ADI-PEG 20 + Venetoclax + Azacitidine for Acute Myeloid Leukemia

Recruiting at2 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Polaris Group

Must be taking: Venetoclax, Azacitidine

Disqualifiers: Favorable risk AML, CNS involvement, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial tests a new combination treatment for high-risk AML patients. It uses an enzyme to starve cancer cells and two drugs to make them die and stop growing. The goal is to improve outcomes for patients who may not respond well to standard treatments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you can use hydroxyurea to control white blood cell count until 48 hours before starting the trial treatment.

What data supports the effectiveness of the drug ADI-PEG 20 for treating acute myeloid leukemia?

In a study combining ADI-PEG 20 with low-dose cytarabine for acute myeloid leukemia, the overall response rate was 44.4% in evaluable patients, with a higher response rate of 71.4% in treatment-naïve patients. Additionally, ADI-PEG 20 has shown antitumor activity in other cancers like melanoma and hepatocellular carcinoma, suggesting its potential effectiveness in targeting certain cancer cells. ^{1 2 3 4 5}

Is ADI-PEG 20 generally safe for humans?

ADI-PEG 20 has been tested in various clinical trials for different cancers, showing it is generally well-tolerated. Common side effects include low blood cell counts, such as thrombocytopenia (low platelet count), anemia (low red blood cell count), and neutropenia (low white blood cell count). One patient had an allergic reaction, but no dose-limiting toxicities were reported. ^{1 2 3 5 6}

What makes the drug ADI-PEG 20 combined with venetoclax and azacitidine unique for treating acute myeloid leukemia?

The drug ADI-PEG 20 combined with venetoclax and azacitidine is unique because it includes ADI-PEG 20, which is not commonly used in standard treatments for acute myeloid leukemia. This combination may offer a novel approach by potentially targeting cancer cells differently, as ADI-PEG 20 works by depleting arginine, an amino acid that some cancer cells need to grow. ^{7 8 9 10 11}

Research Team

John S Bomalaski, MD

Principal Investigator

Polaris Group

Eligibility Criteria

This trial is for adults with high-risk Acute Myeloid Leukemia (AML). It's specifically for those aged 65 or older who can't have intensive chemotherapy due to age, heart disease, previous treatments, or risk of treatment-related death. Participants need a reasonable life expectancy and controlled white blood cell count. They must also have adequate kidney and liver function but cannot join if they've had certain prior AML treatments or have leukemia in the brain/spinal cord.

Inclusion Criteria

Cohort 2: Untreated AML per ELN criteria with high risk features; Age ≥ 65 years and ineligible for intensive chemotherapy because of older than 75 years, cardiac disease or prior anthracycline use or high probability of treatment-related mortality; Life expectancy reasonably adequate for evaluating the treatment; White blood cell (WBC) count of 10 × 109/L or less. (Use of hydroxyurea to control WBC is allowed till 48 hours prior to protocol treatment); Adequate renal function: Creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance > 40 mL/minute (measured or calculated according to the Cockcroft-Gault formula); Adequate liver function: Total bilirubin ≤ 1.5 x ULN; ALT and AST both ≤ 2.5 x institutional ULN or ≤ 5 times the ULN for patients with leukemic involvement of liver

I am over 18 and have AML with more than 10% blasts in my blood or bone marrow.

Exclusion Criteria

Prior treatment for antecedent hematological disorders with hypomethylating agent (more than 2 cycles, those with exposure to <2 cycles will be allowed), venetoclax, or chemotherapy for antecedent hematologic disorders (treatment with other agents including hydroxyurea for myelodysplastic syndrome or myeloproliferative neoplasm is permitted); Favorable risk AML per ELN 2017 criteria; Known active CNS involvement by leukemia

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead In

6 patients will be enrolled to be treated with standard dose of azacitidine and venetoclax and the expected RP2D of ADI-PEG 20

1 cycle

Treatment

Participants receive ADI-PEG 20, venetoclax, and azacitidine for up to 24 cycles or 104 doses of ADI-PEG 20

Up to 103 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ADI-PEG 20 (Enzyme)

Trial Overview The study tests ADI-PEG 20 combined with venetoclax and azacitidine in patients with AML. Venetoclax and azacitidine are standard first-line therapies; this trial adds ADI-PEG 20 to see if it improves outcomes. The study has two parts: one for previously treated patients (Phase IA) and another for untreated elderly patients at high risk (Phase IB).

Participant Groups

Group I: Untreated AML With High Risk Features Experimental Treatment 1 Intervention

Untreated AML per 2022 WHO criteria with high-risk features and not a candidate for intensive chemotherapy because of age 60 years or older, age-related comorbidities, cardiac disease, prior anthracycline use, high probability of treatment-related mortality, or otherwise would not benefit from intensive chemotherapy treatment.

Group II: Previously Treated AML Experimental Treatment 1 Intervention

Previously treated AML based on the revised revised 2022 WHO criteria with age at least 18 years.

Who Is Running the Clinical Trial?

