Pediatric-Inspired Chemotherapy for Leukemia

Not currently recruiting at 3 trial locations

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Disqualifiers: Ph+ ALL, Burkitt's ALL, HIV, others

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

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 investigates whether a combination of chemotherapy drugs commonly used in children can effectively and safely treat adults with acute lymphoblastic leukemia (ALL) that lacks the Philadelphia chromosome. The treatment involves several cycles of different chemotherapy drugs, including 6-Mercaptopurine, Cyclophosphamide, Cytarabine, Daunorubicin, Dexamethasone, PEG-Asparaginase, Prednisone, and Vincristine, administered over time. It targets adults who have not received prior treatment for ALL and have a version of the disease without the specific chromosome abnormality, known as Ph Negative. Participants should have been diagnosed with precursor B-cell or T-cell ALL or certain types of lymphoma and should not have received any previous ALL treatments, except for some basic medications. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people, offering participants a chance to contribute to important advancements in leukemia treatment.

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

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are taking medications for conditions like active infections or other serious health issues, you may need to discuss this with the trial team.

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

Research has shown that the chemotherapy drugs in this trial have been widely used and studied in both children and adults with leukemia. Here's a simple overview of each:

1. **6-Mercaptopurine**: Approved by the FDA for treating acute lymphoblastic leukemia (ALL) in both children and adults, this drug is usually well-tolerated, though some patients might experience side effects like low blood sugar.

2. **Cyclophosphamide**: Used for various cancers, including blood cancers, this drug has safety data supporting its use in children. It requires careful use, especially if there's a risk of urinary tract infections.

3. **Cytarabine**: Known for treating blood cancers, this drug has shown better response rates in children. Due to its potential toxicity, careful monitoring is important.

4. **Daunorubicin**: Effective for leukemia and studied in children, this strong drug necessitates regular monitoring to manage side effects.

5. **Dexamethasone**: Often used to reduce inflammation, this medication is generally safe. However, it may affect unborn children, so discussing any risks is important if pregnancy is a factor.

6. **PEG-Asparaginase**: Linked to fewer allergic reactions compared to other forms of asparaginase, this drug may cause side effects such as liver issues or blood clotting problems.

7. **Prednisone**: As a corticosteroid, prednisone helps manage leukemia symptoms. Long-term use may cause slowed growth in children.

8. **Vincristine**: Approved by the FDA for leukemia, this drug is used with other medications. While effective, it can have side effects, particularly affecting the nervous system.

Overall, these drugs have proven safety records in treating leukemia, especially in children. The aim is to adapt successful pediatric treatments for adults with ALL. While each drug has potential side effects, they are typically well-tolerated with proper monitoring. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this pediatric-inspired chemotherapy regimen for leukemia because it adapts successful childhood leukemia treatments for adults, aiming to improve outcomes. Unlike the standard adult protocols, which often rely heavily on high-dose chemotherapy, this regimen uses a combination of drugs in a strategic series of phases, resembling the treatment cycles used in pediatrics. This approach is designed to be more adaptable to the patient's condition, with flexibility in timing and dosing, potentially reducing side effects while maintaining effectiveness. By incorporating drugs like PEG-Asparaginase, which is not typically used in adult regimens, this treatment could offer a new mechanism of action that targets leukemia cells differently.

What evidence suggests that this combination of chemotherapy drugs could be effective for treating adult patients with Ph Negative ALL?

Research has shown that the combination of chemotherapy drugs used for children with acute lymphoblastic leukemia (ALL) may also benefit adults. In this trial, participants will receive a pediatric-inspired chemotherapy regimen. Studies have found that 6-mercaptopurine and methotrexate help prevent cancer recurrence in children with ALL. Cyclophosphamide has effectively treated leukemia in children, with many responding well. High-dose cytarabine has produced strong results, with high survival rates in children with acute myeloid leukemia. Even in lower doses, daunorubicin has been effective for children with ALL, leading to good survival rates without events. Dexamethasone reduces the risk of cancer recurrence, especially in the brain and spinal cord, compared to prednisone. PEG-asparaginase plays a crucial role in successful treatment plans for children with ALL, improving survival rates. How well children respond to prednisone strongly indicates treatment success. Vincristine is a key component of treatment plans inspired by those used for children, leading to better outcomes. These drugs, when used together, have a proven track record of effectiveness in treating ALL in children and are now being tested for adults in this trial. ^{6 7 8 9 10}

Who Is on the Research Team?

Jae Park, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults aged 18-60 with newly diagnosed Ph Negative Acute Lymphoblastic Leukemia (ALL) who haven't been treated yet. They must have good kidney, liver, and heart function, an ECOG performance status of 0-2, and be willing to use birth control. People with certain other conditions or previous ALL treatments are excluded.

