Venetoclax for Chronic Lymphocytic Leukemia

Overseen By Rachel Adams

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Must not be taking: Strong CYP3A4 inhibitors

Disqualifiers: Pregnancy, Uncontrolled infection, Other malignancy, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

75 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: The drug venetoclax treats chronic lymphocytic leukemia (CLL). Researchers want to find better treatments for CLL. To do that, they need to learn how the drug affects CLL cancer cells and the immune system. Objective: To learn about genetic changes that happen during treatment of CLL with venetoclax. Eligibility: Adults ages 18 and older with relapsed or refractory CLL after at least 1 prior therapy Design: Participants will be screened under a separate protocol. In Phase 1, participants will get venetoclax free of charge through the NIH. Venetoclax is started at a low dose. The dose will be increased every week until participants reach their maximum tolerable dose. This usually take about 5 weeks. Participants will visit the NIH at least once per week. Visits will be about 4 hours. They may have to stay in the hospital to be observed. In Phase 2, participants will continue to get the drug through their local cancer doctor and their health insurance. Patients will also visit the NIH every 6 months, or if their disease progresses. At the NIH participants will have regular health assessments. These will include physical exams and a review of the medicines they are taking. They will talk about how they are feeling. The study included the following tests: Blood draws CT scans: Participants will lie in a machine that takes pictures of the body (maximum 3 per year) Bone marrow biopsies: A small amount of marrow will be taken out of the participant s hip bone with a needle. Optional lymph node biopsies: A small piece of the participant s tissue will be taken out with a needle. The study will last at least 2 years.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot use strong CYP3A4 inhibitors or other systemic cancer treatments while participating. It's best to discuss your current medications with the trial team.

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

Venetoclax is effective for treating Chronic Lymphocytic Leukemia (CLL), achieving response rates of about 80% in patients with relapsed or refractory CLL and showing longer progression-free survival when combined with obinutuzumab compared to traditional chemoimmunotherapy. It is also effective in combination with rituximab, providing durable responses and manageable safety in patients with relapsed or refractory CLL. ^{1 2 3 4 5}

What safety data exists for Venetoclax in humans?

In a study involving patients with a specific type of blood disorder, 19% experienced serious side effects, with 7% due to infections. This suggests that while Venetoclax can be effective, it may also cause significant side effects in some people. ^{6 7 8 9 10}

What makes the drug Venetoclax unique for treating chronic lymphocytic leukemia?

Venetoclax is unique because it is a first-in-class, oral drug that selectively inhibits the BCL-2 protein, which helps cancer cells survive. This mechanism allows it to effectively treat chronic lymphocytic leukemia, especially in patients with relapsed or refractory conditions, and it can be used alone or in combination with other therapies like obinutuzumab or rituximab. ^{1 2 3 5 11}

Research Team

Christopher MT Pleyer, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

Adults over 18 with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) who've had at least one prior therapy. Participants must have active disease, be able to take oral medication, and agree to use contraception if necessary. They can't join if they've used BCL-2 inhibitors before, have uncontrolled infections or other serious health issues, are pregnant/nursing, or have certain blood count levels.

Inclusion Criteria

My bone marrow is failing and getting worse.

I have anemia or low platelet count.

I have lost 10% or more of my weight in the last 6 months.

Exclusion Criteria

Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk

I am not currently pregnant or nursing.

I am currently receiving treatment for cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

Ramp-up Phase

Participants receive venetoclax starting at a low dose, with weekly increases until reaching the maximum tolerable dose

5 weeks

At least 1 visit per week (in-person)

Treatment Continuation

Participants continue venetoclax treatment through their local cancer doctor, with regular health assessments and optional follow-up at NIH

At least 2 years

Every 6 months (in-person at NIH) or as needed

Follow-up

Participants are monitored for safety and effectiveness after treatment

Ongoing

Treatment Details

Interventions

• Venetoclax

Trial Overview The trial is testing how venetoclax affects CLL cancer cells and the immune system. It involves a ramp-up phase where doses increase weekly until the maximum tolerable dose is reached. Afterward, participants continue treatment locally but visit NIH every six months for tests like blood draws, CT scans, and bone marrow biopsies.

