Venetoclax + Ibrutinib + Obinutuzumab for Chronic Lymphocytic Leukemia

Not currently recruiting at 987 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding venetoclax, a cancer treatment, to the standard regimen of ibrutinib and obinutuzumab can more effectively prevent the recurrence of chronic lymphocytic leukemia, a type of blood cancer. Researchers are also evaluating whether patients can discontinue ibrutinib after a year if their cancer becomes undetectable. The study seeks participants with chronic lymphocytic leukemia or small lymphocytic lymphoma who have not received prior treatment and experience symptoms affecting daily life, such as swollen lymph nodes or unintentional weight loss. As a Phase 3 trial, it represents the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking treatment.

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.

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

Research shows that the combination of ibrutinib, obinutuzumab, and venetoclax is generally safe for people with chronic lymphocytic leukemia (CLL). One study found this combination to be a safe initial treatment for previously untreated patients, indicating that most handle the treatment well.

Although no major differences in overall survival were observed, it is important to note that every treatment can have side effects. Long-term research also supports the safety of venetoclax with obinutuzumab, which are already used to treat CLL. This provides additional confidence that adding venetoclax to the usual treatment is likely safe.

Patients should consult their healthcare provider to understand how this treatment might work for them. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine multiple medications to tackle chronic lymphocytic leukemia (CLL) in a new way. Ibrutinib, obinutuzumab, and venetoclax work together to target different aspects of cancer cells: ibrutinib inhibits a specific protein that helps cancer cells survive, obinutuzumab is an antibody that flags cancer cells for the immune system, and venetoclax prompts cancer cells to self-destruct by blocking a protein that prevents cell death. This multi-pronged approach is different from typical treatments that might focus on just one mechanism. By using these drugs in combination, there’s potential for more effective cancer cell elimination and possibly improved outcomes for patients.

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

This trial will compare two treatment regimens for chronic lymphocytic leukemia (CLL). Studies have shown that adding venetoclax to ibrutinib and obinutuzumab significantly improves outcomes for patients with CLL. In this trial, one arm will receive ibrutinib and obinutuzumab, while another will receive ibrutinib, obinutuzumab, and venetoclax. Research indicates that using ibrutinib and venetoclax together reduces the risk of disease progression or death by 72.7% compared to other treatments. Patients receiving venetoclax and obinutuzumab, with or without ibrutinib, have also demonstrated better results in achieving minimal residual disease and longer periods without cancer progression. Overall, long-term evidence supports the safety and effectiveness of these treatments, especially when used together. This suggests that adding venetoclax could be a promising option for treating CLL. ^{2 5 6 7 8}

Who Is on the Research Team?

Jennifer A Woyach

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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 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]

Citations

1. onclive.com onclive.com/view/ibrutinib-venetoclax-combo-demonstrates-sustained-teae-free-pfs-in-first-line-cll

Ibrutinib/Venetoclax Combo Demonstrates Sustained ... Results showed that ibrutinib plus venetoclax reduced the risk of disease progression or death by 72.7% compared with the control arm.

2. targetedonc.com targetedonc.com/view/venetoclax-and-obinutuzumab-with-without-ibrutinib-improves-efficacy-in-cll

Venetoclax and Obinutuzumab With/Without Ibrutinib ... Adult patients with chronic lymphocytic leukemia had significantly better minimal residual disease and progression-free survival results ...

3. venclextahcp.com venclextahcp.com/cll/efficacy/ven-g/data.html

VENCLEXTA efficacy results: 6-year overall survival 1 Learn about VENCLEXTA® 6-year overall survival and treatment efficacy results. See full safety and Prescribing Information for more details.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03737981

NCT03737981 | Testing the Addition of a New Anti-cancer ... Giving ibrutinib and obinutuzumab with venetoclax may work better at treating chronic lymphocytic leukemia compared to ibrutinib and obinutuzumab. Detailed ...

5. ajmc.com ajmc.com/view/6-year-data-support-fixed-duration-ven-obi-for-untreated-cll

6-Year Data Support Fixed-Duration Ven-Obi for Untreated ... Long-term data support the safety and efficacy of venetoclax (Venclexta) and obinutuzumab (Gazyva) in chronic lymphocytic leukemia (CLL).

6. onclive.com onclive.com/view/venetoclax-plus-obinutuzumab-with-or-without-ibrutinib-extends-pfs-in-first-line-cll

Venetoclax Plus Obinutuzumab With or Without Ibrutinib ... No significant differences in overall survival were noted among the treatment groups. SHOW MORE. Venetoclax plus obinutuzumab with or without ...

7. targetedonc.com targetedonc.com/view/triplet-combination-of-ibrutinib-venetoclax-and-obinutuzumab-effective-as-initial-cll-treatment

Triplet Combination of Ibrutinib, Venetoclax, and ... ... ibrutinib (Imbruvica), and venetoclax (Venclexta) is a safe initial therapy for treatment-naïve patients with chronic lymphocytic leukemia (CLL)

8. ahdbonline.com ahdbonline.com/issues/2019/2019-payers-guide-mid-year-addendum/2806-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 ...