Venetoclax + FLAG Chemotherapy for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Michigan Rogel Cancer Center

Must not be taking: Bcl-2 antagonists, CYP3A inducers

Disqualifiers: APL, CML, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of drugs to determine their effectiveness in treating secondary acute myeloid leukemia (AML). The goal is to see if this treatment can achieve complete remission, meaning no signs of cancer remain after treatment. The trial will test a mix of chemotherapy drugs with venetoclax (also known as Venclexta). Individuals newly diagnosed with secondary AML who have not started other treatments, except for hydroxyurea, are likely suitable candidates for this study. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot receive antileukemic therapy other than hydroxyurea before starting the trial. It's best to discuss your current medications with the study team to get specific guidance.

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

Research has shown that venetoclax, when combined with chemotherapy for acute myeloid leukemia (AML), is generally well-tolerated. Studies have found that venetoclax alone isn't very effective, but it works better when paired with treatments like chemotherapy.

In one study, patients who received venetoclax with chemotherapy showed positive results, indicating that this treatment can be both effective and safe. However, side effects such as low blood cell counts can occur, which is common with chemotherapy. Researchers are studying this combination further to better understand its safety and effectiveness.

Venetoclax is already approved by the FDA for certain conditions, providing some reassurance about its safety. However, as with any treatment, it is crucial to consider the potential benefits and risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Venetoclax combined with FLAG chemotherapy for treating Acute Myeloid Leukemia (AML) because it offers a unique approach by targeting the cancer cells' ability to manage energy. Venetoclax works by inhibiting the BCL-2 protein, which is essential for cancer cell survival, making cancer cells more susceptible to dying off. When paired with the FLAG (or CLAG) chemotherapy regimen, which is a standard but powerful treatment for AML, this combination has the potential to enhance the effectiveness of the chemotherapy. This synergy could lead to better treatment outcomes, especially for patients who haven't responded well to existing options.

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

Research has shown that combining venetoclax with strong chemotherapy can effectively treat acute myeloid leukemia (AML). In this trial, participants will receive venetoclax with either FLAG or CLAG induction chemotherapy. One study found that 86% of AML patients who received a similar combination treatment achieved complete remission, meaning their cancer signs disappeared. Venetoclax works by making cancer cells more vulnerable to chemotherapy. This new treatment approach holds promise, especially for patients with challenging cases, such as secondary AML. ^{1 4 5 6 7}

Who Is on the Research Team?

Dale Bixby, MD, PhD

Principal Investigator

University of Michigan Rogel Cancer Center

Are You a Good Fit for This Trial?

Adults diagnosed with secondary acute myeloid leukemia (AML) who haven't had treatment for it, except possibly hydroxyurea or leukopheresis. They should be in relatively good health (ECOG PS ≤ 2), able to understand and consent to the study, and commit to its duration. Adequate organ function is required, and they must use effective contraception if of childbearing potential.

Inclusion Criteria

I can understand and am willing to sign the consent form.

My organs are functioning well.

I can take care of myself and perform daily activities.

Exclusion Criteria

Consumed specific fruits within a defined period prior to the initiation of study treatment

I am not on specific leukemia treatments except for hydroxyurea or Bcl-2 inhibitors.

Pregnant women or women who are breastfeeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Induction chemotherapy with FLAG or CLAG starting on day 1 and venetoclax given on days 3-16. G-CSF component continues until count recovery.

16 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of complete remission and toxicity.

up to 43 days

Long-term Follow-up

Participants are monitored for progression-free survival, overall survival, and event-free survival.

6 months to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• FLAG Protocol
• Venetoclax

Trial Overview The trial tests a new chemotherapy combo using Venetoclax with either FLAG or CLAG protocol on patients with newly diagnosed secondary AML. The goal is to see how many achieve complete remission after this frontline therapy based on an evaluation of 20 participants.

How Is the Trial Designed?

