Ibrutinib + Pembrolizumab for Leukemia and Lymphoma

Overseen By Alexis Mark

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Joshua Brody

Must not be taking: Immunosuppressants, Steroids, Monoclonal antibodies, others

Disqualifiers: Immunodeficiency, Active TB, Autoimmune, 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: 2

Duration: up to 1 year

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of two experimental drugs, ibrutinib (Imbruvica) and pembrolizumab (KEYTRUDA or MK-3475), to determine the optimal dose and assess their effectiveness against certain blood cancers like leukemia and lymphoma. Ibrutinib blocks a protein that aids cancer cell growth, while pembrolizumab enhances the immune system's ability to fight tumor cells. The trial will also monitor side effects from this combination. Individuals with relapsed or hard-to-treat chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) who have previously received treatment might be suitable candidates for this study. As a Phase 1, Phase 2 trial, the study aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you have had certain treatments like chemotherapy or radiation therapy within 2 weeks before starting the trial, or if you are on systemic steroid therapy or other immunosuppressive treatments within 7 days before the trial.

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

Previous studies have generally found ibrutinib to be well-tolerated for treating certain blood cancers, such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). It is already approved for these conditions in some countries, including the U.S. The most common side effects are mild and include diarrhea, tiredness, and nausea.

The FDA has approved pembrolizumab for treating melanoma, as it helps the immune system fight cancer cells. Although not yet approved for MCL or CLL, it has been tested in these conditions. Some people experience side effects like tiredness, skin rash, or joint pain.

The combination of ibrutinib and pembrolizumab remains experimental, with researchers testing their safety and effectiveness together. This is the first use of these two drugs in combination, so researchers are closely monitoring for any new or unexpected side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining Ibrutinib and Pembrolizumab for treating relapsed or refractory Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL) because these drugs bring innovative mechanisms to the table. Most treatments for these conditions focus on chemotherapy or targeted therapies that attack specific cancer cell proteins. However, Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor, which blocks signals crucial for cancer cell survival, while Pembrolizumab is an immune checkpoint inhibitor that empowers the immune system to recognize and destroy cancer cells. By combining these two, the treatment not only targets the cancer directly but also boosts the body's immune response, offering a potentially more effective approach than existing options.

What evidence suggests that the combination of ibrutinib and pembrolizumab could be effective for leukemia and lymphoma?

In this trial, researchers are exploring the combination of ibrutinib and pembrolizumab to improve treatment for participants with relapsed/refractory Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL). Previous studies have shown that ibrutinib is very effective in treating both MCL and CLL. For MCL, research suggests that ibrutinib may stop cancer cells from growing by blocking certain enzymes, leading to better outcomes when used early in treatment. Pembrolizumab has shown potential in helping the immune system attack cancer cells, although it is not yet approved for MCL or CLL. In CLL, ibrutinib has been found to lower the risk of death compared to standard treatments, with strong long-term results. ^{6 7 8 9 10}

Who Is on the Research Team?

Joshua Brody

Principal Investigator

Icahn School of Medicine at Mount Sinai

Are You a Good Fit for This Trial?

Adults over 18 with chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) who can provide consent and have measurable disease. They must be in good health otherwise, not pregnant, agree to use contraception, and haven't used certain other treatments recently like immunosuppressives or live vaccines.

Inclusion Criteria

I am a man who can father a child and will use birth control during and for 4 months after the study.

Be willing and able to provide written informed consent/assent for the trial

I agree to provide a recent biopsy sample of my tumor.

Exclusion Criteria

I haven't had cancer treatment with antibodies in the last 4 weeks or still have side effects.

Has a condition, therapy, or abnormality that might confound trial results or interfere with participation

Has psychiatric or substance abuse disorders that would interfere with trial requirements

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead-in Treatment

Participants receive a 28-day lead-in of ibrutinib

4 weeks

1 visit (in-person)

Treatment

Participants receive a 21-day cycle of pembrolizumab and daily ibrutinib

up to 1 year

1 visit every 21 days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Ibrutinib
• Pembrolizumab

Trial Overview The trial is testing a combination of two drugs: Ibrutinib, which blocks an enzyme that helps blood cancer cells grow; and Pembrolizumab, an antibody designed to help the immune system fight tumor cells. This study aims to find the right dose and see if this experimental combo works for CLL/MCL.

How Is the Trial Designed?

Group I: Participants with MCL Experimental Treatment 2 Interventions

Participants with relapsed/ refractory Mantle Cell Lymphoma (MCL)

Group II: Participants with CLL Experimental Treatment 2 Interventions

Participants with relapsed/ refractory Chronic Lymphocytic Leukemia (CLL) or 17p- CLL

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?

Joshua Brody

Lead Sponsor

Trials

2

Recruited

40+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

The combination of ibrutinib and nivolumab demonstrated an acceptable safety profile in 141 patients with relapsed or refractory B-cell malignancies, with only one dose-limiting toxicity reported, indicating that this treatment approach is generally safe for patients.

