Triple Therapy for Chronic Lymphocytic Leukemia

Overseen By Nitin Jain, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must be taking: Ibrutinib

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: Autoimmune diseases, Cardiovascular disease, 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: 8

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of a drug combination for individuals with chronic lymphocytic leukemia (CLL) or Richter transformation (RT). It tests various combinations of ipilimumab (Yervoy), nivolumab (Opdivo), and ibrutinib (Imbruvica) to determine the optimal dose and monitor side effects. The goal is to assess whether these drugs can help the immune system attack cancer and prevent cancer cells from growing and spreading. This trial may suit individuals who have tried at least one therapy for CLL or RT and require further treatment or have specific high-risk features. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive potentially groundbreaking therapy.

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

If you are currently taking ibrutinib, you can continue it without interruption. For other oral targeted therapies, a short break of 3 days is required before starting the trial. The protocol does not specify about other medications, so it's best to discuss with the trial team.

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

Research has shown that using nivolumab and ibrutinib together is safe for patients with chronic lymphocytic leukemia (CLL) and Richter transformation (RT). In previous studies, 61% of patients responded well to this combination without major safety issues.

Ibrutinib alone has undergone extensive study and is generally safe, with patients tolerating it well over long periods. The combination with ipilimumab is still under investigation for safety, but early results appear promising.

Ipilimumab and nivolumab have been used together in other cancers and are usually well-tolerated, though some individuals may experience side effects like tiredness or a skin rash.

This trial is in its early stages, focusing on safety and determining the best dose. The treatments have been studied separately and in some combinations before, providing some confidence in their safety. However, the full safety profile of this specific combination is still being explored. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the triple therapy of Ibrutinib, Ipilimumab, and Nivolumab for chronic lymphocytic leukemia (CLL) because it combines different mechanisms of action to enhance treatment efficacy. Unlike traditional therapies that primarily target cancer cells directly, this combination includes Ibrutinib, which inhibits a protein called Bruton's tyrosine kinase, disrupting cancer cell survival signals. Ipilimumab and Nivolumab are immune checkpoint inhibitors that unleash the body's immune system to recognize and attack cancer cells more effectively. This multi-faceted approach could offer improved outcomes for CLL patients by targeting both the cancer cells and bolstering the immune response against them.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia and Richter transformation?

Studies have shown that combining nivolumab and ibrutinib holds promise for treating chronic lymphocytic leukemia (CLL) and Richter transformation (RT). One study found that 61% of patients with high-risk CLL responded well to this combination. In this trial, participants in Part B will receive a combination of nivolumab, ipilimumab, and ibrutinib. Nivolumab and ipilimumab help the immune system attack cancer cells, while ibrutinib blocks certain enzymes that cancer cells need to grow. Research suggests that this combination may help manage CLL and RT, offering hope for better outcomes. ^{2 4 6 7 8}

Who Is on the Research Team?

Nitin Jain, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with chronic lymphocytic leukemia (CLL) or Richter transformation (RT), who have had prior treatments for CLL or are untreated with high-risk features, can join. They must be in good general health based on specific blood tests and agree to use effective contraception. Excluded are those with severe lung disease, certain heart conditions, uncontrolled hypertension, active infections, hepatitis B/C or HIV, recent major surgery or other cancer treatments.

Inclusion Criteria

Patients or their legally authorized representative must provide written informed consent

I have CLL or SLL that didn't respond to or came back after treatment, or I haven't been treated but have high-risk genetics.

Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (beta-human chorionic gonadotropin [hCG]) pregnancy test result within 14 days prior to the first dose of treatment and must agree to use an effective contraception method during the study and for 23 weeks following the last dose of the study drugs. Females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy. Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 31 weeks following the last dose of study drugs

Exclusion Criteria

Patients who have uncontrolled hypertension (defined as sustained systolic blood pressure >= 140 mmHg or diastolic >= 90 mmHg)

Patient is pregnant or breast-feeding

You are currently using an experimental drug for treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part A

Patients receive ipilimumab IV over 90 minutes on day 1 and ibrutinib PO QD. Treatment repeats every 3 weeks for up to 4 cycles.

