Pegcrisantaspase + Venetoclax for Acute Myeloid Leukemia

Overseen By Ashkan Emadi, M.D.,Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Maryland, Baltimore

Must not be taking: Investigational agents

Disqualifiers: APL, Severe pancreatitis, Stroke, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two treatments, pegcrisantaspase (an experimental treatment) and venetoclax, to assess their safety and tolerability for individuals with relapsed or refractory acute myeloid leukemia (AML). Researchers aim to determine the optimal dose that patients can tolerate with minimal side effects. The trial includes different groups testing various doses of the two drugs to identify the most effective combination. Suitable candidates have AML that has returned or is unresponsive to treatment and have already tried up to three 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 therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but you cannot be on other investigational agents, chemotherapy, or immunotherapy. Some medications, like biologic agents, must be stopped at least 1 week before starting the trial.

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

Research has shown that combining pegcrisantaspase and venetoclax may help treat acute myeloid leukemia (AML). This combination has proven effective in studies, particularly when other treatments have failed. While the primary goal was to assess efficacy, researchers also gathered some safety information.

Venetoclax, a key component of this combination, already has FDA approval for certain types of leukemia, indicating it has been tested and found safe in other contexts. Early trials using pegcrisantaspase with venetoclax have not revealed any unexpected safety issues. However, since this study is in an early stage, it aims to gather more information about safety and optimal dosing.

Participants will receive varying doses of the drugs to determine the safest and most effective combination. This careful approach ensures that any side effects are closely monitored and managed. Researchers will continue to collect safety information as more participants join the trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Pegcrisantaspase combined with Venetoclax for treating Acute Myeloid Leukemia (AML) because this approach leverages a unique mechanism. Unlike standard treatments like chemotherapy, which broadly attack dividing cells, Venetoclax specifically targets and inhibits BCL-2, a protein that helps cancer cells survive. Pegcrisantaspase, used alongside, breaks down a crucial amino acid that leukemia cells need, starving them. This dual approach not only targets leukemia cells more precisely but also has the potential to enhance treatment effectiveness and reduce side effects compared to traditional therapies.

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

This trial will evaluate the combination of pegcrisantaspase and venetoclax for acute myeloid leukemia (AML). Studies have shown that these two drugs together effectively combat AML by attacking cancer cells in different ways, enhancing their potency. Research indicates that this combination can be beneficial even when other treatments have failed, particularly in patients with relapsed or treatment-resistant AML. Early data show that this treatment can lead to complete remissions, where all signs of cancer disappear, in patients who have undergone multiple treatments. This promising approach might be a breakthrough for those facing challenging cases of AML. ^{2 3 4 5 6}

Who Is on the Research Team?

Vu H Duong, MD

Principal Investigator

University of Maryland, Baltimore

Are You a Good Fit for This Trial?

Adults diagnosed with relapsed or refractory acute myeloid leukemia (R/R AML) who have tried up to three prior treatments. Suitable for those with certain genetic mutations if they've had specific inhibitors, and post stem cell transplant patients without severe graft versus host disease. Must not have other active cancers, recent investigational drug use, or uncontrolled illnesses.

Inclusion Criteria

My AML has returned or didn't respond to 1-3 treatments. I've tried FLT3 or IDH inhibitors if applicable.

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

My liver and kidney functions are within the required limits.

Exclusion Criteria

Patients with the following clinical histories are excluded: severe pancreatitis not related to cholelithiasis. Severe acute pancreatitis is defined by lipase elevation >5X ULN and with signs or symptoms, unprovoked deep venous thrombosis (DVT), pulmonary emboli, hemorrhagic or thromboembolic stroke, other malignancies requiring systemic chemotherapy, immunotherapy or targeted therapy in the last three months, Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible, Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that per site Principal Investigator's judgment would limit compliance with study requirements, Pregnant women and female patients who are lactating and do not agree to stop breastfeeding, Uncontrolled active seizure, Any other clinical conditions that in the opinion of the investigator would make the subject unsuitable for the study

My leukemia is a specific type known as APL with a certain genetic feature.

My blood has more than 100,000 immature cells per microliter. I may use hydroxyurea for a short time.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax daily and pegcrisantaspase biweekly as part of a 28-day treatment cycle

12 months

Biweekly visits for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Pegcrisantaspase
• Venetoclax

Trial Overview The trial is testing the combination of two drugs: Venetoclax and pegcrisantaspase (Ven-PegC), in adults with R/R AML to find safe dosage levels and assess tolerability. It aims to determine the maximum doses that do not cause unacceptable side effects.

How Is the Trial Designed?