Participant Groups

Group I: Relapsed/Refractory CLL pts Experimental Treatment 1 Intervention

Ages 18 and older

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

Approved in United States as Venclexta for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Approved in European Union as Venclyxto for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Findings from Research

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]

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]

In a study of 18 pediatric and young adult patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL), venetoclax demonstrated a complete remission rate of 61%, indicating its potential efficacy in this population.

No new safety concerns were identified with venetoclax, with myelosuppression being the most common side effect, and no deaths occurred within 30 days of starting treatment, suggesting it is a safe option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax for Children and Adolescents with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. Gibson, A., Trabal, A., McCall, D., et al.[2022]

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 a study of 43 patients with light-chain amyloidosis (AL) treated with venetoclax, the overall hematologic response rate was 68%, with 63% achieving very good partial response (VGPR) or complete response (CR), indicating that venetoclax is an effective treatment option for AL.

Patients with the t(11;14) genetic alteration had significantly better outcomes, with an 81% hematologic response rate and a median progression-free survival (PFS) that was not reached, compared to 40% response and a median PFS of 6.7 months for those without this alteration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis. Premkumar, VJ., Lentzsch, S., Pan, S., et al.[2021]

In a study involving 15 patients with metastatic colorectal cancer, the combination of irinotecan and thalidomide showed promising results, with 20% of evaluable patients achieving complete responses and 20% achieving partial responses.

The treatment was well-tolerated, with a notable lack of severe gastrointestinal toxicities (grade 3/4), suggesting that this regimen could be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan and thalidomide in metastatic colorectal cancer. Govindarajan, R.[2018]

Irinotecan, a water-soluble analogue of camptothecin, effectively targets DNA topoisomerase I to induce cancer cell death, showing activity against various cancers including leukemia and colorectal cancer, with a dose-response relationship observed in phase I trials.

The drug's pharmacokinetics reveal significant interpatient variability, with adverse effects like neutropenia and diarrhea correlating with plasma concentrations of irinotecan and its active metabolite SN-38, highlighting the importance of monitoring these levels to optimize treatment and minimize toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of irinotecan. Chabot, GG.[2018]

In a phase II study involving 30 patients with various hematological malignancies, CPT-11 (irinotecan hydrochloride) showed an overall response rate of 23% for non-Hodgkin's lymphoma and varying rates for other types of leukemia, indicating some efficacy in treating these conditions.

Major toxicities were observed, including high rates of leukopenia (91%) and gastrointestinal issues, particularly with regimen B, suggesting that while CPT-11 may be effective, careful monitoring of side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[An early phase II study of CPT-11 (irinotecan hydrochloride) in patients with hematological malignancies]. Ohno, R., Yoshida, Y., Oguro, M., et al.[2018]

A specific transport system, identified as the ME3277 transport system, is crucial for the secretion of the lactone form of CPT-11 into the gastrointestinal lumen, which may influence its gastrointestinal toxicity.

Inhibitors of other transport proteins like Bcrp, Mrp2, and P-glycoprotein did not affect the secretion of CPT-11 lactone, highlighting the unique role of the ME3277 system in this process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of secretory intestinal transport of the lactone form of CPT-11. Takemoto, I., Itagaki, S., Chiba, M., et al.[2018]

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]

References

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

Venetoclax: First Global Approval. [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. Switzerland pubmed.ncbi.nlm.nih.gov

Venetoclax for Children and Adolescents with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. [2022]

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

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

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

Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis. [2021]

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

Irinotecan and thalidomide in metastatic colorectal cancer. [2018]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of irinotecan. [2018]

9. Japan pubmed.ncbi.nlm.nih.gov

[An early phase II study of CPT-11 (irinotecan hydrochloride) in patients with hematological malignancies]. [2018]

10. Germany pubmed.ncbi.nlm.nih.gov

Characterization of secretory intestinal transport of the lactone form of CPT-11. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. [2021]