Preliminary results showed promising efficacy, with overall response rates of 61% in high-risk chronic lymphocytic leukaemia, 33% in follicular lymphoma, and 36% in diffuse large B-cell lymphoma, suggesting that this combination therapy could be effective for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study. Younes, A., Brody, J., Carpio, C., 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]

Ibrutinib, a Bruton's kinase inhibitor, has shown a high overall response rate of 68% in patients with relapsed or refractory mantle cell lymphoma, with a median progression-free survival of 13.9 months, indicating its efficacy as a treatment option.

In a phase 3 trial for chronic lymphocytic leukemia, ibrutinib demonstrated a significantly higher response rate (43% vs. 4% for ofatumumab) and improved overall survival (90% vs. 81% at 12 months), while being well tolerated with no dose-limiting toxicity, making it a suitable option for older patients and those not eligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of a novel, Bruton's tyrosine kinase inhibitor, ibrutinib. Lee, CS., Rattu, MA., Kim, SS.[2021]

Ibrutinib is an effective oral therapy for chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma, mantle cell lymphoma, and Waldenstrom's macroglobulinaemia, providing a significant alternative to traditional chemotherapy.

The You&i™ support program enhances patient experience by connecting them with nurses for guidance on treatment and side effects, demonstrating positive feedback from both patients and health professionals in a tested NHS hospital setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imbruvica®▾(ibrutinib) patient support programme for chronic lymphocytic leukaemia and mantle cell lymphoma. Murthy, V., Weaving, S., Paneesha, S.[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 is the first FDA-approved drug that inhibits Burton's tyrosine kinase (BTK), effectively reducing B-cell proliferation and promoting apoptosis, making it a significant treatment for relapsed chronic lymphocytic leukemia and Waldenström's macroglobulinemia.

Despite its efficacy, ibrutinib can lead to serious side effects, including rare but severe hemorrhagic events, as demonstrated by a case of back pain caused by iliopsoas muscle hemorrhage in a patient after starting the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spontaneous Iliopsoas Muscle Hemorrhage Secondary to Ibrutinib (Imbruvica; Pharmacyclics): Brief Report. Sarcon, A., Botta, GP., Patel, N., et al.[2018]

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 is a first-in-class oral Bruton's tyrosine kinase inhibitor that effectively blocks B-cell signaling, leading to reduced proliferation and increased cell death in B cell malignancies, including chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL).

It has received FDA approval for treating MCL in previously treated patients based on phase Ib/II study results and is currently undergoing further phase III trials for CLL, diffuse large B cell lymphoma (DLBCL), and other B cell cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib: first global approval. Cameron, F., Sanford, M.[2022]

Ibrutinib (Imbruvica) is an effective treatment for chronic lymphocytic leukemia, targeting specific pathways to inhibit cancer cell growth.

Tasimelteon (Hetlioz) is beneficial for individuals with non-24-hour sleep-wake disorder, helping to regulate sleep patterns, while anti-inhibitor coagulant complex (Feiba) is used to prevent or reduce bleeding episodes in patients with hemophilia A or B, demonstrating its efficacy in managing bleeding risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmaceutical approval update. Goldenberg, MM.[2021]

Citations

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Efficacy of pembrolizumab monotherapy and in ... Here we report updated results of this trial ... ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.

2. 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 ...

3. imbruvica.com imbruvica.com/cll/imbruvica-for-cll-sll

IMBRUVICA® (ibrutinib) for CLL/SLL IMBRUVICA® Has Helped Many Adults With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Live Longer1,2. 56%. lower risk of death*.

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. actr.amegroups.org actr.amegroups.org/article/view/11456/html

Ibrutinib's role in early-stage chronic lymphocytic leukemia While it theoretically has fewer side effects than ibrutinib, its efficacy over “watch-and-wait” in early-stage CLL remains unproven, with definitive results ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02332980

Study Details | NCT02332980 | Pembrolizumab Alone or ... This phase II trial studies how well pembrolizumab alone or with idelalisib or ibrutinib works in treating patients with chronic lymphocytic leukemia or ...

7. mountsinai.org mountsinai.org/clinical-trials/study-to-evaluate-safety-preliminary-efficacy-of-ibrutinib-pembrolizumab-in-patients-with-chronic-lymphocytic-leukemia-cll-mantle-cell-lymphoma-mcl

Study to Evaluate the Safety and Preliminary Efficacy of ... Pembrolizumab is not FDA approved to treat patients with chronic lymphocytic leukemia [CLL] and mantle cell lymphoma [MCL]. Eligibility: Inclusion Criteria ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03425591

NCT03425591 | A Study of Ibrutinib in the Treatment ... Study population include chronic lymphocytic leukemia (CLL) or mantle-cell lymphoma (MCL) participants who were or will be treated by ibrutinib per routine ...

9. patlynk.com patlynk.com/trial/NCT03153202

Study to Evaluate the Safety and Preliminary Efficacy of ... Pembrolizumab is not FDA approved to treat patients with chronic lymphocytic leukemia \[CLL\] and mantle cell lymphoma \[MCL\]. (1) Objective: a. (Phase 1) ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4484687/

A critical appraisal of ibrutinib in the treatment of mantle cell ... This article appraises the currently available data on safety and efficacy from clinical trials of ibrutinib in the management of MCL and CLL, ...