cRIB Protocol for Pediatric Leukemia

Overseen By David McCall, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Secondary tumor, CNS pathology, cardiovascular disease, infections, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle

27 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of medicines to determine if they can help control pediatric leukemia, a type of blood cancer. The treatment includes drugs delivered into the spine and other medications targeting cancer cells. One key drug being tested is Blinatumomab (also known as Blincyto), used to treat certain types of leukemia. Suitable participants include those under 25 years old with specific types of leukemia that have not responded well to previous treatments. Participants should also have leukemia cells displaying specific markers on their surface. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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, certain medications like single-dose intravenous cytarabine, steroids, or hydroxyurea are allowed before starting the study without a washout period (time without taking certain medications). 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?

Previous studies have shown that blinatumomab commonly causes side effects like fever and headaches. However, more serious issues, such as cytokine release syndrome (CRS), a severe immune reaction, and nervous system problems, can also occur. Cyclophosphamide is known to be safe and effective for children, though it carries some risk of infection. Cytarabine, often used to treat leukemia in the spine, has shown better response rates in children than in adults.

Dexamethasone has been used in children, but it can affect unborn babies, so caution is advised. Inotuzumab ozogamicin can cause serious reactions, such as infections and low blood cell counts. Mercaptopurine is safe and effective for children with leukemia, although it might cause low blood sugar in very young children. Methotrexate has been found safe for children, with no new safety concerns reported. Prednisone is known to be safe for children, but long-term use might slow growth.

Rituximab can lead to serious side effects, which can sometimes be fatal if they occur during the first dose. Lastly, vincristine is FDA-approved for treating leukemia in children and is generally well-tolerated, though it can cause digestive issues. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the cRIB Protocol for pediatric leukemia because it combines a range of drugs, like blinatumomab and inotuzumab ozogamicin, which are not traditionally used together in current treatments. This protocol aims to target leukemia cells more effectively by using these drugs in a specific sequence and dosage. Blinatumomab, for example, is a bispecific T-cell engager that directs the body's immune system to attack cancer cells, while inotuzumab ozogamicin is an antibody-drug conjugate that delivers a potent chemotherapy directly to leukemia cells. By exploring these combined mechanisms, researchers hope to improve outcomes and reduce side effects compared to standard chemotherapy regimens.

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

This trial will evaluate various treatments for pediatric leukemia. Studies have shown that blinatumomab, one of the treatments in this trial, significantly improves the time children with leukemia remain disease-free when combined with standard chemotherapy, with over 50% experiencing no recurrence. Cyclophosphamide, another treatment option, is a well-established therapy for acute leukemia in children, achieving a high cure rate of about 90%. Research indicates that cytarabine, also under study, is effective, with some studies showing up to 96% of patients achieving complete remission. Dexamethasone, included in this trial, is often preferred over similar drugs because it lowers the chances of recurrence and improves survival rates. Inotuzumab ozogamicin has shown high response rates, with many patients having little to no detectable disease. Methotrexate, part of the trial treatments, significantly reduces the risk of relapse and improves long-term survival. Rituximab, when used with chemotherapy, greatly increases the chances of remaining free from disease events. Vincristine, also included in the trial, is a crucial part of leukemia treatment plans, contributing to positive outcomes for many patients. ^{3 5 6 7 8}

Who Is on the Research Team?

David McCall, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for pediatric to young adult patients (1-25 years old) with relapsed or refractory B-cell lineage acute lymphocytic leukemia. They must have a certain level of physical ability, proper liver and kidney function, and not be pregnant or breastfeeding. Participants need to use effective contraception and cannot have uncontrolled infections, HIV, hepatitis B/C, severe heart conditions, active GvHD requiring treatment, or other serious medical issues.

Inclusion Criteria

I have leukemia in my brain but don't feel any symptoms.

Baseline laboratory data within specified limits

I am between 1 and 24 years old.

Exclusion Criteria

I have Down syndrome or a bone marrow failure condition.

