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

Trial Summary

What is the purpose of this trial?

To learn if cyclophosphamide, vincristine, and dexamethasone (called mini hyper-CVD) in combination with intrathecal (delivered into the spine) chemotherapy (methotrexate, hydrocortisone, cytarabine) and compressed rituximab, blinatumomab, and inotuzumab ozogamicin (called cRIB) can help to control the disease.

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.

What data supports the effectiveness of the drugs used in the cRIB Protocol for Pediatric Leukemia?

Research shows that blinatumomab, a key drug in the cRIB Protocol, has been effective in treating relapsed or refractory acute lymphoblastic leukemia (ALL) in children, with response rates between 34% to 66%. Additionally, a case study reported successful remission in a child with high-risk B-ALL using a combination of chemotherapy and immunotherapy, including blinatumomab, inotuzumab ozogamicin, and rituximab. ^{1 2 3 4 5}

What safety data exists for Blinatumomab in treating pediatric leukemia?

Blinatumomab has been associated with serious side effects like cytokine release syndrome (a severe immune reaction) and neurologic events (such as seizures and confusion) in children with leukemia. However, it is considered a well-tolerated treatment option, with lower rates of serious adverse events compared to standard chemotherapy. ^{6 7 8 9 10}

What makes the cRIB Protocol for Pediatric Leukemia treatment unique?

The cRIB Protocol is unique because it combines chemotherapy with a condensed sequence of immunotherapy drugs, including rituximab, inotuzumab ozogamicin, and blinatumomab, which have shown promise in treating relapsed or refractory pediatric leukemia. This approach aims to reduce toxicities and improve remission rates compared to traditional chemotherapy alone. ^{1 5 11 12 13}

Research Team

David McCall, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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 am still recovering from my last cancer treatment.

I have Down syndrome or a bone marrow failure condition.

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

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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, 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 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 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, 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 (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]

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]

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]

References

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

Mini-hyper CVD + CRIB (condensed rituximab, inotuzumab ozogamicin, and blinatumomab) for refractory pediatric B-acute lymphoblastic leukemia. [2022]

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

Moving immunotherapy into the front line in ALL. [2020]

3. United States 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. [2023]

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

Blinatumomab for First-Line Treatment of Children and Young Persons With B-ALL. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Exposure-adjusted adverse events comparing blinatumomab with chemotherapy in advanced acute lymphoblastic leukemia. [2020]

7. England pubmed.ncbi.nlm.nih.gov

FDA Supplemental Approval: Blinatumomab for Treatment of Relapsed and Refractory Precursor B-Cell Acute Lymphoblastic Leukemia. [2019]

8. Switzerland pubmed.ncbi.nlm.nih.gov

The safety of blinatumomab in pediatric patients with acute lymphoblastic leukemia: A systematic review and meta-analysis. [2022]

9. United States 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. [2020]

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

FDA Approval: Blinatumomab. [2021]

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

Results of a pilot study for the treatment of childhood acute nonlymphoblastic leukemia. [2019]

12. Switzerland 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. [2023]

13. Slovakia pubmed.ncbi.nlm.nih.gov

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