Venetoclax Combination Therapy for Acute Myeloid Leukemia

Overseen By Amberley Kemic, RN

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Medical College of Wisconsin

Disqualifiers: Infections, DNA fragility syndromes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 10 weeks

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding venetoclax, a targeted therapy, to other drugs can improve treatment for acute myeloid leukemia (AML), a type of blood cancer. The researchers aim to determine if this new combination enhances patient response compared to standard treatments. The study includes two groups: one for patients with Down syndrome and one for those without. Suitable participants have experienced a relapse or have not responded to previous treatments and currently have measurable AML in their bone marrow. The trial is open to individuals without ongoing infections and who are not allergic to the study drugs. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, if you are taking strong or moderate CYP3A4 inhibitors or P-glycoprotein inhibitors, your venetoclax dose may need to be adjusted. It's best to discuss your current medications with the study team.

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

A previous study found that the combination of venetoclax, azacitidine, and vorinostat was safe for patients with acute myeloid leukemia (AML). Most side effects were expected and manageable, with low white blood cell counts and fever being the main issues, common in cancer treatments.

Research has shown that this combination is well tolerated, even in children with recurring or hard-to-treat AML, suggesting it might be safe for different age groups. No additional warnings or precautions have been noted specifically for this combination in AML trials.

As this trial is in an early stage, researchers are still studying the safety details. However, initial findings regarding its safety are promising. Always consult a healthcare provider to understand what this may mean personally. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for AML?

Researchers are excited about this combination therapy for Acute Myeloid Leukemia (AML) because it introduces Venetoclax, a drug that blocks the BCL-2 protein, which cancer cells use to avoid self-destruction. Unlike traditional chemotherapy treatments, Venetoclax targets this specific protein, potentially leading to more effective cancer cell elimination. Additionally, the combination with Azacitidine, Vorinostat, Fludarabine, and Cytarabine may enhance the overall treatment effectiveness by attacking the leukemia cells through multiple pathways, offering hope for improved outcomes compared to current standard treatments like standalone chemotherapy. This approach could lead to faster and more comprehensive responses in patients with AML, whether or not they have Down Syndrome.

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

This trial will evaluate the effectiveness of a combination therapy involving venetoclax, azacitidine, and vorinostat for treating acute myeloid leukemia (AML). Studies have shown that this combination can be effective. Specifically, one study indicated that 66.4% of patients who couldn't undergo intensive chemotherapy achieved remission. Another study found that 75% of children with AML that had returned or was difficult to treat had a complete response. Additionally, research shows that using venetoclax and azacitidine together can lead to a complete response in about 29.9% of patients, with another 50.5% showing significant improvement. These findings suggest that adding venetoclax to the treatment plan might improve the overall response for AML patients. Participants in this trial will receive this combination therapy, with specific regimens for those with and without Down Syndrome. ^{6 7 8 9 10}

Who Is on the Research Team?

Michael Burke, MD

Principal Investigator

Medical College of Wisconsin

Are You a Good Fit for This Trial?

This trial is for AML patients who've relapsed or didn't respond to initial treatments. They must have recovered from previous therapies, have no severe infections or GVHD if post-transplant, and meet specific organ function criteria. Pregnant women can't participate, and contraception is required for those of childbearing potential.

Inclusion Criteria

My cancer has returned after treatment or did not respond to initial treatments.

My AML is detectable in my bone marrow.

My kidney and liver tests are within normal ranges.

Exclusion Criteria

Significant concurrent disease, illness, psychiatric disorder, or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results

Patients with a known allergy to any of the drugs used in the study

Patients with any positive fungal culture within 30 days prior to enrollment or evidence of disseminated fungal disease

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax, azacitidine, and vorinostat followed by standard chemotherapy over two 35-day cycles

10 weeks

Multiple visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

42 months

What Are the Treatments Tested in This Trial?

Interventions

• Azacitadine
• Cytarabine
• Filgrastim
• Fludarabine
• Venetoclax
• Vorinostat

Trial Overview The study tests adding venetoclax to azacitidine and vorinostat before standard chemo in AML patients. The goal is to improve treatment response by combining these drugs with chemotherapy agents like cytarabine and fludarabine.

How Is the Trial Designed?

Group I: AML without Down Syndrome Experimental Treatment 6 Interventions

The subject receives 2 courses of therapy approximately 35 days each. Venetoclax: Days 1-14 Azacitidine and Vorinostat: Days 1-5 Filgrastim Days: 5 start and continue until post-nadir ANC \> 500 cells/mm3 Fludarabine and Cytarabine Days 6 - 10 IT Cytarabine Day 0 or 1, optional between day 35 and 42

Group II: AML with Down Syndrome Experimental Treatment 6 Interventions

The subject receives 2 courses of therapy approximately 35 days each. Venetoclax: Days 1-14 Azacitidine and Vorinostat: Days 1-5 Filgrastim Days: 5 start and continue until post-nadir ANC \> 500 cells/mm3 Fludarabine and Cytarabine Days 6 - 10 IT Cytarabine Day 0 or 1, optional between day 35 and 42

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

Approved in United States as Vidaza for:

• Myelodysplastic Syndrome
• Acute Myeloid Leukemia

Approved in European Union as Vidaza for:

• Myelodysplastic Syndrome
• Acute Myeloid Leukemia
• Juvenile Myelomonocytic Leukemia

Who Is Running the Clinical Trial?

