Combination Chemotherapy for Acute Lymphoblastic Leukemia

Overseen By Jain Nitin, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Pregnancy, HIV, Hepatitis B/C, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding ponatinib (also known as Iclusig) to a chemotherapy regimen with mini-hyper-CVD and venetoclax can improve remission rates for patients with difficult-to-treat T-cell acute lymphoblastic leukemia. The trial targets patients whose cancer has either returned or not responded well to previous treatments. Eligible participants should have this type of leukemia, have undergone at least one prior treatment, and currently not have serious heart 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 requires that you stop taking any medications or herbal supplements that strongly affect the liver enzyme CYP3A4 at least 7 days before starting ponatinib or within 3 days of starting venetoclax. You should also avoid consuming grapefruit, Seville oranges, or star fruit within 3 days before starting venetoclax.

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

Research has shown that mini-hyper CVD, a type of chemotherapy, is safe and generally well-tolerated by patients with relapsed or hard-to-treat acute lymphoblastic leukemia (ALL). Studies indicate it has a high success rate and is manageable for most patients.

Ponatinib, another treatment in this trial, presents a more complicated safety profile. Some studies have reported serious side effects, such as blockages in the arteries, severe infections, and bleeding. However, adjusting the dose can manage many of these side effects. Ponatinib is already approved for other blood cancers, suggesting a known safety record, but its risks should be carefully considered.

Venetoclax, the third treatment, also has known safety information. It's used for certain blood cancers, like chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). A main concern is the risk of tumor lysis syndrome (TLS), which occurs when cancer cells break down too quickly and release substances into the blood. This risk can be managed by gradually increasing the dose under medical supervision.

Overall, while these treatments show promise, each has specific safety considerations that participants should discuss with their healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Acute Lymphoblastic Leukemia because they combine innovative therapies that target cancer cells in new ways. Unlike standard chemotherapy, Mini-hyper CVD is designed to be administered in a condensed form that may reduce side effects while maintaining effectiveness. Ponatinib, a targeted therapy, acts on specific proteins (such as BCR-ABL) that drive leukemia cell growth, offering a precision approach. Venetoclax uniquely disrupts cancer cell survival pathways by inhibiting the BCL-2 protein, which can help in killing leukemia cells more effectively. Together, these treatments offer a multi-faceted attack on leukemia, potentially improving outcomes compared to traditional methods.

What evidence suggests that this trial's treatments could be effective for acute lymphoblastic leukemia?

Research has shown that mini-hyper-CVD chemotherapy holds promise for treating acute lymphoblastic leukemia (ALL). One study found that 83% of patients responded well to this treatment. In this trial, participants may receive mini-hyper-CVD as one of the treatment options. Ponatinib, another option in this trial, has proven effective for patients with Philadelphia chromosome-positive ALL, with some studies showing high survival rates. Venetoclax, also under study in this trial, achieved complete remission in over 90% of patients when combined with low-intensity chemotherapy in one study. These treatments have individually succeeded in treating leukemia, suggesting that together, they could be even more effective. ^{1 3 6 7 8}

Who Is on the Research Team?

Jain Nitin, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with relapsed or refractory T-cell acute lymphoblastic leukemia who've had previous treatments, have a certain level of bone marrow involvement, and are in decent physical condition (ECOG ≤2). They must have proper liver and kidney function, not be pregnant or breastfeeding, agree to use contraception, and can't join if they have uncontrolled infections, recent heart issues, or other serious health problems.

Inclusion Criteria

Women of childbearing potential must have a negative pregnancy test result and agree to use effective contraception

My T-cell acute lymphoblastic leukemia has not responded to previous treatments.

Patients must provide written informed consent

Exclusion Criteria

I don't have any severe health or mental conditions that could affect the study.

I do not have severe heart disease.

