Triple Drug Combo for Myeloid Leukemia

Not currently recruiting at 2 trial locations

Overseen By Jacqueline S. Garcia, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Jacqueline Garcia, MD

Must not be taking: CYP3A inducers

Disqualifiers: Active malignancy, CNS AML, others

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

Compensation: Varies

Number of Visits: 32

Duration: Indefinite

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of a new combination of three drugs—venetoclax, decitabine (a chemotherapy drug), and navitoclax—for treating advanced myeloid malignancies, which are serious blood cancers. The trial explores different doses to determine the safest and most effective level. It suits individuals with specific myeloid diseases, such as myelofibrosis or acute myeloid leukemia, who lack other treatment options. Participants must exhibit specific symptoms, like a high percentage of certain cells in the blood or bone marrow, and must be able to swallow pills. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot take certain medications like hydroxyurea close to the start of the trial. If you're on venetoclax, a washout period (time without taking the medication) is required. Some medications that affect liver enzymes may need to be adjusted or stopped.

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

Research shows that the combination of venetoclax, decitabine, and navitoclax is generally safe for patients. Studies have found that venetoclax with decitabine is safe, even for older patients with acute myeloid leukemia (AML). This combination has been tested in patients who previously tried other treatments, and it proved manageable.

Previous trials also tested adding navitoclax to this mix. The results showed that most patients handled this combination well, even those with multiple prior treatments. Some side effects occurred, but they were considered acceptable given the situation.

Since this trial is in its early phase, it closely monitors safety and how the body reacts to the treatment. Participants will be watched carefully for any side effects or issues. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this triple drug combo for myeloid leukemia because it combines Decitabine, Venetoclax, and Navitoclax in a way that targets cancer cells more aggressively than current standard treatments. Unlike traditional chemotherapy, Venetoclax and Navitoclax work by inhibiting proteins that help cancer cells survive, potentially leading to more effective cancer cell death. Additionally, these drugs can be taken orally, which is a more convenient option compared to the intravenous methods commonly used in standard treatments. This combination has the potential to offer a more targeted approach with possibly fewer side effects, making it a promising option for patients.

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

Research has shown that using venetoclax with decitabine may help treat acute myeloid leukemia (AML), particularly in older adults. Studies have found this combination to be effective and safe for patients who might not tolerate stronger treatments. Venetoclax has also proven effective for other blood cancers, such as non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). In this trial, participants will receive a combination of venetoclax, decitabine, and navitoclax. Adding navitoclax could enhance the effectiveness of venetoclax, although research on this three-drug combination continues. Early results are promising, suggesting it could be a strong option for treating advanced myeloid cancers. ^{6 7 8 9 10}

Who Is on the Research Team?

Jacqueline S. Garcia, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults diagnosed with advanced myeloid malignancies such as Myeloid Leukemia or Myelodysplastic Syndrome, who have not responded to certain previous treatments, can join. They must be in good general health with proper liver and kidney function, able to swallow pills, and willing to use contraception if of childbearing potential.

Inclusion Criteria

Subject must voluntarily sign and date an informed consent

Subjects must be able to swallow pills

Subjects must have a diagnosis of one of the following: Myelofibrosis in accelerated phase (AP-MF) with 10-19% blasts in bone marrow or blood, Myelofibrosis in blast phase (BP-MF) with ≥ 20% blasts in bone marrow or blood, Untreated secondary AML (s-AML) including therapy-related disease or known antecedent MDS or MDS/MPN, MDS/MPN overlap syndromes (e.g. CMML) with ≥ 5% blasts, MDS with excess blasts defined as ≥ 5% blasts and meeting specific criteria, ECOG performance status ≤ 2, Baseline platelet count ≥ 25 x 10^9/L, Subjects must have adequate organ function (AST, ALT, bilirubin, renal function, aPTT, INR, prior treatment-related toxicities, CYP3A inhibitors), Female subjects must meet specific criteria if not postmenopausal

Exclusion Criteria

My leukemia has spread to my brain or spinal cord.

I haven't had leukemia treatment in the last 14 days, except for hydroxyurea.

I have never been treated with navitoclax or any BCL-XL inhibitors.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of navitoclax, venetoclax, and decitabine in cycles of 28 days, with treatment continuing indefinitely until disease progression, unacceptable toxicity, or withdrawal.

