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Alkylating agents

Venetoclax with Chemotherapy for AML and MDS

Phase 1

Recruiting

Led By Jacqueline S. Garcia, MD

Research Sponsored by Jacqueline Garcia, MD

Eligibility Criteria Checklist

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

Must have

Patients must have a prior diagnosis of high-risk MDS or high-risk AML or therapy-related MDS or high-risk chronic myelomonocytic leukemia (CMML) or MDS/MPN unclassifiable (MDS/MPN-U)

Patient must have a matched related or an 8/8 unrelated donor option for his/her allo-HCT

Must not have

Malabsorption syndrome or other conditions precluding enteral administration

Receiving anti-microbial agents

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 12 months

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing the safety of adding Venetoclax to a standard conditioning regimen for bone marrow transplantation, as well as the safety of combining Venetoclax with azacitidine or oral decitabine/cedazuridine as maintenance therapy after transplant, in order to possibly prevent disease recurrence.

Who is the study for?

Adults diagnosed with AML, MDS, CMML, or MDS/MPN who are suitable for a bone marrow transplant using reduced intensity conditioning. They must have an ECOG performance status ≤ 2 (which means they can do some activity), adequate blood counts without recent transfusions, no severe acute GVHD if on low-dose prednisone, normal liver and kidney function tests, agree to use contraception during the study and understand the consent form. Excluded are those with prior transplants, untreated brain involvement of disease, certain dietary restrictions before treatment starts (like grapefruit), malabsorption issues that affect oral drug intake, active heart disease in last 6 months or uncontrolled infections.

What is being tested?

The trial is testing Venetoclax added to Fludarabine + Busulfan as pre-transplant conditioning therapy and combined with Azacitidine or Decitabine/Cedazuridine post-transplant as maintenance therapy. The aim is to see if these combinations can safely eliminate remaining leukemia cells before transplant and prevent recurrence after.

What are the potential side effects?

Potential side effects include digestive problems like nausea and diarrhea; lowered blood cell counts leading to increased infection risk; fatigue; possible liver dysfunction indicated by elevated bilirubin levels; infusion-related reactions from drugs given through veins; and potential interactions affecting other medications.

Eligibility Criteria

Inclusion Criteria

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

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I was diagnosed with a high-risk blood cancer or related condition.

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I have a donor match for my bone marrow transplant.

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I can take care of myself but might not be able to do heavy physical work.

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I am eligible for a stem cell transplant with a less intense preparation.

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I am 18 years old or older.

Exclusion Criteria

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

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I cannot take medicine by mouth due to a digestive condition.

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I am currently taking medication to fight an infection.

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I haven't had chemotherapy, radiotherapy, or experimental treatments in the last 14 days.

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My bone marrow test shows more than 10% blasts for MDS or MDS/MPN, or more than 5% for AML.

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I am advised to undergo intensive chemotherapy or radiation before a transplant.

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I have a severe ongoing medical or mental health condition.

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I have an active HIV infection.

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I do not have any untreated infections.

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I am advised to take FLT3 inhibitor or other therapies for AML after a stem cell transplant.

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I have an ongoing heart condition.

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I have had a stem cell transplant from a donor.

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My cancer has spread to my brain and is causing symptoms.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 12 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~12 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and 12 months for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

MTD of Venetoclax with Azacitidine as Maintenance Therapy

MTD of Venetoclax with Busulfan and Fludarabine

MTD of Venetoclax with Decitabine/cedazuridine as Maintenance Therapy

Secondary study objectives

Compare Incidences of Mortality and Survival Between Participants in Part 1, Part 2 and Part 3

Cumulative incidence of acute graft versus host disease (GVHD) and chronic GVHD following allo-HCT

Donor granulocyte chimerism percentage

+6 more

Side effects data

From 2022 Phase 3 trial • 389 Patients • NCT02005471

33%

Neutropenia

11%

SARS-CoV-2 test positive

11%

Sepsis

11%

Abdominal pain

11%

Pneumonia

11%

Rhinovirus infection

11%

COVID-19

11%

Gastroenteritis

11%

Pneumonia pseudomonal

11%

Electrocardiogram QT prolonged

11%

Anaemia

11%

Neutrophil count decreased

11%

Hypokalaemia

11%

Febrile neutropenia

11%

Supraventricular tachycardia

11%

Blood creatinine increased

11%

White blood cell count decreased

11%

Dermatitis

100%

80%

60%

40%

20%

Study treatment Arm

Bendamustine + Rituximab Crossover Substudy

Venetoclax + Rituximab Re-Treatment Substudy

Venetoclax + Rituximab Main Study

Bendamustine + Rituximab Main Study

Awards & Highlights

No Placebo-Only Group

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

Trial Design

1Treatment groups

Experimental Treatment

Group I: VenetoclaxExperimental Treatment5 Interventions

This study has three periods: 1) Screening 2) Treatment with venetoclax + FluBu2 chemotherapy and transplantation and 3) Post-Transplant follow up. Dose escalations begin in level I with dose cohorts and rules for escalation/de-escalation. Part 1 dose escalation will occur using a 3+3 approach. Post-transplant period includes routine follow-up. * Venetoclax: 6-7 total doses based on level assigned * Busulfan: given 2x daily for 4 days * Fludarabine: given 1x daily for 4 days Part 2 post-transplant period includes therapy with azacitidine and venetoclax. Dose escalation will occur using a 10+10 approach. * Venetoclax: 14 doses for 8-12 cycles based on level assigned * Azacitidine: 5 doses for 8-12 cycles based on level assigned Part 3 post-transplant period includes therapy with oral decitabine/cedazuridine and venetoclax. Dose escalation will occur using a 10+10 approach. * Venetoclax: 14 doses for 8 cycles * Decitabine/cedazuridine: 3 doses for 8 cycles

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Busulfan

2008

Completed Phase 4

~1710

Azacitidine

2012

Completed Phase 3

~1440