Venetoclax + Azacitidine for Myelodysplastic Syndrome

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: BCL2 inhibitors

Disqualifiers: Low-risk MDS, Pregnant, Cognitively impaired, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4-8 weeks per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of combining venetoclax (a cancer treatment) and azacitidine (a chemotherapy drug) for patients with high-risk myelodysplastic syndrome (MDS) that has returned or is unresponsive to other treatments. These drugs aim to stop cancer cells from growing and spreading. The trial suits those with high-risk MDS who have not succeeded with previous treatments, especially if the condition affects daily life. Participants will receive the drugs in cycles to determine the best dosage while monitoring any side effects. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, hydroxyurea is allowed to lower white cell count before starting venetoclax.

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

Research has shown that combining venetoclax and azacitidine has been tested for safety in people with certain blood cancers. Studies suggest that this combination can sometimes work better than azacitidine alone. Regarding safety, research found that the combination is generally well-tolerated, though some people experienced side effects, such as low blood counts, infections, and fatigue.

Since this trial is in its early stages, researchers are closely monitoring safety. Early-phase trials aim to find the right dose and check for any side effects. While venetoclax and azacitidine are used in other treatments, the specific safety details for this combination in high-risk myelodysplastic syndrome remain under study. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of venetoclax and azacitidine for treating myelodysplastic syndrome because it offers a novel approach compared to existing treatments. While standard therapies mainly focus on modifying the bone marrow environment or boosting blood cell production, venetoclax works by targeting and inhibiting the BCL-2 protein, which helps cancer cells survive. This unique mechanism may lead to more effective cancer cell death. Additionally, the combination with azacitidine, which is already used to treat this condition, could potentially enhance the overall efficacy, offering new hope for patients who may not respond adequately to current treatments.

What evidence suggests that venetoclax and azacitidine might be effective for myelodysplastic syndrome?

Research has shown that using venetoclax with azacitidine effectively treats high-risk myelodysplastic syndrome (MDS). In this trial, participants will receive this combination. One study found that more patients experienced remission, meaning a reduction or disappearance of cancer signs, with this combination compared to azacitidine alone. Another review highlighted its particular effectiveness for MDS and its promise in treating related blood cancers like acute myeloid leukemia (AML). This treatment stops cancer cells from growing and dividing, helping to control the disease. Overall, evidence suggests that venetoclax and azacitidine together can be a strong treatment option for MDS. ^{1 2 3 4 6}

Who Is on the Research Team?

Guillermo Garcia-Manero

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with high-risk myelodysplastic syndrome that's either come back or isn't responding to treatment. They should have normal bilirubin and creatinine levels, not be pregnant or breastfeeding, and agree to use contraception. People who've had BCL2 inhibitor therapy or have low-risk MDS aren't eligible.

Inclusion Criteria

Alanine aminotransferase (ALT) < 4 x ULN unless considered due to leukemic involvement

For phase II, patients will be divided into 2 cohorts: Cohort A: patients with HMA-naive high-risk MDS (Int-2 or high risk by the IPSS with overall score >= 1.5) with excess blasts > 5%. Cohort B: patients with relapsed/refractory MDS post-HMA failure (defined as prior receipt of 4 cycles of HMA therapy with failure to attain a response, or progression of disease or relapse at any time after prior response to HMA therapy) with > 5% blasts are eligible. Note: Patients with chronic myelomonocytic leukemia (CMML) and therapy-related MDS are eligible. Hydroxyurea is allowed to lower the white cell count =< 10,000/ul prior to initiation of venetoclax

Total bilirubin < 3 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement

Exclusion Criteria

My MDS is classified as low or intermediate-1 risk.

I have cognitive impairment.

I have previously received BCL2 inhibitor therapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax orally once daily on days 1-7 or 1-14 and azacitidine subcutaneously or intravenously over 15 minutes on days 1-5. Cycles repeat every 4-8 weeks in the absence of disease progression or unacceptable toxicity.

4-8 weeks per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 3-6 months for up to 5 years.

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Venetoclax

Trial Overview The trial is testing the combination of two chemotherapy drugs, Venetoclax and Azacitidine, to find the safest dose and see how well they work together in treating patients with aggressive forms of myelodysplastic syndrome.

How Is the Trial Designed?

Group I: Treatment (venetoclax, azacitidine) Experimental Treatment 2 Interventions

Patients receive venetoclax orally PO QD on days 1-7 or 1-14 and azacitidine SC or IV over 15 minutes on days 1-5. Cycles repeat every 4-8 weeks in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza 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+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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 rat model, combining thalidomide with irinotecan (CPT-11) significantly reduced the dose-limiting toxicities such as diarrhea and blood cell count decreases associated with CPT-11 treatment.

