Daratumumab + Ibrutinib for Chronic Lymphocytic Leukemia

Overseen By Mir Ali

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Jennifer Woyach

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: Stroke, Autoimmune anemia, Richter's, 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: 14

Duration: 48 weeks

15 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you require certain medications like warfarin or strong CYP3A inhibitors. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Daratumumab and Ibrutinib for treating Chronic Lymphocytic Leukemia?

Ibrutinib has shown effectiveness as a first-line treatment for chronic lymphocytic leukemia, improving outcomes like progression-free survival when used alone or with other drugs. This suggests potential benefits when combined with Daratumumab, although specific studies on this combination are not mentioned. ^{1 2 3 4 5}

Is the combination of Daratumumab and Ibrutinib safe for treating chronic lymphocytic leukemia?

Ibrutinib, used for chronic lymphocytic leukemia, has shown an acceptable safety profile in various studies, with less than 10% of patients stopping treatment due to side effects. Common side effects include diarrhea, fatigue, and nausea, but it is generally well-tolerated. ^{1 6 7 8 9}

What makes the drug combination of Daratumumab and Ibrutinib unique for treating chronic lymphocytic leukemia?

The combination of Daratumumab and Ibrutinib is unique because it combines two different mechanisms: Daratumumab targets CD38 on cancer cells, while Ibrutinib inhibits Bruton's tyrosine kinase, which is crucial for cancer cell survival. This dual approach may offer enhanced effectiveness compared to using either drug alone. ^{1 10 11 12 13}

What is the purpose of this trial?

This phase Ib trials studies the side effects of daratumumab and ibrutinib and how well they work in treating patients with symptomatic chronic lymphocytic leukemia. Monoclonal antibodies, such as daratumumab, may interfere with the ability of cancer cells to grow and spread. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving daratumumab and ibrutinib may work better in treating patients with chronic lymphocytic leukemia.

Research Team

Jennifer Woyach, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with symptomatic chronic lymphocytic leukemia (CLL) who need treatment and haven't had chemotherapy, immunotherapy, or targeted therapy before. Participants must have certain blood counts, no history of severe allergic reactions to monoclonal antibodies, no active infections like hepatitis B/C or HIV, and not be pregnant or breastfeeding. They should also not have any serious heart conditions or other illnesses that could interfere with the study.

Inclusion Criteria

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (unless due to liver involvement)

Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials; men must agree to not donate sperm during and after the study; for females, these restrictions apply for 1 month after the last dose of study drug; for males, these restrictions apply for 3 months after the last dose of study drug

Positive hepatitis serology:

Exclusion Criteria

Patients who have had chemotherapy, immunotherapy, radiotherapy, or investigational therapy within 28 days prior to entering the study or those who have not recovered from adverse events due to agents administered more than 28 days earlier; steroids for control of disease related symptoms are permitted

History of stroke or intracranial hemorrhage within 6 months prior to randomization

Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon); patients may be eligible if able to be taken off warfarin and started on an alternative anticoagulant

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daratumumab IV and ibrutinib PO for up to 12 courses, each lasting 28 days

48 weeks

Weekly visits for the first 2 months, bi-weekly for months 3-6, then monthly

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Every 12 weeks

Treatment Details

Interventions

• Daratumumab
• Ibrutinib

Trial Overview The trial is testing the combination of daratumumab (a monoclonal antibody) and ibrutinib (an enzyme blocker) to see if they are more effective in treating CLL compared to current treatments. The study will monitor how these drugs affect cancer cell growth and spread by analyzing biomarkers in the lab.

Participant Groups

Group I: Treatment (daratumumab, ibrutinib) Experimental Treatment 4 Interventions

Patients receive daratumumab IV on days 1, 8, 15, and 22 of courses 1-2, days 1 and 15 of courses 3-6, and day 1 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Beginning course 2, patients also receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Darzalex for:

• Relapsed and refractory multiple myeloma
• Newly diagnosed multiple myeloma in combination with bortezomib, melphalan, and prednisone

Approved in United States as Darzalex for:

• Multiple myeloma in patients who have received at least three prior therapies
• Newly diagnosed multiple myeloma in combination with bortezomib, melphalan, and prednisone
• Relapsed or refractory multiple myeloma in combination with lenalidomide and dexamethasone

Who Is Running the Clinical Trial?

Jennifer Woyach

Lead Sponsor

Trials

4

Recruited

100+

Findings from Research

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 shown high effectiveness as a first-line treatment for chronic lymphocytic leukemia in real-world settings, with 12-month overall survival rates between 95% and 96% and progression-free survival rates ranging from 89% to 93% across various studies involving 112 to 2033 patients.

