Chemotherapy for Acute Lymphoblastic Leukemia

Not currently recruiting at 262 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4/5 inducers

Disqualifiers: Pregnancy, Breastfeeding, BCR-ABL1, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of combination chemotherapy for young patients with acute lymphoblastic leukemia (ALL). It focuses on patients whose cancer might return or spread, particularly those with genetic traits that make them sensitive to targeted drugs. The trial uses a mix of chemotherapy drugs, including Daunorubicin Hydrochloride, to kill cancer cells in various ways. This approach may suit patients recently diagnosed with B-ALL who have genetic markers indicating a higher risk of recurrence. As a Phase 3 trial, this treatment is in the final step before FDA approval, providing patients access to potentially effective therapies early.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions avoiding certain drugs for seizure disorders, so it's best to discuss your specific medications with the trial team.

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

Research shows that the chemotherapy drugs used in this trial have varying safety levels. Daunorubicin is well-researched and generally safe, though it can cause heart problems in some individuals. Dexamethasone is effective but may increase the risk of treatment-related deaths compared to prednisone. Doxorubicin, approved by the FDA for leukemia, can cause heart issues, especially at higher doses.

Etoposide is safe for children, but its effectiveness in adults remains unclear. Hydrocortisone is safe when used correctly, though it has affected fertility in animal studies. Mercaptopurine, FDA-approved for leukemia, is safe but may require monitoring to avoid side effects.

Methotrexate can cause serious liver damage if not monitored. Pegaspargase is commonly used and generally safe, though it may cause allergic reactions in some children. Prednisone, another steroid, is used safely but requires careful monitoring to prevent side effects.

Thioguanine is safe for ongoing leukemia treatment but requires careful dosing. Topotecan, FDA-approved for some cancers, can lower blood cell counts. Vincristine is well-tolerated and has been used in leukemia treatment for many years.

This trial is in phase 3, indicating that the safety of these drugs is well-researched. However, like any treatment, risks exist, and side effects should be monitored. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for acute lymphoblastic leukemia (ALL) because they combine a variety of chemotherapeutic agents, each with unique mechanisms that could enhance treatment effectiveness. Unlike the standard of care, which typically involves single or limited-agent chemotherapy, this approach uses a broader combination of drugs like Daunorubicin, Dexamethasone, and Vincristine, which are known for their potent anti-cancer effects. This comprehensive approach aims to target leukemia cells more aggressively and from multiple angles, potentially leading to improved outcomes and reduced relapse rates. Additionally, the use of agents like Pegaspargase introduces novel enzyme-based treatment that can disrupt leukemia cell metabolism, offering a fresh angle in attacking the disease.

What evidence suggests that this trial's treatments could be effective for acute lymphoblastic leukemia?

This trial will evaluate various chemotherapy regimens for treating acute lymphoblastic leukemia (ALL) in children. Participants in different arms of this trial will receive combinations of chemotherapy drugs. Daunorubicin, which some participants may receive, helped 83% of patients achieve a complete response, meaning the cancer was no longer detectable. Dexamethasone significantly lowers the risk of the cancer returning in the brain or spinal cord compared to prednisone. Methotrexate, included in some treatment arms, has shown that more than 80% of patients with certain types of ALL remain free of major health events for five years. Pegaspargase, also part of the trial, has an 84.9% success rate in helping patients stay event-free for five years. Vincristine, used in various arms, plays a crucial role in improving outcomes for children with ALL. These treatments work by killing cancer cells, stopping their growth, or preventing them from spreading. ^{6 7 8 9 10}

Who Is on the Research Team?

Michael J Burke

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for young patients with high-risk B acute lymphoblastic leukemia and specific mutations that make them sensitive to certain drugs. They must meet organ function requirements, have no major heart conduction issues, not be pregnant or breastfeeding, agree to use contraception if of childbearing potential, and cannot have received prior cytotoxic chemotherapy.

Inclusion Criteria

Patients must be enrolled on APEC14B1 and consented to Eligibility Screening on the Part A consent form prior to enrollment on AALL1131