Polaris Group

Lead Sponsor

Trials

25

Recruited

3,400+

Headquarters

Cayman Islands

Known For

Anti-Cancer Therapies

Top Products

ADI-PEG 20

Findings from Research

ADI-PEG 20, a pegylated enzyme that depletes arginine, was found to be well tolerated when combined with standard chemotherapy (gemcitabine and nab-paclitaxel) in patients with metastatic pancreatic cancer, with a recommended phase 2 dose of 36 mg/m2 weekly.

The treatment showed promising efficacy, with an overall response rate of 45.5% and a median overall survival time of 11.3 months among patients receiving the recommended dose, indicating potential benefits for both previously treated and untreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1/1B trial of ADI-PEG 20 plus nab-paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma. Lowery, MA., Yu, KH., Kelsen, DP., et al.[2022]

The combination of pegylated arginine deiminase (ADI-PEG20) and low-dose cytarabine (LDC) in a phase I study showed a promising overall response rate (ORR) of 44.4% in 18 evaluable acute myeloid leukemia (AML) patients, with a median overall survival of 8.0 months.

The treatment was well-tolerated, with no dose-limiting toxicities reported, although common grade III/IV toxicities included thrombocytopenia (61%) and anemia (52%), indicating a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of ADI-PEG20 plus low-dose cytarabine for the treatment of acute myeloid leukemia. Tsai, HJ., Hsiao, HH., Hsu, YT., et al.[2021]

ADI-PEG20 is an innovative anticancer enzyme that effectively depletes arginine, which is crucial for certain tumors like malignant melanoma and hepatocellular carcinoma that cannot produce it themselves.

Early Phase I - II trials have demonstrated that ADI-PEG20 has antitumor activity and manageable side effects, but further large-scale Phase II and randomized Phase III trials are necessary to fully assess its efficacy in treating these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pegylated arginine deiminase: a novel anticancer enzyme agent. Feun, L., Savaraj, N.[2019]

In a phase II trial involving 43 patients with relapsed/refractory acute myeloid leukemia (AML), pegylated arginine deiminase (ADI-PEG20) showed a disease control rate of 42.9%, with complete responses in 9.5% of evaluable patients, indicating some efficacy in ASS-deficient cancers.

The study found that while arginine depletion was correlated with better responses, ASS deficiency alone was not enough to guarantee a positive outcome, highlighting the need for predictive biomarkers to identify which patients might benefit from ADI-PEG20 treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory or Poor-Risk Acute Myeloid Leukemia Patients. Tsai, HJ., Jiang, SS., Hung, WC., et al.[2019]

In a phase I study involving 18 patients with advanced solid tumors, the combination of pegylated arginine deiminase (ADI-PEG 20) and docetaxel showed manageable toxicity, with only one instance of dose-limiting toxicity and common hematologic side effects like leukopenia.

The treatment demonstrated promising clinical activity, with four partial responses and seven patients achieving stable disease, leading to further studies planned for specific cancer types at a recommended phase II dose of 36 mg/m².

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 Plus Docetaxel in Patients with Advanced Malignant Solid Tumors. Tomlinson, BK., Thomson, JA., Bomalaski, JS., et al.[2022]

In a phase 1b study involving 25 patients, the combination of pegylated arginine deiminase (ADI-PEG 20) and pembrolizumab was found to be safe, although there was a higher-than-expected incidence of Grade 3/4 neutropenia in 40% of patients.

Treatment with ADI-PEG 20 led to increased T cell infiltration in tumors, which may enhance the effectiveness of pembrolizumab, with partial responses observed in 24% of heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus Pembrolizumab in advanced solid cancers. Chang, KY., Chiang, NJ., Wu, SY., et al.[2021]

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 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 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 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]

Venetoclax, when combined with azacitidine, has shown effectiveness in treating a 73-year-old patient with acute myeloid leukemia (AML) who was undergoing dialysis and ineligible for standard therapies.

The combination of venetoclax and azacitidine appears to be a safe and feasible treatment option for AML patients with comorbidities, such as those requiring dialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Administration of combined venetoclax and azacitidine in a patient with acute myeloid leukemia and multiple comorbidities undergoing dialysis: A case report. Akagi, Y., Yamashita, Y., Kosako, H., et al.[2023]

References

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

A phase 1/1B trial of ADI-PEG 20 plus nab-paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma. [2022]

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

Phase I study of ADI-PEG20 plus low-dose cytarabine for the treatment of acute myeloid leukemia. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Pegylated arginine deiminase: a novel anticancer enzyme agent. [2019]

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

A Phase II Study of Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory or Poor-Risk Acute Myeloid Leukemia Patients. [2019]

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

Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 Plus Docetaxel in Patients with Advanced Malignant Solid Tumors. [2022]

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

Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus Pembrolizumab in advanced solid cancers. [2021]

7. England pubmed.ncbi.nlm.nih.gov

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

8. 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]

9. England pubmed.ncbi.nlm.nih.gov

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

10. England pubmed.ncbi.nlm.nih.gov

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

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

Administration of combined venetoclax and azacitidine in a patient with acute myeloid leukemia and multiple comorbidities undergoing dialysis: A case report. [2023]