Venetoclax + Blinatumomab for Acute Lymphoblastic Leukemia

Recruiting at 10 trial locations

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Dexamethasone

Disqualifiers: Down syndrome, Secondary B-ALL, 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: 19

153 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests the addition of venetoclax and/or blinatumomab to usual chemotherapy for treating infants with newly diagnosed acute lymphoblastic leukemia (ALL) with a KMT2A gene rearrangement (KMT2A-rearranged \[R\]) or without a KMT2A gene rearrangement (KMT2A-germline \[G\]). Venetoclax is in a class of medications called B-cell lymphoma-2 (Bcl-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Blinatumomab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. 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. Adding venetoclax and/or blinatumomab to standard chemotherapy may be more effective at treating patients with ALL than standard chemotherapy alone, but it may also cause more side effects. This clinical trial evaluates the safety and effectiveness of adding venetoclax and/or blinatumomab to chemotherapy for the treatment of infants with KMT2A-R or KMT2A-G ALL.

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

The trial does not specify if you need to stop taking your current medications, but it does mention that certain steroids and chemotherapy drugs are allowed before enrollment. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Blinatumomab for treating acute lymphoblastic leukemia?

Blinatumomab has shown promising results in treating relapsed or refractory acute lymphoblastic leukemia (ALL), with response rates ranging from 34% to 66% in heavily pretreated patients. It has also demonstrated improved survival and reduction in disease markers compared to standard treatments in some studies. ^{1 2 3 4 5}

Is the combination of Venetoclax and Blinatumomab safe for treating acute lymphoblastic leukemia?

Blinatumomab has been shown to have a favorable safety profile in treating relapsed or refractory acute lymphoblastic leukemia, with some side effects like infections, blood-related issues, and neurotoxicity. It is generally considered safe when managed by experienced centers, even in patients who cannot tolerate traditional chemotherapy. ^{6 7 8 9 10}

How is the drug Venetoclax + Blinatumomab different from other treatments for acute lymphoblastic leukemia?

The combination of Venetoclax and Blinatumomab is unique because it combines Venetoclax, which targets cancer cell survival, with Blinatumomab, an immunotherapy that engages T-cells to attack leukemia cells. This dual approach may offer a novel mechanism of action compared to standard chemotherapy, potentially improving outcomes for patients with acute lymphoblastic leukemia. ^{2 3 4 6 11}

Research Team

Erin H Breese

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for infants under the age of 1 year with newly diagnosed acute lymphoblastic leukemia (ALL), either with or without a KMT2A gene rearrangement. They must have B-ALL or at least 50% B lineage in cases of mixed phenotype acute leukemia, and be over 36 weeks gestational age.

Inclusion Criteria

I am enrolled in APEC14B1 and agreed to screening before starting treatment on AALL2321.

I have been newly diagnosed with a specific type of leukemia (B-ALL or ALAL with at least 50% B lineage).

My leukemia cells test positive for CD19.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Steroid Prephase

All patients receive prednisone or prednisolone orally or nasogastrically three times daily or methylprednisolone intravenously three times daily for 7 days prior to the start of induction therapy

1 week

Daily visits for 7 days

Induction

Patients receive a combination of chemotherapy drugs including venetoclax, daunorubicin, vincristine, dexamethasone, calaspargase pegol, and intrathecal therapy

5 weeks

Multiple visits for drug administration

Blinatumomab Block 1

Patients receive blinatumomab intravenously and intrathecal therapy

4 weeks

Continuous IV infusion and scheduled intrathecal therapy

Consolidation

Patients receive cyclophosphamide, cytarabine, mercaptopurine, and intrathecal therapy

8 weeks

Scheduled visits for drug administration

MARMA

Patients receive mercaptopurine, high dose methotrexate, leucovorin, intrathecal therapy, high dose cytarabine, and recombinant crisantaspase

7 weeks

Scheduled visits for drug administration

Blinatumomab Block 2

Patients receive blinatumomab intravenously and intrathecal therapy

4 weeks

Continuous IV infusion and scheduled intrathecal therapy

Delayed Intensification

Patients receive a combination of chemotherapy drugs including calaspargase pegol, dexamethasone, thioguanine, vincristine, daunorubicin, cytarabine, and cyclophosphamide

