Combination Therapy for Chronic Lymphocytic Leukemia

Recruiting at 989 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Congestive heart failure, Hepatitis C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 3

Duration: 19 cycles (approximately 19 months)

720 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase III trial studies how well ibrutinib and obinutuzumab with or without venetoclax work in treating patients with chronic lymphocytic leukemia. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Obinutuzumab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving ibrutinib, obinutuzumab, and venetoclax may work better than giving ibrutinib and obinutuzumab in treating patients with chronic lymphocytic leukemia.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on strong CYP3A inhibitors or inducers, or warfarin within 30 days before starting the study. You also cannot be on any other investigational agents.

What data supports the effectiveness of the drug combination therapy for chronic lymphocytic leukemia?

Research shows that the combination of venetoclax with obinutuzumab and ibrutinib with venetoclax is effective in treating chronic lymphocytic leukemia, with significant improvements in progression-free survival and response rates compared to other treatments. These combinations have shown promising results in both previously untreated and relapsed/refractory cases. ^{1 2 3 4 5}

What makes the combination therapy of Ibrutinib, Obinutuzumab, and Venetoclax unique for treating chronic lymphocytic leukemia?

This combination therapy is unique because it combines three drugs that target different aspects of cancer cell survival, potentially offering a more effective treatment option for chronic lymphocytic leukemia (CLL). Ibrutinib and Venetoclax have shown promising results in improving outcomes compared to traditional chemoimmunotherapy, and the addition of Obinutuzumab may enhance these effects, providing a chemotherapy-free option for patients. ^{1 3 4 5 6}

Research Team

Tait D Shanafelt

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

Adults aged 18-70 with chronic lymphocytic leukemia who haven't had prior CLL treatments, have progressive symptoms or blood abnormalities, and meet specific health criteria. They must not be pregnant/breastfeeding, have certain heart conditions or infections, take strong CYP3A inhibitors/inducers, or have other active cancers.

Inclusion Criteria

Total bilirubin =< 1.5 x ULN

SGOT/SGPT =< 3.0 x ULN

I am not currently using corticosteroids, or only using low doses for non-blood related conditions.

Exclusion Criteria

I have severe heart failure.

Positive serology for hepatitis B

On other investigational agents

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive ibrutinib, obinutuzumab, and venetoclax in Arm A or ibrutinib and obinutuzumab in Arm B. Treatment repeats every 28 days for up to 19 cycles.

19 cycles (approximately 19 months)

Multiple visits for drug administration and monitoring

Follow-up

Participants are monitored for response and disease progression. Follow-up includes regular visits every 3 months for the first 2 years, every 6 months for years 3-5, and annually for years 6-10.

Up to 10 years

Regular visits every 3 to 12 months

Treatment Details

Interventions

• Ibrutinib
• Obinutuzumab
• Venetoclax

Trial Overview The trial is testing if adding Venetoclax to Ibrutinib and Obinutuzumab treatment provides better outcomes for chronic lymphocytic leukemia patients than just Ibrutinib and Obinutuzumab. It includes biospecimen collection, CT scans, bone marrow biopsies, and quality-of-life assessments.

Participant Groups

Group I: Arm A (ibrutinib, obinutuzumab, venetoclax) Experimental Treatment 7 Interventions

Patients receive ibrutinib PO daily on days 1-28 and obinutuzumab IV over 4 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-6. Patients also receive venetoclax PO QD on days 1-28 of cycles 3-14. Treatment repeats every 28 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo biopsy and CT scans before and after treatment and collection of blood throughout the study.

Group II: Arm B (ibrutinib, obinutuzumab) Active Control 6 Interventions

Patients receive ibrutinib PO and obinutuzumab as in arm A. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo biopsy and CT scans before and after treatment and collection of blood 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+

Findings from Research

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

In a phase 3 trial with 523 patients, the combination of ibrutinib and venetoclax significantly improved progression-free survival compared to the traditional FCR treatment, with only 12 patients experiencing disease progression or death in the ibrutinib-venetoclax group versus 75 in the FCR group.

The study also found that 65.9% of patients on ibrutinib-venetoclax achieved undetectable measurable residual disease (MRD) in bone marrow after 5 years, indicating effective disease control, although there was a higher incidence of serious cardiac adverse events in this group compared to FCR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. Munir, T., Cairns, DA., Bloor, A., et al.[2023]

In a retrospective study of 22 patients with chronic lymphocytic leukaemia (CLL) who progressed on ibrutinib, the combination of ibrutinib and venetoclax resulted in a median overall survival of 47.1 months, indicating potential efficacy in this challenging patient group.

For 11 patients with double-refractory CLL, the same combination therapy led to a median overall survival of 27.0 months, suggesting that this treatment may provide a valuable option for patients who have limited alternatives after failing standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined ibrutinib and venetoclax for treatment of patients with ibrutinib-resistant or double-refractory chronic lymphocytic leukaemia. Hampel, PJ., Rabe, KG., Call, TG., et al.[2022]

The combination of venetoclax with rituximab showed remarkable efficacy and a manageable safety profile in treating chronic lymphocytic leukemia (CLL), both in relapsed/refractory cases and as a first-line therapy for high-risk patients.

Similarly, the combination of ibrutinib with venetoclax also demonstrated striking efficacy, suggesting that these combinations could become new standard treatment options for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. Wanner, D., Steurer, M.[2020]

In a phase 2 study involving 80 previously untreated high-risk and older patients with chronic lymphocytic leukemia (CLL), the combination of ibrutinib and venetoclax resulted in a high response rate, with 88% achieving complete remission after 12 cycles of treatment.

The treatment was well-tolerated, with an adverse-event profile similar to that of the individual drugs, although three patients experienced tumor lysis syndrome, indicating the need for monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib and Venetoclax for First-Line Treatment of CLL. Jain, N., Keating, M., Thompson, P., et al.[2023]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Combined ibrutinib and venetoclax for treatment of patients with ibrutinib-resistant or double-refractory chronic lymphocytic leukaemia. [2022]

5. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Ibrutinib and Venetoclax for First-Line Treatment of CLL. [2023]