Venetoclax + Cladribine for Acute Myeloid Leukemia

Recruiting at 1 trial location

Overseen By Derek Schatz

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Colorado, Denver

Must be taking: Hypomethylating agents, Venetoclax

Must not be taking: Cladribine

Disqualifiers: CNS involvement, Uncontrolled infection, 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: 6 months

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs, Venetoclax (a targeted therapy) and Cladribine (a chemotherapy drug), for treating acute myeloid leukemia (AML) that has not responded to previous treatments. Researchers focus on cases with a specific type of AML, such as monocytic or monoblastic, or those with a Ras pathway mutation. Participants should have AML that has returned or not improved after treatment with a hypomethylating agent and Venetoclax. Individuals facing this specific challenge with their AML treatment might be a good fit for the study. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it does allow the use of hydroxyurea and/or leukapheresis to manage white blood cell counts, so some medications might be permitted. It's best to discuss your specific medications with the trial team.

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

Research has shown that the combination of cladribine and venetoclax is generally well-tolerated by patients with acute myeloid leukemia (AML). Studies have found that this treatment can lead to strong and lasting improvements in some patients. While effective, it can have side effects, such as low blood cell counts, nausea, or tiredness. However, careful monitoring and supportive care usually manage these effects.

Safety data from clinical studies suggest that the venetoclax and azacitidine combination is generally safe and well-tolerated. Patients did not experience any unexpected side effects. Common side effects include low blood counts, which are expected and monitored during treatment.

Both combinations are part of ongoing research to ensure safety and effectiveness. Participants in trials receive close supervision to manage any side effects that may occur. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for acute myeloid leukemia, which often include chemotherapy drugs like cytarabine and anthracyclines, the combination of Venetoclax and Cladribine offers a unique approach. Venetoclax targets cancer cells by inhibiting the BCL-2 protein, which helps the cancer cells survive, while Cladribine disrupts DNA synthesis, leading to cell death. Researchers are excited about these treatments because they work together to target leukemia cells more precisely and potentially with fewer side effects than traditional chemotherapy. Additionally, this regimen's alternating cycle with Aza/Ven (Azacitidine and Venetoclax) could offer a more dynamic and personalized treatment plan for patients who may not respond to standard treatments.

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

Research has shown that using cladribine and venetoclax together may help treat acute myeloid leukemia (AML), especially in patients unresponsive to other treatments. In this trial, one group of participants will receive cladribine plus venetoclax. Studies found that about 80% of AML patients showed no signs of the disease after this treatment. Long-term results were also positive, with 76% of patients remaining in remission for at least two years, suggesting the treatment could lead to lasting remission for many. Another group in this trial will receive alternating cycles of venetoclax with azacitidine and cladribine with venetoclax. Combining venetoclax with azacitidine has improved survival rates compared to azacitidine alone. These findings suggest that these drug combinations could be effective options for people with AML. ^{2 6 7 8 9}

Who Is on the Research Team?

Christine McMahon, MD

Principal Investigator

University of Colorado, Denver

Are You a Good Fit for This Trial?

This trial is for adults over 18 with a specific type of Acute Myeloid Leukemia (AML) that hasn't responded to previous treatments. Women must be postmenopausal, surgically sterile, or use contraception; men need to use contraception too. Participants should have an expected lifespan of at least 12 weeks and be physically able enough to do daily activities with some effort.

Inclusion Criteria

Subject must voluntarily sign an informed consent, approved by the Institutional Research Board (IRB), prior to the initiation of any research-related screening or study procedures.

My liver tests are within normal limits, or slightly elevated due to my condition.

My AML didn't respond or came back after treatment with HMA and venetoclax.

Exclusion Criteria

I had cancer before, but it was either skin cancer, in situ breast or cervix cancer, or treated prostate cancer.

Subject is known to be positive for HIV. HIV testing is not required.

My acute myeloid leukemia (AML) has spread to my brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cladribine and venetoclax in 28-day cycles, with cladribine administered intravenously on days 1-5 and venetoclax orally on days 1-28.

6 months

Monthly visits for each cycle

Consolidation

Alternating 28-day cycles of Aza/Ven and Clad/Ven for responders, continuing until disease progression or treatment failure.

Variable, up to 4 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment, with a focus on overall survival and event-free survival.

Minimum of 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Cladribine
• Venetoclax

Trial Overview The study tests Cladribine combined with Venetoclax and Azacitidine in patients whose AML has returned or didn't respond after initial treatment. It's specifically for those who've had hypomethylating agents plus Venetoclax before and now have limited options.

How Is the Trial Designed?

Group I: Cladribine plus Venetoclax Experimental Treatment 2 Interventions

Subjects will receive cladribine at a dose of 5mg/m2 daily via intravenous infusion on days 1 through 5 of a 28 day cycle. Concomitantly, venetoclax will be administered orally at a dose of 100mg on day 1, 200mg on day 2, and 400mg daily on days 3 through 28.

Group II: Alternating Aza/Ven and Clad/Ven Experimental Treatment 3 Interventions

Alternating 28-day consolidation cycles of Aza/Ven (even cycles) and Clad/Ven (odd cycles), while those who do not respond will come off the study.

