Daratumumab + Ibrutinib for Chronic Lymphocytic Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must be taking: BTK inhibitors

Must not be taking: Warfarin, CYP3A modulators

Disqualifiers: COPD, Asthma, HIV, Hepatitis, 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: 1

Duration: 6 cycles (28 days each)

11 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well daratumumab and ibrutinib work in treating patients with chronic lymphocytic leukemia that has come back (relapsed) or has not responded to previous treatment (refractory). Daratumumab is a monoclonal antibody which works with the body's immune system to destroy cancer cells. 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 compared to ibrutinib alone.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use warfarin, other vitamin K antagonists, or strong CYP3A modulators. It's best to discuss your current 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 other treatments like Daratumumab. ^{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}

Research Team

Sikander Ailawadhi

Principal Investigator

Mayo Clinic

Eligibility Criteria

This trial is for adults with chronic lymphocytic leukemia (CLL) that has returned or didn't respond to treatment. They must have been on ibrutinib previously, have measurable disease, and be in decent physical condition. Participants need normal blood counts and liver function, not be pregnant or nursing, use effective birth control, and can't have severe lung conditions or other serious health issues.

Inclusion Criteria

I was previously treated with ibrutinib and stopped, except due to severe side effects, but can safely take it again.

Absolute neutrophil count >= 1000/mm^3 (obtained =< 14 days prior to registration)

I have been treated with ibrutinib.

Exclusion Criteria

I am of childbearing age and not using birth control.

I have not had major surgery in the last 4 weeks.

I have had moderate to severe asthma in the last 2 years or currently have uncontrolled asthma.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daratumumab IV and ibrutinib PO in cycles, with daratumumab administered on specific days of each cycle and ibrutinib taken daily starting from cycle 2

6 cycles (28 days each)

IV visits on days 1, 8, 15, 22 of cycles 1-2; days 1, 15 of cycles 3-6; day 1 of subsequent cycles

Follow-up

Participants are monitored for safety, effectiveness, and progression-free survival after treatment

Up to 5 years

Treatment Details

Interventions

• Daratumumab
• Ibrutinib

Trial Overview The DIRECT Study is testing the combination of daratumumab (a monoclonal antibody) with ibrutinib (an enzyme blocker) against CLL that's relapsed or refractory. The goal is to see if this combo works better than just using ibrutinib alone for these patients.

Participant Groups

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

Patients receive daratumumab IV on days 1, 8, 15, and 22 of cycles 1-2, on days 1 and 15 of cycles 3-6, and then on day 1 of subsequent cycles. Beginning in cycle 2, patients also receive ibrutinib PO QD on days 1-28. Cycles 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?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

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]

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]

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]

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. 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]

11. 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]

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

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

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]