9 weeks

Scheduled visits for drug administration

Maintenance

Patients receive mercaptopurine, methotrexate, and intrathecal therapy in cycles

Up to 2 years

Regular visits every 12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Treatment Details

Interventions

• Blinatumomab
• Venetoclax

Trial Overview The study tests adding Venetoclax, a drug that blocks proteins cancer cells need to survive, and/or Blinatumomab, an antibody interfering with cancer growth, to standard chemotherapy in treating infant ALL. It aims to see if this combination is more effective than chemotherapy alone.

Participant Groups

Group I: Steroid Prephase(prednisone, prednisolone, methylprednisolone) Experimental Treatment 11 Interventions

All patients receive prednisone or prednisolone PO or NG TID or methylprednisolone IV TID for 7 days prior to the start of induction therapy (on days 1-7).

Group II: Safety Phase Cohort Experimental Treatment 23 Interventions

See Detailed Description for Safety Phase Cohort.

Group III: Arm C Experimental Treatment 25 Interventions

See Detailed Description for Arm C.

Group IV: Arm B, Cohort 4 Experimental Treatment 23 Interventions

See Detailed Description for Arm B, Cohort 4.

Group V: Arm B, Cohort 3 Experimental Treatment 23 Interventions

See Detailed Description for Arm B, Cohort 3.

Group VI: Arm B, Cohort 2 Experimental Treatment 23 Interventions

See Detailed Description for Arm B, Cohort 2.

Group VII: Arm B, Cohort 1 Experimental Treatment 23 Interventions

See Detailed Description for Arm B, Cohort 1.

Group VIII: Arm A Experimental Treatment 22 Interventions

See Detailed Description for Arm A.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Blinatumomab pharmacokinetics were effectively modeled using a one-compartment linear model, showing a clearance rate of 2.22 L/h and a central volume of 5.98 L, based on data from 674 patients.

Body surface area (BSA) significantly affects the clearance of blinatumomab, particularly in pediatric patients, suggesting that BSA-based dosing is important for lighter patients to ensure effective treatment while minimizing variability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Blinatumomab in Pediatric and Adult Patients with Hematological Malignancies. Clements, JD., Zhu, M., Kuchimanchi, M., et al.[2021]

A survey of 150 Children's Oncology Group institutions revealed that most patients receiving blinatumomab for B-lineage acute lymphoblastic leukemia are treated in outpatient settings, with only 9% requiring hospitalization for the full 28-day infusion cycle.

There is significant variability in hospitalization practices, with smaller institutions tending to report longer stays, highlighting the need for standardization in care coordination for blinatumomab administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delivery of Care for Pediatric Patients Receiving Blinatumomab: A Children's Oncology Group Study. Withycombe, JS., Kubaney, HR., Okada, M., 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 a phase 2 study, blinatumomab demonstrated a significant overall survival benefit for patients with relapsed/refractory Ph(-) B-precursor acute lymphoblastic leukemia, with a mean survival of 76.1 months compared to 39.8 months for historical patients receiving standard chemotherapy.

At 60 months, 12.6% of patients treated with blinatumomab were still alive, which is more than double the 5.4% survival rate of historical controls, indicating its potential as a more effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estimating Long-Term Survival of Adults with Philadelphia Chromosome-Negative Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia Treated with Blinatumomab Using Historical Data. Barlev, A., Lin, VW., Katz, A., et al.[2021]

Blinatumomab is a groundbreaking treatment for B-cell precursor relapsed/refractory acute lymphoblastic leukemia (ALL), showing the ability to induce deep remissions in some patients, but many still do not respond or relapse, highlighting the need for improved treatment strategies.

