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

16 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial evaluates the side effects of uproleselan, azacitidine, and venetoclax in treating older or unfit patients with treatment naive acute myeloid leukemia. Uproleselan may help block the formation of growths that may become cancer. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving uproleselan with azacitidine and venetoclax may help kill more cancer cells.

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.

What data supports the effectiveness of the drug combination Uproleselan, Azacitidine, and Venetoclax for treating Acute Myeloid Leukemia?

Research shows that combining Venetoclax with Azacitidine improves remission rates and survival in older patients with acute myeloid leukemia compared to using Azacitidine alone. This combination is considered effective and is used as a first-line therapy for elderly patients with this condition. ^{1 2 3 4 5}

Is the combination of Uproleselan, Azacitidine, and Venetoclax safe for treating acute myeloid leukemia?

The combination of Venetoclax and Azacitidine has been studied for safety in patients with acute myeloid leukemia, showing common blood-related side effects. These studies suggest that while the treatment can be effective, it may also lead to hematologic toxicities (blood-related side effects), which are important to monitor. ^{1 2 3 4 6}

What makes the drug combination of Uproleselan, Azacitidine, and Venetoclax unique for treating Acute Myeloid Leukemia?

This drug combination is unique because it combines Uproleselan, which may help protect healthy cells during chemotherapy, with Azacitidine and Venetoclax, which work together to target and kill cancer cells. This approach aims to enhance treatment effectiveness while potentially reducing side effects, offering a novel strategy for patients with Acute Myeloid Leukemia. ^{7 8 9 10 11}

Research Team

Brian Jonas, MD

Principal Investigator

University of California, Davis

Eligibility Criteria

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

I am between 18 and 74 years old and have at least one health condition.

ECOG performance status of:

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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 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]

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 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]

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 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]

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]

References

1. 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]

2. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021]

3. Switzerland 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. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. [2022]

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

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Single-institution experience of venetoclax combined with azacitidine in newly diagnosed acute myeloid leukemia patients. [2023]

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

Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Clinical advances with topoisomerase I inhibitors in gastrointestinal malignancies. [2019]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Multicenter phase I study of irinotecan plus raltitrexed in patients with 5-fluorouracil-refractory advanced colorectal cancer. [2018]

10. Greece 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. [2018]

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

Phase I and pharmacokinetic study of exatecan mesylate (DX-8951f): a novel camptothecin analog. [2017]