I am still recovering from my last cancer treatment.

I am currently experiencing symptoms of Graft-versus-Host Disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive mini-hyper-CVD with inotuzumab ozogamicin, blinatumomab, and rituximab in 28-day cycles with a 7-day rest period between cycles

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Blinatumomab
• Cyclophosphamide
• Cytarabine
• Dexamethasone
• Inotuzumab ozogamicin
• Mercaptopurine
• Methotrexate
• Pegfilgrastim
• Prednisone
• Rituximab
• Vincristine

Trial Overview

The study tests mini hyper-CVD chemotherapy combined with intrathecal chemo and condensed doses of rituximab, blinatumomab, inotuzumab ozogamicin (cRIB). It aims to see if this regimen can control the disease better in those who can't receive standard treatments due to intolerance or risk factors.

How Is the Trial Designed?

Group I: Leukemia CNS1 or 2 Experimental Treatment 11 Interventions

Each study block, or cycle, is 28 days. Between every cycle below, Participants will have a 7-day rest period in which no study drug is given.

Group II: Leukemia CNS 3 Experimental Treatment 11 Interventions

Each study block, or cycle, is 28 days. Between every cycle below, Participants will have a 7-day rest period in which no study drug is given.

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

Approved in European Union as Blincyto for:

• Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL)
• High-risk first relapse BCP-ALL

Approved in United States as Blincyto for:

• Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL)
• First or second complete remission with minimal residual disease (MRD)

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

Blinatumomab (Blina) is a safe and effective first-line treatment for children and young persons with chemotherapy-intolerant or chemotherapy-resistant B-ALL, showing high response rates (97%) in patients with minimal residual disease before treatment.

In a study of 105 patients, those treated with Blina had similar event-free survival (EFS) and overall survival (OS) rates compared to matched controls receiving standard chemotherapy, indicating that Blina can be a viable alternative to intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blinatumomab for First-Line Treatment of Children and Young Persons With B-ALL. Hodder, A., Mishra, AK., Enshaei, A., et al.[2023]

Blinatumomab has been approved for treating relapsed or refractory precursor B-cell acute lymphoblastic leukemia (ALL), showing a significant improvement in overall survival and complete remission rates compared to standard chemotherapy, with a median survival of 7.7 months versus 4.0 months for chemotherapy.

In clinical trials, blinatumomab demonstrated a complete remission rate of 34% in Philadelphia chromosome (Ph)-negative ALL and 31% in Ph-positive ALL, while also presenting some adverse events like cytokine release syndrome and neurological issues, although it had fewer cases of neutropenia and infections compared to standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Supplemental Approval: Blinatumomab for Treatment of Relapsed and Refractory Precursor B-Cell Acute Lymphoblastic Leukemia. Pulte, ED., Vallejo, J., Przepiorka, D., et al.[2019]

Blinatumomab (Blincyto) received accelerated FDA approval for treating relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL) based on a trial with 185 adults, showing a complete remission rate of 32% and a median response duration of 6.7 months.

While blinatumomab is effective, it is associated with serious side effects like cytokine release syndrome and neurological events, along with common adverse reactions such as fever, headache, and neutropenia, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval: Blinatumomab. Przepiorka, D., Ko, CW., Deisseroth, A., et al.[2021]

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]

A 5-year-old boy with high-risk B-acute lymphoblastic leukemia (B-ALL) achieved minimal residual disease-negative remission after receiving a novel treatment regimen combining chemotherapy and immunotherapy, which included rituximab, inotuzumab ozogamicin, and blinatumomab.

The treatment was well tolerated, leading to a successful transplant without significant infections or toxicities, marking the first reported use of this condensed sequential therapy in a pediatric leukemia patient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mini-hyper CVD + CRIB (condensed rituximab, inotuzumab ozogamicin, and blinatumomab) for refractory pediatric B-acute lymphoblastic leukemia. McCall, D., Jabbour, E., Roth, M., et al.[2022]

Blinatumomab, a bispecific T-cell-engaging antibody, has shown a response rate of 34% to 66% in heavily pretreated children with relapsed/refractory acute lymphoblastic leukemia (R/R-ALL), making it a promising treatment option, especially as a bridge to stem cell transplantation.

