Venetoclax + Cladribine for Acute Myeloid Leukemia

Recruiting at 1 trial location

Overseen by Christine McMahon, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial uses Cladribine and Venetoclax to treat a specific type of leukemia that hasn't responded to other treatments. Cladribine has been used effectively in treating various blood cancers, including hairy cell leukemia. It targets patients with a type of leukemia who didn't improve with previous therapies. The treatment works by stopping cancer cells from growing and making them easier to kill.

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.

What data supports the effectiveness of the drug combination Venetoclax and Cladribine for treating Acute Myeloid Leukemia?

Research shows that adding Venetoclax to treatments like 5-azacitidine or low-dose cytarabine improves remission rates and survival in patients with acute myeloid leukemia, especially those who are older or cannot handle intensive chemotherapy. This suggests that the combination of Venetoclax and Cladribine could also be effective for similar patients. ^{1 2 3 4 5}

Is the combination of Venetoclax and Cladribine safe for treating Acute Myeloid Leukemia?

The combination of Venetoclax with other drugs like low-dose cytarabine and azacitidine has shown a manageable safety profile in patients with Acute Myeloid Leukemia, with common side effects including low potassium levels, vomiting, and constipation. This suggests that Venetoclax, when combined with other treatments, is generally safe for human use in this context. ^{2 3 6 7 8}

How is the drug Venetoclax + Cladribine unique for treating acute myeloid leukemia?

The combination of Venetoclax and Cladribine for acute myeloid leukemia is unique because it combines Venetoclax, a drug that targets cancer cell survival, with Cladribine, a nucleoside analog that disrupts DNA synthesis in cancer cells. This combination aims to improve treatment outcomes by using two different mechanisms to attack the cancer. ^{1 2 6 9 10}

Research Team

Christine McMahon, MD

Principal Investigator

University of Colorado, Denver

Eligibility Criteria

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

I am 18 years old or older.

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 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.

Trial Timeline

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

Treatment Details

Interventions

• Azacitidine (Anti-metabolites)
• Cladribine (Anti-metabolites)
• Venetoclax (BCL-2 Inhibitor)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Aviva Abosch

University of Colorado, Denver

Chief Medical Officer since 2019

MD

Uday B. Kompella

University of Colorado, Denver

Chief Executive Officer since 2015

PhD in Pharmaceutical Sciences

The Leukemia and Lymphoma Society

Collaborator

Trials

87

Recruited

26,200+

E. Anders Kolb

The Leukemia and Lymphoma Society

Chief Executive Officer since 2024

MD from Sidney Kimmel Medical College at Thomas Jefferson University

Gwen Nichols

The Leukemia and Lymphoma Society

Chief Medical Officer since 2016

MD from Columbia University

Findings from Research

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]

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 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]

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]

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]

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 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]

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]

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 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]

References

1. United States 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. [2023]

2. China 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]. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of glasdegib versus venetoclax combined with low-dose cytarabine in acute myeloid leukemia. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Venetoclax plus low-dose cytarabine in Japanese patients with untreated acute myeloid leukaemia ineligible for intensive chemotherapy. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with nucleoside analogs in acute myelogenous leukemia. [2023]

7. China 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]. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

10. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021]