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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of two drugs, daratumumab (Darzalex) and ibrutinib (Imbruvica), in treating chronic lymphocytic leukemia (CLL), a type of blood cancer. Researchers seek to understand potential side effects and how these drugs might inhibit the growth and spread of cancer cells. The trial is recruiting individuals with CLL who experience symptoms like severe fatigue or large lymph nodes and have not received prior cancer treatments. As a Phase 1 trial, the research focuses on understanding the treatment's effects in people, offering participants the chance to contribute to groundbreaking research.

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.

Is there any evidence suggesting that daratumumab and ibrutinib are likely to be safe for humans?

Research shows that both daratumumab and ibrutinib are usually well-tolerated by patients. In different studies, fewer than 10% of patients stopped taking ibrutinib due to side effects. For daratumumab, some patients experienced issues, such as a decrease in white blood cells, which help fight infections. There were also reports of serious reactions with daratumumab.

These medicines have been used together in other studies for patients with chronic lymphocytic leukemia. The combination has shown promise, with a safety profile manageable for many patients. While side effects can occur, they don't affect everyone. Always discuss any concerns with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Daratumumab and Ibrutinib for treating Chronic Lymphocytic Leukemia (CLL) because this approach targets the disease in a novel way. Daratumumab is a monoclonal antibody that directly attacks cancer cells by binding to CD38 on their surface, potentially enhancing the immune system's response. Ibrutinib, on the other hand, inhibits Bruton's tyrosine kinase (BTK), a key player in the pathway that cancer cells use to grow. Together, these treatments might offer a more comprehensive attack on CLL compared to traditional therapies, which typically focus on chemotherapy or single-drug approaches. This combination could lead to more effective disease control with potentially fewer side effects.

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

Research has shown that using daratumumab and ibrutinib together might help treat chronic lymphocytic leukemia (CLL). In this trial, participants will receive both daratumumab, a medicine that stops cancer cells from growing, and ibrutinib, which has proven more effective than usual treatments for some CLL patients, especially those with certain genetic traits. Studies suggest that combining these two drugs could be more effective than using ibrutinib alone. This approach aims to improve treatment for CLL patients by attacking cancer cells in different ways. ^{1 2 6 7 8}

Who Is on the Research Team?

Jennifer Woyach, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

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 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 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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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 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]

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. clinicaltrial.be clinicaltrial.be/en/details/7657?per_page=100&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

Daratumumab and Ibrutinib in Treating Patients With Sympt... I. To characterize the safety of treatment with daratumumab and ibrutinib for previously untreated chronic lymphocytic leukemia (CLL). II. To ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7153674/

Efficacy of Ibrutinib-Based Regimen in Chronic ... Ibrutinib has shown to have better efficacy than standard chemoimmunotherapy in del17 positive chronic lymphocytic leukemia (CLL) patients; however its role ...

4. pharmaceutical-technology.com pharmaceutical-technology.com/data-insights/daratumumab-johnson-johnson-chronic-lymphocytic-leukemia-cll-likelihood-of-approval/

Daratumumab by Johnson & Johnson for Chronic ... According to GlobalData, Phase I drugs for Chronic Lymphocytic Leukemia (CLL) have a 69% phase transition success rate (PTSR) indication benchmark for ...

5. jnj.com jnj.com/innovativemedicine/us/news-center/oncology/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 ... IMBRUVICA® is a kinase inhibitor indicated for the treatment of: Adult patients with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL).

6. 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 ... Consistently High 5.5-Year Progression-Free Survival Rates in Patients with and without Bulky Baseline Lymphadenopathy ≥5 cm are Associated with ...

7. prnewswire.com prnewswire.com/news-releases/janssen-to-present-the-strength-and-promise-of-its-hematologic-malignancies-portfolio-and-pipeline-at-ash-2021-301416710.html

Janssen to Present the Strength and Promise of its ... The most common hematologic laboratory abnormalities (≥40%) with DARZALEX FASPRO® are decreased leukocytes, decreased lymphocytes, decreased ...

8. withpower.com withpower.com/trial/phase-3-leukemia-lymphoid-8-2020-6a402

Daratumumab + Ibrutinib for 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 ...