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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—calaspargase pegol-mknl, decitabine, and venetoclax—to determine their effectiveness in controlling T-cell leukemia-lymphoma (T-ALL and T-LLy) that has returned or is resistant to treatment. The study will also assess the safety of using these drugs together. Suitable participants include those with relapsed or hard-to-treat T-ALL or T-LLy who can swallow tablets and do not have other uncontrolled health issues. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

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 there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the drugs calaspargase pegol-mknl, decitabine, and venetoclax have been studied together to assess their effects on cancer patients, particularly those with T-cell leukemia-lymphoma. Although detailed safety information from these studies remains limited, testing these drugs in humans suggests they demonstrated some safety in earlier research stages.

Calaspargase pegol-mknl, a modified enzyme used in cancer treatment, has been studied with other drugs for its ability to kill cancer cells. Decitabine acts as a chemotherapy drug, while venetoclax targets specific cancer cells. Researchers are examining how these treatments work together and how well patients tolerate them.

While some risk of side effects exists, as is common with cancer treatments, ongoing research suggests these risks might be manageable. Trial participants will be closely monitored to ensure their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment combination for T-cell leukemia-lymphoma because it brings together three powerful drugs: Calaspargase Pegol-mknl, Decitabine, and Venetoclax. Unlike standard chemotherapy, which targets all rapidly dividing cells, Venetoclax specifically targets proteins that help cancer cells survive, potentially leading to fewer side effects. Calaspargase Pegol-mknl is a unique enzyme that breaks down nutrients cancer cells need to grow, while Decitabine reactivates genes that suppress tumors. This combination offers a targeted approach that might be more effective and less toxic than existing treatments.

What evidence suggests that this drug combination could be effective for T-Cell Leukemia-Lymphoma?

This trial will evaluate the combination of three drugs—calaspargase pegol-mknl, decitabine, and venetoclax—as a potential treatment for relapsed or hard-to-treat T-Cell Acute Lymphoblastic Leukemia (T-ALL) and T-Cell Lymphoblastic Lymphoma (T-LLy). Research suggests that these drugs can work together to kill more cancer cells. Venetoclax targets a protein that helps cancer cells survive, making it easier for them to die. Decitabine influences gene expression in cancer cells, while calaspargase pegol-mknl aids in breaking down proteins within these cells. By employing different mechanisms, this combination aims to attack the cancer more effectively. ^{1 2 3 4 5}

Who Is on the Research Team?

David McCall, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 not pregnant and agree to use birth control.

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

I am between 1 month and 21 years old.

Exclusion Criteria

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

Subjects of childbearing potential unwilling to use approved contraception

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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 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 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]

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]

Citations

1. ckb-core.genomenon.com ckb-core.genomenon.com/clinicalTrial/show?nctId=NCT06561074

NCT06561074 : Clinical Trial Detail - CKB CORE - Genomenon Title, A Phase 2 Study to Evaluate Efficacy of Calaspargase Pegol-mknl and Decitabine Combined With Venetoclax in Pediatric, Adolescent, and Young Adult ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06561074

NCT06561074 | A Phase 2 Study to Evaluate Efficacy of ... A Phase 2 Study to Evaluate Efficacy of Calaspargase Pegol-mknl and Decitabine Combined With Venetoclax in Pediatric, Adolescent, and Young Adult Patients ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06561074?term=CALASPARGASE%20PEGOL&viewType=Table&rank=6

A Phase 2 Study to Evaluate Efficacy of Calaspargase ... An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-06907

Calaspargase Pegol-mknl and Decitabine Combined with ... Giving calaspargase pegol-mknl and decitabine in combination with venetoclax may kill more cancer cells in pediatric, adolescent and young adult patients with ...

5. clin.larvol.com clin.larvol.com/trial-detail/NCT06561074

Cell Lymphoblastic Lymphoma (T-LLy) Impact Score 4A Phase 2 Study to Evaluate Efficacy of Calaspargase Pegol-mknl and Decitabine Combined With Venetoclax in Pediatric, Adolescent, ...