Venetoclax for Relapsed Hairy Cell Leukemia

Recruiting at 7 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents

Disqualifiers: Pregnancy, Malabsorption, Allergic reactions, 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: 1

Duration: Up to 19 months

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests venetoclax to evaluate its effectiveness for individuals with hairy cell leukemia that has returned after treatment. Venetoclax may inhibit cancer cell growth by blocking a protein essential for their survival. This trial suits those whose hairy cell leukemia has recurred after previous treatments and who have not yet tried venetoclax. Participants will take venetoclax daily in cycles, with regular check-ups and tests to monitor progress. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on other investigational agents, and live vaccines should not be given within 4 weeks before, during, or 30 days after the study treatment.

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

Research has shown that venetoclax is generally safe for treating certain cancers. It targets cancer cells that rely on a protein called Bcl-2 for survival, helping to kill the cancer cells while sparing other cells.

In previous studies, patients generally tolerated venetoclax well. However, like any treatment, it can cause side effects. Some patients reported fatigue or low blood cell counts, which can increase infection risk. These side effects are carefully monitored during treatment.

The FDA has already approved venetoclax for other conditions, such as chronic lymphocytic leukemia, indicating that its safety is well understood. However, each person's experience may vary, so discussing any concerns with the medical team is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for hairy cell leukemia?

Venetoclax is unique because it targets a specific protein called BCL-2, which plays a crucial role in the survival of cancer cells. Most treatments for hairy cell leukemia, like chemotherapy or immunotherapy, focus on broadly attacking cancer cells or boosting the immune system. Venetoclax, however, directly inhibits BCL-2, leading to the death of cancer cells while potentially sparing more of the healthy cells. This targeted approach may result in fewer side effects and could offer a promising alternative for patients who have relapsed or not responded to standard treatments.

What evidence suggests that venetoclax might be an effective treatment for relapsed hairy cell leukemia?

Research shows that venetoclax, the treatment under study in this trial, can help treat certain blood cancers by blocking a protein that cancer cells need to survive. In patients with hairy cell leukemia that has returned or hasn't responded to other treatments, early results suggest venetoclax can help manage the disease. Some studies have shown promising outcomes, with patients experiencing slower cancer cell growth. These findings suggest venetoclax might be a good option for patients whose hairy cell leukemia has returned. ^{1 3 6 7 8}

Who Is on the Research Team?

Robert J Kreitman

Principal Investigator

National Cancer Institute LAO

Are You a Good Fit for This Trial?

This trial is for adults over 18 with relapsed hairy cell leukemia after prior treatment, who can't have BRAF therapy and haven't tried Venetoclax. They need functioning kidneys, acceptable liver tests, and a decent performance status. People with treated hepatitis C or controlled HIV are eligible; those with chronic hepatitis B must be on suppressive therapy.

Inclusion Criteria

Total bilirubin ≤ 3 x institutional upper limit of normal (ULN) unless consistent with Gilbert's (ratio between total and direct bilirubin > 5)

I can take care of myself but may not be able to do heavy physical work.

My hepatitis B virus load is undetectable with treatment.

Exclusion Criteria

I have previously been treated with venetoclax.

I do not have conditions that affect how my body absorbs nutrients.

Patients who are receiving any other investigational agents

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax orally once daily on days 1-28 of each cycle, repeating every 28 days for up to 19 cycles

Up to 19 months

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

4 weeks

1 visit (in-person) at 30 days post-treatment

What Are the Treatments Tested in This Trial?

Interventions

• Venetoclax

Trial Overview The study is testing Venetoclax's effectiveness in patients whose hairy cell leukemia has returned. It involves taking the drug and undergoing various assessments like blood tests, bone marrow procedures, CT scans, and MRIs to see how well it works against cancer cells.

How Is the Trial Designed?

