Triple Therapy for CLL/SLL

Not currently recruiting at 3 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, Warfarin

Disqualifiers: Autoimmune disorders, 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: 7

Duration: Up to 12 cycles (28 days each)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and understand the side effects of combining three treatments—lenalidomide, ibrutinib (also known as Imbruvica, a type of targeted therapy), and rituximab—for individuals with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that is resistant or has recurred. These treatments harness the body's immune system to combat cancer cells or inhibit their growth. The study targets those whose CLL/SLL has spread, cannot be surgically removed, or hasn't responded to other treatments. It suits individuals who haven't had recent cancer treatments and are not allergic to the study drugs. Participants should have measurable disease, meaning tumors or affected areas visible through tests or exams. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires that you do not take any other approved anti-cancer therapies or investigational agents while participating. Additionally, you must not have taken chemotherapy within 21 days or monoclonal antibodies within 6 weeks before starting the trial. If you are on corticosteroids, you must reduce the dose to less than 20 mg per day of prednisone or equivalent at least 7 days before starting the trial.

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

Research has shown that the combination of ibrutinib, lenalidomide, and rituximab has been tested in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). These studies found this combination to be generally safe, meaning that while side effects may occur, they are usually not severe and can be managed by doctors.

One study examined ibrutinib alone and found it beneficial and well-tolerated by patients. This suggests that ibrutinib, when combined with lenalidomide and rituximab, might also be safe for patients.

As this trial is in an early stage, its primary goal is to determine the best dose and monitor for side effects. While there could be unknown risks, previous studies provide a solid foundation for understanding its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ibrutinib, lenalidomide, and rituximab for treating chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) because it targets the cancer in multiple ways. Ibrutinib blocks a protein that helps cancer cells survive and grow, lenalidomide boosts the immune system to attack cancer, and rituximab specifically targets and destroys cancerous B-cells. Unlike standard treatments, which often focus on just one mechanism, this triple therapy aims to enhance effectiveness by attacking the cancer from different angles simultaneously. This comprehensive approach could potentially improve outcomes and reduce the likelihood of disease progression.

What evidence suggests that this triple therapy could be effective for CLL/SLL?

In this trial, participants will receive a combination of ibrutinib, lenalidomide, and rituximab, known as the iR2 regimen. Research has shown that ibrutinib, compared to rituximab, helps patients with relapsed or hard-to-treat chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) live longer without disease progression. It also improves treatment response and overall survival. However, studies have found that adding lenalidomide to ibrutinib and rituximab does not increase effectiveness compared to ibrutinib alone or with rituximab. Despite this, the triple combination may boost the immune system in these patients, showing promise by possibly enhancing immune responses. ^{3 4 5 6 7}

Who Is on the Research Team?

Kieron Dunleavy

Principal Investigator

MedStar Georgetown University Hospital

Are You a Good Fit for This Trial?

This trial is for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma that's returned, spread, or can't be surgically removed. Eligible participants must not have severe allergies to the drugs being tested, no recent heart issues or strokes, and should not be pregnant. They need functioning major organs and cannot have used certain treatments recently.

Inclusion Criteria

My cancer is advanced, cannot be surgically removed, and standard treatments are not effective.

I have been treated for CLL or SLL and need further treatment.

I have not had major surgery in the last 28 days.

Exclusion Criteria

I do not have moderate or severe liver problems.

Serologic status reflecting active hepatitis B or C infection

I haven't had chemotherapy in the last 3 weeks or monoclonal antibody treatment in the last 6 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive rituximab IV on day 1 (up to 6 cycles), lenalidomide PO QD on days 1-21 (up to 12 cycles), and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 12 cycles (28 days each)

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

10 years

Every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Ibrutinib
• Lenalidomide
• Rituximab

Trial Overview The trial tests a combination of lenalidomide with ibrutinib and rituximab to see how well they work together against cancer cells. It's in phase I to determine side effects and the best dose. The study includes collecting biospecimens, bone marrow biopsies, imaging tests like CT scans and MRIs.

How Is the Trial Designed?

Group I: Treatment (lenalidomide, ibrutinib, rituximab) Experimental Treatment 8 Interventions

Patients receive rituximab IV on day 1 (up to 6 cycles), lenalidomide PO QD on days 1-21 (up to 12 cycles), and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECG on screening and CT scan or MRI, bone marrow biopsy and blood sample collection throughout the study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Chronic lymphocytic leukemia (CLL) is a complex B-cell cancer that often relapses after traditional treatments, highlighting the need for new therapeutic options.

