Combination Therapy for Chronic Lymphocytic Leukemia

Not currently recruiting at 1014 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)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of a drug combination—ibrutinib and obinutuzumab—against chronic lymphocytic leukemia (CLL), a type of blood cancer, with or without venetoclax. Ibrutinib stops cancer cell growth, obinutuzumab aids the immune system in attacking cancer cells, and venetoclax blocks a protein essential for cancer cell survival. The trial aims to determine if adding venetoclax enhances treatment effectiveness. Suitable participants have been diagnosed with CLL and experience significant symptoms like frequent fevers, night sweats, or worsening blood counts. As a Phase 3 trial, this study represents the final step before FDA approval, providing an opportunity to access potentially effective treatment early.

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.

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

Research has shown that the combination of ibrutinib, obinutuzumab, and venetoclax is generally safe and well-tolerated for people with chronic lymphocytic leukemia. In earlier studies, patients took these drugs together and managed the treatment without major issues. While some side effects occurred, they were usually manageable and did not hinder the treatment's effectiveness.

Patients taking these medications experienced strong and lasting improvements, indicating the treatment's effectiveness. This combination has shown promise in controlling the disease, supporting its use in further research.

As with any treatment, side effects can occur. However, extensive studies have clarified the safety of these drugs. Anyone considering joining a trial should discuss potential risks and benefits with their doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a fresh approach to tackling chronic lymphocytic leukemia (CLL). Most treatments for CLL, like chemotherapy and monoclonal antibodies, work by targeting cancer cells directly or boosting the immune system to attack them. However, the combination of ibrutinib, obinutuzumab, and venetoclax used in one of the treatment arms brings together three different mechanisms of action. Ibrutinib disrupts signals that cancer cells need to survive, obinutuzumab targets and tags cancer cells for destruction by the immune system, and venetoclax induces cancer cell death by inhibiting a protein that helps them survive. This triple threat aims to more effectively control the disease by attacking it from multiple angles. Meanwhile, the dual therapy with ibrutinib and obinutuzumab provides a potentially less intensive option, still combining targeted signaling disruption with immune system activation.

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

In this trial, participants in Arm A will receive a combination of ibrutinib, venetoclax, and obinutuzumab. Research has shown that using ibrutinib and venetoclax together can reduce the risk of CLL progression or death by 72.7% compared to a control group. Adding obinutuzumab to this regimen as an initial treatment for CLL appears promising, as it may help slow the disease.

Participants in Arm B will receive ibrutinib and obinutuzumab. Studies indicate that using ibrutinib with obinutuzumab as a first treatment offers a chemotherapy-free option with significant survival benefits for those who haven't been treated for CLL before. This combination is known for reducing reactions during infusions and improving patient outcomes. Overall, these treatments show strong potential in managing CLL. ^{6 7 8 9 10}

Who Is on the Research Team?

Tait D Shanafelt

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

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 do not have any other active cancer besides the one being treated.

Exclusion Criteria

I have severe heart failure.

Positive serology for hepatitis B

On other investigational agents

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02537613

A Study of Ibrutinib + Obinutuzumab in Patients With ... This research study is evaluating a combination of two drugs, ibrutinib and obinutuzumab, as a possible treatment for Chronic Lymphocytic Leukemia (CLL).

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8800600/

Ibrutinib plus Obinutuzumab as Frontline Therapy for ... Ibrutinib plus obinutuzumab as frontline therapy for chronic lymphocytic leukemia is associated with a lower rate of infusion-related reactions and with ...

3. ahdbonline.com ahdbonline.com/issues/2019/2019-payers-guide-mid-year-addendum/imbruvica-ibrutinib-plus-gazyva-obinutuzumab-first-chemotherapy-free-combination-approved-as-first-line-treatment-for-patients-with-cll-or-sll

Imbruvica (Ibrutinib) plus Gazyva (Obinutuzumab) First ... AbbVie announces U.S. FDA approval of Imbruvica (ibrutinib) plus obinutuzumab (Gazyva)-first chemotherapy-free, anti-CD20 combination regimen approved for ...

4. onclive.com onclive.com/view/ibrutinib-plus-obinutuzumab-elicits-intriguing-survival-benefits-in-relapsed-refractory-cll

Ibrutinib Plus Obinutuzumab Elicits Intriguing Survival ... The combination of ibrutinib (Imbruvica) and obinutuzumab (Gazyva) could represent a promising treatment option for patients with relapsed/refractory chronic ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5504213/

Comparative Efficacy of Ibrutinib Versus Obinutuzumab + ... US FDA expands IMBRUVICA® (ibrutinib) label to include overall survival data in previously untreated chronic lymphocytic l eukemia (CLL).

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02427451

Study Details | NCT02427451 | Bcl-2 Inhibitor GDC-0199 in ... This phase Ib/II trial studies the best dose and safety of Bcl-2 inhibitor GDC-0199 in combination with obinutuzumab and ibrutinib and to see how well they ...

7. ashpublications.org ashpublications.org/bloodneoplasia/article/1/3/100034/517258/Ibrutinib-and-venetoclax-in-combination-for

Ibrutinib and venetoclax in combination for chronic ... The combination of ibrutinib and venetoclax has emerged as a promising therapeutic strategy for patients with chronic lymphocytic leukemia (CLL).

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6182267/

Phase 1b study of obinutuzumab, ibrutinib, and venetoclax ... We found this regimen to be safe and tolerable in CLL, and capable of inducing deep responses, justifying future study in our ongoing phase 2 cohorts.

9. sciencedirect.com sciencedirect.com/science/article/pii/S2950328024000347

Ibrutinib and venetoclax in combination for chronic ... The combination of ibrutinib and venetoclax has emerged as a promising therapeutic strategy for patients with chronic lymphocytic leukemia (CLL).

10. evidence.nejm.org evidence.nejm.org/doi/full/10.1056/EVIDoa2200006

Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic ... Ibrutinib-venetoclax, an all-oral, once-daily, fixed-duration combination, demonstrated superior PFS and deeper and better sustained responses.