Thalidomide altered the pharmacokinetics of CPT-11, increasing its plasma concentration while decreasing the levels of its toxic metabolite SN-38, suggesting that thalidomide may help mitigate the harmful effects of CPT-11 through pharmacokinetic modulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic mechanisms for reduced toxicity of irinotecan by coadministered thalidomide. Yang, XX., Hu, ZP., Chan, SY., et al.[2019]

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 phase 1b study involving 44 patients with relapsed/refractory higher-risk myelodysplastic syndromes (MDS), the combination of venetoclax and azacitidine demonstrated significant activity, with a median overall survival of 12.6 months after prior treatment failure with hypomethylating agents.

The treatment resulted in hematological improvements, including complete remission in 7% of patients and transfusion independence in 36%, indicating that venetoclax plus azacitidine can provide meaningful clinical benefits for patients with limited options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. Zeidan, AM., Borate, U., Pollyea, DA., et al.[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]

Irinotecan, a water-soluble analogue of camptothecin, effectively targets DNA topoisomerase I to induce cancer cell death, showing activity against various cancers including leukemia and colorectal cancer, with a dose-response relationship observed in phase I trials.

The drug's pharmacokinetics reveal significant interpatient variability, with adverse effects like neutropenia and diarrhea correlating with plasma concentrations of irinotecan and its active metabolite SN-38, highlighting the importance of monitoring these levels to optimize treatment and minimize toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of irinotecan. Chabot, GG.[2018]

A 71-year-old patient with recurrent cervical cancer who is a compound heterozygote for UGT1A1*6 and UGT1A1*28 experienced significant hematotoxicity (grade 4 neutropenia, grade 3 anemia, and grade 4 thrombocytopenia) while receiving irinotecan hydrochloride (CPT-11) at a dose of 60 mg/m², indicating potential risks associated with this treatment in similar patients.

Despite the absence of previous case reports linking serious adverse events to CPT-11 in this genetic context, the observed severe side effects suggest that careful monitoring and dose adjustments are necessary for patients with these UGT1A1 variants undergoing combined chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent cervical cancer in a patient who was compound heterozygous for UGT1A1*6 and UGT1A1*28 presenting with serious adverse events during irinotecan hydrochloride/nedaplatin therapy. Takatori, E., Shoji, T., Miura, Y., et al.[2018]

In a study of 43 patients with light-chain amyloidosis (AL) treated with venetoclax, the overall hematologic response rate was 68%, with 63% achieving very good partial response (VGPR) or complete response (CR), indicating that venetoclax is an effective treatment option for AL.

Patients with the t(11;14) genetic alteration had significantly better outcomes, with an 81% hematologic response rate and a median progression-free survival (PFS) that was not reached, compared to 40% response and a median PFS of 6.7 months for those without this alteration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis. Premkumar, VJ., Lentzsch, S., Pan, S., et al.[2021]

Irinotecan (CPT-11) has demonstrated a broad range of antitumor activity across various cancer types, including lymphoma, leukemia, and several solid tumors, although most studies have focused on colorectal and gastrointestinal cancers.

Preliminary results indicate that irinotecan shows modest but reproducible activity in multiple cancers, suggesting the need for further well-designed clinical trials to better understand its efficacy and optimal use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan in lymphoma, leukemia, and breast, pancreatic, ovarian, and small-cell lung cancers. Rosen, LS.[2018]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10100228/

A phase 1b study of venetoclax and azacitidine ... Poor outcome of patients with myelodysplastic syndrome after azacitidine treatment failure. Clin Lymphoma Myeloma Leuk. 2013;13(6):711‐715. [DOI] [PubMed] ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04160052

Venetoclax and Azacitidine for the Treatment of High-Risk ... This phase I/II trial studies the side effects and best dose of venetoclax when given together with azacitidine in treating patients with high-risk ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04401748

NCT04401748 | Study Of Venetoclax Tablet With ... The purpose of this study is to see how safe and effective venetoclax and azacitidine (AZA) combination are when compared to AZA and a placebo (contains no ...

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

Full article: The efficacy and safety of venetoclax and ... The present meta-analysis demonstrated that the Ven + AZA regimen is efficacious for the treatment of AML and MDS, with it being more effective for ND-AML than ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa2012971

Azacitidine and Venetoclax in Previously Untreated Acute ... The incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone.

6. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04401748/

Clinical Trial: NCT04401748 The purpose of this study is to see how safe and effective venetoclax and azacitidine (AZA) combination are when compared to AZA and a placebo.