White Blood Cell Count (WBC) Criteria: Age 1-9.99 years: WBC >= 50 000/uL, Age 10-30.99 years: Any WBC, Age 1-30.99 years: Any WBC with Testicular leukemia, CNS leukemia (CNS3), Steroid pretreatment, Patients must have newly diagnosed B lymphoblastic leukemia (2008 World Health Organization [WHO] classification) (also termed B-precursor acute lymphoblastic leukemia); patients with Down syndrome are also eligible, Organ function requirements for patients with Ph-like ALL and a predicted TKI-sensitive mutation: patients identified as Ph-like with a TKI-sensitive kinase mutation must have assessment of organ function performed within 3 days of study entry onto the dasatinib arm of AALL1131, Creatinine clearance or radioisotope glomerular filtration rate (GFR) > 70mL/min/1.73 m^2 or a serum creatinine based on age/gender, Direct bilirubin =< 3 x upper limit of normal (ULN) for age, Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 10 x upper limit of normal (ULN) for age, Shortening fraction >= 27% by echocardiogram, or ejection fraction >= 50% by gated radionuclide study, Patients must have an electrocardiogram (EKG) fewer than 6 days prior to enrollment on the dasatinib arm; patients who have had cardiac assessments by echocardiogram or radionuclide scan at the beginning of induction do not need to have these repeated prior to study entry; correct QT interval (QTc) < 450 msec on baseline electrocardiogram as measured by the Friderica or Bazett formula, No major conduction abnormality (unless a cardiac pacemaker is present), No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% at sea level if there is clinical indication for determination, Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled; however, drugs that induce CYP3A4/5 (carbamazepine, oxcarbazepine, phenytoin, primidone, phenobarbital) should be avoided, Eligibility criteria for the Longitudinal, Computerized Assessment of Neurocognitive Functioning study: Patients must be aged 6 to 13 years at time of B-ALL diagnosis, enrolled on AALL1131, Patients must be English-, French- or Spanish-speaking (languages in which the assessment is available), Patients must have no known history of neurodevelopmental disorder prior to diagnosis of B-ALL (e.g., Down syndrome, Fragile X, William's Syndrome, mental retardation), Patients must have no significant visual impairment that would prevent computer use and recognition of the visual test stimuli, Eligibility criteria for the National Cancer Institute (NCI) standard risk patients from AALL0932 enrolling on this study at the end of Induction: Effective March 19, 2018, patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 or the HR B-ALL stratum of this study at the end of Induction, Effective Amendment 6, patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 or the VHR stratum of AALL1131, Patients enrolled on AALL0932, with Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the DS HR B-ALL stratum of this study at the end of Induction, All patients and/or their parents or legal guardians must sign a written informed consent, All institutional, Food and Drug Administration (FDA), and NCI requirements for human studies must be met

Exclusion Criteria

With the exception of steroid pretreatment or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for either the current diagnosis of B-ALL or any cancer diagnosed prior to the initiation of protocol therapy on AALL1131; patients cannot have secondary B-ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy; patients receiving prior steroid therapy may be eligible for AALL1131, Patients with BCR-ABL1 fusion are not eligible for post-induction therapy on this study but may be eligible to enroll in a successor Children's Oncology Group (COG) Philadelphia positive (Ph+) ALL trial by day 15 Induction, DS HR B-ALL patients with Induction failure or BCR-ABL1, Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs, Lactating females are not eligible unless they have agreed not to breastfeed their infant, Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained, Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive induction chemotherapy comprising various drugs including cytarabine, vincristine sulfate, daunorubicin hydrochloride, dexamethasone, pegaspargase, and methotrexate.

5 weeks

Consolidation Therapy

Patients receive consolidation therapy with cyclophosphamide, cytarabine, mercaptopurine, methotrexate, vincristine sulfate, and pegaspargase. Radiotherapy is administered for testicular leukemia.

8 weeks

Interim Maintenance Therapy

Patients receive interim maintenance therapy with vincristine sulfate, high-dose methotrexate, leucovorin calcium, and mercaptopurine.

9 weeks

Delayed Intensification Therapy

Patients receive delayed intensification therapy with vincristine sulfate, dexamethasone, doxorubicin hydrochloride, methotrexate, pegaspargase, cyclophosphamide, cytarabine, and thioguanine.

8 weeks

Maintenance Therapy

Patients receive maintenance therapy with vincristine sulfate, prednisone, methotrexate, and mercaptopurine. Treatment repeats every 12 weeks for 2 years (females) or 3 years (males).

2-3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

10 years

What Are the Treatments Tested in This Trial?

Interventions

• Daunorubicin Hydrochloride
• Dexamethasone
• Doxorubicin Hydrochloride
• Etoposide
• Hydrocortisone Sodium Succinate
• Leucovorin Calcium
• Mercaptopurine
• Methotrexate
• Pegaspargase
• Prednisone
• Radiation Therapy
• Thioguanine
• Topotecan Hydrochloride
• Vincristine Sulfate

Trial Overview The study tests how well a combination of chemotherapy drugs works against aggressive B acute lymphoblastic leukemia in children and young adults. It includes various medications like Dasatinib and Dexamethasone among others, given in different doses and combinations to see which is most effective at killing cancer cells.

How Is the Trial Designed?

Group I: Group III PH-like predicted TKI-sensitive kinase mutation Experimental Treatment 13 Interventions

Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details.

Group II: Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Experimental Treatment 15 Interventions

Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details.