Recent advancements in CLL treatment include a variety of novel drugs such as ibrutinib and idelalisib, which are showing promise in improving patient outcomes compared to conventional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel agents for chronic lymphocytic leukemia. Wu, M., Akinleye, A., Zhu, X.[2021]

Ibrutinib and idelalisib, two B-cell receptor signaling inhibitors, have shown significant clinical activity in treating chronic lymphocytic leukemia (CLL), particularly in relapsed or refractory cases, and have been FDA-approved for this use.

Both drugs are generally well tolerated, even by older patients, with mild and self-resolving side effects; however, clinicians should be aware of specific adverse events that could limit their use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia. Falchi, L., Baron, JM., Orlikowski, CA., et al.[2020]

In the phase 3 HELIOS trial involving 578 patients with previously treated chronic lymphocytic leukemia (CLL), the combination of ibrutinib and bendamustine-rituximab (BR) significantly improved progression-free survival (PFS) compared to placebo+BR, with a median PFS not reached for ibrutinib+BR versus 14.3 months for placebo+BR.

The treatment with ibrutinib+BR also resulted in a higher rate of minimal residual disease (MRD)-negative responses (26.3% vs. 6.2% for placebo+BR), indicating a deeper response to therapy, while the safety profile remained consistent with earlier reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Fraser, G., Cramer, P., Demirkan, F., et al.[2023]

Zanubrutinib (zanu) has been shown to significantly improve progression-free survival compared to bendamustine-rituximab in treatment-naive patients with chronic lymphocytic leukemia (CLL), indicating its efficacy as a first-line treatment option.

In a direct comparison with ibrutinib, zanu demonstrated a better safety profile and enhanced clinical efficacy, leading to its approval by the FDA and EMA as a preferred treatment for CLL/SLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option. Molica, S., Tam, C., Allsup, D., et al.[2023]

Acalabrutinib, a selective BTK inhibitor, has been FDA approved for treating chronic lymphocytic leukemia (CLL) and shows improved efficacy and safety compared to standard treatments, including ibrutinib.

In multinational phase 1/2 and phase 3 studies, acalabrutinib demonstrated significant effectiveness in treatment-naïve and relapsed refractory CLL patients, with fewer treatment-limiting toxicities such as atrial fibrillation and bleeding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib and Its Therapeutic Potential in the Treatment of Chronic Lymphocytic Leukemia: A Short Review on Emerging Data. Isaac, K., Mato, AR.[2020]

Acalabrutinib, a Bruton's tyrosine kinase inhibitor, has been shown to be effective and safe for treating chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with significant improvements in efficacy observed in both monotherapy and combination treatments.

In clinical studies, acalabrutinib demonstrated a high rate of molecular remission when combined with venetoclax, while maintaining an acceptable safety profile, although some adverse events occurred in over 20% of patients, including myelosuppression and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib and its use in the treatment of chronic lymphocytic leukemia. Egyed, M., Lueff, S., Borbely, J., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5911578/

Ibrutinib versus rituximab in relapsed or refractory chronic ... Ibrutinib improved PFS, ORR, and OS compared with rituximab and displayed a manageable safety profile in Asian patients with relapsed/refractory CLL/SLL.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5894261/

A phase 1 study of lenalidomide and ibrutinib in combination ... R, L, and I in relapsed/ refractory CLL do not appear to be more effective than the R + L doublet or I alone.

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2310063

Chronic Lymphocytic Leukemia Therapy Guided by ... The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2473952920310442

A phase 1 study of lenalidomide and ibrutinib in ... These are the first results of the combination of rituximab, lenalidomide, and ibrutinib in any line of treatment of CLL. The concept for the ...

5. thelancet.com thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00508-9/fulltext

The iR2 regimen (ibrutinib plus lenalidomide and rituximab ... Ibrutinib restores immune cell numbers and function in first-line and relapsed/refractory chronic lymphocytic leukemia

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02077166

Study Details | NCT02077166 | Ibrutinib in Combination ... This Phase 1b/2 study is designed to assess the safety and efficacy of ibrutinib in combination with lenalidomide and rituximab in subjects with relapsed/ ...

7. clinicaltrial.be clinicaltrial.be/en/details/76919?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

Lenalidomide, Ibrutinib, and Rituximab in Treating Patien... To determine the safety and tolerability of the combination of lenalidomide, ibrutinib and rituximab in previously treated chronic lymphocytic ...