Venetoclax for Chronic Lymphocytic Leukemia

Overseen By Christine E Gruessner, M.D.

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how venetoclax affects cancer cells and the immune system in individuals with chronic lymphocytic leukemia (CLL) that has returned or resisted previous treatments. The study aims to understand genetic changes during treatment to improve future therapies. It suits those whose CLL has returned or persisted after at least one treatment and who experience severe symptoms like significant weight loss, extreme fatigue, or frequent fevers. Participants will receive the drug at gradually increased doses and undergo regular check-ups, blood tests, and scans. The trial lasts at least two years, with the initial phase at the NIH and later phases managed by local doctors. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to advancements in CLL therapy.

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.

Is there any evidence suggesting that venetoclax is likely to be safe for humans?

Research has shown that venetoclax has been tested in people with chronic lymphocytic leukemia (CLL). These studies found that most patients generally tolerate venetoclax well. Some studies examined venetoclax alone, while others combined it with additional treatments. For instance, when used with drugs like rituximab, venetoclax has a well-understood safety profile, indicating researchers have extensive knowledge of its safety.

Although the drug is usually considered safe, side effects can occur. Common ones include low blood cell counts, infections, and digestive issues like nausea. Discuss any concerns about side effects with a doctor.

Venetoclax has FDA approval for treating CLL, indicating a strong safety record for this condition. However, since each patient is different, discussing this with a healthcare provider is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Venetoclax is unique because it specifically targets and inhibits the BCL-2 protein, which is crucial for the survival of chronic lymphocytic leukemia (CLL) cells. Unlike traditional treatments such as chemotherapy or immunotherapy, Venetoclax works by directly inducing cancer cell death, potentially leading to faster and more effective disease control. Researchers are excited about Venetoclax because it offers a new mechanism of action that may overcome resistance seen with other therapies, providing hope for patients with relapsed or refractory CLL.

What is the effectiveness track record for venetoclax in treating chronic lymphocytic leukemia?

Research has shown that venetoclax, the treatment under study in this trial, effectively treats chronic lymphocytic leukemia (CLL), particularly for patients who have not responded to other treatments. One study found that 71% to 79% of patients with difficult-to-treat CLL responded to venetoclax. Another study reported a 60% overall response rate, with some patients achieving complete remission, meaning no signs of cancer were detected. Venetoclax works by blocking a protein called BCL2, which helps cancer cells survive. By blocking this protein, venetoclax aids in killing the cancer cells. Overall, evidence supports venetoclax as a promising treatment for CLL. ^{4 5 6 7 8}

Who Is on the Research Team?

Christine E Gruessner, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

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]

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]

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]

Citations

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

The potential of venetoclax (ABT-199) in chronic lymphocytic ... In the phase I trial in R/R CLL and lymphoma patients, the ORR with ibrutinib was 60%, including 16% CRs and median PFS of 13.6 months. Results varied by ...

2. 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 ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01889186?term=venetoclax&viewType=Table&rank=6

NCT01889186 | A Study of the Efficacy of ABT-199 in ... This was an open-label, multicenter, global study to determine the efficacy of ABT-199 ( Venetoclax ) monotherapy in participants with relapsed/refractory (R/R) ...

4. ascopubs.org ascopubs.org/doi/10.1200/jco.2014.32.15_suppl.tps7121

A phase 2 open-label study of the efficacy of ABT-199 ... This Phase 2 multinational study is designed to evaluate ABT-199 monotherapy in patients with R/R CLL harboring del(17p). Methods: ABT-199 ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1513257

Targeting BCL2 with Venetoclax in Relapsed Chronic ... Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, ...

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

VEN+R Safety Data for CLL/SLL - venclexta VENCLEXTA-based regimens offer well-studied safety profiles with exposure limited to 2 years1* · No ongoing treatment exposure · VEN+R safety from the MURANO ...

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

Safety and Efficacy of a Combination of Venetoclax (GDC ... We present preliminary efficacy and updated safety data from an ongoing phase 1b study (NCT01685892) evaluating this combination in R/R or treatment-naïve (TN) ...