Indefinite

Cycle-based visits every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, with disease assessments every 4 months up to 2 years.

Up to 2 years

Every 4 months

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• Navitoclax
• Venetoclax

Trial Overview The trial is testing the safety of a new combination treatment for myeloid cancers using three drugs: Navitoclax, Venetoclax, and Decitabine. The goal is to see how well patients tolerate this regimen and what effects it has on their disease.

How Is the Trial Designed?

Group I: Recommended Phase 2 Dose Level: Venetoclax + Decitabine + Navitoclax [AML and Non-AML] Experimental Treatment 3 Interventions

RP2D \[AML and Non-AML\] Decitabine \[intravenously (IV) preferred\] To be determined based on dose escalation design. Venetoclax \[orally\] To be determined based on dose escalation design. Navitoclax \[orally\] To be determined based on dose escalation design. Cycle length=28 days Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.

Group II: Dose Level 2: Venetoclax + Decitabine + Navitoclax [AML] Experimental Treatment 3 Interventions

Dose Level 2 \[AML\] Decitabine \[intravenously (IV) preferred\] Cycle 1+: dosing on days 1-5 Venetoclax \[orally\] Cycle 1: ramp-up on day 1-2, days 3-21 continued dosing in absence of strong/moderate CYP3A inhibitor and reduced doses dependent on presence of moderate or strong CYP3A inhibitor Cycle 2+: dosing on days 1-21 Navitoclax \[orally\] Cycle 1: dosing on days 3-14 Cycle 2+: dosing on days 1-14 Cycle length=28 days Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.

Group III: Dose Level 1: Venetoclax + Decitabine + Navitoclax [AML and Non-AML] Experimental Treatment 3 Interventions

Dose Level 1 \[AML and Non-AML\] Decitabine \[intravenously (IV) preferred\] Cycle 1+: dosing on days 1-5 Venetoclax \[orally\] Cycle 1: ramp-up starting on day 1-2 then days 3-14 continued dosing in absence of strong/moderate CYP3A inhibitor and reduced doses dependent on presence of moderate or strong CYP3A inhibitor Cycle 2+: dosing days 1-14 Navitoclax \[orally\] Cycle 1: Dosing days 3-14 Cycle 2+: dosing on days 1-14 Cycle length=28 days Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.

Group IV: Dose Level 0: Decitabine + Venetoclax + Navitoclax [AML and Non-AML] Experimental Treatment 3 Interventions

Dose Level 0 \[AML and Non-AML\] Decitabine \[intravenously (IV) preferred\] Venetoclax Cycle 1: ramp-up days 1-2 and days 3-14 absence of strong/moderate CYP3A inhibitor and reduced doses dependent on presence of moderate or strong CYP3A inhibitor Cycle 2+: dosing days 1-14 Navitoclax Cycle 1: dosing days 3-14; Cycle 2+: dosing on days 1-14 Cycle length=28 days Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.

Group V: Dose Level -1: Venetoclax + Decitabine + Navitoclax [Non-AML] Experimental Treatment 3 Interventions

Dose Level -1 \[Non-AML\] Decitabine \[intravenously (IV) preferred\] Cycle 1+:dosing \[intravenously (IV) preferred\] on days 1-3 Venetoclax \[orally\] Cycle 1: ramp-up of starting day 1-2 then days 3-7 continued dosing in absence of strong/moderate CYP3A inhibitor and reduced doses dependent on presence of moderate or strong CYP3A inhibitor Cycle 2+: dosing on days 1-7 Navitoclax \[orally\] Cycle 1: Dosing days 3-14 Cycle 2+: continued dosing on days 1-14 Cycle length=28 days Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.

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

Approved in European Union as Dacogen for:

• Acute myeloid leukemia
• Myelodysplastic syndromes

Approved in United States as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Canada as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Jacqueline Garcia, MD

Lead Sponsor

Trials

3

Recruited

130+

AbbVie

Industry Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Published Research Related to This Trial

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 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 study comparing older adults with newly diagnosed acute myeloid leukemia (AML), those treated with the combination of decitabine (DEC) and venetoclax (VEN) had a significantly longer median overall survival of 13.4 months compared to 8.3 months for those receiving DEC alone.