Medical College of Wisconsin

Lead Sponsor

Trials

645

Recruited

1,180,000+

Published Research Related to This Trial

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 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., et al.[2023]

In a Japanese subgroup of the phase 3 VIALE-A trial, venetoclax-azacitidine significantly improved overall survival rates compared to placebo-azacitidine, with 67% of patients alive at 12 months versus 46% in the placebo group.

The treatment also resulted in a high complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 67%, while maintaining a safety profile similar to the global study, indicating it is a viable first-line treatment for Japanese patients with acute myeloid leukemia ineligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Yamamoto, K., Shinagawa, A., DiNardo, CD., et al.[2023]

In a study of 50 adults with acute myeloid leukemia (AML) in Mexico and Peru, venetoclax-based therapy showed a high complete response rate of 78.6% in newly diagnosed patients and 45.5% in those with relapsed/refractory disease, indicating its efficacy in treating AML.

The median overall survival was 9.6 months for newly diagnosed patients and 8 months for relapsed/refractory patients, suggesting that venetoclax is a viable treatment option even in real-world settings, despite common hematologic toxicities and dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. Gómez-De León, A., Demichelis-Gómez, R., Pinedo-Rodríguez, A., et al.[2022]

In elderly patients with newly diagnosed acute myeloid leukemia (AML), venetoclax at a dose of 400 mg once daily (QD) combined with hypomethylating agents (HMA) significantly increased the probability of response, while 600 mg QD was optimal when combined with low-dose cytarabine (LDAC).

The study, which included 304 patients across two treatment groups, found that higher doses of venetoclax (≥800 mg QD) led to tolerability issues, but did not significantly increase the risk of serious adverse events, indicating that lower doses can maximize efficacy while maintaining safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing venetoclax dose in combination with low intensive therapies in elderly patients with newly diagnosed acute myeloid leukemia: An exposure-response analysis. Agarwal, S., Gopalakrishnan, S., Mensing, S., et al.[2020]

In patients with newly diagnosed unfit acute myeloid leukemia (AML), the combination of azacitidine and venetoclax is a standard first-line treatment.

However, patients with TP53-mutated AML and poor-risk cytogenetics do not benefit from adding venetoclax to azacitidine, suggesting that alternative treatment regimens should be considered for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. Green, SD., Zeidner, JF.[2023]

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 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 pooled analysis of treatment-naïve patients with FLT3-mutant acute myeloid leukemia, the combination of venetoclax and azacitidine resulted in a significantly higher composite complete remission rate (67%) compared to azacitidine alone (36%), with a median overall survival of 12.5 months versus 8.6 months.

The treatment was found to be safe, with no unexpected toxicities reported, indicating that venetoclax + azacitidine is a promising option for older patients or those with comorbidities who are ineligible for intensive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia. Konopleva, M., Thirman, MJ., Pratz, KW., 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 study of 60 patients with acute myeloid leukemia (AML), the combination of venetoclax and azacitidine (Ven+AZA) demonstrated a high response rate, with 70.8% of previously untreated patients unfit for standard chemotherapy achieving complete remission (CR) or CR with incomplete hematological recovery (CRi) after one cycle.

Ven+AZA was found to be safe and tolerable, with some patients achieving minimal residual disease (MRD) negativity, particularly in those with favorable genetic mutations like NPM1, IDH1/IDH2, and TP53, indicating its potential effectiveness in specific patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. Yu, WJ., Jia, JS., Wang, J., et al.[2022]

Citations

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Combination therapy involving azacitidine for acute ... AZA-Venetoclax Combo Shows 66.4 % Remission in Unfit AML Patients: A significant survival milestone in treating Unfit AML. •. Personalized AML Treatments ...

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Venetoclax, Azacitidine, Vorinostat and FLAG for Pediatric ... Three patients (75%) achieved complete response (CR) with 1 patient developing progressive disease. All 3 patients achieving a CR also achieved ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11923426/

Efficacy and safety of venetoclax plus azacitidine for ... As of May 2023, 107 patients received venetoclax and azacitidine combination at the RP2D. Best response of CR or marrow CR was observed in 29.9% and 50.5% (mOR, ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40496033/

Outcomes of patients with Acute Myeloid Leukemia ... Our findings contribute to the growing evidence that venetoclax combined with azacitidine is an effective treatment option for elderly patients with AML.

5. clin.larvol.com clin.larvol.com/abstract-detail/ASH%202024/73812092

ASH 2024: Venetoclax, Azacitidine, Vorinostat and FLAG ... Venetoclax, Azacitidine, Vorinostat and FLAG for Pediatric Patients with Relapsed/Refractory Acute Myeloid Leukemia. Authors.

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. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40826699/

Venetoclax combined with azacitidine in elderly acute ... Venetoclax combined with azacitidine in elderly acute myeloid leukemia: A retrospective comparison of 14-day vs 28-day dosing regimens.

8. tandfonline.com tandfonline.com/doi/full/10.1080/16078454.2023.2198098

Full article: The efficacy and safety of venetoclax and ... The most common adverse effects of this regimen are grade 3–4 neutropenia and neutropenia with fever. KEYWORDS: Meta-analysis · acute myeloid leukemia ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124089109

Venetoclax, Azacitidine, Vorinostat and FLAG for Pediatric ... Our Phase I study and real-world data report Ven with 5-azacitidine, vorinostat, and FLAG was well tolerated with promising response rates in pediatric R/R AML.

10. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/20/NCT04102020/SAP_001.pdf

Statistical Analysis Plan for Study M19-708 Phase 3 Study of Venetoclax and Azacitidine Versus. Best Supportive Care as Maintenance Therapy for. Patients with Acute Myeloid Leukemia (AML) ...