Venetoclax + Ibrutinib + Obinutuzumab for Chronic Lymphocytic Leukemia

Recruiting at 962 trial locations

Overseen By Shannon B. Keating

Age: 65+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must be taking: Ibrutinib, Obinutuzumab

Must not be taking: Anticoagulants, Strong CYP3A inhibitors

Disqualifiers: Heart failure, Recent stroke, 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: Unknown

Duration: 56 weeks

454 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase III trial compares adding a new anti-cancer drug (venetoclax) to the usual treatment (ibrutinib plus obinutuzumab) in older patients with chronic lymphocytic leukemia who have not received previous treatment. The addition of venetoclax to the usual treatment might prevent chronic lymphocytic leukemia from returning. This trial also will investigate whether patients who receive ibrutinib plus obinutuzumab plus venetoclax and have no detectable chronic lymphocytic leukemia after 1 year of treatment, can stop taking ibrutinib. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with obinutuzumab may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. 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 and obinutuzumab with venetoclax may work better at treating chronic lymphocytic leukemia compared to ibrutinib and obinutuzumab.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before joining. If you are on warfarin, you must stop it at least 10 days before starting the study. If you are taking strong CYP3A inhibitors or inducers, you need to stop them 14 days before joining.

What data supports the effectiveness of the drug combination Venetoclax, Ibrutinib, and Obinutuzumab for treating Chronic Lymphocytic Leukemia?

Research shows that the combination of Venetoclax and Ibrutinib improves outcomes in patients with chronic lymphocytic leukemia compared to traditional chemoimmunotherapy. Additionally, Venetoclax combined with Obinutuzumab has been shown to result in longer progression-free survival and higher response rates in untreated patients. ^{1 2 3 4 5}

Is the combination of Venetoclax, Ibrutinib, and Obinutuzumab safe for treating chronic lymphocytic leukemia?

The combination of Venetoclax, Ibrutinib, and Obinutuzumab has been shown to be generally safe in humans, with manageable side effects. Notable side effects include neutropenia (low white blood cell count), which can be managed with supportive care and dose adjustments. Overall, these treatments have been well-tolerated in clinical trials for chronic lymphocytic leukemia and other conditions. ^{2 3 5 6 7}

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

This drug combination is unique because it combines three powerful agents that target different aspects of chronic lymphocytic leukemia (CLL) and has shown superior progression-free survival compared to some traditional treatments. It is particularly beneficial for patients who have not responded to other treatments, offering a new option for those with resistant forms of CLL. ^{1 2 3 4 7}

Research Team

Jennifer A Woyach

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

This trial is for older patients (65+) with untreated chronic lymphocytic leukemia who meet specific health criteria, such as certain blood cell counts and organ function. They must not have had previous CLL treatments except for steroids or rituximab for autoimmune complications, and they should be able to swallow pills without significant gastrointestinal issues.

Inclusion Criteria

I am 65 years old or older.

I had hepatitis C but have been treated and now have no detectable virus.

My condition is intermediate risk with enlarged lymph nodes or liver/spleen but no anemia or low platelets.

Exclusion Criteria

I am not taking, or have stopped taking, strong CYP3A4/5 inducers for the last 14 days.

I have never had Richter's transformation or prolymphocytic leukemia.

I have not received treatment for CLL/SLL, except for steroids or specific autoimmune treatments.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ibrutinib and obinutuzumab, with venetoclax added in Arm II, for up to 14 cycles of 28 days each

56 weeks

Maintenance/Observation

Participants in Arm I continue ibrutinib, while Arm II participants achieving BM MRD negative CR undergo observation

Long-term

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 10 years

Treatment Details

Interventions

• Ibrutinib
• Obinutuzumab
• Venetoclax

Trial Overview The study tests adding Venetoclax, a BCL-2 inhibitor that may block cancer cell survival proteins, to the usual treatment of Ibrutinib and Obinutuzumab in treating CLL. It will also explore if patients can stop taking Ibrutinib after one year if no detectable CLL remains.

Participant Groups

Group I: Arm II (ibrutinib, obinutuzumab, venetoclax) Experimental Treatment 4 Interventions

Patients receive ibrutinib PO QD on days 1-28. Patients also receive obinutuzumab IV on days 1, 2, 8, and 15 of cycle 1, and on day 1 of cycles 2-6. Beginning cycle 3, patients also receive venetoclax PO QD on days 1-28. Treatment repeats every 28 days for 14 cycles in the absence of disease progression or unacceptable toxicity. All patients will then receive a 15th cycle of ibrutinib. Beginning cycle 16, patients who do not achieve a BM MRD negative CR, receive ibrutinib PO QD every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve a BM MRD negative CR undergo observation every 3 cycles for 6 years, then every 6 cycles thereafter.

Group II: Arm I (ibrutinib, obinutuzumab) Active Control 2 Interventions

Patients receive ibrutinib PO QD on days 1-28. Patients also receive obinutuzumab IV on days 1, 2, 8, and 15 of cycle 1, and on day 1 of cycles 2-6. Treatment repeats every 28 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 15, patients receive ibrutinib PO QD every 28 days in the absence of disease progression or unacceptable toxicity.

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 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]

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 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]

After a median follow-up of 46 months in the GLOW study, patients with untreated chronic lymphocytic leukaemia who received ibrutinib-venetoclax had a significantly better progression-free survival rate (74.6%) compared to those treated with chlorambucil-obinutuzumab (24.8%), indicating the efficacy of the ibrutinib-venetoclax combination as a first-line treatment.

While there were treatment-related deaths in both groups, the overall mortality was lower in the ibrutinib-venetoclax group (15 deaths) compared to the chlorambucil-obinutuzumab group (30 deaths), suggesting a potentially safer profile for the ibrutinib-venetoclax regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Niemann, CU., Munir, T., Moreno, C., et al.[2023]

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]

The combination of venetoclax, ibrutinib, and obinutuzumab is well tolerated in patients with relapsed and untreated mantle cell lymphoma (MCL), with no dose-limiting toxicities reported and a maximum tolerated dose of 400 mg per day established for venetoclax.

High response rates were observed, with a complete response rate of 67% in relapsed patients and 86.6% in untreated patients, along with significant minimal residual disease clearance in 71.5% of relapsed and 100% of untreated patients after three cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Le Gouill, S., Morschhauser, F., Chiron, D., et al.[2021]

In a retrospective study of 14 patients with chronic lymphocytic leukemia (CLL) treated with the venetoclax and obinutuzumab (VenG) regimen, 73% developed grade 3 or 4 neutropenia, indicating a high incidence of this side effect.

The study suggests that the high rate of neutropenia may be linked to patients having more comorbidities and high-risk disease features, highlighting the need for further research on supportive treatments to manage this side effect and allow for optimal dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. Samuels, C., Abbott, D., Niemiec, S., et al.[2022]

References

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

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

2. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

3. England pubmed.ncbi.nlm.nih.gov

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

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

Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. [2023]

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

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

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

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. [2021]

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

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. [2022]