Group III: Group II Arm B (VHR B-ALL - Exp Arm1) (CLOSED 02/15/2017) Experimental Treatment 13 Interventions

Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details.

Group IV: Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Experimental Treatment 15 Interventions

Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details.

Group V: Group I Arm A (HR B-ALL) Experimental Treatment 14 Interventions

Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details.

Group VI: DS HR B-ALL (SER) Experimental Treatment 14 Interventions

Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details.

Group VII: DS HR B-ALL (RER) Experimental Treatment 13 Interventions

Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details.

Group VIII: Group II Arm A (VHR B-ALL - Control Arm) Active Control 14 Interventions

Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details.

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

Approved in United States as Daunorubicin Hydrochloride for:

• Acute myeloid leukemia (AML)
• Acute lymphoblastic leukemia (ALL)

Approved in European Union as Daunorubicin Hydrochloride for:

• Acute myeloid leukemia (AML)
• Acute lymphoblastic leukemia (ALL)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 88 children with acute lymphoblastic leukemia, two treatment protocols showed high complete remission rates of 92-96%, with protocol 0276/A demonstrating a significantly lower relapse rate of 4% compared to 28% in protocol 0171.

The long-term outcomes were promising, with 60% of children from protocol 0171 remaining alive in complete remission for over 10 years, while protocol 0276/A showed even better results with over 70% of complete responders in continuous remission for up to 57 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of acute lymphoblastic leukemia in children. Long-term results of two trials. Cáp, J., Koza, I., Misíková, Z., et al.[2007]

The pilot study of the MDAC regimen (gemtuzumab ozogamicin, DaunoXome, cytarabine, and cyclosporine-A) in 8 patients with refractory acute myelogenous leukemia showed that the inclusion of cyclosporine-A is feasible, potentially helping to counteract multi-drug resistance.

However, the regimen was associated with significant toxicities, including high rates of sepsis (63%) and hyperbilirubinemia (54%), indicating that while the treatment may be viable, it carries considerable risks for patients with advanced AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot study of gemtuzumab ozogamicin, liposomal daunorubicin, cytarabine and cyclosporine regimen in patients with refractory acute myelogenous leukemia. Apostolidou, E., Cortes, J., Tsimberidou, A., et al.[2019]

In a study of 50 children with acute lymphoblastic leukemia (ALL) who were in their first to fifth relapse, a three-drug reinduction regimen including etoposide (VP-16) led to a complete remission in 34% of patients who received at least two courses of treatment.

The results suggest that prior resistance to teniposide (VM-26) does not prevent patients from responding to VP-16, indicating that higher doses and more frequent administration of VP-16 may effectively overcome resistance, although further research is needed for long-term treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etoposide (VP-16) with prednisone and vincristine for the treatment of refractory acute lymphoblastic leukemia. Abromowitch, M., Bowman, WP., Ochs, J., et al.[2017]

In a study of 31 pediatric patients with relapsed acute lymphoblastic leukemia (ALL), topotecan administered before standard induction therapy resulted in an impressive 89.3% response rate, significantly reducing circulating blast cells.

The combination of topotecan with standard induction therapy led to a 74.2% complete response rate, indicating that this regimen is effective and well-tolerated, despite some hematologic and gastrointestinal toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of topotecan in combination with dexamethasone, asparaginase, and vincristine in pediatric patients with acute lymphoblastic leukemia in first relapse. Hijiya, N., Stewart, CF., Zhou, Y., et al.[2015]

In a study involving 490 children with high-risk B-precursor acute lymphoblastic leukemia (ALL), two treatment regimens were compared, showing that both regimens achieved a high remission rate of 97%.

While regimen B, which involved more intensive myelosuppressive combinations, showed a higher estimated 4-year event-free survival (EFS) of 69.4% compared to 61.6% for regimen A, the difference was not statistically significant, and regimen B was associated with more frequent toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial. Lauer, SJ., Shuster, JJ., Mahoney, DH., et al.[2019]

In a study of 56 untreated childhood acute lymphoblastic leukemia (ALL) patients, the complete remission rates were similar across three treatment regimens, indicating that adding anthracyclines (daunorubicin or adriamycin) did not significantly improve remission outcomes compared to vincristine and prednisone alone.

However, the anthracycline regimens led to increased granulocytopenia and a higher rate of infectious complications, suggesting that while they may offer some theoretical benefits, their use could result in greater morbidity without improving long-term remission or survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and cytokinetic aspects of remission induction of childhood acute lymphoblastic leukemia (ALL): addition of an anthracycline to vincristine and prednisone. Sallan, SE., Camitta, BM., Frei, E., et al.[2019]

Citations

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Treatment of Acute Lymphoblastic Leukemia HIGH RISK ... Reduction of the dose of daunorubicin, and recent studies have shown that the use of high doses of anthracyclines has not brought higher response rates or ...

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