Triple Therapy for Chronic Lymphocytic Leukemia

Overseen By Nitin Jain, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CTLA-4, PD-1, PD-L1, CD137

Disqualifiers: Active malignancy, Cardiovascular disease, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: Up to 14 cycles (Cohort I) or 25 cycles (Cohort II), each cycle lasting 28 days

65 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three treatments—atezolizumab (Tecentriq), obinutuzumab (Gazyva), and venetoclax (Venclexta)—to evaluate their effectiveness against chronic lymphocytic leukemia (CLL) and similar conditions that have returned or resisted previous treatments. The researchers aim to harness the power of the immune system and chemotherapy to stop cancer cells from growing and spreading. They seek participants with CLL, small lymphocytic lymphoma, or Richter syndrome, particularly those whose cancer has returned or resisted other treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to significant advancements in cancer 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, if you are on high-dose steroids or immune suppression medications, these need to be stopped at least 3 days before starting the study drugs. Also, you cannot take strong CYP3A inhibitors or inducers within 7 days of starting venetoclax.

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

Research has shown that the combination of atezolizumab, obinutuzumab, and venetoclax is generally well-tolerated by patients with certain types of cancer. Studies have found that this combination can lead to high rates of cancer remission, although some patients experienced immune-related side effects. These side effects, linked to the body's immune response, can be serious but are manageable with medical care.

In another study with a similar group of patients, this drug combination proved safe and promising, even for those who had undergone extensive previous treatments. This offers hope, especially for patients whose cancer has returned or is resistant to treatment.

While detailed safety data for this specific trial is not yet available, the safe use of these drugs together in other studies provides some reassurance. Potential participants should discuss any concerns with their healthcare provider to fully understand what this means for their health. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of atezolizumab, obinutuzumab, and venetoclax for chronic lymphocytic leukemia (CLL) because this triple therapy brings a new approach to treatment. While standard treatments for CLL often involve chemotherapy or targeted therapies like ibrutinib and rituximab, this regimen uses a combination of two monoclonal antibodies and a BCL-2 inhibitor. Atezolizumab and obinutuzumab are designed to enhance the immune system's ability to target and destroy cancer cells, while venetoclax specifically targets and disrupts cancer cell survival mechanisms. This combination could potentially offer a more effective and targeted response, reducing the reliance on traditional chemotherapy and its associated side effects.

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

This trial will evaluate the combination of atezolizumab, obinutuzumab, and venetoclax for chronic lymphocytic leukemia (CLL). Research has shown that these three treatments together can lead to high remission rates in people with CLL, particularly for those whose cancer has returned or is resistant to standard treatments. Atezolizumab and obinutuzumab help the immune system attack cancer cells, while venetoclax stops cancer cells from growing. This approach shows potential in managing CLL and related conditions like small lymphocytic lymphoma and Richter syndrome, though it can cause immune-related side effects. The combination has proven particularly effective when other treatments have failed, but close monitoring for side effects is crucial. Participants in this trial will receive this combination therapy, with variations in the treatment schedule between Cohort I and Cohort II. ^{1 2 3 4 6}

Who Is on the Research Team?

Nitin Jain, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults over 18 with chronic lymphocytic leukemia, small lymphocytic lymphoma, or Richter syndrome that's untreated or resistant to treatment. They must be in good physical condition (ECOG ≤2), have normal liver and kidney function, not be pregnant or breastfeeding, agree to use effective contraception, and have no major health issues like uncontrolled hypertension or recent strokes.

Inclusion Criteria

I have been diagnosed with CLL, SLL, or RT and have not received any treatment.

I can take care of myself and am up and about more than half of my waking hours.

My kidney and liver are working well.

Exclusion Criteria

My CLL has spread to my brain or its coverings.

I do not have any untreated or uncontrolled infections.

I haven't had any cancer except for certain types in the past 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive obinutuzumab, atezolizumab, and venetoclax in cycles. Cohort I receives treatment for up to 14 cycles, and Cohort II for up to 25 cycles.

Up to 14 cycles (Cohort I) or 25 cycles (Cohort II), each cycle lasting 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Obinutuzumab
• Venetoclax

Trial Overview The trial is testing a combination of atezolizumab (an immune system booster) with obinutuzumab and venetoclax (chemotherapy drugs). It aims to see if this mix can better stop the growth of cancer cells in patients with certain blood cancers compared to current treatments.

How Is the Trial Designed?

Group I: Cohort II (obinutuzumab, atezolizumab, venetoclax) Experimental Treatment 4 Interventions

Patients receive obinutuzumab intravenously IV over 4-6 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-9 and atezolizumab IV over 30-60 minutes on days 3-4 of cycle 1 and on days 1-2 of cycles 2-9. Treatment repeats every 28 days for 9 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 2, patients receive venetoclax PO on days 1-28. Treatment repeats every 28 days for 25 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Cohort I (obinutuzumab, atezolizumab, venetoclax) Experimental Treatment 4 Interventions

Patients receive obinutuzumab IV over 4-6 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-9 and atezolizumab IV over 30-60 minutes on days 3-4 of cycle 1 and on days 1-2 of cycles 2-9. Treatment repeats every 28 days for 9 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 3, patients also receive venetoclax PO on days 1-28. Treatment repeats every 28 days for 14 cycles in the absence of disease progression or unacceptable toxicity.

