Ibrutinib + Blinatumomab for Acute Lymphoblastic Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Brian Jonas

Must not be taking: CYP3A inhibitors, Warfarin

Disqualifiers: T-ALL, CNS leukemia, GVHD, 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

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well ibrutinib and blinatumomab work in treating patients with B acute lymphoblastic leukemia that has come back or is not responding to treatment. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as blinatumomab, may interfere with the ability of cancer cells to grow and spread. Giving ibrutinib and blinatumomab may work better in treating patients with relapsed or refractory B acute lymphoblastic leukemia.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it mentions that eligibility will be determined based on whether your medications affect the study drugs. It's best to discuss your current medications with the trial investigator.

What data supports the effectiveness of the drug Blinatumomab for Acute Lymphoblastic Leukemia?

Research shows that Blinatumomab, a type of immunotherapy, has been effective in treating relapsed or hard-to-treat acute lymphoblastic leukemia (ALL) by activating the body's immune cells to attack cancer cells. Studies have shown that it can lead to significant remission in some patients, especially when used as a bridge to further treatments like stem cell transplants. ^{1 2 3 4 5}

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

Blinatumomab, used for treating acute lymphoblastic leukemia, has shown a favorable safety profile compared to traditional chemotherapy. Common side effects include cytokine release syndrome (a reaction that can cause fever and low blood pressure) and neurological issues like seizures, but these are generally manageable with treatment adjustments. ^{1 4 6 7 8}

How is the drug combination of Ibrutinib and Blinatumomab unique for treating Acute Lymphoblastic Leukemia?

The combination of Ibrutinib and Blinatumomab is unique because Ibrutinib targets specific proteins involved in B-cell signaling, which is crucial in certain types of leukemia, while Blinatumomab is a type of immunotherapy that helps the immune system attack cancer cells. This dual approach may offer a novel way to treat Acute Lymphoblastic Leukemia by combining targeted therapy with immunotherapy. ^{9 10 11 12 13}

Research Team

Brian Jonas, MD

Principal Investigator

University of California, Davis

Eligibility Criteria

This trial is for adults with B acute lymphoblastic leukemia that's returned or isn't responding to treatment. They must have proper liver and kidney function, no major bleeding disorders, not be pregnant or breastfeeding, and agree to use effective birth control. People can't join if they've had certain recent treatments, active central nervous system leukemia, severe heart conditions, or are positive for HIV/HCV/HBV without a negative PCR result.

Inclusion Criteria

I can care for myself but may need occasional help.

I agree to use two effective birth control methods during and 90 days after treatment.

My current medications won't interfere with the trial drugs.

Exclusion Criteria

You have had allergic reactions to medications that are similar to ibrutinib, blinatumomab, or other drugs being used in this study.

I have not received any live vaccines in the last 4 weeks.

I have graft-versus-host disease that is moderate to severe.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive ibrutinib and blinatumomab to induce remission

7 weeks

Multiple visits for drug administration and monitoring

Consolidation Therapy

Patients with CR/CRi receive further treatment to consolidate remission

Up to 18 weeks

Regular visits for drug administration and monitoring

Maintenance Therapy

Patients receive ongoing treatment to maintain remission

Ongoing, 28-day cycles

Monthly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Blinatumomab
• Ibrutinib

Trial Overview The trial tests the combination of Ibrutinib (which blocks enzymes needed for cancer cell growth) and Blinatumomab (a monoclonal antibody that may stop cancer cells from growing). It aims to see if this combo is more effective in patients with relapsed/refractory B acute lymphoblastic leukemia.

Participant Groups

Group I: Treatment (ibrutinib, blinatumomab) Experimental Treatment 2 Interventions

INDUCTION THERAPY: Patients receive ibrutinib PO QD on days 1-49 of course 1 and days 1-42 of course 2, and blinatumomab IV on days 8-35 of course 1 and days 1-28 of course 2 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY: Patients with CR/CRi after Induction Therapy receive ibrutinib PO QD on days 1-42 and blinatumomab IV on days 1-28. Treatment repeats every 42 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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?

