Venetoclax in Patients With MDS or AML in Relapse After AHSCT
Study Details
Study Description
Brief Summary
Study to assess venetoclax + azacitidine and donor lymphocyte infusion (DLI) in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with blasts < 30% in relapse after allohematopoietic stem cell transplantation (AHSCT).
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1/Phase 2 |
Detailed Description
A phase I-II study to assess venetoclax + azacitidine and donor lymphocyte infusion (DLI) in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with blasts < 30% in relapse after allohematopoietic stem cell transplantation (AHSCT).
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: venetoclax + azacitidine +/- donor lymphocyte infusion Venetoclax + azacitidine +/- donor lymphocyte infusion (maximum 12 cycles). Venetoclax: on D1 to D14 of 28 days cycle ; Phase I: 4 dose levels: 50, 100, 200, 400 mg/d, starting dose at 100 mg ; Phase II: dose defined in the phase I. Azacitidine 75 mg/m²/d or 50 mg/m²/d (if allohematopoietic stem cell transplantation relapse < 4 months) x 5 days (on D1 to D5 of 28 days cycle). |
Drug: venetoclax + azacitidine +/- donor lymphocyte infusion
Venetoclax will be given once daily orally on days 1 to 14 for all cycles. Venetoclax + azacitidine +/- donor lymphocyte infusion (12 cycles maximum)
Other Names:
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Outcome Measures
Primary Outcome Measures
- Phase I: Dose-finding study [At the end of cycle 1 of venetoclax + azacitidine (each cycle is 28 days)]
Evaluation of Dose-limiting toxicity (DLT) to determine the optimal dose level in terms of both toxicity and safety for venetoclax + azacitidine
- Phase II: Overall improvement rate of venetoclax + azacitidine +/- DLI [After 8 cycles of venetoclax + azacitidine (each cycle is 28 days)]
Response assessment performed according to modified IWG (International Working Group) 2006 criteria for myelodysplastic syndrome and to European Leukemia Net criteria for acute myeloid leukemia
Secondary Outcome Measures
- Toxicity assessment [At 42 months (at end of study)]
Adverse events analyzed by frequency, NCI CTCAE 5.0 grade, and causality
- Graft-versus-Host-Disease (GVHD) rate [At 42 months (at end of study)]
Acute and chronic graft-versus-host-disease (GVHD) rate assessment (graft-versus-host events analyzed by frequency and grade)
- Duration of response [At 42 months (at end of study)]
Duration of response defined as time from the date of the first observed response (complete or partial) to the date of first subsequent documented disease progression or relapse or death
- Overall survival [At 42 months (at end of study)]
Overall Survival defined as time from the date of the first dose of venetoclax to the date of death or end of study
- Progression-free survival [At 42 months (at end of study)]
Progression-free Survival for patients with at least a partial response defined as time from the date of the first dose of venetoclax to the date of the first documented disease progression or relapse or death
- Event-free survival [At 42 months (at end of study)]
Event-free Survival defined as time from the date of the first dose of venetoclax to the date of earliest disease progression or death
Other Outcome Measures
- Correlation between patient overall mutational status before and after treatment [At 42 months (at end of study)]
Mutational analysis performed by NGS (next-generation sequencing) at screening and then at each protocol evaluation (post 4, 6 and 8 cycles of venetoclax + azacitidine and at end of study)
- Prognostic impact of Minimal Residual Disease (MRD) on outcome [At 42 months (at end of study)]
Minimal Residual Disease (MRD) assessment by flow cytometry and allelic variant frequency (VAF) of baseline mutations
Eligibility Criteria
Criteria
Inclusion Criteria:
- Documented relapse of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with marrow blasts < 30% (with white blood cells (WBC) < 15000/mm3), after allohematopoietic stem cell transplantation.
Relapse of MDS or AML is defined as :
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Return to pretreatment bone marrow blast percentage
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Decrement of at least 50% from maximum remission
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Age ≥ 18 years.