Inclusion Criteria

My liver is functioning well, with specific blood test levels within normal limits.

I agree to use effective birth control during and for 4 months after treatment.

I have ALL with CNS involvement and can get additional treatments for it.

Exclusion Criteria

I have had treatment for ALL, but only steroids or hydroxyurea.

Pregnant women or women who are breast-feeding

My leukemia is identified as Mature B-cell (Burkitt's).

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Phase I

Participants receive the first cycle of chemotherapy drugs

4-6 weeks

Induction Phase II

Participants receive the second cycle of chemotherapy drugs

4-6 weeks

Intensification I

Participants receive the third cycle of chemotherapy drugs

4-6 weeks

Re-induction I

Participants receive the fourth cycle of chemotherapy drugs

4-6 weeks

Intensification II

Participants receive the fifth cycle of chemotherapy drugs

4-6 weeks

Re-induction II

Participants receive the sixth cycle of chemotherapy drugs

4-6 weeks

Maintenance

Participants continue with a long-term treatment part

36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• 6-Mercaptopurine
• Cyclophosphamide
• Cytarabine
• Daunorubicin
• Dexamethasone
• Leucovorin
• Methotrexate
• PEG-Asparaginase
• Prednisone
• Vincristine

Trial Overview The trial is testing a 'Pediatric-Inspired' chemotherapy regimen in adults with ALL to see if it's safe and effective. It includes drugs like Daunorubicin and Vincristine among others used in children's treatment protocols for leukemia.

How Is the Trial Designed?

Group I: Leukemia Patients Experimental Treatment 12 Interventions

The treatment plan has 6 treatment cycles. The cycle names are listed in the following order: Induction Phase I - Induction Phase II - Intensification I - Re-induction I - Intensification II - Re-induction II Each cycle is given over a period of 4-6 weeks and the interval between them can range between 1-3 weeks. Based the patients medical condition, the doctor may decide to change the timing of the drugs, the interval between the drugs in a cycle, or the interval between the cycles. After receiving all cycles you will continue with a 36 months treatment part that is called Maintenance.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Lehigh Valley Health Network

Collaborator

Shire

Industry Sponsor

Trials

457

Recruited

96,000+

Pierre S. Sayad

Shire

Chief Medical Officer

MD from Loma Linda University

Flemming Ornskov

Shire

Chief Executive Officer since 2013

PhD in Medicine from Aarhus University

Duke University

Collaborator

Trials

2,495

Recruited

5,912,000+

Weill Medical College of Cornell University

Collaborator

Trials

1,103

Recruited

1,157,000+

Lehigh Valley Health Network

Collaborator

Trials

4

Recruited

8,100+

Published Research Related to This Trial

The combination of vincristine, dexamethasone, and L-asparaginase (VXL) showed synergistic effects in treating pediatric acute lymphoblastic leukemia (ALL) in both laboratory and mouse models, significantly delaying disease progression by up to 146 days.

Pharmacokinetic analysis indicated that the combination therapy increased the systemic exposure of dexamethasone, which may enhance the effectiveness of the treatment, providing a promising platform for testing new drugs in clinical trials for relapsed or refractory ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic modeling of an induction regimen for in vivo combined testing of novel drugs against pediatric acute lymphoblastic leukemia xenografts. Szymanska, B., Wilczynska-Kalak, U., Kang, MH., et al.[2021]

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 randomized trial involving over 1000 children with standard-risk acute lymphoblastic leukemia (ALL), dexamethasone was found to significantly reduce the risk of central nervous system relapses compared to prednisone, with a 6-year relapse rate of 3.7% versus 7.1%.

The study also showed that dexamethasone improved event-free survival rates at 6 years (85%) compared to prednisone (77%), indicating that dexamethasone may be a more effective treatment option in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Bostrom, BC., Sensel, MR., Sather, HN., et al.[2021]

A multicenter phase II clinical trial involving 39 adults aged 20-60 with acute lymphoblastic leukemia (ALL) showed that a pediatric-inspired chemotherapy regimen using pegaspargase resulted in a high complete response rate of 97%.

While the treatment was associated with significant toxicities, such as grade 3-4 hyperbilirubinemia and hypertriglyceridemia, these were manageable, and the overall survival rate at 3 years was 76.4%, indicating that pegaspargase can be safely integrated into intensive chemotherapy for adults with ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pediatric-inspired chemotherapy incorporating pegaspargase is safe and results in high rates of minimal residual disease negativity in adults up to age 60 with Philadelphia chromosome-negative acute lymphoblastic leukemia. Geyer, MB., Ritchie, EK., Rao, AV., et al.[2021]

In a study of 33 patients with relapsed acute lymphoblastic leukemia (ALL), 64% achieved complete remission after a combination treatment involving multiple chemotherapy agents, indicating the treatment's efficacy.