The treatment demonstrated a strong response rate, with 71% to 90% of patients responding positively, and a significant majority (91% at 12 months and 87% at 24 months) did not require new treatment, indicating its sustained efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Literature Review of Real-World Effectiveness Results Data for First-Line Ibrutinib in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma. Lee, P., Kistler, KD., Douyon, L., et al.[2023]

Ibrutinib, a BTK inhibitor, has been shown to significantly improve clinical outcomes for patients with chronic lymphocytic leukemia, as demonstrated in two phase III trials.

When used alone or in combination with rituximab, ibrutinib enhances progression-free survival compared to traditional chemoimmunotherapy regimens, suggesting it should be considered a standard treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Ibrutinib Confirmed for CLL. [2019]

Ibrutinib is an effective oral treatment for patients with relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia (CLL), showing a 68% overall response rate in MCL and significant improvements in progression-free survival and overall survival in CLL patients, including those with specific genetic mutations.

The drug has a good safety profile, with less than 10% of patients discontinuing treatment due to adverse effects, making it a promising option for patients with various B-cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ibrutinib: A new drug of B-cell malignancies]. Thieblemont, C.[2021]

In a phase 1b/2 study involving 61 patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), the combination of ibrutinib and durvalumab showed an overall response rate of 25%, with the highest response in non-GCB DLBCL patients (38%).

The treatment was generally well-tolerated, with common side effects including diarrhea, fatigue, and nausea, and a notable 20% of patients experienced immune-related adverse events, indicating that while the combination therapy is effective, it also carries additional risks compared to single-agent treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and activity of ibrutinib in combination with durvalumab in patients with relapsed or refractory follicular lymphoma or diffuse large B-cell lymphoma. Herrera, AF., Goy, A., Mehta, A., et al.[2021]

In a phase 1b study involving patients with relapsed/refractory chronic lymphocytic leukemia, the combination of ibrutinib with bendamustine and rituximab (BR) showed a high overall response rate of 93.3%, with significant improvements in complete responses over time.

The study demonstrated that ibrutinib can enhance the efficacy of chemoimmunotherapy without adding prolonged hematologic toxicity, suggesting a promising treatment strategy for patients with this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Brown, JR., Barrientos, JC., Barr, PM., et al.[2021]

Zanubrutinib, a next-generation BTK inhibitor, shows promising efficacy in treating chronic lymphocytic leukemia (CLL) with minimal off-target effects compared to ibrutinib, which is known for its adverse events due to off-target kinase inhibition.

A Phase III study is underway to directly compare the safety and effectiveness of zanubrutinib against ibrutinib in patients with relapsed or refractory CLL, highlighting the potential for zanubrutinib to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Hillmen, P., Brown, JR., Eichhorst, BF., et al.[2021]

In a phase 3 trial involving 652 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), zanubrutinib demonstrated superior progression-free survival compared to ibrutinib, with a hazard ratio of 0.65, indicating a significant reduction in the risk of disease progression or death.

Zanubrutinib also had a better safety profile than ibrutinib, resulting in fewer adverse events that led to treatment discontinuation, particularly fewer cardiac events, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. Brown, JR., Eichhorst, B., Hillmen, P., et al.[2023]

The Phase III HELIOS trial is designed to evaluate the efficacy of adding ibrutinib to the standard treatment of bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia, with a focus on progression-free survival as the primary endpoint.

Eligible patients will receive a maximum of six cycles of BR, and the study will also assess safety, overall survival, and patient-reported outcomes, providing a comprehensive evaluation of ibrutinib's benefits compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The HELIOS trial protocol: a phase III study of ibrutinib in combination with bendamustine and rituximab in relapsed/refractory chronic lymphocytic leukemia. Hallek, M., Kay, NE., Osterborg, A., et al.[2021]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial. [2021]

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

Systematic Literature Review of Real-World Effectiveness Results Data for First-Line Ibrutinib in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma. [2023]

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

First-Line Ibrutinib Confirmed for CLL. [2019]

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

Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. [2022]

6. France pubmed.ncbi.nlm.nih.gov

[Ibrutinib: A new drug of B-cell malignancies]. [2021]

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

Safety and activity of ibrutinib in combination with durvalumab in patients with relapsed or refractory follicular lymphoma or diffuse large B-cell lymphoma. [2021]

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

The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. [2021]

9. England pubmed.ncbi.nlm.nih.gov

ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. [2021]

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

Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. [2022]

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

Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. [2023]

12. England pubmed.ncbi.nlm.nih.gov

The HELIOS trial protocol: a phase III study of ibrutinib in combination with bendamustine and rituximab in relapsed/refractory chronic lymphocytic leukemia. [2021]

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

Predictive significance of selected gene mutations in relapsed and refractory chronic lymphocytic leukemia patients treated with ibrutinib. [2021]