Atezolizumab is already approved in United States, European Union for the following indications:

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

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]

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

P388R cells, a pleiotropically resistant cell line, showed significant resistance to the antifolate drugs trimetrexate (TMQ) and BW 301U, with resistance levels of 22-fold and 15-fold, respectively, compared to the sensitive P388S cells.

The calcium channel blocker verapamil (VER) was able to partially overcome the resistance to TMQ by enhancing its uptake in P388R cells, indicating that drug transport mechanisms play a crucial role in the efficacy of antifolate treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross resistance of pleiotropically drug resistant P338 leukemia cells to the lipophilic antifolates trimetrexate and BW 301U. Klohs, WD., Steinkampf, RW., Besserer, JA., et al.[2019]

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 an oral medication that selectively inhibits the BCL-2 protein, which helps cancer cells survive, thereby restoring the ability of these malignant cells to undergo programmed cell death (apoptosis).

It has been approved in the USA for treating chronic lymphocytic leukaemia (CLL) in patients with a specific genetic marker (17p deletion) who have already undergone at least one prior therapy, and it is being studied for various other blood cancers and conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. Deeks, ED.[2018]

Venetoclax (Venclexta) is an effective treatment for chronic lymphocytic leukemia, targeting specific cancer cells to improve patient outcomes.

Riboflavin 5'-phosphate solutions (Photrexa Viscous and Photrexa) are used to treat progressive keratoconus, enhancing corneal strength and stability through a non-invasive procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmaceutical Approval Update. Kaufman, MB.[2020]

In a study involving 382 patients with untreated advanced colorectal cancer, the addition of trimetrexate (TMTX) to the standard treatment of 5-fluorouracil (5-FU) and leucovorin (LCV) resulted in increased severe diarrhea but did not improve overall survival (OS) or progression-free survival (PFS).

The trial found that while TMTX led to more significant toxicities, including a 41% incidence of grade 3 or 4 diarrhea compared to 28% in the placebo group, it did not enhance treatment efficacy, as response rates and quality of life scores were similar between the TMTX and placebo groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer. Blanke, CD., Shultz, J., Cox, J., et al.[2020]

In a study involving 65 patients with relapsed childhood leukemia (c/preB-ALL, T-ALL, and AML), it was found that relapsed cases were significantly more resistant to methotrexate (MTX) compared to initial cases, indicating a challenge in treatment efficacy.

Novel antifolates like trimetrexate (TMQ) and GW1843U89 showed potential to overcome this resistance, suggesting they could be effective alternatives for treating MTX-resistant leukemia, particularly in T-ALL and relapsed c/preB-ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circumvention of methotrexate resistance in childhood leukemia subtypes by rationally designed antifolates. Rots, MG., Pieters, R., Peters, GJ., et al.[2021]

In a study of 93 children with acute lymphoblastic leukemia, both the Capizzi regimen (escalating doses of methotrexate) and high-dose methotrexate (HD-MTX) showed similar overall toxicity rates, with 28.7% for Capizzi and 29.8% for HD-MTX, indicating that both regimens are associated with significant toxicities.

Mucositis was more prevalent in the HD-MTX group (14.6%) compared to the Capizzi group (5.5%), suggesting that while both regimens are effective, HD-MTX may carry a higher risk for this specific toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse effects with intravenous methotrexate in children with acute lymphoblastic leukemia/lymphoma: a retrospective study. Mandal, P., Samaddar, S., Chandra, J., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02846623

NCT02846623 | Atezolizumab, Obinutuzumab, and ... Giving atezolizumab, obinutuzumab, and venetoclax may work better in treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or Richter ...

2. cllsociety.org cllsociety.org/2025/04/first-line-atezolizumab-venetoclax-obinutuzumab-for-cll/

First-line Atezolizumab-Venetoclax-Obinutuzumab for CLL Atezolizumab-venetoclax-obinutuzumab produced high remission rates, but immune-related side effects limit its usefulness as a frontline CLL ...

3. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00396-6/abstract

Atezolizumab, venetoclax, and obinutuzumab combination ... Atezolizumab, venetoclax, and obinutuzumab combination in Richter transformation diffuse large B-cell lymphoma (MOLTO): a multicentre, single-arm, phase 2 trial

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.TPS7575

A multicenter, open label, uncontrolled, phase II clinical ... Preliminary data of atezolizumab alone or in combination with obinutuzumab showed to be safe and promising in heavily pretreated DLBCL. We ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39082668/

6-year results of the randomized phase 3 CLL14 study The sustained long-term survival and QoL benefits support the use of 1-year fixed-duration Ven-Obi in CLL.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04082897

NCT04082897 | ObinutuzuMab AtezOlizumab and ... This study is a multicenter, open-label, uncontrolled, phase II trial aimed to establish the safety and tolerability of venetoclax, atezolizumab and ...