Chemotherapy for Acute Lymphoblastic Leukemia

Recruiting at 251 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

5949 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase III trial studies how well combination chemotherapy works in treating young patients with newly diagnosed B acute lymphoblastic leukemia that is likely to come back or spread, and in patients with Philadelphia chromosome (Ph)-like tyrosine kinase inhibitor (TKI) sensitive mutations. Chemotherapy drugs, 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 more than one drug (combination chemotherapy) and giving the drugs in different doses and in different combinations may kill more cancer cells.

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.

What data supports the effectiveness of the drugs used in the chemotherapy for Acute Lymphoblastic Leukemia?

Research shows that a combination of drugs like vincristine, prednisone, and daunorubicin can lead to complete remission in some patients with acute lymphoblastic leukemia, although the addition of anthracyclines like daunorubicin may increase the risk of infections. Additionally, high-dose daunorubicin in elderly patients has shown a 73% complete remission rate, indicating its potential effectiveness. ^{1 2 3 4 5}

Is chemotherapy for acute lymphoblastic leukemia generally safe in humans?

Research shows that chemotherapy drugs like daunorubicin and etoposide, used in treating acute lymphoblastic leukemia, have been administered safely in humans, though they can cause side effects like myelosuppression (reduced bone marrow activity) and infections. These treatments have been used in various studies, demonstrating their safety profile in humans, even though they may cause some toxicities. ^{1 2 6 7 8}

What makes this chemotherapy treatment for acute lymphoblastic leukemia unique?

This chemotherapy treatment for acute lymphoblastic leukemia is unique because it combines multiple drugs, including Daunorubicin, Dexamethasone, and Vincristine, which are used in various combinations to induce remission and maintain it. The inclusion of drugs like PEG-L-asparaginase, which has been shown to be effective in high-risk cases, and the use of a multi-drug regimen aim to improve remission rates and survival outcomes compared to single-drug therapies. ^{9 10 11 12 13}

Research Team

Michael J Burke

Principal Investigator

Children's Oncology Group

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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 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]

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]

References

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

Etoposide (VP-16) with prednisone and vincristine for the treatment of refractory acute lymphoblastic leukemia. [2017]

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

High-dose daunorubicin as liposomal compound (Daunoxome) in elderly patients with acute lymphoblastic leukemia. [2019]

3. United States 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. [2019]

4. United States 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. [2015]

5. Germany pubmed.ncbi.nlm.nih.gov

Vindesine, prednisone, and daunomycin in acute lymphoblastic leukemia in relapse. [2019]

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

Pilot study of gemtuzumab ozogamicin, liposomal daunorubicin, cytarabine and cyclosporine regimen in patients with refractory acute myelogenous leukemia. [2019]

7. Japan pubmed.ncbi.nlm.nih.gov

Acute and late toxicities of pirarubicin in the treatment of childhood acute lymphoblastic leukemia: results from a clinical trial by the Japan Association of Childhood Leukemia Study. [2018]

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

4'-demethylepipodophyllotoxin 9-(4,6-o-2-thenylidene-beta-D-glucopyranoside) (NSC-122819; VM-26) and 4'-demethylepipodophyllotoxin 9-(4.6-0-ethylidene-beta-D-glucopyranoside) (NSC-141540; VP-16-213) in childhood cancer: preliminary observations. [2016]

9. Slovakia pubmed.ncbi.nlm.nih.gov

Treatment of acute lymphoblastic leukemia in children. Long-term results of two trials. [2007]

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

Intensified PEG-L-asparaginase and antimetabolite-based therapy for treatment of higher risk precursor-B acute lymphoblastic leukemia: a report from the Children's Oncology Group. [2018]

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

Bortezomib, Dexamethasone, Mitoxantrone, and Vinorelbine (BDMV): An Active Reinduction Regimen for Children With Relapsed Acute Lymphoblastic Leukemia and Asparaginase Intolerance. [2020]

12. England 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. [2019]

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

Vincristine, prednisone and L-asparaginase in the induction of remission in children with acute lymphoblastic leukemia following relapse. [2019]