Triple Drug Combo for Myeloid Leukemia

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

16 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this research study is to test the safety of a new three drug combination of navitoclax, decitabine, and venetoclax to treat advanced myeloid malignancies. The names of the drugs involved in this study are: * Venetoclax * Decitabine * Navitoclax

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.

What data supports the effectiveness of the drug combination for myeloid leukemia?

Research shows that combining venetoclax with decitabine improves survival and response rates in older patients with acute myeloid leukemia compared to decitabine alone. In one study, patients receiving the combination had a longer median overall survival of 13.4 months compared to 8.3 months for those on decitabine alone. ^{1 2 3 4 5}

What safety data exists for the combination of venetoclax and decitabine in humans?

The combination of venetoclax and decitabine has been studied in elderly patients with acute myeloid leukemia (AML) and is generally well tolerated. Common side effects include nausea, diarrhea, constipation, fatigue, and low white blood cell counts. Serious side effects like neutropenia (low levels of a type of white blood cell) and anemia (low red blood cell count) were also observed, but no tumor lysis syndrome (a serious condition caused by the rapid breakdown of cancer cells) was reported. ^{1 2 3 6 7}

What makes the triple drug combo for myeloid leukemia unique?

The triple drug combo for myeloid leukemia, which includes Decitabine, Navitoclax, and Venetoclax, is unique because it combines a hypomethylating agent (Decitabine) with Venetoclax, a drug that targets BCL-2 proteins to help kill cancer cells, and Navitoclax, which may enhance the effectiveness of Venetoclax. This combination is particularly promising for older patients or those unfit for intensive chemotherapy, offering improved survival rates and response rates compared to Decitabine alone. ^{1 2 3 6 7}

Research Team

Jacqueline S. Garcia, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

I am 18 years old or older.

Subject must voluntarily sign and date an informed consent

Subjects must be able to swallow pills

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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]

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 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 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]

References

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

Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. [2022]

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

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. [2021]

3. China pubmed.ncbi.nlm.nih.gov

[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience]. [2023]

4. 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]

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

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

6. England 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. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

A real-world study of infectious complications of venetoclax combined with decitabine or azacitidine in adult acute myeloid leukemia. [2022]