The combination therapy also resulted in a higher response rate of 70.3% versus 24.3% for DEC monotherapy, indicating that DEC+VEN is more effective in treating AML without increasing short-term mortality rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. Kwag, D., Cho, BS., Bang, SY., et al.[2022]

In a study of 81 patients with acute myeloid leukemia (AML) receiving venetoclax with decitabine or azacitidine, 72.8% experienced infections, with the most common pathogens being Candida albicans and Klebsiella pneumonia.

The study found that the incidence of infectious complications was lower with this treatment compared to conventional chemotherapy, and high leukemia burden and fever were identified as significant risk factors for developing infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world study of infectious complications of venetoclax combined with decitabine or azacitidine in adult acute myeloid leukemia. Zhu, LX., Chen, RR., Wang, LL., et al.[2022]

In a phase 2 trial involving 168 patients with acute myeloid leukaemia (AML), the combination of venetoclax and a 10-day regimen of decitabine resulted in a high overall response rate of 74%, with particularly impressive results in newly diagnosed AML patients (89%).

The treatment demonstrated a manageable safety profile, with common adverse events including neutropenia and infections, and a 30-day mortality rate of only 3.6%, indicating that this combination therapy is both effective and relatively safe for older patients or those unfit for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. DiNardo, CD., Maiti, A., Rausch, CR., et al.[2021]

In a study involving 145 older patients (median age 74) with acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy, the combination of venetoclax with decitabine or azacitidine resulted in a high complete remission (CR) rate of 67%, demonstrating its efficacy in this challenging population.

The treatment was well tolerated, with no cases of tumor lysis syndrome reported, and the median overall survival was 17.5 months, indicating that venetoclax combined with hypomethylating agents is a promising option for elderly patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. DiNardo, CD., Pratz, K., Pullarkat, V., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6499443/

Evaluating venetoclax and its potential in treatment-naïve ... Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17. doi: 10.1182 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04746235

Study Details | NCT04746235 | Venetoclax and ASTX727 ... This phase II trial studies the possible benefits of venetoclax and ASTX727 in treating patients with acute myeloid leukemia that has come back (relapsed)

3. researchgate.net researchgate.net/publication/336384955_A_Phase_1b_Study_of_Venetoclax_ABT-199GDC-0199_in_Combination_with_Decitabine_or_Azacitidine_in_Treatment-Naive_Patients_with_Acute_Myelogenous_Leukemia_Who_Are_to_65_Years_and_Not_Eligible_for_Standa

A Phase 1b Study of Venetoclax (ABT-199/GDC-0199) in ... Venetoclax has demonstrated clinical efficacy in a variety of hematological malignancies, including NHL, CLL, multiple myeloma, and acute ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40632299/

The efficacy and safety of venetoclax combined with ... Our findings demonstrated that the VEN + DEC regimen is both effective and safe for treating elderly patients with AML.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04817241

Testing Oral Decitabine and Cedazuridine (ASTX727) in ... Giving ASTX727 in combination with venetoclax may help in the treatment of patients with higher-risk acute myeloid leukemia. Detailed Description. PRIMARY ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04657081

Study Details | NCT04657081 | Pharmacokinetics, Safety, ... The primary purpose of the study is to rule out drug-drug interactions between ASTX727 and venetoclax combination therapy by evaluating area under the curve ( ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12241227/

The efficacy and safety of venetoclax combined with ... The efficacy and safety of venetoclax combined with decitabine in elderly patients with acute myeloid leukemia: a systematic review and meta- ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6551

Phase II trial of 10-day ASTX727 (decitabine/cedazuridine ... We previously demonstrated safety and encouraging activity of 10-day regimen of IV decitabine with venetoclax (VEN) in R/R AML. In this ...

9. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/4264/533524/Phase-1-Trial-of-Navitoclax-Venetoclax-Decitabine

Phase 1 Trial of Navitoclax/Venetoclax/Decitabine ... Conclusion: The addition of NAV to VEN/DEC at all 3 DLs was tolerable with an acceptable safety profile in heavily pretreated and VEN regimen R/ ...

10. clinicaltrials.gov clinicaltrials.gov/study/NCT05222984

NCT05222984 | Navitoclax, Venetoclax, and Decitabine for ... This phase Ib trial is to find the side effect and best dose of navitoclax when given together with venetoclax and decitabine in treating patients with ...