Group I: Venetoclax + FLAG or CLAG induction chemotherapy Experimental Treatment 2 Interventions

Induction chemotherapy with FLAG starting on day 1 and venetoclax given on days 3-16. The G-CSF component of FLAG will continue until count recovery (ANC at least \> 1000). FLAG dosing will be standard and uniform for all patients and venetoclax dosing will be determined according to institutional guidelines based on the prophylactic antifungal therapy chosen for use during induction therapy. Given the national shortage of Fludarabine, Cladrabine (5mg/m2/day IV over 2 hours) has been substituted (CLAG) with similar toxicity profile.

FLAG Protocol is already approved in United States for the following indications:

Approved in United States as Venclexta for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Who Is Running the Clinical Trial?

University of Michigan Rogel Cancer Center

Lead Sponsor

Trials

303

Recruited

20,700+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

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]

The combination of venetoclax and alvocidib was found to be safe and tolerable in patients with relapsed/refractory Acute Myeloid Leukemia (AML), with no maximum tolerated dose reached, although significant gastrointestinal side effects were common.

The overall response rate to this treatment was modest, with only 11.4% achieving complete or incomplete remission, indicating that while the combination is safe, it may not significantly enhance efficacy compared to using each drug alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia. Jonas, BA., Hou, JZ., Roboz, GJ., et al.[2023]

In a study of 45 patients with newly diagnosed or relapsed/refractory acute myeloid leukemia (AML), the combination of FLAG-IDA and venetoclax achieved a remarkable overall response rate of 98%, with 89% of patients reaching a composite complete remission.

The treatment was associated with manageable non-hematologic adverse events, and after 20 months of follow-up, the estimated 24-month event-free survival and overall survival rates were 64% and 76%, respectively, indicating a favorable outcome compared to historical benchmarks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combined with FLAG-IDA induction and consolidation in newly diagnosed acute myeloid leukemia. DiNardo, CD., Lachowiez, CA., Takahashi, K., et al.[2023]

The combination of venetoclax (VEN) with intensive chemotherapy (FLAG-IDA) shows promising efficacy in treating high-risk acute myeloid leukemia (AML), with complete remission rates ranging from 53% to 89% in newly diagnosed and relapsed/refractory patients across six studies involving 221 patients.

Safety outcomes indicate a significant risk of infections, with rates of neutropenic fever and bacteremia reported between 44-55% and 24-48%, respectively, suggesting that while the regimen is effective, careful monitoring for infections is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of FLAG-Ida-based therapy combined with venetoclax for the treatment for newly diagnosed and relapsed/refractory patients with AML - A systematic review. Sherban, A., Fredman, D., Shimony, S., et al.[2023]

In a study comparing two treatments for relapsed or refractory acute myeloid leukemia (AML), the combination of Venetoclax, low-dose Cytarabine, and Actinomycin D (ACTIVE) showed a significantly higher complete response rate (70%) compared to FLAG-Ida (34%).

ACTIVE also resulted in better overall survival, with patients living an average of 13.1 months compared to 5.1 months for those receiving FLAG-Ida, and had a treatment-related mortality rate of 0%, while FLAG-Ida had a 34% mortality rate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based salvage therapy followed by Venetoclax and DLI maintenance vs. FLAG-Ida for relapsed or refractory acute myeloid leukemia after allogeneic stem cell transplantation. Zucenka, A., Vaitekenaite, V., Maneikis, K., et al.[2022]

In a study comparing treatment regimens for relapsed/refractory acute myeloid leukemia (R/R AML), the venetoclax (VEN) combination therapy showed a comparable overall response rate (59.3%) to intensive chemotherapy (IC) (44.0%), suggesting it is an effective alternative for patients who have failed previous treatments.

