Triple Drug Therapy for Leukemia

Overseen By Nicholas Short

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Investigational agents

Disqualifiers: Active infection, Pancreatitis, Cardiovascular disease, 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: 30

Duration: Up to 24 cycles (28 days each)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—decitabine, venetoclax, and ponatinib—to evaluate their effectiveness against certain types of leukemia, specifically those positive for the Philadelphia chromosome. The goal is to determine if these drugs can effectively control or reduce cancer cell growth in patients with these specific leukemias. This trial suits individuals diagnosed with Philadelphia chromosome-positive acute myeloid leukemia or certain types of chronic myelogenous leukemia, whether newly diagnosed or unresponsive to previous treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does allow prior treatment with corticosteroids, hydroxyurea, or an FDA-approved BCR-ABL tyrosine kinase inhibitor. You should discuss your current medications with the trial team to get specific guidance.

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

Research has shown that the combination of decitabine, venetoclax, and ponatinib is generally safe for people. Studies found that patients tolerated these drugs well, with no deaths occurring within the first 60 days of treatment. Although a couple of deaths were reported, one resulted from worsening leukemia and the other from an infection, suggesting the treatment itself was not the cause. More research is needed to confirm long-term safety. Overall, early results indicate that the treatment is promising and manageable for patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this triple drug therapy for leukemia because it combines decitabine, ponatinib, and venetoclax in a unique approach. Decitabine works by modifying DNA to stop cancer cell growth, while ponatinib targets specific proteins that aid cancer survival, and venetoclax disrupts the energy supply of these cancer cells. This combination targets different pathways within leukemia cells, potentially offering a more comprehensive attack compared to standard treatments. This could lead to improved outcomes and faster responses for patients with leukemia.

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

Research has shown that a combination of three drugs—decitabine, venetoclax, and ponatinib—may effectively treat certain types of leukemia. One study found this combination to be safe and effective in controlling advanced phase chronic myeloid leukemia, with many patients responding well. Decitabine stops cancer cells from growing, venetoclax blocks a protein that cancer cells need to survive, and ponatinib targets enzymes that help cancer cells grow. Together, these drugs effectively fight the disease. These findings suggest this treatment could benefit people with these specific types of leukemia. Participants in this trial will receive this combination therapy to further evaluate its effectiveness. ^{1 2 3 4 5}

Who Is on the Research Team?

Nicholas Short

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with Philadelphia chromosome-positive acute myeloid leukemia or chronic myelogenous leukemia in blast or accelerated phase. Participants must be able to perform daily activities (ECOG <=3), have adequate organ function, and be able to swallow pills. Pregnant women are excluded, and participants must agree to use contraception.

Inclusion Criteria

Aspartate aminotransferase (AST) =< 1.5 x ULN unless due to the underlying leukemia approved by the PI

Alanine aminotransferase (ALT) =< 1.5 x ULN, unless due to the underlying leukemia approved by the PI

Signed informed consent

Exclusion Criteria

I do not have serious heart rhythm problems as decided by my doctor.

Uncontrolled hypertension (diastolic blood pressure > 100 mmHg; systolic > 150 mmHg)

Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ponatinib, venetoclax, and decitabine in cycles. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Up to 24 cycles (28 days each)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

4.5 years

Follow-up at 30 days post-treatment, then every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• Ponatinib
• Venetoclax

Trial Overview The study tests a combination of three drugs: Decitabine, Venetoclax, and Ponatinib. It aims to see how well they work together in stopping cancer cell growth by killing the cells or preventing them from dividing and spreading.

How Is the Trial Designed?

Group I: Treatment (ponatinib, venetoclax, decitabine) Experimental Treatment 3 Interventions

See Detailed Description.

Decitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Dacogen for:

• Acute myeloid leukemia
• Myelodysplastic syndromes

Approved in United States as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Canada as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

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

The VA regimen, combining venetoclax and azacitidine, demonstrated a high complete remission (cCR) rate of 78.8% after the first treatment cycle and 81.8% after prolonged treatment in 66 patients with newly diagnosed acute myeloid leukemia (AML) who were not suitable for conventional chemotherapy.

