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)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial evaluates the effectiveness of combining daratumumab and ibrutinib for patients with chronic lymphocytic leukemia (CLL) that has either returned after treatment or not responded to previous treatments. Daratumumab (also known as Darzalex) helps the immune system attack cancer cells, while ibrutinib blocks certain enzymes to stop cancer cell growth. The trial tests whether using both drugs together is more effective than using ibrutinib alone. It seeks participants with CLL that is unresponsive to previous treatments or has relapsed, particularly those who have undergone frequent treatments. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that daratumumab, a monoclonal antibody, is generally safe and has received FDA approval for several uses, including treating multiple myeloma. However, some serious reactions have been reported, so monitoring during treatment is crucial.

Ibrutinib is another treatment option that stops cancer cells from growing. Studies with previous patients have shown it is usually well-tolerated, though it can sometimes cause side effects like diarrhea, tiredness, and minor bleeding.

While both treatments have been studied individually, the combination of daratumumab and ibrutinib remains under investigation. The current trial is in phase 2, indicating some evidence of safety, but more information is needed to fully understand the risks. Participants will be closely monitored for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this possible treatment for chronic lymphocytic leukemia?

Researchers are excited about the combination of daratumumab and ibrutinib for treating Chronic Lymphocytic Leukemia (CLL) because it offers a novel approach to tackling the disease. Unlike current standard treatments, which often include chemotherapy and monoclonal antibodies, this combination leverages daratumumab's unique ability to target CD38 on cancer cells and ibrutinib's inhibition of Bruton's tyrosine kinase, disrupting cancer cell survival pathways. This dual action not only aims to enhance the effectiveness against CLL but also potentially reduces the reliance on traditional chemotherapy, offering a more targeted and less toxic treatment option.

What evidence suggests that daratumumab and ibrutinib might be an effective treatment for chronic lymphocytic leukemia?

This trial will evaluate the combination of daratumumab and ibrutinib for treating chronic lymphocytic leukemia (CLL). Research has shown that using daratumumab and ibrutinib together might be effective, especially if the disease has returned or hasn't responded to other treatments. Daratumumab helps the immune system find and destroy cancer cells, and some studies have shown that it can reduce the risk of disease progression by half in high-risk patients. Ibrutinib blocks certain proteins that cancer cells need to grow. Together, these treatments are thought to be more effective than ibrutinib alone. This combination aims to improve outcomes for patients with CLL. ^{1 6 7 8 9}

Who Is on the Research Team?

Sikander Ailawadhi

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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 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]

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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04230304

Study Details | NCT04230304 | Daratumumab and Ibrutinib ... Giving daratumumab and ibrutinib may work better in treating patients with chronic lymphocytic leukemia compared to ibrutinib alone. Detailed Description.

2. cancerhealth.com cancerhealth.com/article/studies-highlight-progress-preventing-treating-blood-cancers-precancerous-conditions

Studies Highlight Progress in Preventing and Treating ... In the first study, the drug daratumumab [Darzalex Faspro] cut the risk of disease progression by half in patients who faced a high risk of ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2018-00159

Daratumumab and Ibrutinib in Treating Patients with ... This phase Ib trials studies the side effects of daratumumab and ibrutinib and how well they work in treating patients with symptomatic chronic lymphocytic ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39352001/

Real-world outcomes following ibrutinib dose reduction in ... Ibrutinib DR was associated with fewer outpatient visits and lower CLL/SLL-related medical costs. These findings suggest that utilizing ...

5. innovativemedicine.jnj.com innovativemedicine.jnj.com/us/johnson-johnson-to-showcase-strength-of-its-broad-hematology-portfolio-and-pipeline-at-the-2024-american-society-of-hematology-annual-meeting

Johnson & Johnson to showcase strength of its broad ... Initiating First-Line Fixed-Duration IMBRUVICA® and Venetoclax in Patients with Chronic Lymphocytic Leukemia Improves Overall Survival Outcomes ...

6. jnj.com jnj.com/media-center/press-releases/johnson-johnson-showcases-latest-advancements-in-cancer-innovation-with-more-than-70-clinical-and-real-world-studies-at-asco-and-eha

Johnson & Johnson showcases latest advancements in ... DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) received U.S. FDA approval in May 2020 and is approved for ten indications in multiple ...

7. jnj.com jnj.com/media-center/press-releases/darzalex-faspro-daratumumab-and-hyaluronidase-fihj-shows-51-percent-reduction-in-risk-of-progression-to-active-multiple-myeloma-for-patients-with-high-risk-smoldering-multiple-myeloma

DARZALEX FASPRO® (daratumumab and hyaluronidase ... Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO®. Systemic Reactions In a pooled safety ...

8. firstwordpharma.com firstwordpharma.com/story/5914210

Johnson & Johnson to showcase strength of its broad ... DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) received U.S. FDA approval in May 2020 and is approved for nine indications in multiple myeloma, four of ...

9. darzalex.com darzalex.com/clinical-results/

Clinical Results A study confirmed that DARZALEX FASPRO ® gave patients results comparable to the IV formulation of DARZALEX ® in treating multiple myeloma when used by itself.