Dasatinib + Venetoclax for Chronic Myelogenous Leukemia

Overseen By Hagop Kantarjian

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: TKIs

Disqualifiers: Heart disease, Psychiatric disorders, HIV, 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: 15 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, dasatinib (Sprycel) and venetoclax (Venclexta), to evaluate their effectiveness in treating chronic myelogenous leukemia (CML) in its early stages. These drugs aim to halt cancer cell growth by blocking essential enzymes. Individuals diagnosed with Philadelphia chromosome positive or BCR-ABL1 positive CML within the last year, who have received little to no treatment, may be suitable candidates for this study. The goal is to determine if this combination can effectively manage the disease. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in CML treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that participants should have received minimal prior therapy for CML, except for hydroxyurea and a few doses of cytarabine. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that dasatinib and venetoclax are likely to be safe for humans?

Research shows that the combination of dasatinib and venetoclax is generally well-tolerated in patients with chronic myelogenous leukemia, a type of blood cancer. Studies have found that patients receiving this combination experience similar response rates to when each drug is used alone. This indicates that the combination does not cause unexpected side effects beyond those already known for each drug.

Previous studies on dasatinib alone have shown it to be a safe treatment for leukemia, with most side effects being manageable. Venetoclax, used in other blood cancers, also has a good safety record. It targets and kills cancer cells while sparing most normal cells. While some side effects can occur, they are generally known and can be monitored by doctors.

Overall, both dasatinib and venetoclax have been successfully used in patients, and their combination appears to be a safe option for treating leukemia. However, as with any treatment, discussing potential risks and benefits with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for Chronic Myelogenous Leukemia (CML) typically target the BCR-ABL protein using tyrosine kinase inhibitors like imatinib. However, the combination of dasatinib and venetoclax is unique because it not only targets BCR-ABL with dasatinib but also disrupts cancer cell survival pathways with venetoclax, which inhibits the BCL-2 protein. This dual approach aims to enhance treatment effectiveness by attacking the leukemia cells on two fronts. Researchers are excited about this combination as it offers the potential for a more comprehensive treatment strategy, especially for patients who might not respond well to existing therapies.

What evidence suggests that dasatinib and venetoclax could be effective for chronic myelogenous leukemia?

Research has shown that using dasatinib with venetoclax can effectively treat early-stage chronic myelogenous leukemia (CML). In this trial, participants will initially receive dasatinib, and after three months, venetoclax will be added to their regimen. One study found that this combination resulted in 96% of patients being free from cancer progression after four years, with all patients surviving during that period. This indicates that most patients did not experience cancer worsening and lived through the study period. The treatment was safe, and the results were similar to using dasatinib alone. However, adding venetoclax did not provide additional benefits compared to past results with just dasatinib. Overall, this combination appears promising for patients with this type of leukemia. ^{1 4 6 7 8}

Who Is on the Research Team?

Elias Jabbour, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with early chronic phase chronic myelogenous leukemia that's Philadelphia chromosome positive or BCR-ABL1 positive. They should have minimal prior treatment, good kidney function, and acceptable blood test results. Pregnant women, those with serious heart disease, bleeding disorders, uncontrolled infections or psychiatric conditions are excluded.

Inclusion Criteria

Patients must sign an informed consent indicating they are aware of the investigational nature of this study, in keeping with the policies of the hospital

I am able to care for myself and move around.

Serum glutamate pyruvate transaminase (SGPT) < 3 x ULN

Exclusion Criteria

I am using or will use effective birth control during and 3 months after the study.

Pregnant or breast-feeding women are excluded. All WOCBP must have a negative pregnancy test prior to first receiving investigational product. If the pregnancy test is positive, the patient must not receive study drug and must not be enrolled in the study.

I have or might have long QT syndrome.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive dasatinib orally once daily for 15 years. After 3 months, venetoclax is added for 3 years.

15 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Dasatinib
• Venetoclax

Trial Overview The study tests dasatinib and venetoclax's effectiveness in treating certain leukemia by blocking enzymes needed for cancer cell growth. It’s a phase II trial to see how well these drugs work together in patients who've had little to no previous treatment.

How Is the Trial Designed?

Group I: Treatment (dasatinib, venetoclax) Experimental Treatment 3 Interventions

Patients receive dasatinib PO QD for 15 years in the absence of disease progression or unacceptable toxicity. After 3 months of dasatinib treatment, patients also receive venetoclax PO QD on days 1-14 of each month for 3 years in the absence of disease progression or unacceptable toxicity (patients enrolled prior to 4/1/2018 receive only dasatinib).

