INDUCTION: Patients receive idarubicin Intravenous over 1 hours on days 1-3, cladribine intravenous over 1-2 hours on days 1-5, cytarabine Intravenous over 3 hours on days 1-5 (or days 1-3 for patients over age 60), and quizartinib by mouth daily on days 6-19. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients who achieve CR or CRp after Induction receive idarubicin Intravenous over 1 hours on days 1-2, cladribine Intravenous over 1-2 hours on days 1-3, cytarabine Intravenous over 3 hours on days 1-3, and quizartinib by mouth daily on days 4-28. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients who achieve CR or CRi/CRh after Consolidation receive quizartinib by mouth daily on days 1-28. Treatment repeats every 28 days for up to 12 cycles 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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

The DAF regimen, which includes daunorubicin, fludarabine, and cytarabine, showed a 56% overall response rate in 34 patients with relapsed or refractory acute myeloid leukemia (AML), with 15 out of 16 patients achieving complete remission after the first course.

The treatment was well tolerated, with severe neutropenia and serious infections occurring in a significant number of patients, but no severe long-term complications like liver or kidney failure were observed, indicating a favorable safety profile for this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daunorubicin, cytarabine and fludarabine (DAF) for remission induction in relapsed or refractory acute myeloid leukemia. Evaluation of safety, tolerance and early outcome--Polish Adult Leukemia Group (PALG) pilot study. Hołowiecki, J., Grosicki, S., Kyrcz-Krzemien, S., et al.[2013]

In a Phase 2 clinical trial involving 109 pediatric patients with acute myeloid leukemia (AML) at first relapse, the combination of 2-chlorodeoxyadenosine (2-CDA) and idarubicin showed a 51% overall response rate, with a 46% complete response rate, indicating its potential effectiveness in treating this population.

The treatment had an acceptable safety profile, with significant toxicities including neutropenia (59%) and thrombocytopenia (68%), but no serious cardiac events, suggesting it could be a viable option for frontline therapy in children with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of 2-chlorodeoxyadenosine plus idarubicin for children with acute myeloid leukaemia in first relapse: a paediatric oncology group study. Chaleff, S., Hurwitz, CA., Chang, M., et al.[2021]

In a study of 34 relapsing AML patients treated with CLA-Ida chemotherapy, 52.9% achieved complete remission (CR2), indicating a promising efficacy of this treatment regimen.

The treatment-related mortality was relatively low at 5.9%, and among those who achieved CR2, 23.5% remained in remission after a median follow-up of 6 months, highlighting the potential for successful subsequent allogeneic transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cladribine, cytarabine and idarubicin (CLA-Ida) salvage chemotherapy in relapsed acute myeloid leukemia (AML). Fridle, C., Medinger, M., Wilk, MC., et al.[2019]

The novel IAC regimen (idarubicin, cytarabine, and cladribine) showed a significantly higher complete remission rate in acute myeloid leukemia (AML) patients compared to the low-dose IA regimen, indicating its enhanced efficacy without increasing toxicity.

Prognostic factors such as high white blood cell counts at diagnosis and unfavorable karyotypes were associated with poorer treatment responses, highlighting the importance of these factors in predicting outcomes for AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of Cladribine to Idarubicin and Cytarabine during Induction Increases the Overall Efficacy Rate in Adult Patients with Acute Myeloid Leukemia: A Matched-Pair Retrospective Comparison. Shen, Y., Chen, J., Liu, Y., et al.[2015]

In a phase II trial involving 20 patients with relapsed acute myeloid leukemia (AML), the combination of cladribine, cytarabine, and idarubicin achieved a complete remission rate of 60%, demonstrating its efficacy in this challenging condition.

The treatment was associated with significant toxicity, primarily infections, but when combined with allogeneic stem cell transplantation, it led to a 5-year survival rate of 55% among those who underwent the transplant, indicating potential for long-term survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up of Cladribine, high-dose Cytarabine, and Idarubicin as salvage treatment for relapsed acute myeloid leukemia and literature review. Mayer, K., Hahn-Ast, C., Schwab, K., et al.[2021]

In a study of 309 newly diagnosed acute myeloid leukemia (AML) patients, adding cladribine to the standard treatment of daunorubicin and cytarabine did not significantly change the overall incidence of infectious complications during induction therapy.

While there was a trend towards fewer bacteremias in the cladribine group, the difference was not statistically significant, and both treatment groups had similar recovery rates from infections, indicating that cladribine does not increase infection risk in AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infectious complications in patients with acute myeloid leukemia treated according to the protocol with daunorubicin and cytarabine with or without addition of cladribine. A multicenter study by the Polish Adult Leukemia Group (PALG). Lech-Maranda, E., Seweryn, M., Giebel, S., et al.[2013]

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 phase II trial involving 63 patients aged over 60 with acute myeloid leukaemia (AML), the addition of intermittent cladribine to intermediate-dose cytosine arabinoside and idarubicin resulted in a higher complete remission rate of 62%, compared to 35% for the two-drug therapy alone.

The treatment was well-tolerated with limited toxicity, and the median survival was 14 months, indicating that this combination therapy could be a promising option for older AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased remissions from one course for intermediate-dose cytosine arabinoside and idarubicin in elderly acute myeloid leukaemia when combined with cladribine. A randomized population-based phase II study. Juliusson, G., Höglund, M., Karlsson, K., et al.[2019]

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]

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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Daunorubicin, cytarabine and fludarabine (DAF) for remission induction in relapsed or refractory acute myeloid leukemia. Evaluation of safety, tolerance and early outcome--Polish Adult Leukemia Group (PALG) pilot study. [2013]

2. England pubmed.ncbi.nlm.nih.gov

Phase II study of 2-chlorodeoxyadenosine plus idarubicin for children with acute myeloid leukaemia in first relapse: a paediatric oncology group study. [2021]

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

Cladribine, cytarabine and idarubicin (CLA-Ida) salvage chemotherapy in relapsed acute myeloid leukemia (AML). [2019]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Addition of Cladribine to Idarubicin and Cytarabine during Induction Increases the Overall Efficacy Rate in Adult Patients with Acute Myeloid Leukemia: A Matched-Pair Retrospective Comparison. [2015]

5. England pubmed.ncbi.nlm.nih.gov

Long-term follow-up of Cladribine, high-dose Cytarabine, and Idarubicin as salvage treatment for relapsed acute myeloid leukemia and literature review. [2021]

6. Canada pubmed.ncbi.nlm.nih.gov

Infectious complications in patients with acute myeloid leukemia treated according to the protocol with daunorubicin and cytarabine with or without addition of cladribine. A multicenter study by the Polish Adult Leukemia Group (PALG). [2013]

7. Australia pubmed.ncbi.nlm.nih.gov

Fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin for relapsed childhood acute myeloid leukemia. [2018]

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

Increased remissions from one course for intermediate-dose cytosine arabinoside and idarubicin in elderly acute myeloid leukaemia when combined with cladribine. A randomized population-based phase II study. [2019]

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

Remission induction therapy of untreated acute myeloid leukemia using a non-cytarabine-containing regimen of idarubicin, etoposide, and carboplatin. [2015]

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

Idarubicin, high-dose cytarabine and etoposide for remission induction in therapy-related acute myeloid leukemia. [2019]

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

Idarubicin, high-dose cytarabine, and etoposide for induction of remission in acute leukemia. [2013]