Brian Jonas

Lead Sponsor

Trials

5

Recruited

80+

Pharmacyclics LLC.

Industry Sponsor

Trials

114

Recruited

13,800+

Dr. Maky Zanganeh

Pharmacyclics LLC.

Chief Executive Officer

Degree from Louis Pasteur University in Strasbourg, France; MBA from Schiller International University in France

Dr. Ellie Im

Pharmacyclics LLC.

Chief Medical Officer

MD from an unspecified institution

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

Blinatumomab, a bispecific T-cell engager, significantly improves overall survival in adults and children with relapsed and refractory B-cell acute lymphoblastic leukemia (ALL), showing a median overall survival of 7.7 months compared to 4.0 months with standard chemotherapy.

The drug achieved a complete measurable residual disease response in 78% of patients in the phase II BLAST trial, but it is associated with potential side effects, including cytokine release syndrome and neurotoxicity in about 15% and 65% of patients, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Systematic Review of Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Engaging an Old Problem With New Solutions. Halford, Z., Coalter, C., Gresham, V., 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]

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-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]

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, 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 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]

Ibrutinib is a first-in-class oral Bruton's tyrosine kinase inhibitor that effectively blocks B-cell signaling, leading to reduced proliferation and increased cell death in B cell malignancies, including chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL).

It has received FDA approval for treating MCL in previously treated patients based on phase Ib/II study results and is currently undergoing further phase III trials for CLL, diffuse large B cell lymphoma (DLBCL), and other B cell cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib: first global approval. Cameron, F., Sanford, M.[2022]

Ibrutinib, a BTK inhibitor, shows strong effectiveness against pre-B-cell acute lymphoblastic leukemia (B-ALL), significantly prolonging survival in mouse models and demonstrating sensitivity in pre-BCR+ ALL cells at therapeutic concentrations.

The drug works by disrupting pre-BCR signaling and deactivating the PI3K/Akt pathway, while also modulating key regulators and reducing cell migration, suggesting it could be a promising targeted therapy for this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK. Kim, E., Hurtz, C., Koehrer, S., et al.[2021]

Ibrutinib is an effective treatment for chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL), showing better outcomes than traditional therapies like chlorambucil and ofatumumab in phase III trials involving elderly and previously-treated patients.

The drug has a good safety profile, although it can cause some adverse effects like bleeding and atrial fibrillation; it is recommended in treatment guidelines for patients with high-risk disease, including those with specific genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib: A Review in Chronic Lymphocytic Leukaemia. Deeks, ED.[2021]

Ibrutinib is a targeted therapy specifically designed for treating chronic lymphocytic leukemia (CLL), which is a type of cancer that affects the blood and bone marrow.

This novel treatment works by inhibiting Bruton's tyrosine kinase (BTK), a key enzyme that helps cancer cells survive and proliferate, leading to improved patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. Parmar, S., Patel, K., Pinilla-Ibarz, J.[2021]

Ibrutinib has significantly improved treatment outcomes for chronic lymphocytic leukemia (CLL) by irreversibly inhibiting Bruton tyrosine kinase (BTK), leading to better overall and progression-free survival in various patient subgroups, including those with relapsed disease and 17p deletion.

Despite its effectiveness, ibrutinib has limitations such as low complete remission rates and the potential for resistance, prompting research into combination therapies, particularly with venetoclax, which has shown high complete response rates and undetectable minimal residual disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib combinations in CLL therapy: scientific rationale and clinical results. Timofeeva, N., Gandhi, V.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

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

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

A Systematic Review of Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Engaging an Old Problem With New Solutions. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Bispecific antibodies in acute lymphoblastic leukemia therapy. [2021]

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

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

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

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

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

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

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

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

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

Ibrutinib: first global approval. [2022]

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

Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK. [2021]

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

Ibrutinib: A Review in Chronic Lymphocytic Leukaemia. [2021]

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

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. [2021]

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

Ibrutinib combinations in CLL therapy: scientific rationale and clinical results. [2022]