CC-486 + Venetoclax for Acute Myeloid Leukemia

Recruiting at 1 trial location

Overseen By Constance Brecl

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Colorado, Denver

Must be taking: CC-486, Venetoclax

Disqualifiers: Active CNS AML, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: 28

35 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose of CC-486 (an oral medication) combined with venetoclax for individuals with acute myeloid leukemia (AML) that has recurred or is unresponsive to treatment. Participants will receive varying doses of CC-486 to identify the most effective combination with venetoclax. Those diagnosed with AML who have tried at least one unsuccessful treatment may qualify for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, providing an opportunity to be among the first to receive this new treatment combination.

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

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

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

Research shows that the combination of CC-486 and venetoclax has been tested for safety in patients with acute myeloid leukemia (AML). CC-486, a pill form of azacitidine, has received FDA approval for some AML patients, indicating its safety in other contexts. Venetoclax is also approved for AML, particularly for older patients or those unfit for intense treatment, and is often used with azacitidine.

Studies have found that this combination is generally well-tolerated. Some patients experienced side effects, but these were usually manageable. Common side effects include low blood cell counts and digestive issues like nausea. Although rare, more serious side effects can occur. Discussing potential risks with a doctor is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CC-486 combined with Venetoclax for treating Acute Myeloid Leukemia (AML) because this combination might offer a new way to tackle the disease. Unlike existing treatments that often rely on traditional chemotherapy, this approach uses CC-486, an oral form of azacitidine, and Venetoclax, a BCL-2 inhibitor, to target cancer cells more precisely. This combination could potentially improve the effectiveness of the treatment while minimizing some of the harsh side effects associated with chemotherapy. Additionally, the ease of taking CC-486 orally might offer a more convenient option for patients compared to intravenous treatments.

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

Studies have shown that azacitidine, the active ingredient in CC-486, combined with venetoclax, can improve outcomes for patients with acute myeloid leukemia (AML). Research indicates that this combination can help some patients live longer. In this trial, participants will receive different dosages of CC-486 alongside venetoclax. Previous studies have demonstrated that oral azacitidine (CC-486) is effective for patients with AML in remission. Venetoclax makes cancer cells more likely to die. Together, these drugs aim to fight leukemia in different ways, potentially increasing their effectiveness when used together. ^{1 2 3 4 6}

Who Is on the Research Team?

Daniel Pollyea, MD

Principal Investigator

University of Colorado, Denver

Are You a Good Fit for This Trial?

This trial is for adults with Acute Myeloid Leukemia (AML) who have already tried at least one treatment. They should expect to live at least 12 weeks, be able to perform daily activities with some limitations (ECOG ≤2), and have good kidney and liver function. Women must be postmenopausal or surgically sterile; men must agree to use contraception. Participants can't join if they have severe heart issues, uncontrolled infections, active CNS leukemia, HIV/hepatitis B/C infection, certain other cancers or are pregnant/breastfeeding.

Inclusion Criteria

Subject must have a projected life expectancy of at least 12 weeks.

I have AML (not APL type) confirmed by WHO criteria and have received at least one treatment.

I am unable to have children due to surgery.

Exclusion Criteria

You are allergic or have a strong reaction to azacitidine or mannitol.

Pregnant or breast-feeding females. A pregnancy test will be obtained at the time of screening.

I do not have any major health issues unrelated to leukemia.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment - Dose Escalation

Participants receive CC-486 and venetoclax with dose escalation to determine the maximum tolerated dose (MTD).

28 days per cycle

Inpatient monitoring for tumor lysis syndrome during initial days

Treatment - Expansion Phase

Participants receive venetoclax with the MTD of CC-486 in relapsed/refractory patients.

28 days per cycle

Bone marrow biopsies on day 28 of every 3rd cycle for responders

Follow-up

Participants are monitored for safety and effectiveness after treatment, with bone marrow biopsies every 6 months after one year.

7 years

What Are the Treatments Tested in This Trial?

Interventions

• CC-486
• Venetoclax

Trial Overview The study tests a combination of two drugs: CC-486 (oral azacitidine) and Venetoclax in patients with relapsed/refractory AML. It's an open-label Phase I trial where everyone knows what treatment they're getting. The first part finds the maximum tolerated dose of CC-486 combined with Venetoclax; the second expands this dose in more patients.

How Is the Trial Designed?

Group I: Dose Expansion Cohort Experimental Treatment 2 Interventions

CC-486 MTD will be determine following the completion of Cohort 1 and Cohort 2 with venetoclax at 400 mg/day PI regimen for 28 days.

Group II: Cohort 2 CC-486 300 mg Experimental Treatment 2 Interventions

CC-486 300 mg will be administered orally on days 1-14 of a 28-day cycle. Venetoclax will be administered days 1-3, with the following schema: 100 mg on day 1, 200 mg on day 2, 400 mg on day 3, and it will be continued at 400mg thereafter until day 28, the completion of cycle 1.