Group I: Cohort 600mg Venetoclax, 1000 IU/m ² of Pegcrisantaspase Experimental Treatment 1 Intervention

The subject will take 600mg of Venetoclax every day as a pill by mouth and a dose of 1000 IU/m ² of Pegcrisantaspase in an IV every 14 days ( Per cycle)

Group II: Cohort 400mg of Venetoclax, 750 IU/m ² of Pegcrisantaspase Experimental Treatment 1 Intervention

The subject will take 400mg of Venetoclax every day as a pill by mouth and a dose of 750 IU/m ² of Pegcrisantaspase in an IV every 14 days ( per cycle)

Group III: Cohort 400mg of Venetoclax, 500 IU/m ² of Pegcrisantaspase Experimental Treatment 1 Intervention

The subject will take 400mg of Venetoclax every day as a pill by mouth and a dose of 500 IU/m ² of Pegcrisantaspase in an IV every 14 days ( per cycle)

Group IV: Cohort 400mg of Venetoclax, 1000 IU/m² of Pegcrisantaspase Experimental Treatment 1 Intervention

The subject will take 400mg of Venetoclax every day as a pill by mouth and a dose of 1000 IU/m² of Pegcrisantaspase in an IV every 14 days ( per cycle)

Who Is Running the Clinical Trial?

University of Maryland, Baltimore

Lead Sponsor

Trials

729

Recruited

540,000+

Published Research Related to This Trial

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 26 adult patients with relapsed/refractory acute myeloid leukemia (R/R AML), the combination of venetoclax (VEN) with demethylating agents (azacitidine or decitabine) resulted in a 57.7% overall response rate, including 13 complete responses, indicating its efficacy as a salvage therapy.

Patients who achieved minimal residual disease negativity had significantly better overall survival and event-free survival, highlighting the importance of this outcome in improving long-term prognosis for R/R AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Observation of Venetoclax Combined with Demethylating Agents on the Treatment of Relapsed/Refractory Acute Myeloid Leukemia]. Wang, Y., Huang, SL., Zhang, XX., et al.[2023]

In a study of 43 patients with acute myeloid leukemia (AML) treated with venetoclax and hypomethylating agents (HMAs), outpatient initiation of venetoclax was found to be safe, with only one case (2.5%) of laboratory tumor lysis syndrome (TLS) and no clinical TLS episodes reported.

The 30-day mortality rate after starting venetoclax was 0%, indicating that the outpatient ramp-up approach does not compromise patient safety in this treatment setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor lysis syndrome risk in outpatient versus inpatient administration of venetoclax and hypomethlators for acute myeloid leukemia. Pelcovits, A., Moore, J., Bakow, B., et al.[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]

In a study of 51 patients with relapsed or refractory acute myeloid leukemia (RR-AML), venetoclax (VEN) showed a low complete remission (CR) rate of 12.4%, indicating limited effectiveness in this heavily pretreated population.

The median overall survival (OS) for patients treated with VEN was only 104 days, with 28% of patients experiencing treatment interruptions due to toxicity, highlighting the challenges and risks associated with this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Venetoclax in Patients with Relapsed or Refractory Acute Myeloid Leukemia: The PETHEMA Registry Experience. Labrador, J., Saiz-Rodríguez, M., de Miguel, D., et al.[2022]

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 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 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, a targeted oral agent, has significantly improved treatment outcomes for acute myeloid leukemia (AML), especially in older patients or those unable to undergo intensive chemotherapy, establishing a new standard of care when combined with hypomethylating agents or low-dose cytarabine.

The combination of venetoclax with other therapies, such as FLT-3 inhibitors and IDH inhibitors, is leading to better clinical results, marking a major advancement in AML treatment after decades of limited changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in acute myeloid leukemia - current and future directions. Lachowiez, C., DiNardo, CD., Konopleva, M.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/ct2/show/record/NCT04666649

Pegcrisantaspase in Combination With Venetoclax for Treatment ... Pegcrisantaspase and venetoclax combination is highly effective against acute myeloid leukemia (AML), mechanistically driven synergism between glutamine ...

2. onclive.com onclive.com/view/venetoclax-pegcrisantaspase-combo-offers-potential-to-overcome-venetoclax-resistance-in-r-r-aml

Venetoclax/Pegcrisantaspase Combo Offers Potential to ... Ashkan Emadi, MD, PhD, discusses early efficacy signals with venetoclax plus pegcrisantaspase in relapsed/refractory AML.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10976320/

Venetoclax and pegcrisantaspase for complex karyotype ... While results of Ven in combination with DNMTIs for newly diagnosed AML patients are encouraging, Ven in combination with DNMTIs is less ...

4. onclive.com onclive.com/view/venetoclax-plus-pegc-may-overcome-resistance-to-prior-bcl-2-inhibitors-in-r-r-aml

Venetoclax Plus PegC May Overcome Resistance to Prior ... The addition of pegcrisantaspase to venetoclax may overcome resistance to prior BCL-2 inhibitor–based regimens for patients with relapsed/ ...

5. hematologyadvisor.com hematologyadvisor.com/news/acute-leukemia-aml-venetoclax-pegcrisantaspase-efficacy-treatment-risk/

Venetoclax With Pegcrisantaspase Shows Efficacy in AML The combination of pegcrisantaspase and venetoclax is a novel regimen that can induce CRs in heavily pretreated patients with AML, even with ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04666649

Study Details | NCT04666649 | Pegcrisantaspase in ... Pegcrisantaspase and venetoclax combination is highly effective against acute myeloid leukemia (AML), mechanistically driven synergism between glutamine ...