Group I: Treatment (venetoclax) Experimental Treatment 7 Interventions

Patients receive venetoclax PO QD on days 1-28 of each cycle. Treatment repeats every 28 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI and blood sample collection throughout the study. Patients may undergo bone marrow biopsy and/or aspiration on study. Additionally, patients with known or suspected CNS disease undergo lumbar puncture throughout the study.

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 Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

Oral administration of irinotecan showed similar efficacy to intravenous administration against various human colon carcinoma xenografts, achieving complete responses in five out of seven tested lines, particularly at higher doses.

The study found that oral irinotecan resulted in significantly higher systemic exposure of its active metabolite, SN-38, compared to intravenous administration, suggesting that oral dosing could be an effective alternative for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Studies of the efficacy and pharmacology of irinotecan against human colon tumor xenograft models. Zamboni, WC., Stewart, CF., Cheshire, PJ., et al.[2018]

The maximum tolerated dose (MTD) of irinotecan for patients with the UGT1A1 *1/*1 genotype is 310 mg/m2, while for those with the *1/*28 genotype, it is 260 mg/m2, indicating that genetic differences can influence drug tolerance in metastatic colorectal cancer treatment.

Bevacizumab does not significantly affect the pharmacokinetics of irinotecan, suggesting that the dosing adjustments based on genotype can be made without concern for altered drug metabolism due to this additional treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer. Toffoli, G., Sharma, MR., Marangon, E., et al.[2022]

A new administration schedule for irinotecan (CPT-11) in 19 patients with recurrent ovarian carcinomas significantly reduced severe side effects like leukocytopenia and diarrhea compared to previous methods, with rates dropping from 57.1% to 36.8% and from 19.2% to 0%, respectively.

The total response rate of 26% in this study was comparable to earlier studies, suggesting that this new dosing schedule effectively maintains the anti-cancer efficacy of CPT-11 while minimizing adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent, repetitive administrations of irinotecan (CPT-11) reduces its side-effects. Fujii, H., Koshiyama, M., Konishi, M., et al.[2019]

A 71-year-old patient with recurrent cervical cancer who is a compound heterozygote for UGT1A1*6 and UGT1A1*28 experienced significant hematotoxicity (grade 4 neutropenia, grade 3 anemia, and grade 4 thrombocytopenia) while receiving irinotecan hydrochloride (CPT-11) at a dose of 60 mg/m², indicating potential risks associated with this treatment in similar patients.

Despite the absence of previous case reports linking serious adverse events to CPT-11 in this genetic context, the observed severe side effects suggest that careful monitoring and dose adjustments are necessary for patients with these UGT1A1 variants undergoing combined chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent cervical cancer in a patient who was compound heterozygous for UGT1A1*6 and UGT1A1*28 presenting with serious adverse events during irinotecan hydrochloride/nedaplatin therapy. Takatori, E., Shoji, T., Miura, Y., et al.[2018]

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]

The study established the maximum tolerated dose (MTD) for the combination treatment NALIRIFOX in patients with metastatic pancreatic ductal adenocarcinoma, with 32 out of 56 patients receiving the MTD, indicating a manageable safety profile despite some patients experiencing severe treatment-related adverse events.

Patients treated with NALIRIFOX showed a median progression-free survival of 9.2 months and overall survival of 12.6 months, suggesting that this treatment regimen may be effective for this difficult-to-treat cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line liposomal irinotecan with oxaliplatin, 5-fluorouracil and leucovorin (NALIRIFOX) in pancreatic ductal adenocarcinoma: A phase I/II study. Wainberg, ZA., Bekaii-Saab, T., Boland, PM., et al.[2021]

In a study of 24 patients with unfit or relapsed/refractory AML, the combination of venetoclax (VEN), hypomethylating agents (HMAs), and low-dose chemotherapy resulted in a high overall response rate of 83.3%, with 84.6% of unfit patients achieving complete remission (CR).

