What is the mechanism of action of this treatment?

The most common treatments for Acute Myeloid Leukemia (AML) include hypomethylating agents (HMAs) such as azacitidine and decitabine, and the BCL-2 inhibitor venetoclax. HMAs work by incorporating into DNA and inhibiting DNA methyltransferases, leading to hypomethylation of DNA and reactivation of tumor suppressor genes, which can induce cell differentiation and apoptosis in leukemic cells. Venetoclax targets the BCL-2 protein, which is often overexpressed in AML cells and helps them evade apoptosis. By inhibiting BCL-2, venetoclax promotes programmed cell death in these cancer cells. These mechanisms are crucial for AML patients, especially those resistant to standard treatments, as they offer alternative pathways to induce cancer cell death and improve patient outcomes.

What side effects are associated with this type of intervention?

Common treatments for Acute Myeloid Leukemia (AML) include hypomethylating agents like decitabine and azacitidine, often combined with other drugs such as venetoclax or vorinostat. Known side effects of these treatments include hematologic toxicities such as cytopenias (low blood cell counts), febrile neutropenia (fever with low neutrophil count), and increased risk of infections. Non-hematologic side effects can include gastrointestinal issues (nausea, vomiting, diarrhea), fatigue, and liver enzyme abnormalities. Specific to vorinostat, there can be dose-limiting toxicities like QTc prolongation, which affects heart rhythm. Venetoclax may also cause tumor lysis syndrome, a potentially serious condition resulting from the rapid breakdown of cancer cells.

What prior FDA approvals exist?

The FDA has approved several treatments for Acute Myeloid Leukemia (AML), including hypomethylating agents like azacitidine and decitabine, which are often used in patients unfit for intensive chemotherapy. Venetoclax, a BCL-2 inhibitor, has also been approved in combination with hypomethylating agents for newly diagnosed AML in elderly patients or those unfit for intensive chemotherapy. Other notable approvals include midostaurin for FLT3-mutated AML and gemtuzumab ozogamicin, an antibody-drug conjugate targeting CD33. These treatments reflect a trend towards targeted therapies and combination regimens to improve outcomes in AML patients.

What other types of research exist?

Promising novel alternatives for treating AML patients resistant to hypomethylating agents and venetoclax include: 1) Nintedanib combined with low-dose cytarabine, which has shown growth inhibitory and pro-apoptotic effects in myeloid leukemic cells. 2) Azacitidine plus gilteritinib, which has demonstrated a higher overall response rate compared to azacitidine plus placebo. 3) Venetoclax combined with BCR-ABL tyrosine kinase inhibitors, which has shown synergism in preclinical studies and some clinical activity in advanced myeloid leukemias.

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Anti-metabolites

Venetoclax + Cladribine for Acute Myeloid Leukemia

Phase 2

Recruiting

Led By Christine McMahon, MD

Research Sponsored by University of Colorado, Denver

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Age ≥ 18 years

Adequate liver function, as demonstrated by: Aspartate aminotransferase (AST) ≤ 3.0 x ULN, Alanine aminotransferase (ALT) ≤ 3.0 x ULN, Total bilirubin ≤ 1.5 x ULN, unless considered to be due to leukemic organ involvement or Gilbert's syndrome. In subjects with Gilbert's syndrome, bilirubin needs to be ≤ 4 x ULN

Must not have

Subject has known active central nervous system (CNS) involvement of AML.

Subject has received prior treatment with cladribine for AML.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up minimum of 3 years off study

Awards & highlights

No Placebo-Only Group

Summary

This trial uses Cladribine and Venetoclax to treat a specific type of leukemia that hasn't responded to other treatments. Cladribine has been used effectively in treating various blood cancers, including hairy cell leukemia. It targets patients with a type of leukemia who didn't improve with previous therapies. The treatment works by stopping cancer cells from growing and making them easier to kill.

Who is the study for?

This trial is for adults over 18 with a specific type of Acute Myeloid Leukemia (AML) that hasn't responded to previous treatments. Women must be postmenopausal, surgically sterile, or use contraception; men need to use contraception too. Participants should have an expected lifespan of at least 12 weeks and be physically able enough to do daily activities with some effort.

What is being tested?

The study tests Cladribine combined with Venetoclax and Azacitidine in patients whose AML has returned or didn't respond after initial treatment. It's specifically for those who've had hypomethylating agents plus Venetoclax before and now have limited options.

What are the potential side effects?

Potential side effects include nausea, vomiting, diarrhea, low blood counts leading to increased infection risk or bleeding problems, liver issues indicated by abnormal blood tests, kidney function changes requiring close monitoring, and general fatigue.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am 18 years old or older.

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My liver tests are within normal limits, or slightly elevated due to my condition.

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My leukemia is confirmed as AML without APL, with specific characteristics or mutations.

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I can perform daily activities with minimal assistance.

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My kidneys work well, with a creatinine clearance rate of 60 mL/min or more.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My acute myeloid leukemia (AML) has spread to my brain or spinal cord.

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I have been treated with cladribine for my AML.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ minimum of 3 years off study

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~minimum of 3 years off study

This trial's timeline: 3 weeks for screening, Varies for treatment, and minimum of 3 years off study for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Overall response rate (ORR)

Secondary study objectives

Adverse Events

Duration of response

Event-free survival

+2 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

2Treatment groups

Experimental Treatment

Group I: Cladribine plus VenetoclaxExperimental Treatment2 Interventions

Subjects will receive cladribine at a dose of 5mg/m2 daily via intravenous infusion on days 1 through 5 of a 28 day cycle. Concomitantly, venetoclax will be administered orally at a dose of 100mg on day 1, 200mg on day 2, and 400mg daily on days 3 through 28.

Group II: Alternating Aza/Ven and Clad/VenExperimental Treatment3 Interventions

Alternating 28-day consolidation cycles of Aza/Ven (even cycles) and Clad/Ven (odd cycles), while those who do not respond will come off the study.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Venetoclax

2019

Completed Phase 3

~2240

Cladribine

2014

Completed Phase 4

~4410

Azacitidine

2012

Completed Phase 3

~1440

0 / 7Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Acute Myeloid Leukemia (AML) include hypomethylating agents (HMAs) such as azacitidine and decitabine, and the BCL-2 inhibitor venetoclax. HMAs work by incorporating into DNA and inhibiting DNA methyltransferases, leading to hypomethylation of DNA and reactivation of tumor suppressor genes, which can induce cell differentiation and apoptosis in leukemic cells. Venetoclax targets the BCL-2 protein, which is often overexpressed in AML cells and helps them evade apoptosis. By inhibiting BCL-2, venetoclax promotes programmed cell death in these cancer cells. These mechanisms are crucial for AML patients, especially those resistant to standard treatments, as they offer alternative pathways to induce cancer cell death and improve patient outcomes.

Epigenetic deregulation in myeloid malignancies.Molecular targeting in acute myeloid leukemia.Epigenetic therapy: azacytidine and decitabine in acute myeloid leukemia.