Imetelstat + Chemotherapy for Acute Myeloid Leukemia

Recruiting at 14 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Children's Oncology Group

Must not be taking: Corticosteroids, Investigational drugs

Disqualifiers: Pregnancy, Uncontrolled infection, Seizure disorder, others

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

Compensation: Varies

Number of Visits: 1

Duration: 8 weeks

36 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of imetelstat in combination with fludarabine and cytarabine in treating patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or juvenile myelomonocytic leukemia (JMML) that has not responded to previous treatment (refractory) or that has come back after a period of improvement (recurrent). Imetelstat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as fludarabine 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. Giving imetelstat in combination with fludarabine and cytarabine may work better in treating patients with refractory or recurrent AML, MDS, and JMML.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does mention that patients currently receiving other anti-cancer agents are not eligible, except for those on hydroxyurea, which must be stopped 24 hours before starting the trial. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the drug combination Imetelstat, Cytarabine, and Fludarabine for treating acute myeloid leukemia?

Research shows that combinations including Cytarabine and Fludarabine are effective in treating acute myeloid leukemia (AML). For instance, a study found that a regimen with Fludarabine and Cytarabine achieved complete remission in 35% of patients with refractory AML, indicating potential effectiveness of these drugs in AML treatment. ^{1 2 3 4 5}

What makes the drug Imetelstat + Chemotherapy unique for treating acute myeloid leukemia?

The combination of Imetelstat with chemotherapy drugs like Cytarabine and Fludarabine is unique because it explores a novel mechanism of action by targeting telomerase, an enzyme that cancer cells use to maintain their ability to divide indefinitely. This approach is different from traditional chemotherapy, which primarily targets rapidly dividing cells. ^{1 2 6 7 8}

Research Team

Alexandra M Stevens

Principal Investigator

Pediatric Early Phase Clinical Trial Network

Eligibility Criteria

This trial is for children and teenagers (1-18 years old) with certain types of leukemia or myelodysplastic syndrome that haven't improved after treatment or have returned. Participants must have specific levels of cancer cells in their bone marrow, confirmed by lab tests.

Inclusion Criteria

I have fully recovered from my previous cancer treatments.

I am between 1 and 18 years old.

I meet the specific requirements for my treatment plan.

Exclusion Criteria

My corticosteroid dose is changing.

I am taking medication to prevent graft-versus-host disease after a transplant.

Patients with certain medical conditions or infections, prior solid organ transplantation, or inability to comply with safety monitoring

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive imetelstat IV on days 1 and 8, fludarabine IV on days 2-6, and cytarabine IV on days 2-6 of each cycle. Treatment repeats every 28 days for up to 2 cycles.

8 weeks

Multiple visits for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

5 years

Periodic visits for monitoring

Treatment Details

Interventions

• Cytarabine
• Fludarabine
• Imetelstat

Trial Overview The trial is testing the highest safe dose of Imetelstat combined with Fludarabine and Cytarabine in young patients. It aims to find out if this combination can better treat refractory or recurrent acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and juvenile myelomonocytic leukemia (JMML).

Participant Groups

Group I: Treatment (Imetelstat, fludarabine, cytarabine) Experimental Treatment 11 Interventions

Patients receive imeletstat IV over 2 hours on days 1 and 8, fludarabine IV over 1 hour on days 2-6, and cytarabine IV over 1-3 hours on days 2-6 of each cycle. Patients also receive cytarabine IT or methotrexate IT, and hydrocortisone IT at the provider's discretion. Patients then receive leucovorin calcium IV or PO 24 and 30 hours after each IT triples dose. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, bone marrow biopsy and/or aspirate, blood sample collection, and lumbar puncture for CSF sample collection during screening and on the trial.

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

Approved in United States as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia
• Meningeal leukemia

Approved in European Union as Depocyt for:

• Lymphomatous meningitis

Approved in Canada as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia

Who Is Running the Clinical Trial?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

Geron Corporation

Industry Sponsor

Trials

20

Recruited

1,500+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a pilot study involving 17 patients with acute myeloid leukemia (AML), the combination of fludarabine, topotecan, and cytarabine (FTA) resulted in a 35% complete remission rate, indicating its potential efficacy in treating this condition.

