Uproleselan + Azacitidine + Venetoclax for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Brian Jonas

Must not be taking: CYP3A inducers

Disqualifiers: Acute promyelocytic leukemia, CNS involvement, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle, up to 6 cycles

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—uproleselan, azacitidine, and venetoclax—to evaluate their combined effect against acute myeloid leukemia (AML), a type of blood cancer. Uproleselan may help prevent cancer growth, azacitidine (also known as Vidaza) can stop cancer cells from growing or spreading, and venetoclax targets a protein essential for cancer cell survival. The goal is to determine if these drugs together can kill more cancer cells in patients who are older or have other health issues that make them unfit for traditional treatments. The trial seeks participants recently diagnosed with AML who have not started other treatments. 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 combination therapy.

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. However, you cannot use other investigational agents or certain anticancer therapies before and during the trial. It's best to discuss your current medications with the study team.

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

Research shows that combining uproleselan, azacitidine, and venetoclax holds promise for treating acute myeloid leukemia (AML) in older or less fit patients. Studies have found that this combination leads to higher rates of complete remission, where the cancer becomes undetectable, and causes fewer severe side effects, such as painful mouth inflammation, compared to some other treatments. Additionally, these studies reported fewer deaths during the initial treatment phase.

Azacitidine and venetoclax are already commonly used for patients who cannot undergo more aggressive chemotherapy, indicating they are generally well-tolerated. Uproleselan, when combined with these drugs, has not shown any unexpected safety issues in studies so far. However, since this trial is still in an early stage, its main goal is to determine the safest dose and monitor for any side effects. While the initial results are encouraging, ongoing research will provide a better understanding of how well this treatment is tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of uproleselan, azacitidine, and venetoclax for treating Acute Myeloid Leukemia (AML) because it brings a fresh approach by targeting multiple pathways crucial for cancer cell survival. Uproleselan is particularly notable as it blocks a protein called E-selectin, which helps cancer cells stick to bone marrow, making them harder to treat. This mechanism allows uproleselan to potentially enhance the effectiveness of other treatments. Meanwhile, azacitidine and venetoclax work together to disrupt cancer cell growth and survival, offering a potent triple-action strategy against AML. This combination could improve outcomes for patients who don't respond well to standard treatments like chemotherapy.

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

This trial will evaluate the combination of uproleselan, azacitidine, and venetoclax for treating acute myeloid leukemia (AML). Research has shown that combining these drugs may be effective. In past studies, patients treated with only azacitidine and venetoclax achieved a complete remission rate of about 38.8%. Adding uproleselan has been linked to higher remission rates and fewer severe side effects, such as mouth sores. This combination appears to help patients live longer and experience fewer complications. Evidence suggests that these drugs together may effectively target and destroy cancer cells. ^{1 2 3 4 6}

Who Is on the Research Team?

Brian Jonas, MD

Principal Investigator

University of California, Davis

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed acute myeloid leukemia who are older or unfit for intensive chemotherapy. They must understand and consent to the study, have a certain level of physical function (ECOG status), and agree to use contraception if necessary. Exclusions include other recent cancers, prior treatments for AML, active infections like HIV or hepatitis, severe medical conditions that could interfere with treatment, or pregnancy.

Inclusion Criteria

ECOG performance status of:

Total bilirubin =< 1.5 x institution's upper limit of normal (ULN) unless related to AML or Gilbert's syndrome

Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria

I haven't taken any strong or moderate CYP3A inducers in the last week.

My heart condition limits my physical activity significantly.

I have had cancer before, but it was either treated successfully over a year ago, was a non-melanoma skin cancer, or was localized prostate or cervical cancer that is now cured.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive uproleselan, azacitidine, and venetoclax. Uproleselan is administered IV over 1 hour every 12 hours on days 1-7, azacitidine IV or SC once daily on days 1-7, and venetoclax orally once daily on days 1-28. Treatment cycles repeat every 28 days for up to 6 cycles.

28 days per cycle, up to 6 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs at 30 days post-treatment and then every 3 months for 1 year.

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Uproleselan
• Venetoclax

Trial Overview The trial tests uproleselan combined with azacitidine and venetoclax in patients who haven't been treated before for acute myeloid leukemia. Uproleselan may prevent cancer growths; azacitidine stops cancer cells from growing by various means; venetoclax blocks proteins essential for cancer cell survival.

How Is the Trial Designed?

Group I: Treatment (uproleselan, azacitidine, venetoclax) Experimental Treatment 3 Interventions

Patients receive uproleselan IV over 1 hour Q12H on days 1-7, azacitidine IV or SC QD on days 1-7, and venetoclax PO QD on days 1-28. Beginning cycle 5, patients achieving MLFS or better response, may receive azacitidine IV or SC QD and uproleselan IV over 1 hour QD on days 1-6 and 8 or days 1-5 and 8-9 or days 1-5. Treatment with uproleselan repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Cycles with azacitidine and venetoclax repeat every 28 days in the absence of disease progression and 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?

Brian Jonas

Lead Sponsor

Trials

5

Recruited

80+

GlycoMimetics Incorporated

Industry Sponsor

Trials

23

Recruited

1,500+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 57 elderly patients (average age 69.9 years) with acute myeloid leukemia, the combination of venetoclax and azacitidine (VEN + AZA) showed a high overall response rate of 87.5% and a complete remission (CR) rate of 68.8%, indicating strong efficacy in this population.

