Venetoclax + Obinutuzumab for Leukemia

(CRISTALLO Trial)

No longer recruiting at 95 trial locations

Overseen By Reference Study ID Number: CO41685 https://forpatients.roche.com/

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Hoffmann-La Roche

Must not be taking: CYP3A inhibitors/inducers, Steroids

Disqualifiers: NHL, SLL, PML, 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: VEN + G: 12 months, FCR/BR: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of a new drug combination, venetoclax and obinutuzumab, for treating Chronic Lymphocytic Leukemia (CLL) compared to current treatments. CLL is a cancer affecting blood and bone marrow. The study will compare two groups: one receiving the new drug combination and the other receiving an existing treatment. Individuals diagnosed with CLL requiring treatment who have not undergone prior treatment may be suitable candidates for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, providing patients an opportunity to access potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have taken certain therapies for lymphoma/leukemia, strong CYP3A inhibitors/inducers, or consumed grapefruit products shortly before starting the trial.

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

Research has shown that the combination of venetoclax and obinutuzumab (VEN + G) is generally well-tolerated by people with chronic lymphocytic leukemia (CLL). In earlier studies, patients found the benefits outweighed the risks. Long-term evidence supports the safety of this treatment. Common side effects include low blood cell counts and infections, but these are usually manageable.

In contrast, the combination of fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR) is well-known for treating CLL. These treatments have been used for a while and have a known safety record. Common side effects include low blood cell counts, nausea, and infections.

Both treatment options have been studied in many patients and have a history of safety. However, like any treatment, potential side effects should be considered. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Venetoclax and Obinutuzumab for leukemia because it offers a unique targeted approach. Venetoclax works by inhibiting the BCL-2 protein, which helps cancer cells survive, making them more susceptible to treatment. Obinutuzumab, an anti-CD20 monoclonal antibody, targets and destroys specific leukemia cells. Unlike traditional chemotherapy regimens like FCR (Fludarabine, Cyclophosphamide, Rituximab) or BR (Bendamustine, Rituximab), this combination is designed to be more precise in its attack on cancer cells while potentially reducing the side effects associated with conventional chemotherapy. This targeted dual-action strategy holds promise for better outcomes and improved quality of life for patients.

What evidence suggests that this trial's treatments could be effective for CLL?

Research shows that using venetoclax and obinutuzumab together, which participants in this trial may receive, holds promise for treating chronic lymphocytic leukemia (CLL). Studies have found that this combination helps patients live longer without disease progression. For patients in good health, it works better than traditional chemoimmunotherapy. Evidence suggests that this treatment is safe, with manageable side effects. Overall, the venetoclax-obinutuzumab combination serves as an effective first choice for treating CLL. ^{3 6 7 8 9}

Who Is on the Research Team?

Clinical trial

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

This trial is for adults over 18 with untreated Chronic Lymphocytic Leukemia (CLL) who are fit (CIRS score ≤6, creatinine clearance ≥70 mL/min), and have a life expectancy of more than 6 months. They must not be pregnant or nursing, agree to use contraception, and should not have certain infections or recent drug treatments that could interfere with the study.

Inclusion Criteria

I agree to either not have sex or use birth control, and not donate sperm.

Ability to comply with the study protocol, in the investigator's judgment

My CLL condition requires treatment.

Exclusion Criteria

I haven't taken steroids for cancer treatment in the last 7 days, except for asthma or topical uses.

My cancer has spread to my brain or spinal cord.

I haven't taken any specific medications in the last 28 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either VEN + G for 12 cycles or FCR/BR for 6 cycles

VEN + G: 12 months, FCR/BR: 6 months

Multiple visits per cycle for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 74 months

What Are the Treatments Tested in This Trial?

Interventions

• Bendamustine
• Cyclophosphamide
• Fludarabine
• Obinutuzumab
• Rituximab
• Venetoclax

Trial Overview The trial compares Venetoclax plus Obinutuzumab against Fludarabine, Cyclophosphamide plus Rituximab or Bendamustine plus Rituximab in treating CLL. Participants will be randomly assigned to one of these two treatment groups to assess effectiveness and safety.

How Is the Trial Designed?

Group I: VEN + G Experimental Treatment 2 Interventions

Participants will receive 12 cycles of treatment (each cycle is 28 days). Venetoclax (VEN) will be administered orally, daily, with a 5-week ramp-up period, starting on Cycle 1, Day 22 and administration will continue until the end of Cycle 12. Obinutuzumab (G) will be administered intravenously (IV) on Days 1 (and 2), 8, and 15 of Cycle 1 and on Day 1 of Cycles 2-6.

Group II: FCR/BR Active Control 4 Interventions

Participants will receive 6 cycles of Fludarabine + Cyclophosphamide + Rituximab (FCR) consisting of a single cycle of a single infusion of rituximab on Day 1 and fludarabine and cyclophosphamide infusions on Days 1-3 of each 28-day cycle or bendamustine (B) as infusions on Days 1 and 2 and a single cycle of rituximab on Day 1 of each 28-day cycle.