Patients receiving the VEN combination had a significantly higher percentage of successful stem cell transplants at blast clearance (86.5% vs. 62.3% for IC), indicating better disease control and potentially lower treatment-related mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective comparison of salvage intensive chemotherapy versus venetoclax-combined regimen in patients with relapsed/refractory acute myeloid leukemia (AML). Park, S., Kwag, D., Kim, TY., et al.[2022]

In a study of 82 adult patients with acute myeloid leukemia (AML), 57% were able to start venetoclax treatment safely in an outpatient setting, demonstrating its feasibility outside of the hospital.

The risk of tumor lysis syndrome (TLS) was very low, with only 2.1% of patients experiencing TLS after starting venetoclax, and 98% of patients did not require hospitalization for TLS within the first week of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. Palmer, S., Patel, A., Wang, C., et al.[2023]

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, a BCL-2 inhibitor, shows promising efficacy in treating acute myeloid leukemia (AML) in older patients, particularly those with poor prognosis and IDH mutations, while maintaining a favorable side-effect profile.

However, resistance to venetoclax can develop quickly when used alone, indicating that combining it with other therapies may be necessary to improve long-term treatment outcomes by overcoming resistance mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapy with a selective BCL-2 inhibitor in older patients with acute myeloid leukemia. Campos, EDV., Pinto, R.[2020]

In a study of 25 patients with acute myeloid leukemia (AML) treated with venetoclax combined with the FLAG-IDA protocol, a high composite complete remission rate of 72% was observed, particularly notable at 91% for patients experiencing post-transplant relapse.

While the treatment showed effectiveness, it was associated with significant risks, including a 12% thirty-day mortality rate and high rates of infectious complications, highlighting the need for careful infection management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with FLAG-IDA-based protocol for patients with acute myeloid leukemia: a real-world analysis. Wolach, O., Frisch, A., Shargian, L., et al.[2022]

The combination of 225 Ac-lintuzumab and venetoclax showed a synergistic effect in killing tumor cells in venetoclax-resistant acute myeloid leukemia (AML) models, indicating a potential new treatment strategy.

This combination therapy not only induced DNA damage but also reduced MCL-1 protein levels, which is linked to resistance against venetoclax, leading to better tumor control and prolonged survival in preclinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. Garg, R., Allen, KJH., Dawicki, W., 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 ... Results were dramatic–venetoclax plus rituximab achieved an 84.9% progression-free survival rate at 2 years, vs the bendamustine plus rituximab arm, which ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9318140/

Targeting Acute Myeloid Leukemia with Venetoclax In a propensity score-matched cohort, AML patients reached an MRD-negative composite CR rate of 86% when treated with venetoclax and intensive chemotherapy, ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03214562

Study Details | NCT03214562 | Venetoclax With ... Giving venetoclax together with combination chemotherapy may work better in treating patients with acute myeloid leukemia. Detailed Description. PRIMARY ...

4. aacrjournals.org aacrjournals.org/bloodcancerdiscov/article/6/1/23/750802/Venetoclax-Based-Combination-Regimens-in-Acute

Venetoclax-Based Combination Regimens in Acute Myeloid ... Of the patients receiving azacitidine–venetoclax combination, 25% had secondary AML and 36% demonstrated poor cytogenetic risk. With a median follow-up of 20.5 ...

5. researchgate.net researchgate.net/publication/339108096_Venetoclax_in_acute_myeloid_leukemia_-_current_and_future_directions

Venetoclax in acute myeloid leukemia – current and future ... Venetoclax in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) has led to improved outcomes in acute myeloid leukemia (AML) and ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118473065

A Phase 1b Study of Venetoclax (ABT-199/GDC-0199) in ... Elderly AML patients (pts) respond poorly to standard chemotherapy, with low overall survival and poor outcomes. Venetoclax (VEN) is a selective, potent, orally ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8225137/

Review of Venetoclax in CLL, AML and Multiple Myeloma In AML, although of limited efficacy as a single agent, venetoclax combination therapy has demonstrated encouraging outcomes including rapid, durable responses ...