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

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well atezolizumab, obinutuzumab, and venetoclax work in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma or Richter syndrome that has come back (recurrent) or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as atezolizumab and obinutuzumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as venetoclax, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving atezolizumab, obinutuzumab, and venetoclax may work better in treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or Richter syndrome.

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.

What data supports the effectiveness of the drug combination including Venetoclax for treating Chronic Lymphocytic Leukemia?

Venetoclax, when used in combination with obinutuzumab, has shown to significantly improve progression-free survival and response rates in patients with previously untreated chronic lymphocytic leukemia, according to the CLL14 trial. Additionally, Venetoclax combined with rituximab has been effective in prolonging progression-free survival in relapsed or refractory cases, demonstrating its potential as a key component in CLL treatment. ^{1 2 3 4 5}

Is there safety data available for the drugs used in the triple therapy for chronic lymphocytic leukemia?

Venetoclax (Venclexta) has been approved for chronic lymphocytic leukemia, indicating it has undergone safety evaluations for this condition. However, no specific safety data for the combination of Atezolizumab, Obinutuzumab, and Venetoclax in chronic lymphocytic leukemia is provided in the available research articles. ^{6 7 8 9 10}

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

This drug combination is unique because it combines Atezolizumab, an immune checkpoint inhibitor, with Obinutuzumab and Venetoclax, which target specific proteins on cancer cells, offering a novel approach that may enhance the immune system's ability to fight chronic lymphocytic leukemia. ^{1 2 3 4 5}

Research Team

Nitin Jain, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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 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 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]

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]

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]

References

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

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

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

3. France pubmed.ncbi.nlm.nih.gov

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

4. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

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

Venetoclax: First Global Approval. [2018]

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

Pharmaceutical Approval Update. [2020]

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

Circumvention of methotrexate resistance in childhood leukemia subtypes by rationally designed antifolates. [2021]

8. England 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. [2020]

9. Ireland pubmed.ncbi.nlm.nih.gov

Cross resistance of pleiotropically drug resistant P338 leukemia cells to the lipophilic antifolates trimetrexate and BW 301U. [2019]

10. India pubmed.ncbi.nlm.nih.gov

Adverse effects with intravenous methotrexate in children with acute lymphoblastic leukemia/lymphoma: a retrospective study. [2021]