Ibrutinib Clinical Trials

What Is Ibrutinib?

Ibrutinib is an FDA-approved medication for chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenstrom macroglobulinemia (WM). It is a type of drug known as a kinase inhibitor. Specifically, ibrutinib works by blocking a protein called Bruton's tyrosine kinase (BTK), which plays a crucial role in the survival and growth of certain cancer cells, particularly B-cells. By inhibiting BTK, ibrutinib aims to kill these cancer cells or stop them from growing.

Beyond its approved uses, ibrutinib is also being investigated in clinical trials for other conditions. These studies explore its potential effectiveness and safety, sometimes at different doses or in combination with other treatments.

Uses and Conditions Under Study

Ibrutinib is extensively studied across a range of blood cancers and other conditions, with a total of 352 trials involving 73,545 participants. The first trial for ibrutinib began in 2011, and studies are ongoing, with the latest projected to conclude in 2026.

• Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): These are the most common leukemias in Western countries, affecting B-cells. Ibrutinib is approved for CLL and is being investigated in 62 trials for CLL and 30 trials for SLL, including recurrent and refractory forms. Studies are exploring its use as an earlier treatment or in combination with other drugs like venetoclax to improve outcomes for patients who are not responding to single-agent ibrutinib.
• Mantle Cell Lymphoma (MCL): This is a rare subtype of non-Hodgkin lymphoma. Ibrutinib is approved for patients with MCL who have received at least one prior treatment. It is being studied in 33 trials for MCL, including recurrent forms, often in combination with other agents to improve response rates.
• Waldenstrom Macroglobulinemia (WM): For this condition, conventional chemotherapy often leads to low complete remission rates and short response durations. Ibrutinib is approved for WM and is being investigated in 14 trials to find innovative approaches that offer both activity and tolerability.
• Other Lymphomas: Ibrutinib is also under investigation for other types of lymphoma, including general Lymphoma (14 trials), Primary Central Nervous System Lymphoma, Diffuse Large B-cell Lymphoma, and Follicular Lymphoma. These studies often combine ibrutinib with other therapies like pembrolizumab or rituximab.
• Chronic Graft-Versus-Host Disease (cGVHD): This condition can occur after allogeneic hematopoietic cell transplantation, affecting quality of life and increasing mortality. Ibrutinib is being studied in 2 trials as an alternative to standard immunosuppression, particularly for patients who do not respond to steroids.
• Richter Transformation (RT): This is a type of blood cancer where CLL transforms into a more aggressive lymphoma. Ibrutinib is being studied in combination with other drugs like blinatumomab to help control RT.
• Pancreatic Adenocarcinoma: This aggressive cancer is being explored in 1 trial to see if ibrutinib can play a role in treatment.
• Food Allergy: Ibrutinib is also being investigated in 1 trial for its potential to inhibit food-induced anaphylaxis in adults with food allergy.

Dosing

Ibrutinib is available as an oral medication, typically taken as capsules or tablets. The standard approved dose for ibrutinib is often 420 mg or 560 mg taken once daily by mouth. Patients are generally advised to swallow the capsules or tablets whole with a glass of water, at the same time each day. Some studies have explored doses up to 840 mg and even 1680 mg daily.

In clinical trials, ibrutinib has been studied at various strengths and in different regimens, sometimes as a single agent (monotherapy) and often in combination with other drugs. For example, in some studies for CLL or SLL, ibrutinib has been combined with venetoclax, where venetoclax involves a weekly dose escalation (e.g., 20mg-50mg-100mg-200mg daily) over 5 weeks before continuing for 12 cycles. Other combinations include ibrutinib with rituximab, obinutuzumab, or chemotherapy regimens. Some trials are also investigating whether lower doses of ibrutinib (e.g., 420 mg compared to higher doses) can be equally effective, potentially reducing side effects and costs.

Each study cycle for ibrutinib and its combinations is typically 28 days. While many trials focus on adult populations, specific pediatric dosing information for ibrutinib was not detailed in the provided data.