Recent randomized controlled trials indicate that blinatumomab leads to a greater reduction in minimal residual disease and improved survival compared to standard treatments, suggesting its potential for frontline use in high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blinatumomab in Pediatric Acute Lymphoblastic Leukemia-From Salvage to First Line Therapy (A Systematic Review). Queudeville, M., Ebinger, M.[2021]

In the phase 3 TOWER study, blinatumomab showed a significant overall survival benefit compared to standard-of-care chemotherapy in adults with relapsed or refractory Philadelphia chromosome-negative B-precursor acute lymphoblastic leukemia, involving 267 patients who received a median of 2 cycles of treatment.

After adjusting for treatment duration, blinatumomab had lower exposure-adjusted event rates for serious adverse events compared to standard chemotherapy, particularly for infections and cytopenias, indicating it is a well-tolerated treatment option despite a higher rate of cytokine-release syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-adjusted adverse events comparing blinatumomab with chemotherapy in advanced acute lymphoblastic leukemia. Stein, AS., Larson, RA., Schuh, AC., et al.[2020]

Blinatumomab shows a favorable safety profile in pediatric patients with B-cell acute lymphoblastic leukemia (ALL), associated with a lower risk of serious adverse events, febrile neutropenia, and infections compared to traditional chemotherapy.

While blinatumomab does not significantly increase the risk of cytokine release syndrome or seizures, it is linked to a higher risk of encephalopathy, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of blinatumomab in pediatric patients with acute lymphoblastic leukemia: A systematic review and meta-analysis. Marrapodi, MM., Mascolo, A., di Mauro, G., et al.[2022]

Blinatumomab was found to be an effective treatment for older patients (median age 75) with newly diagnosed Philadelphia chromosome-negative B-acute lymphoblastic leukemia (ALL), achieving a complete remission rate of 66%.

The 3-year disease-free survival and overall survival rates were both 37%, indicating promising outcomes for this patient population, particularly for those with poor-risk cytogenetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SWOG 1318: A Phase II Trial of Blinatumomab Followed by POMP Maintenance in Older Patients With Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia. Advani, AS., Moseley, A., O'Dwyer, KM., et al.[2023]

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]

Blinatumomab, a bispecific T-cell engager, has been successfully used in 11 pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL) after they experienced severe chemotherapy-induced toxicity, leading to recovery in all cases.

This treatment offers a nonmyelotoxic alternative for patients who cannot tolerate traditional cytotoxic therapies, suggesting it could be a valuable option in managing severe toxicity during leukemia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blinatumomab as a bridge to further therapy in cases of overwhelming toxicity in pediatric B-cell precursor acute lymphoblastic leukemia: Report from the Israeli Study Group of Childhood Leukemia. Elitzur, S., Arad-Cohen, N., Barzilai-Birenboim, S., et al.[2020]

Blinatumomab demonstrated significant therapeutic efficacy in pediatric patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL), achieving a complete response rate of 56% and improving overall survival and event-free survival compared to standard chemotherapy.

The treatment was associated with limited adverse effects, with an adverse event rate of 31%, indicating that blinatumomab is a promising option for children with this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of blinatumomab in children with relapsed/refractory B cell acute lymphoblastic leukemia: A systematic review and meta-analysis. Chen, B., Zou, Z., Zhang, Q., et al.[2023]

Immunotherapy strategies, such as bispecific T-cell engagers and CAR T-cell therapy, are emerging as promising treatments for pediatric leukemia, particularly for children with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

These new approaches aim to reduce the risk of relapse and minimize the long-term toxicities associated with traditional chemotherapy, which can lead to significant health issues in survivors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moving immunotherapy into the front line in ALL. Winters, A., Gore, L.[2020]

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