I do not have uncontrolled heart or blood vessel problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Ponatinib Treatment

Participants receive ponatinib as a single agent for 3 days prior to chemotherapy

3 days

Chemotherapy

Participants receive mini-hyper-CVD chemotherapy in the inpatient setting, starting on day 1 of each cycle

Cycles 2-8

Venetoclax Treatment

Participants receive venetoclax 400mg daily on days 1-14 of each 28-day cycle

14 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Mini-hyper CVD
• Ponatinib
• Venetoclax

Trial Overview The trial is testing whether adding the drug Ponatinib to a combination of mini-hyper CVD chemotherapy and Venetoclax improves remission rates in patients with tough-to-treat T-cell acute lymphoblastic leukemia.

How Is the Trial Designed?

Group I: Venetoclax Experimental Treatment 1 Intervention

Patients will continue venetoclax 400mg daily on days 1-14 of each 28-day cycle.

Group II: Ponatinib Experimental Treatment 1 Intervention

Participants will receive ponatinib (45mg daily) as a single agent for 3 days. These will be called Days -3, -2 and -1

Group III: Mini-hyper-CVD Experimental Treatment 1 Intervention

Chemotherapy will be administered in the inpatient setting, starting on day 1 of each of the cycles 2-8.

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 a study of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia (R/R ETP-ALL), Venetoclax combined with multidrug chemotherapy resulted in a 67.7% overall response rate and a 60% complete response rate, indicating significant efficacy.

The treatment was found to be safe, with manageable hematological toxicities and no severe adverse reactions, suggesting that Venetoclax combined with chemotherapy could be a promising option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical efficacy and safety of venetoclax combined with multidrug chemotherapy in the treatment of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia]. Kong, JY., Zong, LH., Pu, Y., et al.[2023]

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 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 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]

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 medication for treating chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), showing significant efficacy when combined with other therapies like obinutuzumab and azacitidine.

While venetoclax is associated with adverse events such as neutropenia and gastrointestinal disorders, the article emphasizes the importance of managing these side effects to ensure patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical Management of the Venetoclax-Treated Patient in Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia. Waggoner, M., Katsetos, J., Thomas, E., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37131217/

Results of salvage therapy with mini-hyper-CVD and ... With a median follow-up of 48 months, the median overall survival (OS) was 17 months, and the 3 year OS was 40%. The 3 year OS was 34% with mini ...

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/2811/531826/Updated-Results-of-the-Combination-of-Mini-Hyper

Updated Results of the Combination of Mini-Hyper-CVD with ... 7 pts (5%) died within 4 weeks of therapy, all in Cohort 1. The rate of measurable residual disease (MRD) negativity by flow cytometry was 53% ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265024011406

ALL-808 Very Promising Results of the Dose Dense (D-D) ... The DD mini-hyper-CVD-INO-blinatumomab regimen results in high rates of deep MRD negativity and promising early survival outcomes.

4. jhoonline.biomedcentral.com jhoonline.biomedcentral.com/articles/10.1186/s13045-023-01444-2

Results of salvage therapy with mini-hyper-CVD and ... The combination of mini-Hyper-CVD-inotuzumab ± blinatumomab was effective and safe in patients with R-R ALL. The overall response rate was 83%, ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.7011

Updated results from a phase II study of mini-hyper-CVD ... The combination of mini-HCVD plus INO, with or without Blina, in older adults with newly diagnosed Ph-negative ALL resulted in an overall response rate of 99% ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38207208/

A phase 1/2 study of mini-hyper-CVD plus venetoclax in ... We designed a phase 1/2 clinical trial to evaluate the safety and efficacy of low-intensity chemotherapy in combination with venetoclax in adults with relapsed ...

7. lymphoblastic-hub.com lymphoblastic-hub.com/medical-information/mini-hyper-cvd-plus-inotuzumab-ozogamicin-blinatumomab-in-adult-rr-ph-b-all

Mini-hyper-CVD plus inotuzumab ozogamicin ... In this longer-term follow-up analysis, mini-hyper-CVD plus InO ± blinatumomab was found to be effective and well-tolerated in adult patients ...

8. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2650791

Salvage Chemoimmunotherapy With Inotuzumab ... In this phase 2 study, the combination of inotuzumab and mini-HCVD was safe and effective in adults with R/R ALL. The ORR was 78%, and 1-year ...