Side Effects

In clinical trials, the most commonly reported side effect for patients taking Ibrutinib was diarrhea. Across 11 trials involving 2545 patients, 40.3% experienced diarrhea, compared to 29.0% of patients on placebo. Other common side effects included:

• Neutropenia (low white blood cell count): 38.4% of patients on Ibrutinib experienced neutropenia, which was lower than the 45.6% on placebo.
• Nausea: 36.9% of patients on Ibrutinib reported nausea, similar to the 37.2% on placebo.
• Fatigue: 28.6% of patients on Ibrutinib experienced fatigue, compared to 27.7% on placebo.
• Anemia (low red blood cell count): 27.1% of patients on Ibrutinib developed anemia, compared to 24.7% on placebo.
• Pyrexia (fever): 26.2% of patients on Ibrutinib experienced fever, compared to 23.6% on placebo.
• Thrombocytopenia (low platelet count): 24.7% of patients on Ibrutinib developed thrombocytopenia, compared to 17.6% on placebo.
• Rash: 19.5% of patients on Ibrutinib reported a rash, compared to 12.5% on placebo.

These side effects were observed across various trials and patient populations, with the percentages reflecting the overall incidence compared to a placebo group.

Clinical Trial Results

Diffuse Large B-cell Lymphoma (DLBCL)

In a safety and efficacy study (NCT01325701) involving patients with relapsed or refractory DLBCL, Ibrutinib showed an overall response. Among patients receiving 560 mg of Ibrutinib, 24.3% achieved an overall response. For those receiving 840 mg, 12.5% achieved an overall response.

Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

A Phase 3 study (NCT01578707) compared Ibrutinib to ofatumumab in patients with relapsed or refractory CLL. Patients treated with Ibrutinib had a median overall survival of 67.7 months, compared to 65.1 months for those on ofatumumab. The overall response rate (ORR) by independent review was significantly higher with Ibrutinib at 42.6%, versus 4.1% for ofatumumab. Progression-free survival (PFS) by investigator assessment was also notably longer for Ibrutinib, with a median of 44.1 months compared to 8.1 months for ofatumumab. Furthermore, Ibrutinib led to sustained hemoglobin improvement in 69.7% of patients and platelet improvement in 78.4% of patients, compared to 32.6% and 9.4% respectively with ofatumumab.

Another study (NCT01589302) evaluated single-agent Ibrutinib in patients with relapsed or refractory CLL, small lymphocytic lymphoma, or B-cell prolymphocytic leukemia. The overall response rate ranged from 59% to 66%. The 2-year progression-free survival was 64%, and the 2-year overall survival estimates ranged from 66% to 72%.

Relapsed or Refractory CLL or Small Lymphocytic Lymphoma (SLL) in Combination Therapy

A study (NCT01611090) investigated Ibrutinib in combination with bendamustine and rituximab (BR) versus placebo plus BR. The combination of Ibrutinib+BR resulted in an overall response rate of 87.2%, compared to 66.1% for placebo+BR. Progression-free survival was significantly longer with Ibrutinib+BR, reaching a median of 65.12 months compared to 14.32 months for placebo+BR. Additionally, 28.7% of patients on Ibrutinib+BR achieved a minimal residual disease (MRD)-negative response, versus 5.9% on placebo+BR.

Relapsed or Refractory Mantle Cell Lymphoma (MCL)

In a study (NCT01646021) comparing Ibrutinib to temsirolimus in patients with relapsed or refractory MCL, Ibrutinib demonstrated superior outcomes. The overall response rate for Ibrutinib was 77.0%, significantly higher than 46.8% for temsirolimus. Patients on Ibrutinib had a median progression-free survival of 15.6 months, compared to 6.2 months for temsirolimus. The median overall survival was 30.3 months for Ibrutinib versus 23.5 months for temsirolimus. The median duration of response was 23.1 months for Ibrutinib, compared to 6.3 months for temsirolimus, and the median time to next treatment was 31.8 months for Ibrutinib versus 11.6 months for temsirolimus.

Currently Recruiting Trials

Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is currently being investigated in numerous clinical trials, both alone and in combination with other therapies, for a wide range of conditions. These studies aim to further understand its efficacy and safety, and to explore new treatment approaches.

• For Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL), several studies are recruiting:
  • A Phase 2 study (NCT06958705) is evaluating venetoclax consolidation in 79 patients on BTK inhibitor monotherapy.
  • A Phase 1/Phase 2 trial (NCT07052695) tests mosunetuzumab, alone or with a BTK inhibitor like ibrutinib, in 40 participants.
  • A Phase 2 study (NCT06520098) compares BTKi monotherapy with BTKi plus venetoclax in 100 veterans.
  • Janssen is running a Phase 2 study (NCT05963074