Drug Combination for Pediatric Acute Leukemia

Overseen By Branko Cuglievan, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Chemotherapy, Antileukemic agents

Disqualifiers: Uncontrolled conditions, Active infections, others

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

Compensation: Varies

Number of Visits: Unknown

22 Participants Needed

Trial Summary

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 you cannot use other chemotherapeutic or anti-leukemic agents during the study, except for certain cases like intrathecal chemotherapy for CNS leukemia or hydroxyurea for rapidly proliferative disease. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the drug combination for pediatric acute leukemia?

Research shows that combining cladribine and cytarabine is effective for treating childhood acute myeloid leukemia, with a 5-year survival rate of about 50%. Additionally, decitabine-based therapies have shown a 65% overall response rate in treating relapsed or refractory pediatric myeloid neoplasms. ^{1 2 3 4 5}

What safety data exists for the drug combination used in pediatric acute leukemia?

Cladribine, when used in combination with other drugs like cytarabine and decitabine, has been studied for safety in both children and adults with acute myeloid leukemia. Some studies report similar toxicity levels to other treatments, with side effects like neutropenia (low white blood cell count) and infections being common. However, these combinations have shown promising results in improving outcomes for difficult-to-treat leukemia cases. ^{3 6 7 8 9}

What makes the drug combination of Cladribine, Cytarabine, Decitabine, and Sorafenib unique for treating pediatric acute leukemia?

This drug combination is unique because Cladribine enhances the effectiveness of Cytarabine by increasing its active form, which can lead to better outcomes in children with acute myeloid leukemia. Additionally, the combination aims to target specific genetic features of high-risk leukemia, potentially offering a more effective and less toxic treatment option compared to traditional chemotherapy. ^{2 3 5 8 10}

What is the purpose of this trial?

To find the recommended dose of the drug combination cladribine, cytarabine, decitabine, and sorafenib in participants with relapsed/refractory AML, MPAL, and ALAL.

Research Team

Branko Cuglievan

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for children with acute leukemias that have come back or didn't respond to previous treatments. The specific types of leukemia are AML, MPAL, and ALAL. Details on who can join are not provided here.

Inclusion Criteria

My liver is functioning well, according to recent tests.

It has been over 14 days since my last cancer treatment, or 5 half-lives of the treatment.

My kidneys work well enough (creatinine clearance ≥ 30 mL/min).

Exclusion Criteria

I currently have an infection that isn't under control.

History of or any concurrent condition, therapy, or laboratory abnormality that in the Investigator's opinion might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the participants

I do not have any uncontrolled conditions that could make the study unsafe for me.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Participants receive cladribine, cytarabine, decitabine, and sorafenib at varying dose levels to determine safety and tolerability

8 weeks

Weekly visits for dose adjustments and monitoring

Dose Expansion

Participants receive the recommended dose level of cladribine, cytarabine, decitabine, and sorafenib found in Phase 1

8 weeks

Bi-weekly visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Monthly visits

Treatment Details

Interventions

• Cladribine
• Cytarabine
• Decitabine
• Sorafenib

Trial Overview The study aims to find the right dose for a drug combo (cladribine, cytarabine, decitabine, sorafenib) in young patients with certain relapsed/refractory acute leukemias.

Participant Groups

Group I: Phase 1 Experimental Treatment 4 Interventions

Participants enrolled in Phase 1, the dose level of cladribine, cytarabine, decitabine, and sorafenib will depend on when you join this study. Up to 2 dose levels of this drug combination may be tested. Between 3-6 participants will be enrolled in each dose level. The first group of participants will receive the starting dose level of this drug combination. If no intolerable side effects are seen, the next group of participants will receive the higher dose level of this drug combination.

Group II: Dose Expansion Experimental Treatment 4 Interventions

Participants enrolled in Dose Expansion, you will receive cladribine, cytarabine, decitabine, and sorafenib at the recommended dose level found in Phase 1.

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+

Findings from Research

In a study involving 96 children with acute myeloid leukemia (AML), the combination of cladribine and continuous-infusion cytarabine showed promising efficacy, with 5-year event-free survival and overall survival rates of 44.1% and 50.0%, respectively.

While both treatment arms (daily vs. continuous infusion) did not show significant differences in blast percentages or Ara-CTP levels, the continuous infusion (arm B) suggested trends toward better complete remission rates and overall survival, indicating it may be a more effective approach for therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of cladribine and cytarabine is effective for childhood acute myeloid leukemia: results of the St Jude AML97 trial. Rubnitz, JE., Crews, KR., Pounds, S., et al.[2021]

Cladribine (CdA) has shown significant efficacy in treating acute myeloid leukemia (AML), with complete response rates of up to 70% in newly diagnosed adults and around 50% in relapsed/refractory cases, based on various studies.

Despite its effectiveness and similar toxicity profiles to existing treatments, many medical centers have not yet adopted CdA combination regimens for managing these challenging AML populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Revisiting the role of cladribine in acute myeloid leukemia: an improvement on past accomplishments or more old news? Freyer, CW., Gupta, N., Wetzler, M., et al.[2014]

A new low-intensity treatment regimen combining cladribine and low-dose cytarabine alternating with decitabine showed promising results in elderly or unfit patients with acute myeloid leukaemia (AML), with a median disease-free survival of 10.8 months and a median overall survival of 13.8 months based on a study of 118 patients.

The regimen was well tolerated, with only 1% of patients experiencing early death within the first 4 weeks, indicating a favorable safety profile compared to traditional therapies, which often have higher toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial. Kadia, TM., Cortes, J., Ravandi, F., et al.[2019]

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]

References

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

Clofarabine Can Replace Anthracyclines and Etoposide in Remission Induction Therapy for Childhood Acute Myeloid Leukemia: The AML08 Multicenter, Randomized Phase III Trial. [2020]

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

Combination of cladribine and cytarabine is effective for childhood acute myeloid leukemia: results of the St Jude AML97 trial. [2021]

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

Revisiting the role of cladribine in acute myeloid leukemia: an improvement on past accomplishments or more old news? [2014]

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

Real-world experience in treating pediatric relapsed/refractory or therapy-related myeloid malignancies with decitabine, vorinostat, and FLAG therapy based on a phase 1 study run by the TACL consortium. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Targeted drug discovery for pediatric leukemia. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial. [2019]

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

Randomized trial of daily versus weekly administration of 2-chlorodeoxyadenosine in patients with hairy cell leukemia: a multicenter phase III trial (SAKK 32/98). [2019]

8. 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]

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

Interim comparison of a continuous infusion versus a short daily infusion of cytarabine given in combination with cladribine for pediatric acute myeloid leukemia. [2016]

10. Germany pubmed.ncbi.nlm.nih.gov

Randomised Introduction of 2-CDA as Intensification during Consolidation for Children with High-risk AML--results from Study AML-BFM 2004. [2015]