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

Approved in United States as Leustatin for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma
• Multiple sclerosis

Approved in European Union as Litak for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

The Leukemia and Lymphoma Society

Collaborator

Trials

87

Recruited

26,200+

Published Research Related to This Trial

In a study involving 15 Chinese patients with acute myeloid leukemia (AML) who could not tolerate intensive chemotherapy, venetoclax combined with low-dose cytarabine (LDAC) showed a 38% reduction in the risk of death compared to placebo, with a median overall survival of 9.0 months versus 4.1 months for the placebo group.

The treatment resulted in a complete remission rate of 33% among those receiving venetoclax, while no patients in the placebo group achieved remission, indicating that venetoclax with LDAC is an effective option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Venetoclax with low-dose cytarabine for patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy: results from the Chinese cohort of a phase three randomized placebo-controlled trial]. Hu, Y., Jin, J., Zhang, Y., et al.[2021]

In a phase 3 trial involving 211 adults with acute myeloid leukemia (AML) who were not eligible for intensive chemotherapy, the combination of venetoclax and low-dose cytarabine (LDAC) showed a clinically meaningful improvement in overall survival, with a median survival of 8.4 months compared to 4.1 months for LDAC alone.

The treatment also resulted in higher remission rates, with 48% of patients achieving complete remission or complete remission with incomplete blood count recovery, while maintaining a manageable safety profile, despite some significant adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Wei, AH., Montesinos, P., Ivanov, V., et al.[2021]

The combination of venetoclax with hypomethylating agents (HMA) has significantly improved survival rates in patients with acute myeloid leukemia (AML), as demonstrated in a phase 3 study.

Venetoclax is also safe when added to standard intensive regimens, leading to high remission rates and measurable residual disease negativity in both newly diagnosed and relapsed/refractory AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with nucleoside analogs in acute myelogenous leukemia. Ball, BJ., Koller, PB., Pullarkat, V.[2023]

In a study of 6 children with refractory or relapsed acute myeloid leukemia (AML), the combination of venetoclax, azacitidine, and cladribine (VAC regimen) resulted in significant treatment responses, with 4 achieving complete remission and 1 showing partial remission.

Despite severe side effects like grade IV neutropenia and thrombocytopenia, there were no treatment-related deaths or infections, indicating that the VAC regimen is both effective and safe for this vulnerable patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and the Short-Term Efficacy of Venetoclax Combined with Azacitidine Followed by Cladribine in Children with Refractory/Relapsed Acute Myeloid Leukemia]. DU, WW., Liu, SX., Wang, Y., et al.[2023]

In a phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

In a subgroup of 27 Japanese patients with newly diagnosed acute myeloid leukaemia, venetoclax combined with low-dose cytarabine showed a higher complete remission rate (44.4%) compared to placebo (11.1%), indicating potential efficacy in this population.

Despite the higher remission rate, the median overall survival was similar between the venetoclax (4.7 months) and placebo (8.1 months) groups, suggesting limited survival benefit, which may be influenced by small sample size and baseline health differences among patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus low-dose cytarabine in Japanese patients with untreated acute myeloid leukaemia ineligible for intensive chemotherapy. Yamauchi, T., Yoshida, C., Usuki, K., 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 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, 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 phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., et al.[2023]

Citations

1. venclextahcp.com venclextahcp.com/aml/efficacy/ven-aza/survival-results.html

VEN+AZA: Overall survival (OS) data from the VIALE-A trial Fatal adverse reactions occurred in 23% of patients who received VENCLEXTA in combination with azacitidine, with the most frequent (≥2%) being pneumonia (4%), ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10928973/

Meta‑analysis of the efficacy of venetoclax and azacitidine ... The combination of venetoclax and azacitidine demonstrated greater overall efficacy than azacitidine monotherapy for AML treatment. Notably, combination therapy ...

3. ashpublications.org ashpublications.org/blood/article/145/11/1126/534406/Efficacy-and-safety-of-venetoclax-plus-azacitidine

Efficacy and safety of venetoclax plus azacitidine for patients ... Overall, venetoclax plus azacitidine at the RP2D was well tolerated and had favorable outcomes. A phase 3 study (NCT04401748) is ongoing to ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38343151/

Long-term follow-up of VIALE-A: Venetoclax and ... Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04161885

NCT04161885 | A Study Evaluating Safety and Efficacy of ... The main objective of this study is to evaluate the efficacy of venetoclax in combination with azacitidine to improve Overall Survival (OS) in Acute Myeloid ...

6. venclextahcp.com venclextahcp.com/aml/side-effects/ven-aza-safety-profile.html

VEN+AZA: Summary of safety data from the VIALE-A trial A tolerable, manageable, and predictable safety profile1. No additional warnings or precautions were observed in the AML trials for VENCLEXTA (venetoclax ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04161885

NCT04161885 | A Study Evaluating Safety and Efficacy of ... The main objective of this study is to evaluate the efficacy of venetoclax in combination with azacitidine to improve Overall Survival (OS) in Acute Myeloid ...

8. venclexta.com venclexta.com/aml/why-venclexta/venclexta-azacitidine

How Effective is VENCLEXTA® + azacitidine Against AML? In a clinical study, VENCLEXTA + azacitidine was found to help some adults with AML live longer than those treated with azacitidine alone.

9. venclextahcp.com venclextahcp.com/aml/side-effects/ven-dec-safety-profile.html

VEN+DEC: Summary of safety data from Study M14-358 A tolerable, manageable, and predictable safety profile1. No additional warnings or precautions for VENCLEXTA (venetoclax tablets) were observed in the AML ...