While the treatment was effective in inducing remissions, it was associated with significant side effects, particularly hematological issues and infections, suggesting that while the therapy is tolerable, improvements in disease-free survival are necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of relapsed acute lymphocytic leukemia in adults. Freund, M., De Boben, M., Diedrich, H., et al.[2019]

In a pilot study involving 18 children with acute nonlymphoblastic leukemia, 78% achieved complete remission (CR) after treatment, with 50% of those remaining in CR for over 35 months.

The treatment protocol was well tolerated with minimal side effects, suggesting a favorable safety profile, and overall survival rates improved, with 50% of children living for 36 months or longer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a pilot study for the treatment of childhood acute nonlymphoblastic leukemia. Vowels, MR., White, L., Hughes, DO.[2019]

In a pilot study involving 106 children with newly diagnosed non-T-, non-B-cell acute lymphoblastic leukemia, the addition of intermediate-dose methotrexate and cytosine arabinoside to standard therapy showed manageable toxicity, primarily neutropenia and fever.

The study found that event-free survival rates at 4 years were 71% for standard-risk patients and 53% for poor-risk patients, suggesting that this treatment approach may be beneficial and warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot study of intermediate-dose methotrexate and cytosine arabinoside, "spread-out" or "up-front," in continuation therapy for childhood non-T, non-B acute lymphoblastic leukemia. A Pediatric Oncology Group study. Krance, RA., Newman, EM., Ravindranath, Y., et al.[2019]

In a study of 83 children with higher-risk B-lineage acute lymphoblastic leukemia (ALL), 98% achieved remission after receiving intensive intravenous methotrexate (MTX) and mercaptopurine (MP) treatment, indicating high efficacy of this regimen.

The 4-year event-free survival rate was 57.4%, and the treatment was associated with generally mild toxicities, suggesting that intensive MTX/MP is an effective and relatively safe option for postremission therapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensive intravenous methotrexate and mercaptopurine treatment of higher-risk non-T, non-B acute lymphocytic leukemia: A Pediatric Oncology Group study. Camitta, B., Mahoney, D., Leventhal, B., et al.[2017]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4222610/

Mercaptopurine/Methotrexate Maintenance Therapy of ... The antileukemic mechanisms of 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy are poorly understood.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.10030

Adherence to mercaptopurine (6-MP) and habit strength in ... Results: Overall, 81% (n = 42/52) of participants surveyed had high adherence to 6-MP (VASdose ≥95%); 91% (n = 10/11) of patients and 78% (n = ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2772610X23000260

Erythrocyte-incorporated 6-mercaptopurine metabolite ... Childhood acute lymphoblastic leukemia (ALL) maintenance therapy with oral 6-mercaptopurine (6-MP) and methotrexate prevents leukemic relapse by acting ...

4. haematologica.org haematologica.org/article/view/haematol.2020.266320

An international retrospective study for tolerability of 6 ... In this international collaborative study, we comprehensively evaluated the actual 6-MP tolerable dose, frequencies of 6-MP-induced toxicity, and outcomes

5. ashpublications.org ashpublications.org/blood/article/93/9/2817/266656/Prognostic-Importance-of-6-Mercaptopurine-Dose

Prognostic Importance of 6-Mercaptopurine Dose Intensity in ... We conclude that increased dose-intensity of oral 6MP is an important determinant of EFS in ALL, particularly among those children with a homozygous wild-type ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK557620/

Mercaptopurine - StatPearls - NCBI Bookshelf Mercaptopurine (6MP) was approved by the Food and Drug Administration (FDA) for use in acute lymphoblastic leukemia in children and adults as ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2020/009053s040lbl.pdf

PURINETHOL (mercaptopurine) Label - accessdata.fda.gov PURINETHOL is indicated for treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance ...

8. mayoclinic.org mayoclinic.org/drugs-supplements/mercaptopurine-oral-route/description/drg-20064683

Mercaptopurine (oral route) - Side effects & dosage Safety and efficacy have not been established. The oral liquid may cause hypoglycemia (low blood sugar) in children younger than 6 years of age ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0928098715300762

Evaluation of a pediatric liquid formulation to improve 6 ... 6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric ...

10. go.drugbank.com go.drugbank.com/drugs/DB01033

Mercaptopurine: Uses, Interactions, Mechanism of Action Mercaptopurine is an antineoplastic agent used to treat acute lymphocytic leukemia.