Chemotherapy for Leukemia and Lymphoma

Recruiting at 257 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Oncology Group

Must not be taking: Cytotoxic chemotherapy

Disqualifiers: CNS3 leukemia, Testicular leukemia, Pregnancy, 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: 14

9350 Participants Needed

Trial Summary

What is the purpose of this trial?

This partially randomized phase III trial studies the side effects of different combinations of risk-adapted chemotherapy regimens and how well they work in treating younger patients with newly diagnosed standard-risk acute lymphoblastic leukemia or B-lineage lymphoblastic lymphoma that is found only in the tissue or organ where it began (localized). Drugs used in chemotherapy 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), giving the drugs in different doses, and giving the drugs in different combinations may kill more cancer cells.

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

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that patients should not have received any prior cytotoxic chemotherapy for their current diagnosis, except for certain steroid treatments. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination used in the chemotherapy for leukemia and lymphoma?

Research shows that similar drug combinations, like those including cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), are used effectively in treating aggressive lymphomas. These combinations have been shown to improve survival rates in patients with non-Hodgkin's lymphoma. ^{1 2 3 4 5}

Is chemotherapy for leukemia and lymphoma generally safe in humans?

Some chemotherapy drugs used for leukemia and lymphoma, like methotrexate, can cause side effects such as mucositis (painful inflammation and ulceration of the mucous membranes lining the digestive tract). Other drugs, like vindesine sulfate, may cause neurotoxicity (nerve damage), alopecia (hair loss), and leucocytopenia (low white blood cell count). These side effects are common but vary in intensity among patients. ^{6 7 8 9 10}

What makes this chemotherapy treatment for leukemia and lymphoma unique?

This chemotherapy treatment is unique because it combines multiple drugs, including Cyclophosphamide, Cytarabine, Dexamethasone, and others, which are not typically used together in standard regimens. This combination aims to target cancer cells more effectively by using different mechanisms of action, potentially offering a new option for patients who do not respond to conventional treatments. ^{1 3 11 12 13}

Research Team

Anne L Angiolillo

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for young patients with newly diagnosed standard-risk acute lymphoblastic leukemia or localized B-lineage lymphoblastic lymphoma. They must not have had previous cancer treatments, except certain steroids or intrathecal cytarabine. Patients need to agree to use effective contraception if applicable and meet all study requirements.

Inclusion Criteria

Your white blood cell count at the start of the study should be less than 50,000 cells per microliter.

All patients and/or their parents or legal guardians must sign a written informed consent

B-ALL patients must be enrolled on AALL08B1 or APEC14B1 (if open for the classification of newly diagnosed ALL patients) prior to treatment and enrollment on AALL0932

Exclusion Criteria

I haven't had chemotherapy for my current B-ALL/B-LLy or any cancer before starting the AALL0932 protocol, except for steroids or intrathecal cytarabine.

Lactating females unless they have agreed not to breastfeed their infants

I am not pregnant or have a negative pregnancy test if of childbearing age.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive a combination of intrathecal cytarabine, vincristine sulfate, dexamethasone, pegaspargase, and methotrexate to induce remission

4 weeks

Weekly visits for drug administration

Consolidation Therapy

Patients receive vincristine sulfate, mercaptopurine, and methotrexate to consolidate remission

4 weeks

Weekly visits for drug administration

Interim Maintenance I

Patients receive vincristine sulfate and methotrexate to maintain remission

8 weeks

Visits on days 1, 11, 21, 31, and 41

Delayed Intensification

Patients receive a combination of dexamethasone, vincristine sulfate, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, thioguanine, and cytarabine to intensify treatment

8 weeks

Frequent visits for drug administration

Interim Maintenance II

Patients receive vincristine sulfate and methotrexate to maintain remission

8 weeks

Visits on days 1, 11, 21, 31, and 41

Maintenance Therapy

Patients receive vincristine sulfate, dexamethasone, methotrexate, and mercaptopurine to maintain remission over a long-term period

2-3 years

Courses repeat every 12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

10 years

Treatment Details

Interventions

• Cyclophosphamide
• Cytarabine
• Dexamethasone
• Doxorubicin Hydrochloride
• Leucovorin Calcium
• Mercaptopurine
• Methotrexate
• Pegaspargase
• Thioguanine
• Vincristine Sulfate

Trial Overview The trial tests different combinations of chemotherapy drugs on younger patients with specific types of leukemia or lymphoma. It aims to find the best mix and dosage that kills the most cancer cells while monitoring side effects through various stages of treatment.

Participant Groups

Group I: Arm SR DS (12-week cycle maintenance) Experimental Treatment 13 Interventions

See Detailed Description

Group II: Arm LR-M (risk-adapted chemotherapy) Experimental Treatment 8 Interventions

Patients receive consolidation and maintenance therapy. See detailed description.

Group III: Arm LR-C (risk-adapted chemotherapy) Experimental Treatment 12 Interventions

Patients receive consolidation, interim maintenance I, delayed intensification, interim maintenance II, and maintenance therapy. See detailed description.

Group IV: Arm D (risk-adapted chemotherapy) Experimental Treatment 7 Interventions

Patients receive vincristine sulfate IV on day 1; dexamethasone PO BID on days 1-5; higher-dose methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and IT methotrexate on day 1.

Group V: Arm C (risk-adapted chemotherapy) Experimental Treatment 7 Interventions

Patients receive vincristine sulfate IV on day 1; dexamethasone PO BID on days 1-5; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and IT methotrexate on day 1.

