Blinatumomab + Nivolumab (+/- Ipilimumab) for Acute Lymphoblastic Leukemia

Recruiting at 6 trial locations

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anti-PD-1, Anti-CTLA-4

Disqualifiers: Active CNS leukemia, Autoimmune diseases, others

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

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

Compensation: Varies

Number of Visits: 9

Duration: 42 days per cycle, up to 5 cycles

28 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of blinatumomab when given with nivolumab alone or nivolumab and ipilimumab in treating patients with poor-risk CD19+ precursor B-lymphoblastic leukemia that has come back after a period of improvement (relapsed) or has not responded to treatment (refractory). Immunotherapy with monoclonal antibodies, such as blinatumomab, nivolumab, and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

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 treatments like chemotherapy, radiotherapy, or targeted therapy must be stopped a few weeks before starting the trial. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Blinatumomab, Nivolumab, and Ipilimumab for treating Acute Lymphoblastic Leukemia?

Research shows that the combination of nivolumab and ipilimumab has been effective in treating other types of cancer, like advanced lung and kidney cancers, by improving survival rates. This suggests potential benefits for using these drugs together in other cancers, such as Acute Lymphoblastic Leukemia. ^{1 2 3 4 5}

Is the combination of Blinatumomab, Nivolumab, and Ipilimumab safe for humans?

Blinatumomab has been used in treating acute lymphoblastic leukemia and is generally well-tolerated, but it can cause serious side effects like cytokine release syndrome (a severe immune reaction) and neurological issues (such as seizures). These side effects are usually manageable with treatment adjustments. ^{6 7 8 9 10}

What makes the drug combination of Blinatumomab, Nivolumab, and Ipilimumab unique for treating acute lymphoblastic leukemia?

This drug combination is unique because it combines Blinatumomab, a bispecific T-cell engager that activates the immune system to target leukemia cells, with Nivolumab and Ipilimumab, which are immune checkpoint inhibitors that help the immune system recognize and attack cancer cells. This approach leverages the body's own immune response to fight leukemia, offering a novel strategy compared to traditional chemotherapy. ^{9 10 11 12 13}

Research Team

Ivana Gojo

Principal Investigator

JHU Sidney Kimmel Comprehensive Cancer Center LAO

Eligibility Criteria

This trial is for patients aged 16 or older with poor-risk CD19+ precursor B-lymphoblastic leukemia that's relapsed or refractory. It includes those over 60 who can't have standard treatment, and excludes pregnant women, breastfeeding mothers, and individuals with certain health conditions like uncontrolled illnesses or active CNS leukemia.

Inclusion Criteria

Adequate contraception agreement for women of child-bearing potential and men

Specific laboratory criteria including total bilirubin, AST/ALT, and serum creatinine or CrCl

My leukemia is Philadelphia chromosome positive.

Exclusion Criteria

I have lung disease that causes me symptoms.

I have a condition affecting my digestive system.

I have a diagnosed brain condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive blinatumomab IV continuously on days 1-28, with nivolumab IV on day 11 and every 2 weeks, and some receive ipilimumab IV on day 11 and every 6 weeks, for up to 5 cycles

42 days per cycle, up to 5 cycles

Continuous IV for blinatumomab, bi-weekly visits for nivolumab, and every 6 weeks for ipilimumab

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Every 3 months

Treatment Details

Interventions

• Blinatumomab
• Ipilimumab
• Nivolumab

Trial Overview The study tests the safety and optimal doses of blinatumomab combined with nivolumab alone or alongside ipilimumab in treating specific leukemia. These are immunotherapies designed to help the immune system fight cancer by targeting tumor cells' growth.

Participant Groups

Group I: Treatment (blinatumomab, nivolumab, ipilimumab) Experimental Treatment 5 Interventions

Patients receive blinatumomab IV continuously on days 1-28. Treatment repeats every 42 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 30 minutes on day 11 and then every 2 weeks for up to year. Some patients also receive ipilimumab IV over 90 minutes on day 11 and then every 6 weeks for up to 1 year. Patients also undergo bone marrow aspiration and biopsy and blood sample collection throughout the study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

PD-1/PD-L1 inhibitors have limited effectiveness in patients with low PD-L1 expression in advanced non-small cell lung cancer (NSCLC), highlighting the need for improved treatment options.