Understanding how patients respond or resist blinatumomab could help identify those who will benefit most, and combining it with other therapies or using it earlier in treatment protocols may enhance its effectiveness and reduce relapse rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bispecific antibodies in acute lymphoblastic leukemia therapy. Chitadze, G., Laqua, A., Lettau, M., et al.[2021]

In a phase 3 clinical trial involving 669 patients aged 1 to 30 years with first relapse of B-cell acute lymphoblastic leukemia (B-ALL), substituting blinatumomab for intensive chemotherapy in consolidation therapy showed a 2-year disease-free survival rate of 54.4% compared to 39.0% for the chemotherapy group, suggesting a potential benefit of blinatumomab in this high-risk population.

Blinatumomab also demonstrated a better safety profile, with significantly lower rates of serious adverse events such as infections and febrile neutropenia compared to traditional chemotherapy, indicating it may be a safer option for treating relapsed B-ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. Brown, PA., Ji, L., Xu, X., et al.[2021]

Blinatumomab monotherapy demonstrated a complete remission (CR) rate of 54% and a minimal residual disease (MRD) response rate of 43% in treating relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL) across 18 studies involving 1,373 patients.

The treatment showed a manageable safety profile, with 80% of patients experiencing grade ≥3 adverse events, but only 7% experiencing significant neurological toxicity and 3% experiencing cytokine release syndrome, indicating that while effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Blinatumomab for the Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia: A Systemic Review and Meta-Analysis. Liu, H., Xi, R., Mao, D., et al.[2023]

Blinatumomab is an effective treatment for relapsed or refractory B-acute lymphoblastic leukemia (ALL), particularly in patients with minimal residual disease, as it engages T-cells to target CD19 positive B cells.

While it shows promise, blinatumomab can cause significant adverse effects, including infections and neurotoxicity, requiring careful management by experienced medical centers during its continuous four-week infusion administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical applications and safety evaluation of the new CD19 specific T-cell engager antibody construct blinatumomab. Wilke, AC., Gökbuget, N.[2017]

Blinatumomab is a first-in-class bispecific T-cell engager that effectively targets both CD19 on B-cells and CD3 on T-cells, showing a high response rate of 43% for complete remission in patients with relapsed or refractory precursor B-cell acute lymphoblastic leukemia (B-ALL).

Patients treated with blinatumomab had a median overall survival of 6.1 months and 60% achieved minimal residual disease negativity, although common side effects included fever, neurological events, and anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blinatumomab: A First-in-Class Bispecific T-Cell Engager for Precursor B-Cell Acute Lymphoblastic Leukemia. Buie, LW., Pecoraro, JJ., Horvat, TZ., et al.[2018]

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]

In a study involving 255 patients aged 1-30 with low-risk first relapse of B-cell acute lymphoblastic leukemia (B-ALL), blinatumomab combined with chemotherapy showed a significant improvement in disease-free survival (DFS) and overall survival (OS) for patients with bone marrow and extramedullary relapses compared to chemotherapy alone.

Blinatumomab was well tolerated with low adverse event rates, but no significant difference in outcomes was found for patients with isolated extramedullary relapses, indicating a need for new treatment strategies for this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Children's Oncology Group AALL1331: Phase III Trial of Blinatumomab in Children, Adolescents, and Young Adults With Low-Risk B-Cell ALL in First Relapse. Hogan, LE., Brown, PA., Ji, L., et al.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Blinatumomab in Pediatric and Adult Patients with Hematological Malignancies. [2021]

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

Delivery of Care for Pediatric Patients Receiving Blinatumomab: A Children's Oncology Group Study. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Estimating Long-Term Survival of Adults with Philadelphia Chromosome-Negative Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia Treated with Blinatumomab Using Historical Data. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Bispecific antibodies in acute lymphoblastic leukemia therapy. [2021]

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

Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. [2021]

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

Efficacy and Safety of Blinatumomab for the Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia: A Systemic Review and Meta-Analysis. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Clinical applications and safety evaluation of the new CD19 specific T-cell engager antibody construct blinatumomab. [2017]

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

Blinatumomab: A First-in-Class Bispecific T-Cell Engager for Precursor B-Cell Acute Lymphoblastic Leukemia. [2018]

10. 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]

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

Children's Oncology Group AALL1331: Phase III Trial of Blinatumomab in Children, Adolescents, and Young Adults With Low-Risk B-Cell ALL in First Relapse. [2023]