Group VI: Arm B-LLy (4-week cycle maintenance) Experimental Treatment 13 Interventions

See Detailed Description.

Group VII: Arm B (risk-adapted chemotherapy) Experimental Treatment 7 Interventions

Patients receive vincristine sulfate IV on days 1, 29, and 57; dexamethasone PO BID on days 1-5, 29-33, and 57-61; higher-dose methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and IT methotrexate on day 1.

Group VIII: Arm A (risk-adapted chemotherapy) Experimental Treatment 7 Interventions

Patients receive vincristine sulfate IV on days 1, 29, and 57; dexamethasone PO BID on days 1-5, 29-33, and 57-61; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and IT methotrexate on day 1.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase I pilot study involving 18 patients with refractory lymphoid malignancies, the MILD chemotherapy regimen (methotrexate, ifosfamide, l-asparaginase, and dexamethasone) demonstrated a 57% overall response rate, with complete responses in 3 patients and partial responses in 4 patients.

The treatment was generally feasible with acceptable toxicity, although one patient experienced treatment-related death from systemic mucormycosis, and significant hematologic toxicities were observed, particularly in patients with T/NK-cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity and safety of combination chemotherapy with methotrexate, ifosfamide, l-asparaginase and dexamethasone (MILD) for refractory lymphoid malignancies: a pilot study. Tsukune, Y., Isobe, Y., Yasuda, H., et al.[2013]

Pegfilgrastim significantly reduces the incidence of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) compared to no prophylaxis, with evidence from 41 studies including randomized controlled trials and observational studies.

The efficacy and safety profiles of other long-acting G-CSFs, such as lipegfilgrastim and balugrastim, are comparable to pegfilgrastim, although results for other long-acting G-CSFs were mixed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, effectiveness and safety of long-acting granulocyte colony-stimulating factors for prophylaxis of chemotherapy-induced neutropenia in patients with cancer: a systematic review. Pfeil, AM., Allcott, K., Pettengell, R., et al.[2021]

In a study of 389 young patients with good-prognosis aggressive lymphoma, the high dose of CHOEP-21 did not improve event-free or overall survival compared to the standard CHOEP-21 regimen, indicating no clinical benefit from the increased dosage.

The high CHOEP regimen was associated with significantly higher toxicity, including increased rates of severe leukocytopenia, thrombocytopenia, infections, and therapy-related deaths, suggesting that the risks may outweigh any potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-escalated CHOEP for the treatment of young patients with aggressive non-Hodgkin's lymphoma: II. Results of the randomized high-CHOEP trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL). Pfreundschuh, M., Zwick, C., Zeynalova, S., et al.[2020]

In a study of 46 elderly patients (aged 69 and older) with aggressive non-Hodgkin's lymphoma, the chemotherapy regimen (CTVP) combined with granulocyte colony-stimulating factor (G-CSF) resulted in a 74% objective response rate and a 46% complete response rate, demonstrating its efficacy.

The use of G-CSF helped reduce severe neutropenia complications, with only 22% experiencing grade 3 or 4 neutropenia, allowing for outpatient treatment without negatively impacting overall survival (47%) or event-free survival (28%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of granulocyte colony-stimulating factor administration in elderly patients with aggressive non-Hodgkin's lymphoma treated with a pirarubicin-combination chemotherapy regimen. Groupe d'Etudes des Lymphomes de l'Adulte. Guerci, A., Lederlin, P., Reyes, F., et al.[2020]

References

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

Activity and safety of combination chemotherapy with methotrexate, ifosfamide, l-asparaginase and dexamethasone (MILD) for refractory lymphoid malignancies: a pilot study. [2013]

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

Advanced diffuse non-Hodgkin's lymphoma. Analysis of prognostic factors by the international index and by lactic dehydrogenase in an intergroup study. [2019]

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

Elderly patients with aggressive non-Hodgkin's lymphoma treated with CHOP chemotherapy plus granulocyte-macrophage colony-stimulating factor: identification of two age subgroups with differing hematologic toxicity. [2017]

4. Germany pubmed.ncbi.nlm.nih.gov

Cognitive impairment and elevated peripheral cytokines in breast cancer patients receiving chemotherapy. [2023]

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

Risk of acute leukemia following epirubicin-based adjuvant chemotherapy: a report from the National Cancer Institute of Canada Clinical Trials Group. [2013]

6. Germany pubmed.ncbi.nlm.nih.gov

Efficacy, effectiveness and safety of long-acting granulocyte colony-stimulating factors for prophylaxis of chemotherapy-induced neutropenia in patients with cancer: a systematic review. [2021]

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

Antimetabolite-based therapy in childhood T-cell acute lymphoblastic leukemia: a report of POG study 9296. [2009]

8. Japan pubmed.ncbi.nlm.nih.gov

[Administration of vindesine sulfate for the treatment of malignant hematological tumors]. [2015]

9. England pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of granulocyte colony-stimulating factors in cancer patients after chemotherapy: A systematic review and Bayesian network meta-analysis. [2021]

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

Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Dose-escalated CHOEP for the treatment of young patients with aggressive non-Hodgkin's lymphoma: II. Results of the randomized high-CHOEP trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL). [2020]

12. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Comparative evaluation of the efficacy of polychemotherapeutic combinations in mycosis fungoides]. [2015]

13. England pubmed.ncbi.nlm.nih.gov

Effect of granulocyte colony-stimulating factor administration in elderly patients with aggressive non-Hodgkin's lymphoma treated with a pirarubicin-combination chemotherapy regimen. Groupe d'Etudes des Lymphomes de l'Adulte. [2020]