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

Approved in United States as Sprycel for:

• Chronic myeloid leukemia (CML)
• Acute lymphoblastic leukemia (ALL)

Approved in European Union as Sprycel for:

• Chronic myeloid leukemia (CML)
• Acute lymphoblastic leukemia (ALL)

Approved in Canada as Sprycel for:

• Chronic myeloid leukemia (CML)
• Acute lymphoblastic leukemia (ALL)

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The combination of tyrosine kinase inhibitors (TKIs) like dasatinib and ponatinib with the BCL-2 inhibitor venetoclax shows strong synergy in reducing cell viability and inducing apoptosis in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) cells, suggesting a promising new treatment strategy.

In tests with primary Ph(+)ALL patient samples in mice, the dasatinib-venetoclax combination was well-tolerated and demonstrated superior effectiveness compared to either drug alone, indicating its potential to enhance treatment outcomes for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting BCL-2 and ABL/LYN in Philadelphia chromosome-positive acute lymphoblastic leukemia. Leonard, JT., Rowley, JS., Eide, CA., 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 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, a BCL-2 inhibitor, shows promise in combination therapies for newly diagnosed or relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), achieving high remission rates and deep molecular responses.

Despite these encouraging results, there are concerns about side effects such as incomplete blood count recovery and increased infection rates, particularly when used with chemotherapy, and more research is needed to understand the long-term effectiveness and durability of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. Shimony, S., Stone, RM., Stahl, M.[2023]

In a study of 60 patients with high-risk MDS and AML, venetoclax demonstrated a 35% overall response rate, indicating its efficacy as a treatment option for these conditions.

However, the treatment was associated with significant hematologic toxicity, with 86.7% of patients experiencing grade 2 or higher side effects, and infections, particularly pneumonia, being the most common nonhematologic complication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Real-life Turkish Experience of Venetoclax Treatment in High-risk Myelodysplastic Syndrome and Acute Myeloid Leukemia. Gemici, A., Ozkalemkas, F., Dogu, MH., et al.[2022]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02689440

Study Details | NCT02689440 | Dasatinib and Venetoclax ... This phase II trial studies how well dasatinib and venetoclax work in treating patients with Philadelphia chromosome positive or BCR-ABL1 positive early ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38591430/

Combination of dasatinib and venetoclax in newly ... Treatment with dasatinib and venetoclax was safe and effective in CML-CP. The cumulative response rates with the combination were similar to those with single- ...

3. researchgate.net researchgate.net/publication/379695767_Combination_of_dasatinib_and_venetoclax_in_newly_diagnosed_chronic_phase_chronic_myeloid_leukemia

Combination of dasatinib and venetoclax in newly ... However, a clinical trial combining venetoclax with dasatinib in chronic phase CML showed no added benefit compared to historical data of single agent dasatinib ...

4. docwirenews.com docwirenews.com/post/dasatinib-plus-venetoclax-effective-safe-for-chronic-phase-cml

Dasatinib Plus Venetoclax Effective, Safe for Chronic ... A phase II trial calculated a 4-year event-free survival rate of 96% and overall survival rate of 100% from the combination.

5. bloodcancerstoday.com bloodcancerstoday.com/post/dasatinib-plus-venetoclax-is-safe-in-patients-with-early-chronic-phase-cml

Dasatinib Plus Venetoclax Is Safe in Patients with Early ... Dasatinib plus venetoclax is safe and effective in patients with early chronic phase chronic myeloid leukemia compared with dasatinib alone.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5026291/

The potential of venetoclax (ABT-199) in chronic lymphocytic ... Venetoclax (ABT-199): clinical data in chronic lymphocytic leukemia patients ... ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04872790

Study Details | NCT04872790 | Venetoclax, Dasatinib, ... This phase Ib trial studies the effects of venetoclax in combination with dasatinib, prednisone, rituximab and blinatumomab in treating patients with ...

8. jhoonline.biomedcentral.com jhoonline.biomedcentral.com/articles/10.1186/s13045-015-0224-3

ABT-199 (venetoclax) and BCL-2 inhibitors in clinical ... This review focused on the current clinical development of a highly effective class of small molecule BCL-2 inhibitors, including ABT-199/venetoclax.