12 weeks

4 visits (in-person)

Treatment Part B

Patients receive ipilimumab IV over 90 minutes, nivolumab IV over 30 minutes on day 1, and ibrutinib PO QD starting day 7. Treatment repeats every 3 weeks for up to 4 cycles.

12 weeks

4 visits (in-person)

Extension

Patients who benefit from treatment may continue ipilimumab every 12 weeks and nivolumab every 4 weeks for up to 2 years.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

30 days, then every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Ibrutinib
• Ipilimumab
• Nivolumab

Trial Overview The trial is testing the combination of ipilimumab (an immune system booster) with ibrutinib alone or together with nivolumab for treating CLL and RT. It aims to find the safest dose that works best by seeing how these drugs affect cancer growth.

How Is the Trial Designed?

Group I: Part B (ipilimumab, nivolumab, ibrutinib) Experimental Treatment 3 Interventions

Patients receive ipilimumab IV over 90 minutes and nivolumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning day 7 of cycle 1, patients also receive ibrutinib PO QD in the absence of disease progression or unacceptable toxicity. Patients who complete 4 doses of ipilimumab and nivolumab, and are deriving benefit from it, without severe toxicities, may continue to receive ipilimumab every 12 weeks and nivolumab every 4 weeks for up to a total of 2 years.

Group II: Part A (ipilimumab, ibrutinib) Experimental Treatment 2 Interventions

Patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning day 1 of cycle 1, patients also receive ibrutinib PO QD in the absence of disease progression or unacceptable toxicity. Patients who complete 4 doses of ipilimumab and are deriving benefit from it, without severe toxicities, may continue to receive ipilimumab every 12 weeks for up to a total of 2 years.

Ibrutinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in United States as Imbruvica for:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in Canada as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma

Approved in Japan as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Citations

1. 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 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04781855

Ipilimumab, Ibrutinib, and Nivolumab for the Treatment of ... This phase I/Ib trial evaluates the best dose and side effects of ipilimumab in combination with either ibrutinib alone or with ibrutinib and nivolumab

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40353821/

Real-world survival outcomes in first-line ibrutinib-treated ... Of 1242 patients included, 969 and 273 had high- and non-high-risk CLL/SLL, with a mean age of 70.0 and 70.8 years, and a median follow-up of 32 ...

4. news.abbvie.com news.abbvie.com/2020-12-06-Combined-Data-from-Multiple-Phase-3-Studies-of-IMBRUVICA-R-ibrutinib-Show-Efficacy-and-Safety-in-High-Risk-Previously-Untreated-Chronic-Lymphocytic-Leukemia-CLL-and-Real-World-Data-Indicating-Low-Biomarker-Testing-Rates-for-These-Patients

Combined Data from Multiple Phase 3 Studies of ... First-line treatment with IMBRUVICA-based therapies resulted in sustained, long-term efficacy with high 4-year PFS rates in high-risk CLL patients.

5. journals.sagepub.com journals.sagepub.com/doi/10.1177/17588359241285988

Comparative safety of novel targeted therapies in relapsed ... Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood 2019; 133: 1011–1019 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8656120/

Efficacy and Safety of Ibrutinib Therapy in Patients with ... This study aimed to retrospectively evaluate the efficacy, safety, and survival outcome of single-agent ibrutinib therapy in chronic lymphocytic leukemia

7. imbruvicahcp.com imbruvicahcp.com/cll/safety/pooled-long-term-safety

Pooled Long-Term Safety | IMBRUVICA® (ibrutinib) HCP Find the long-term safety and tolerability profile from IMBRUVICA® (ibrutinib) CLL/SLL studies. See Full Prescribing & Safety Information.

8. researchgate.net researchgate.net/publication/330342076_Safety_and_activity_of_ibrutinib_in_combination_with_nivolumab_in_patients_with_relapsed_non-Hodgkin_lymphoma_or_chronic_lymphocytic_leukaemia_a_phase_12a_study

Safety and activity of ibrutinib in combination with ... The combination of ibrutinib and nivolumab led to overall responses in 22 (61%) of 36 patients with high-risk chronic lymphocytic leukaemia or ...