Ibrutinib + Venetoclax vs Chlorambucil + Obinutuzumab for Chronic B-Cell Leukemia

(GLOW Trial)

Not currently recruiting at 135 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Janssen Research & Development, LLC

Disqualifiers: Prior anti-leukemic therapy, del17p, TP53 mutation, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 12-24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to compare two treatment combinations to determine which better prevents chronic B-cell leukemia, a type of blood cancer, from worsening. One group will receive ibrutinib (a targeted therapy) and venetoclax, while the other will receive chlorambucil and obinutuzumab. The trial focuses on how long these treatments can prevent cancer progression. Suitable participants have been diagnosed with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and require treatment to manage their condition. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research shows that combining ibrutinib and venetoclax holds promise for treating chronic lymphocytic leukemia (CLL). Previous studies have linked this combination to good survival rates. Reports suggest it is generally well-tolerated by patients, with some manageable side effects.

Chlorambucil and obinutuzumab are also used to treat CLL. Extensive studies have shown they are generally safe. Chlorambucil can cause side effects like nausea or tiredness, but these are often mild.

Both treatment options have been tested in people, and safety information is available. However, like all treatments, they may not be suitable for everyone. It's important to consult a healthcare provider to understand the potential risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatment combining Ibrutinib and Venetoclax for chronic B-cell leukemia because it employs a powerful one-two punch against cancer cells. Unlike traditional chemotherapy, this combination targets specific proteins that cancer cells rely on to survive and grow. Ibrutinib blocks a protein called Bruton's tyrosine kinase (BTK), which is crucial for cancer cell signaling, while Venetoclax targets the BCL-2 protein that helps cancer cells avoid death. This dual action not only disrupts cancer cell growth but also promotes their destruction, offering a potentially more effective and less toxic approach than existing therapies like Chlorambucil and Obinutuzumab.

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

This trial will compare two treatment options for chronic lymphocytic leukemia (CLL): one group will receive ibrutinib and venetoclax, while another group will receive chlorambucil and obinutuzumab. Research has shown that using ibrutinib and venetoclax together is promising for treating CLL. Studies indicate that this combination offers significant benefits and may help patients live longer without disease progression. It works particularly well for patients with certain genetic changes, such as TP53. Patients who have used this treatment have experienced better results compared to other options. Overall, this combination is a strong choice for managing CLL and offers hope for better disease control. ^{1 4 5 6 7}

Who Is on the Research Team?

Janssen Research & Development, LLC Clinical Trial

Principal Investigator

Janssen Research & Development, LLC

Are You a Good Fit for This Trial?

This trial is for adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), who need treatment and have not had previous anti-leukemic therapy. Participants should be over 65, or 18-64 with certain health conditions, and able to perform daily activities with minimal help.

Inclusion Criteria

I am 65 years old or older.

Exclusion Criteria

I have received treatment for CLL or SLL before.

My cancer has a specific genetic change (del17p or TP53 mutation).

I have not had major surgery in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either ibrutinib plus venetoclax or chlorambucil plus obinutuzumab for multiple cycles

12-24 months

Multiple visits per cycle

Subsequent Therapy Phase

Participants with progressive disease may receive single-agent ibrutinib until disease progression or unacceptable toxicity

Up to 6 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years 10 months

What Are the Treatments Tested in This Trial?

Interventions

• Chlorambucil
• Ibrutinib
• Obinutuzumab
• Venetoclax

Trial Overview The study compares two treatments: Ibrutinib plus Venetoclax versus Chlorambucil plus Obinutuzumab in patients with CLL/SLL. It aims to see which combination is better at stopping the disease from progressing without getting worse.

How Is the Trial Designed?

Group I: Treatment Arm A: Ibrutinib and Venetoclax (I+VEN) Experimental Treatment 3 Interventions

Participants will initially receive ibrutinib (420 mg \[milligrams\]/day) for 3 cycles. Venetoclax dose ramp up (from 20 to 400 mg over 5 weeks) will begin at Cycle 4 and the combination of ibrutinib and venetoclax will be given for 12 cycles (each cycle is equivalent to 28 days). Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity.

Group II: Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb) Active Control 3 Interventions

Participants will receive chlorambucil and obinutuzumab (G-Clb) for 6 cycles. Participants will receive obinutuzumab, 1000 mg intravenously (IV) on Days 1, 8 and 15 of Cycle 1, and on Day 1 of Cycles 2 to 6 and chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight, on Days 1 and 15 of Cycles 1 to 6. Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

Janssen Research & Development, LLC

Lead Sponsor

Trials

1,022

Recruited

6,408,000+

Joaquin Duato

Janssen Research & Development, LLC

Chief Executive Officer since 2022

MBA from ESADE, Master of International Management from Thunderbird School of Global Management

Dr. Jijo James, MD

Janssen Research & Development, LLC

Chief Medical Officer since 2014

MD from St. Johns Medical College, MPH from Columbia University

Pharmacyclics LLC.

Industry Sponsor

Trials

114

Recruited

13,800+

Dr. Maky Zanganeh

Pharmacyclics LLC.

Chief Executive Officer

Degree from Louis Pasteur University in Strasbourg, France; MBA from Schiller International University in France

Dr. Ellie Im

Pharmacyclics LLC.

Chief Medical Officer

MD from an unspecified institution

Published Research Related to This Trial

In a safety run-in cohort of 21 patients with relapsed/refractory mantle cell lymphoma, the combination of ibrutinib and venetoclax showed an impressive overall response rate of 81%, with 62% achieving a complete response after a median follow-up of 31 months.

The study indicated that concurrent administration of ibrutinib and venetoclax is safe, with only three dose-limiting toxicities observed and no new safety concerns, allowing the trial to proceed without an ibrutinib lead-in.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study. Wang, M., Ramchandren, R., Chen, R., et al.[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 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]

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]

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 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]

Citations

1. 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 demonstrated efficacy in patients with activated B-cell-like (ABC) subtype and BCL-2 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4537801/

Pharmacological and protein profiling suggest venetoclax ... Though ibrutinib results in impressive clinical activity in chronic lymphocytic leukemia (CLL), most patients achieve only partial remission due to residual ...

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

Ibrutinib and venetoclax in combination for chronic ... The ibrutinib-venetoclax combination demonstrated promising effectiveness in patients with TP53 abnormalities, although outcomes remain less favorable than ...

4. jnj.com jnj.com/innovativemedicine/us/news-center/oncology/significant-efficacy-benefit-of-imbruvica-ibrutinib-plus-venetoclax-versus-acalabrutinib-plus-venetoclax-in-frontline-treatment-of-patients-with-chronic-lymphocytic-leukaemia-suggested-by-indirect-treatment-comparison

Significant efficacy benefit of IMBRUVICA® (ibrutinib) plus ... Cross-study findings indicate significant clinical benefit of frontline fixed-duration ibrutinib plus venetoclax with improved likelihood of ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02141282

Study Details | NCT02141282 | A Phase 2 Open-Label ... This was an open-label, non-randomized, multicenter, Phase 2 study evaluating the efficacy and safety of ABT-199 in 127 participants with relapsed or ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5026291/

The potential of venetoclax (ABT-199) in chronic lymphocytic ... This review summarizes the role of BCL2 in CLL pathogenesis, the development path targeting its inhibition prior to VEN, and the preclinical and clinical data ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02141282

Study Details | NCT02141282 | A Phase 2 Open-Label ... This was an open-label, non-randomized, multicenter, Phase 2 study evaluating the efficacy and safety of ABT-199 in 127 participants with relapsed or refractory ...