The treatment was found to have a tolerable safety profile, with the most common adverse events being persistent cytopenias and infections, indicating that this combination therapy could be a promising option for high-risk AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-Center Retrospective Clinical Evaluation of Venetoclax Combined with HMAs and Half-Dose CAG for Unfit or Refractory/Relapsed AML. Chen, X., Zhao, Y., Li, Q., et al.[2023]

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]

Irinotecan hydrochloride demonstrated efficacy as a salvage therapy for recurrent and refractory non-Hodgkin lymphoma, achieving a response rate of 37.8% with complete remission in 2 patients and partial remission in 15 patients among 45 evaluable patients.

The treatment was associated with significant adverse effects, including myelosuppression and gastrointestinal toxicity, leading to dose adjustments in about 67% of patients, highlighting the need for careful management of side effects during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan hydrochloride for the treatment of recurrent and refractory non-Hodgkin lymphoma: a single institution experience. Sugiyama, K., Omachi, K., Fujiwara, K., et al.[2019]

A study evaluated the sensitivity of 6 childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cell lines to 10 anticancer drugs, revealing that the relapse-derived cell line YCUB-5R was more resistant to several key drugs compared to the diagnosis-derived cell line YCUB-5.

Etoposide and SN-38 (irinotecan) demonstrated the highest efficacy in inhibiting cell growth, suggesting they could be promising candidates for developing new therapies for childhood BCP-ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemo-sensitivity in a panel of B-cell precursor acute lymphoblastic leukemia cell lines, YCUB series, derived from children. Goto, H., Naruto, T., Tanoshima, R., et al.[2013]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06311227

NCT06311227 | Venetoclax for the Treatment of Patients ... This phase II trial tests how well venetoclax works in treating patients with hairy cell leukemia that has come back after a period of improvement ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36884329/

Venetoclax in Relapsed or Refractory Hairy-Cell Leukemia Venetoclax in Relapsed or Refractory Hairy-Cell Leukemia. N Engl J Med. 2023 Mar 9;388(10):952-954. doi: 10.1056/NEJMc2216135. Authors. Enrico ...

3. venclextahcp.com venclextahcp.com/cll/efficacy/ven-g/data.html

VENCLEXTA efficacy results: 6-year overall survival 1 Learn about VENCLEXTA® 6-year overall survival and treatment efficacy results. See full safety and Prescribing Information for more details.

4. news.abbvie.com news.abbvie.com/2021-06-11-New-Data-Shows-AbbVies-VENCLYXTO-R-VENCLEXTA-R-Fixed-Duration-Combination-Demonstrates-Sustained-Progression-Free-Survival-in-Chronic-Lymphocytic-Leukemia-Patients-after-Three-Years-off-Treatment

New Data Shows AbbVie's VENCLYXTO®/VENCLEXTA® ... The four- year results of the CLL14 study show that 74 percent of patients treated with fixed-duration venetoclax-obinutuzumab remain without ...

5. abbvieclinicaltrials.com abbvieclinicaltrials.com/study/?id=M14-032

A Phase 2 Open-Label Study of the Efficacy and Safety ... This was an open-label, non-randomized, multicenter, Phase 2 study evaluating the efficacy and safety of ABT-199 in 127 participants with relapsed or refractory ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000PharmR.pdf

208573Orig1s000 - accessdata.fda.gov Venetoclax showed selectivity in cell killing in tumor cells dependent on Bcl-2 for survival relative to tumor cells dependent on other anti- ...

7. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/20/NCT02055820/Prot_002.pdf

A Phase IB/II, Open-Label Study Evaluating the Safety and Toxicology assessments completed to date with venetoclax are general toxicology studies with periods of once-daily oral dosing ranging from 2 weeks to 6 months ...

8. researchgate.net researchgate.net/publication/369112973_Venetoclax_in_Relapsed_or_Refractory_Hairy-Cell_Leukemia

Venetoclax in Relapsed or Refractory Hairy-Cell Leukemia Early reports indicate that venetoclax has promise as an active agent in relapsed/ resistant HCL patients [9, 10] . Determining the optimal agents to use in ...