Bendamustine is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Treanda for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in European Union as Ribomustin for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma
• Multiple myeloma

Approved in Canada as Levact for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in Japan as Bendamustine hydrochloride for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Who Is Running the Clinical Trial?

Hoffmann-La Roche

Lead Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Published Research Related to This Trial

In a phase 3 trial involving 432 patients with untreated chronic lymphocytic leukaemia, the combination of venetoclax plus obinutuzumab resulted in significantly longer progression-free survival compared to chlorambucil plus obinutuzumab, with a hazard ratio of 0.31, indicating a strong treatment advantage.

After a median follow-up of 39.6 months post-treatment, patients receiving venetoclax plus obinutuzumab had not yet reached median progression-free survival, while those on chlorambucil plus obinutuzumab had a median of 35.6 months, highlighting the long-term efficacy of the venetoclax regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Al-Sawaf, O., Zhang, C., Tandon, M., et al.[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]

In a study of 389 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), fixed-duration venetoclax plus rituximab (VenR) showed significantly better long-term outcomes compared to bendamustine plus rituximab (BR), with 4-year progression-free survival (PFS) rates of 57.3% versus 4.6%.

Achieving undetectable minimal residual disease (uMRD) at the end of treatment was linked to superior PFS, and patients who received ibrutinib after VenR had a remarkable 100% response rate, highlighting the effectiveness of VenR and its potential for durable responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study. Kater, AP., Wu, JQ., Kipps, T., et al.[2023]

The study analyzed pharmacokinetics and exposure-response parameters of a 400 mg once-daily venetoclax regimen combined with obinutuzumab in 274 patients, confirming its suitability for first-line treatment of chronic lymphocytic leukemia (CLL).

No significant correlations were found between venetoclax exposure and progression-free survival or severe treatment-emergent adverse events, indicating that the treatment is both effective and safe at the studied dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial. Samineni, D., Gibiansky, L., Wang, B., et al.[2022]

In a phase 2 trial involving 70 patients with chronic lymphocytic leukaemia, both 12 cycles of venetoclax consolidation and minimal residual disease-guided consolidation showed similar effectiveness, with around 50% of patients achieving undetectable minimal residual disease in bone marrow after treatment.

While consolidation treatment did not lead to treatment-related deaths, it was associated with a higher incidence of adverse events, particularly infections, indicating that while it may extend treatment duration, it does not significantly improve disease response or reduce relapse risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. Kersting, S., Dubois, J., Nasserinejad, K., et al.[2022]

The combination of venetoclax with bendamustine-rituximab (BR) was found to be safe and tolerable in a study of 60 patients with relapsed/refractory non-Hodgkin's lymphoma, with the recommended phase II dose established at 800 mg daily.

The overall response rate to the treatment was 65%, with a median duration of response of 38.3 months, indicating preliminary efficacy for this combination therapy in managing B-cell NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. de Vos, S., Swinnen, LJ., Wang, D., et al.[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. venclextahcp.com venclextahcp.com/cll/efficacy/ven-g/data.html

VENCLEXTA efficacy results: 6-year overall survival 1 In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients when treated with ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2213093

First-Line Venetoclax Combinations in Chronic ... Venetoclax–obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12031767/

Comparative efficacy of venetoclax-based regiments in the ... Our analysis found that venetoclax-based therapies significantly increased progression-free survival (PFS) (HR 0.30; 95% CI [0.21, 0.43] p < ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118474733

Safety and Efficacy of a Combination of Venetoclax (GDC ... These preliminary data suggest that VEN + G can be safely administered in pts with CLL with no difference in tolerability between R/R and TN subgroups. AEs ...

5. astrazeneca.com astrazeneca.com/media-centre/press-releases/2024/fixed-duration-calquence-plus-venetoclax-demonstrated-superior-pfs-vs-standard-care-previously-untreated-cll-with-77-of-patients-progression-free-3-years-amplify-phase-iii-trial.html

Fixed-duration Calquence plus venetoclax demonstrated ... Calquence plus venetoclax with obinutuzumab reduced the risk of disease progression or death by 58% versus standard of care in this setting

6. venclextahcp.com venclextahcp.com/cll/side-effects/ven-g-safety-profile.html

VEN+G Safety Data for CLL/SLL - venclexta No ongoing treatment exposure1. The fixed duration of VEN+G results in limited treatment exposure. VEN+G safety from the CLL14 trial.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10429845/

PB1938: REAL WORLD EFFECTIVENESS AND SAFETY ... These real-world results confirm the favourable benefit-risk profile of VenO for treatment naive CLL patients as observed in the pivotal CLL14 trial.

8. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/4639/499382/The-Impact-of-Fitness-and-Dose-Intensity-on-Safety

The Impact of Fitness and Dose Intensity on Safety and ... The impact of fitness and dose intensity on safety and efficacy outcomes after Venetoclax-Obinutuzumab in previously untreated chronic lymphocytic leukemia.

9. 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).