Venetoclax for Relapsed Hairy Cell Leukemia

Recruiting at 11 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

Trial Summary

What is the purpose of this trial?

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 (relapsed). Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival.

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.

What data supports the effectiveness of the drug Venetoclax for treating relapsed Hairy Cell Leukemia?

Venetoclax has shown effectiveness in treating other blood-related conditions, such as relapsed/refractory multiple myeloma and light-chain amyloidosis, with a high response rate in patients with specific genetic markers. This suggests potential effectiveness in similar blood cancers like Hairy Cell Leukemia. ^{1 2 3 4 5}

Is Venetoclax generally safe for humans?

In a study involving patients with a specific type of blood disorder, Venetoclax was generally well-tolerated, with serious side effects occurring in 19% of patients, including 7% due to infections. This suggests that while Venetoclax can cause some serious side effects, it is generally considered safe for use in humans. ^{1 2 6 7 8}

How is the drug Venetoclax unique for treating relapsed hairy cell leukemia?

Venetoclax is unique because it is an oral drug that selectively inhibits the BCL-2 protein, which helps cancer cells survive. This mechanism is different from traditional chemotherapy, offering a targeted approach that has shown effectiveness in other blood cancers like chronic lymphocytic leukemia. ^{9 10 11 12 13}

Research Team

Robert J Kreitman

Principal Investigator

National Cancer Institute LAO

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: Treatment (venetoclax) Experimental Treatment 6 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.

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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 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]

References

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

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

2. Australia 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. [2018]

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

Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer. [2022]

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

Studies of the efficacy and pharmacology of irinotecan against human colon tumor xenograft models. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Chemo-sensitivity in a panel of B-cell precursor acute lymphoblastic leukemia cell lines, YCUB series, derived from children. [2013]

6. England 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. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Intermittent, repetitive administrations of irinotecan (CPT-11) reduces its side-effects. [2019]

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

Irinotecan hydrochloride for the treatment of recurrent and refractory non-Hodgkin lymphoma: a single institution experience. [2019]

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

Venetoclax: First Global Approval. [2018]

10. New Zealand 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. [2023]

11. France pubmed.ncbi.nlm.nih.gov

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

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

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

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

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