However, the treatment was associated with significant side effects, as 41% of patients experienced severe diarrhea, highlighting the need for careful monitoring and further investigation of FTA's safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fludarabine, topotecan, and cytarabine regimen is active in patients with refractory acute myelogenous leukemia. Giles, FJ., Cortes, JE., Kantarjian, HM., et al.[2013]

The combination of CLAG (cladribine, cytarabine, granulocyte colony-stimulating factor) and imatinib mesylate (IM) showed a 37% overall response rate in a phase II study involving 38 patients with relapsed or refractory acute myeloid leukemia (AML), indicating potential efficacy in this challenging patient population.

The treatment was well tolerated, with a median overall survival of 11.1 months and a median progression-free survival of 4.9 months, suggesting that this regimen could be a viable option for patients with poor-risk AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of CLAG Regimen Combined With Imatinib Mesylate for Relapsed or Refractory Acute Myeloid Leukemia. Mirza, AS., Lancet, JE., Sweet, K., et al.[2018]

In a phase III trial involving 112 newly diagnosed AML patients under 60 years, the FLAI regimen (fludarabine, cytarabine, and idarubicin) resulted in a significantly higher complete remission (CR) rate of 74% compared to 51% for the ICE regimen (idarubicin, Ara-C, and etoposide).

FLAI was associated with lower rates of both hematological and non-hematological toxicities, particularly gastrointestinal issues, making it a safer option for induction treatment in AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients. Russo, D., Malagola, M., de Vivo, A., et al.[2013]

Clofarabine combined with cytarabine (Ara-C) showed a 53% overall response rate in 30 adult patients with relapsed or refractory acute myeloid leukemia (AML), including a 47% complete remission rate, demonstrating its efficacy in both untreated and previously treated patients.

The treatment was particularly beneficial for older patients with a history of cardiovascular disease, providing a viable option for remission induction that could lead to curative hematopoietic stem cell transplantation, despite a 30-day mortality rate of 20%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Report of a phase II study of clofarabine and cytarabine in de novo and relapsed and refractory AML patients and in selected elderly patients at high risk for anthracycline toxicity. Agura, E., Cooper, B., Holmes, H., et al.[2021]

In a study of 15 patients with refractory or relapsed acute myeloid leukemia (AML), high-dose cytarabine (ARA-36) achieved a complete remission rate of 60%, demonstrating significant efficacy as a salvage therapy.

Despite the promising remission rates, the one-year overall survival was only 54%, indicating that while ARA-36 is effective, the prognosis for these high-risk patients remains poor, with manageable but notable toxicities observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose cytarabine as salvage therapy for relapsed or refractory acute myeloid leukemia--is more better or more of the same? Wolach, O., Itchaki, G., Bar-Natan, M., et al.[2019]

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]

The Mito-FLAG treatment regimen for relapsed or refractory acute myeloid leukemia (r/r AML) demonstrated a high overall response rate of 75.8%, with 56.1% of patients achieving complete remission after treatment.

Patients who successfully transitioned to allogeneic hematopoietic stem cell transplantation (alloHSCT) experienced significantly improved median overall survival of 17 months compared to just 3 months for those who did not undergo the transplant, highlighting the importance of this treatment pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of patients with relapsed or refractory acute myeloid leukemia treated with Mito-FLAG salvage chemotherapy. Mühleck, R., Scholl, S., Hilgendorf, I., et al.[2022]

Lenvatinib demonstrated a dose-dependent inhibition of acute myeloid leukemia (AML) cell growth in vitro, suggesting its potential as an effective treatment option.

In vivo studies showed that lenvatinib significantly restricted the growth of AML tumors in mice, indicating its efficacy in a living organism model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The multiple-kinase inhibitor lenvatinib inhibits the proliferation of acute myeloid leukemia cells. Feng, F., Li, X., Li, R., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

A fludarabine, topotecan, and cytarabine regimen is active in patients with refractory acute myelogenous leukemia. [2013]

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

A Phase II Study of CLAG Regimen Combined With Imatinib Mesylate for Relapsed or Refractory Acute Myeloid Leukemia. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients. [2013]

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

Report of a phase II study of clofarabine and cytarabine in de novo and relapsed and refractory AML patients and in selected elderly patients at high risk for anthracycline toxicity. [2021]

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

High-dose cytarabine as salvage therapy for relapsed or refractory acute myeloid leukemia--is more better or more of the same? [2019]

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

New chemotherapeutic agents in acute myeloid leukemia. [2013]

7. Germany pubmed.ncbi.nlm.nih.gov

Outcome of patients with relapsed or refractory acute myeloid leukemia treated with Mito-FLAG salvage chemotherapy. [2022]

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

The multiple-kinase inhibitor lenvatinib inhibits the proliferation of acute myeloid leukemia cells. [2023]