The treatment was generally safe, with manageable adverse effects, primarily neutropenia, thrombocytopenia, and anemia, and showed better outcomes in patients with specific gene mutations (IDH1/2 or NPM1) and those experiencing rebound thrombocytosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience]. Sun, L., Ye, SJ., Zhou, N., et al.[2023]

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]

A case of early-relapsed high-risk T-cell acute lymphoblastic leukemia (T-ALL) with high BCL-2 expression was successfully treated with a combination of decitabine and venetoclax, leading to complete remission (CR).

The results suggest that decitabine and venetoclax may work synergistically in treating BCL-2 positive acute lymphoblastic leukemia, indicating a potential new therapeutic strategy for this high-risk group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T-cell lymphoblastic leukemia. Zappone, E., Cencini, E., Defina, M., et al.[2020]

In a study involving 145 older patients (median age 74) with acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy, the combination of venetoclax with decitabine or azacitidine resulted in a high complete remission (CR) rate of 67%, demonstrating its efficacy in this challenging population.

The treatment was well tolerated, with no cases of tumor lysis syndrome reported, and the median overall survival was 17.5 months, indicating that venetoclax combined with hypomethylating agents is a promising option for elderly patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. DiNardo, CD., Pratz, K., Pullarkat, V., et al.[2021]

In a study of 22 heavily pre-treated patients with relapsed or refractory acute myeloid leukaemia (RR-AML), the combination of venetoclax and decitabine resulted in a 45.5% overall response rate, with 40.9% achieving complete remission, demonstrating its efficacy in a real-world setting.

While the treatment was effective, it was associated with significant side effects, including grade IV neutropenia and thrombocytopenia in all patients, but no deaths were attributed to the treatment side effects, indicating that the adverse effects were manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting. Tong, J., Zhao, N., Hu, X., et al.[2022]

In a phase 2 trial involving 168 patients with acute myeloid leukaemia (AML), the combination of venetoclax and a 10-day regimen of decitabine resulted in a high overall response rate of 74%, with particularly impressive results in newly diagnosed AML patients (89%).

The treatment demonstrated a manageable safety profile, with common adverse events including neutropenia and infections, and a 30-day mortality rate of only 3.6%, indicating that this combination therapy is both effective and relatively safe for older patients or those unfit for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. DiNardo, CD., Maiti, A., Rausch, CR., et al.[2021]

In a comparison of two combination therapies for acute myeloid leukemia—glasdegib+low-dose cytarabine (LDAC) and venetoclax+LDAC—no statistically significant differences in overall survival or complete remission rates were found, suggesting similar efficacy.

When choosing between these treatments, factors like safety profiles, ease of administration, and patient preferences will be important since both therapies appear equally effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of glasdegib versus venetoclax combined with low-dose cytarabine in acute myeloid leukemia. Tremblay, G., Daniele, P., Bell, T., et al.[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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04188405

NCT04188405 | Decitabine, Venetoclax, and Ponatinib for ... Giving decitabine, venetoclax, and ponatinib may help to control Philadelphia chromosome-positive acute myeloid leukemia or myeloid blast phase or accelerated ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39303729/

Decitabine, venetoclax, and ponatinib for advanced phase ... The combination of decitabine, venetoclax, and ponatinib is safe and shows promising activity in patients with advanced phase chronic myeloid leukaemia.

3. asco.org asco.org/abstracts-presentations/ABSTRACT422842

A phase 2 study of the combination of decitabine (DAC) ... Results: From Jul 2020 to Jan 2023, 15 pts were treated, 4 with CML-AP, 10 with CML-MBP and 1 with Ph+ AML (Table). 11 pts (73%) had prior TKI exposure, ...

4. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2019-0610.html

A Phase II Study of the Combination of Decitabine ... This phase II trial studies how well the combination of decitabine, venetoclax, and ponatinib work for the treatment of Philadelphia chromosome-positive acute ...

5. researchgate.net researchgate.net/publication/384095269_Decitabine_venetoclax_and_ponatinib_for_advanced_phase_chronic_myeloid_leukaemia_and_Philadelphia_chromosome-positive_acute_myeloid_leukaemia_a_single-arm_single-centre_phase_2_trial

Decitabine, venetoclax, and ponatinib for advanced phase ... Consistent with the aboveoutlined mechanisms, co-targeting BCR::ABL1 using ponatinib significantly enhanced the anti-tumor efficacy of venetoclax in vivo.