Drug Combination for T-Cell Leukemia-Lymphoma

Overseen By David McCall, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A inducers, CYP3A inhibitors

Disqualifiers: Secondary tumor, CNS pathology, 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

Compensation: Varies

Number of Visits: Unknown

Duration: Induction cycles, specifics not provided

22 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you should avoid certain foods and medications like grapefruit and strong CYP3A inducers close to the start of the trial. It's best to discuss your current medications with the study team.

Is the drug combination including Venetoclax generally safe for humans?

Venetoclax has been shown to have an acceptable safety profile in patients with chronic lymphocytic leukemia (CLL), although it can cause notable side effects like neutropenia (a low level of neutrophils, a type of white blood cell), which can be managed with supportive care and dose adjustments. ^{1 2 3 4 5}

What makes this drug combination unique for treating T-cell leukemia-lymphoma?

This drug combination is unique because it includes venetoclax, which targets the BCL-2 protein to help cancer cells die, and decitabine, a hypomethylating agent that can modify DNA to stop cancer growth. This combination has shown promise in treating relapsed T-cell acute lymphoblastic leukemia, a condition with limited treatment options. ^{6 7 8 9 10}

What is the purpose of this trial?

To learn if giving the study drugs calaspargase pegol-mknl and decitabine in combination with venetoclax can help to control relapsed/refractory T-ALL and T-LLy. The safety of this drug combination will also be studied.

Research Team

David McCall, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for young patients with T-cell acute lymphoblastic leukemia or lymphoma who have not responded to previous treatments. Participants should be in a specific age range, typically pediatric to young adult.

Inclusion Criteria

I am on short-term steroids or have had limited cyclophosphamide doses.

I am not pregnant and agree to use birth control.

I am between 1 month and 21 years old.

Exclusion Criteria

I have severe liver disease, cirrhosis, or I actively abuse alcohol.

I have had another type of cancer or a serious blood disease, but there may be exceptions.

Subjects of childbearing potential unwilling to use approved contraception

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Calaspargase pegol-mknl, Decitabine, and Venetoclax to evaluate efficacy and safety in relapsed/refractory T-ALL and T-LLy

Induction cycles, specifics not provided

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term follow-up

Monitoring of adverse events and overall survival

Up to 1 year

Treatment Details

Interventions

• Calaspargase Pegol-mknl
• Decitabine
• Venetoclax

Trial Overview The study tests if calaspargase pegol-mknl and decitabine combined with venetoclax can control relapsed/refractory T-ALL and T-LLy. It's a phase 2 trial, which means it focuses on the efficacy of the treatment and monitors safety.

Participant Groups

Group I: Treatment w/Calaspargase pegol-mknl + Decitabine + Venetoclax Experimental Treatment 3 Interventions

Calaspargase Pegol-mknl is already approved in European Union, United States for the following indications:

Approved in European Union as Besponsa for:

• Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)

Approved in United States as Besponsa for:

• Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients 1 year and older

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

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 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 involving 272 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), higher concentrations of venetoclax led to a quicker reduction in lymphocyte counts and tumor size, resulting in a high objective response rate (ORR) of 84.8% at a daily dose of 400 mg.

Importantly, increasing the dose of venetoclax did not correlate with a higher risk of serious adverse events like neutropenia or infections, suggesting that the 400 mg daily regimen is both effective and safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. Freise, KJ., Jones, AK., Eckert, D., et al.[2018]

In a retrospective study of 14 patients with chronic lymphocytic leukemia (CLL) treated with the venetoclax and obinutuzumab (VenG) regimen, 73% developed grade 3 or 4 neutropenia, indicating a high incidence of this side effect.

The study suggests that the high rate of neutropenia may be linked to patients having more comorbidities and high-risk disease features, highlighting the need for further research on supportive treatments to manage this side effect and allow for optimal dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. Samuels, C., Abbott, D., Niemiec, S., et al.[2022]

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]

A patient with relapsed T-cell acute lymphoblastic leukemia (T-ALL) showed a clinical response to venetoclax, an oral BCL-2 inhibitor, combined with a hypomethylating agent, highlighting a potential new treatment strategy for this challenging condition.

Given that less than 7% of patients with relapsed T-ALL achieve long-term survival, targeting antiapoptotic proteins like BCL-2 could offer a promising approach to improve outcomes in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax and decitabine for treatment of relapsed T-cell acute lymphoblastic leukemia: A case report and review of literature. Farhadfar, N., Li, Y., May, WS., et al.[2021]

The combination of ruxolitinib and venetoclax shows a dose-dependent effect on T cell acute lymphoblastic leukemia (T-ALL) but does not improve survival in a xenograft model, leading to increased leukemic infiltration in the central nervous system (CNS).

Adding the CXCR4 inhibitor plerixafor to the treatment regimen enhances survival and reduces clinical symptoms, suggesting that targeting the CXCR4-CXCL12 axis may be necessary for achieving better outcomes in T-ALL therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration. Walker, KL., Rinella, SP., Hess, NJ., et al.[2022]

In a study comparing older adults with newly diagnosed acute myeloid leukemia (AML), those treated with the combination of decitabine (DEC) and venetoclax (VEN) had a significantly longer median overall survival of 13.4 months compared to 8.3 months for those receiving DEC alone.

The combination therapy also resulted in a higher response rate of 70.3% versus 24.3% for DEC monotherapy, indicating that DEC+VEN is more effective in treating AML without increasing short-term mortality rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. Kwag, D., Cho, BS., Bang, SY., et al.[2022]

References

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

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

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

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

3. Switzerland pubmed.ncbi.nlm.nih.gov

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. [2018]

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

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. [2022]

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

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

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

Venetoclax and Decitabine in Pediatric Refractory T-cell Lymphoblastic Lymphoma. [2023]

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

Venetoclax in Combination with Decitabine for Relapsed T-Cell Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Cell Transplant. [2020]

8. Saudi Arabia pubmed.ncbi.nlm.nih.gov

Venetoclax and decitabine for treatment of relapsed T-cell acute lymphoblastic leukemia: A case report and review of literature. [2021]

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

CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration. [2022]

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

Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. [2022]