The treatment was associated with a median overall survival (OS) of 11.5 months, and achieving minimal residual disease (MRD) negativity (<0.1%) was more common with VEN + AZA compared to traditional chemotherapy, although older patients (≥75 years) and those with higher ECOG scores faced more challenges in achieving MRD negativity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-institution experience of venetoclax combined with azacitidine in newly diagnosed acute myeloid leukemia patients. Yu, H., Wang, C., Lei, Y., 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]

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]

The combination of irinotecan and raltitrexed is feasible for treating advanced colorectal cancer, showing mild toxicity and an overall response rate of 17% in patients who had previously not responded to 5-fluorouracil.

Diarrhea was identified as the main dose-limiting toxicity, but its severity was comparable to that seen with irinotecan alone, indicating that the combination does not increase the risk of severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase I study of irinotecan plus raltitrexed in patients with 5-fluorouracil-refractory advanced colorectal cancer. Aparicio, J., de las Peñas, R., Vicent, JM., et al.[2018]

Premetrexed disodium (MTA) shows promising anti-proliferative effects against colon cancer, especially when combined with oxaliplatin or SN38, demonstrating synergistic activity in both standard and 5-fluorouracil-resistant cancer cells.

The combination of MTA with oxaliplatin resulted in additive antitumor effects with minimal toxicity in mouse models, suggesting a potential for safer and more effective chemotherapy regimens for colon cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed disodium combined with oxaliplatin, SN38, or 5-fluorouracil, based on the quantitation of drug interactions in human HT29 colon cancer cells. Raymond, E., Louvet, C., Tournigand, C., et al.[2018]

Irinotecan has been shown to significantly prolong survival in patients with 5-FU-resistant colorectal cancer compared to best supportive care or 5-FU-based chemotherapy, based on Phase III studies.

Combining irinotecan with other treatments, such as raltitrexed or oral fluoropyrimidines, has shown promising results in terms of safety and efficacy, with response rates exceeding 30% and median survival benefits in various cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical advances with topoisomerase I inhibitors in gastrointestinal malignancies. Armand, JP., Cunningham, D., van Cutsem, E., et al.[2019]

The maximum-tolerated dose (MTD) of Exatecan mesylate (DX-8951f) for patients with advanced solid tumors was determined to be 2.4 mg/m², with granulocytopenia identified as the dose-limiting toxicity (DLT) for minimally pretreated patients.

While no complete or partial responses were observed, four patients achieved stable disease, indicating some level of efficacy; the pharmacokinetic profile of DX-8951f was linear, suggesting predictable behavior at the administered doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic study of exatecan mesylate (DX-8951f): a novel camptothecin analog. Royce, ME., Hoff, PM., Dumas, P., et al.[2017]

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]

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 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 study of nine AML patients with acquired resistance to venetoclax, the typical BCL2 mutation associated with resistance was not found, suggesting that this mutation is not necessary for developing resistance in AML.

The study identified that existing mutations, particularly the expansion of FLT3-ITD, were primarily responsible for venetoclax resistance, indicating that monitoring these mutations could help in developing strategies to prevent or overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. Zhang, X., Qian, J., Wang, H., et al.[2022]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/1503/532938/Updated-Results-of-a-Phase-I-Study-of-Uproleselan

Updated Results of a Phase I Study of Uproleselan Combined ... Azacitidine (AZA) plus venetoclax (VEN) is standard of care for induction chemotherapy (IC) ineligible AML and leads to a complete remission (CR) rate of 38.8% ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124042502

Updated Results of a Phase I Study of Uproleselan ... A Phase I/II study of UPRO combined with IC in AML established a recommended Phase II dose (RP2D) and showed clinical activity (DeAngelo 2022).

3. onclive.com onclive.com/view/a-phase-i-study-of-uproleselan-combined-with-azacitidine-and-venetoclax-for-the-treatment-of-older-or-unfit-patients-with-treatment-na-ve-acute-myeloid-leukemia

A Phase I Study of Uproleselan Combined with Azacitidine ... - UPRO was associated with higher CR/CRi and MRD negative (MRD-ve) rates, lower induction mortality, and less severe mucositis compared to ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11017789/

Phase 1/2 study of uproleselan added to chemotherapy in ... Among the 25 newly diagnosed patients who received uproleselan at 10 mg/kg in combination with 7 + 3, the median OS rate was 12.6 months (95% CI, 9.9 to not ...

5. ir.glycomimetics.com ir.glycomimetics.com/news-releases/news-release-details/glycomimetics-announces-new-uproleselan-clinical-data-will-be

GlycoMimetics Announces New Uproleselan Clinical Data Will ... Data from multiple clinical trials studying uproleselan in patients with acute myeloid leukemia (AML) have been accepted for presentation at the 66 th American ...

6. onclive.com onclive.com/view/dr-daver-on-the-investigation-of-uproleselan-plus-azacitidine-and-venetoclax-in-aml

Dr Daver on the Investigation of Uproleselan Plus ... At a median follow-up of 43.2 months, the median overall survival was 14.7 months (95% CI, 12.1-18.7) with the combination vs 9.6 months (95% CI ...