Group III: Cohort 1 CC-486 200 mg Experimental Treatment 2 Interventions

CC-486 200 mg will be administered orally on days 1-14 of a 28-day cycle. Venetoclax will be administered days 1-3, with the following schema: 100 mg on day 1, 200 mg on day 2, 400 mg on day 3, and it will be continued at 400mg thereafter until day 28, the completion of cycle 1.

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

Venetoclax combined with hypomethylators and low-dose cytarabine has shown high response rates and improved overall survival in older, untreated patients with acute myeloid leukemia, based on preliminary data from small, uncontrolled studies.

The efficacy of venetoclax appears to stem from its ability to target leukemia stem cells by altering the metabolic environment, which is particularly effective in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Why are hypomethylating agents or low-dose cytarabine and venetoclax so effective? Pollyea, DA., Jordan, CT.[2020]

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 has significantly improved treatment outcomes for elderly and unfit patients with acute myeloid leukemia, but resistance to the drug remains a significant challenge.

The study by Bhatt et al. identifies a general mechanism for the development of resistance to venetoclax and suggests potential treatment strategies for managing venetoclax-resistant cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitochondria in Their Prime Drive Venetoclax Response in Acute Myeloid Leukemia. Kriegbaum, MC., Wennerberg, K.[2021]

A lower dosage of Venetoclax (100 mg) combined with Azacitidine showed favorable outcomes in newly diagnosed acute myeloid leukemia (AML) patients, with a median overall survival of 17 months and an overall response rate of 69.4% based on a study of 36 patients.

The study suggests that even with dose reductions of Venetoclax, the combination therapy remains effective, indicating a potential strategy to manage therapy-related toxicity while still achieving significant treatment responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced duration and dosage of venetoclax is efficient in newly diagnosed patients with acute myeloid leukemia. Cui, J., Chen, X., Li, C., et al.[2023]

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]

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]

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 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 Phase 3 clinical trial, venetoclax combined with low-dose cytarabine showed improved response rates and overall survival in patients with newly diagnosed acute myeloid leukemia who couldn't undergo intensive chemotherapy, supporting its efficacy.

In an expanded access study in Japan involving 14 patients, the safety profile of venetoclax was consistent with previous findings, with neutropenia being the most common serious side effect, indicating that careful management of adverse events is crucial in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy: an expanded access study in Japan. Asada, N., Ando, J., Takada, S., et al.[2023]

Venetoclax is an oral medication with a favorable side-effect profile that shows promise in treating acute myeloid leukemia (AML), particularly for patients with refractory or relapsed cases.

This drug can serve as a bridge to hematopoietic cell transplant for curative treatment and may significantly extend survival for older patients who cannot tolerate more aggressive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCL2 Inhibition by Venetoclax: Targeting the Achilles' Heel of the Acute Myeloid Leukemia Stem Cell? Pullarkat, VA., Newman, EM.[2021]

Venetoclax is an effective oral medication for treating chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), showing significant efficacy when combined with other therapies like obinutuzumab and azacitidine.

While venetoclax is associated with adverse events such as neutropenia and gastrointestinal disorders, the article emphasizes the importance of managing these side effects to ensure patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical Management of the Venetoclax-Treated Patient in Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia. Waggoner, M., Katsetos, J., Thomas, E., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05287568

CC-486 and Venetoclax for Acute Myeloid Leukemia ... This is an open label, dose escalation Phase I single institution pilot study for relapsed and refractory AML patients using CC-486 (oral azacitidine) with ...

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

Azacitidine and Venetoclax in Previously Untreated Acute ... Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12320475/

Reduced-dose azacitidine plus venetoclax as maintenance ... Based on this data, the US Food and Drug Administration (FDA) approved oral azacitidine (CC-486) in 2020 for patients with AML in first CR/CRi ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04161885

NCT04161885 | A Study Evaluating Safety and Efficacy of ... The main objective of this study is to evaluate the efficacy of venetoclax in combination with azacitidine to improve Overall Survival (OS) in Acute Myeloid ...

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

Evaluating venetoclax and its potential in treatment-naïve ... Relapsed acute myeloid leukemia is less sensitive to venetoclax + azacitidine due to leukemia stem cell resistance driven by fatty acid metabolism and can ...

6. ashpublications.org ashpublications.org/blood/article/145/12/1237/517960/How-I-treat-patients-with-AML-using-azacitidine

How I treat patients with AML using azacitidine and venetoclax Venetoclax (VEN) received full approval in October 2020 for use in older patients who are unfit with acute myeloid leukemia (AML) combined with either ...