Dual immunotherapy, combining PD-1 and CTLA-4 inhibitors, shows promise for better long-term survival in NSCLC, with ongoing research focused on identifying optimal patient groups and ensuring safety through multidisciplinary approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Dual Immunotherapy in Advanced Non-small Cell Lung Cancer: the Progress and Clinical Application]. Deng, H., Wang, L., Yang, Y., et al.[2022]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

Nivolumab combined with ipilimumab significantly improves overall survival in adult patients with intermediate/poor-risk advanced renal cell carcinoma compared to sunitinib, with a hazard ratio of 0.63, indicating a 37% reduction in the risk of death.

In the study involving 1096 patients, the median overall survival was not reached for the nivolumab + ipilimumab group, while it was 25.95 months for the sunitinib group, highlighting the potential of this combination therapy for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. Ali, S., Camarero, J., Hennik, P., et al.[2021]

Two cases of patients with multiple in-transit metastatic melanomas were successfully treated using intensity-modulated radiotherapy (IMRT) combined with immune checkpoint inhibitors ipilimumab or nivolumab.

The combination of IMRT and immune checkpoint inhibitors suggests a potential enhancement of antitumor effects, indicating a promising approach for improving treatment outcomes in melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment of multiple in-transit melanomas on the leg with intensity-modulated radiotherapy and immune checkpoint inhibitors: Report of two cases. Fujimura, T., Kambayashi, Y., Furudate, S., et al.[2018]

Blinatumomab is a promising new treatment for adults with relapsed or refractory B-cell acute lymphoblastic leukemia, showing effectiveness in targeting and destroying tumor cells by engaging both T-cells and B-cells.

While there are potential side effects like immunological toxicities and cytokine release syndrome, most patients tolerate blinatumomab well, indicating a favorable safety profile compared to traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical use of blinatumomab for B-cell acute lymphoblastic leukemia in adults. Lee, KJ., Chow, V., Weissman, A., et al.[2022]

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 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, shows significant efficacy in treating refractory or relapsed acute lymphoblastic leukemia (ALL), achieving complete response rates of 39% to 69% and a median overall survival of 7.7 months, compared to 4.0 months with traditional chemotherapy.

The treatment has a favorable safety profile, with manageable side effects such as cytokine-release syndrome and reversible neurological issues, making it a promising option for both adult and pediatric patients with R/R ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotargeting relapsed or refractory precursor B-cell acute lymphoblastic leukemia - role of blinatumomab. Queudeville, M., Handgretinger, R., Ebinger, M.[2020]

Blinatumomab represents a significant advancement in immunotherapy for relapsed or refractory acute lymphoblastic leukemia (ALL), demonstrating unprecedented efficacy by stimulating a strong T-cell response, which is a departure from traditional chemotherapy.

While blinatumomab offers promising benefits, it also presents unique immunological toxicities and complex administration requirements, necessitating careful consideration of its use compared to other emerging therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blinatumomab: enlisting serial killer T-cells in the war against hematologic malignancies. Rogala, B., Freyer, CW., Ontiveros, EP., et al.[2023]

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, 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 study of 20 patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) treated with blinatumomab, 20% experienced extramedullary relapse, indicating a significant concern for this type of relapse after treatment.

The median time to extramedullary relapse was 179 days, with relapses occurring in various organs, suggesting that while blinatumomab is effective, there is a need for further research to prevent these relapses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of relapse patterns in patients with acute lymphoblastic leukemia treated with blinatumomab. Lau, KM., Saunders, IM., Goodman, AM.[2021]

References

1. China pubmed.ncbi.nlm.nih.gov

[Dual Immunotherapy in Advanced Non-small Cell Lung Cancer: the Progress and Clinical Application]. [2022]

2. France pubmed.ncbi.nlm.nih.gov

[Combination strategies for checkpoint inhibition: Current practices and perspectives]. [2023]

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

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. [2021]

4. England pubmed.ncbi.nlm.nih.gov

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. [2021]

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

Successful treatment of multiple in-transit melanomas on the leg with intensity-modulated radiotherapy and immune checkpoint inhibitors: Report of two cases. [2018]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Clinical use of blinatumomab for B-cell acute lymphoblastic leukemia in adults. [2022]

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

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

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. New Zealand pubmed.ncbi.nlm.nih.gov

Immunotargeting relapsed or refractory precursor B-cell acute lymphoblastic leukemia - role of blinatumomab. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Blinatumomab: enlisting serial killer T-cells in the war against hematologic malignancies. [2023]

11. 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]

12. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Characterization of relapse patterns in patients with acute lymphoblastic leukemia treated with blinatumomab. [2021]