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Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
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Patient must have adequate organ function:
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Serum creatinine < 2 mg/dL or calculated creatinine clearance ≥ 30 mL/min for patients with creatinine levels > 1.5 times Upper Limit of Normal
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Serum total bilirubin ≤ 2.5 times Upper Limit of Normal or direct bilirubin ≤ Upper Limit of Normal for patients with total bilirubin levels ≥ 2 mg/d
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Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 times Upper Limit of Normal
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Alkaline phosphatase ≤ 5 times Upper Limit of Normal (if > 2.5 times Upper Limit of Normal, then liver fraction should be ≤ 2.5 times Upper Limit of Normal).
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Patient not refractory to platelet transfusions.
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Female subject of childbearing potential must practice at least one protocol specified method of birth control, starting on Study Day 1 through at least 30 days after the last dose of venetoclax or 3 months after the last dose of azacitidine.
Not being of childbearing potential is defined as:
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Age > 55 years with no menses for 12 or more months without an alternative medical cause, or
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Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause AND an Follicle Stimulating Hormone (FSH) level > 40 IU/L, or
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Permanent surgical sterility (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
- Female subjects of childbearing potential must have negative results for pregnancy test performed:
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At Screening with a serum sample obtained within 14 days prior to the first study drug administration, and
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Prior to dosing with urine sample obtained on Cycle 1 Day 1, if it has been > 7 days since obtaining the serum pregnancy test results.
Female subjects who are not of childbearing potential at Screening do not require pregnancy testing.
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Male subjects sexually active with female partner(s) of childbearing potential, must agree from first dose of study drug(s) through at least 30 days after the last dose of venetoclax or 3 months after the last dose of azacitidine, whichever is later, to practice the protocol specified contraception.
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Patient is available for periodic blood sampling, study related assessments, and appropriate clinical management at the treating institution for the duration of the study.
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Patient has the ability to understand and willingness to sign an informed consent form indicating the investigational nature of the study.
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Patient is able to swallow capsules.
Exclusion Criteria:
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Patient has active and uncontrolled infection.
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Patient has active acute or chronic Graft-versus-Host-Disease (GVHD).
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Patient receives more than 1mg/kg/day prednisolone.
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Patient has uncontrolled intercurrent illness or circumstances that could limit compliance with the study, including but not limited to the following: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, pancreatitis, or psychiatric or social conditions that may interfere with patient compliance.
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Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of initial dosing with study drug.
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Patient has known human immunodeficiency virus (HIV) infection or HIV-related malignancy.
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Patient has clinically active hepatitis B or hepatitis C infection.
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Patient has a known allergy or hypersensitivity to any component of venetoclax or azacitidine.
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Patient with a "currently active" second malignancy, other than non-melanoma skin cancer and carcinoma in situ of the cervix, should not be enrolled. Patients are not considered to have a "currently active" malignancy if they have completed therapy for a prior malignancy, are disease free from prior malignancies for > 5 years or are considered by their physician to be at less than 30% risk of relapse.
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Patient has received growth factors such as erythropoietin alfa (EPO) or granulocyte colony-stimulating factor (G-CSF) or has received non cytotoxic agents (including low dose oral chemotherapy) in the 30 days before inclusion. In case of previous cytotoxic treatment, an interval of 3 months is required.
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Patient is on any systemic steroids that have not been stabilized to the equivalent of ≤ 10 mg/day prednisone during the 4 weeks prior to the start of the study drugs.
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Patients with clinical evidence of Central Nervous System leukemia.
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Patient has a history of Gastrointestinal surgery or other procedures that might interfere with the absorption or swallowing of the study drugs.
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Subject enrolled in a Dose-Escalation cohort has received strong or moderate CYP3A (Cytochrome P450, family 3, subfamily A) inhibitors within 3 days prior to the first dose of study drug.
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Patient is unable to take and/or tolerate oral medications on a continuous basis.
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Patient is pregnant or breastfeeding within the projected duration of the study.
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Subject has a malabsorption syndrome or other condition that precludes an enteral route of administration.
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Absence of social security.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | CHU d'Amiens Picardie - Site sud | Amiens | France | 80054 | |
2 | CHU d'Angers | Angers | France | 49933 | |
3 | CHU de Grenoble | Grenoble | France | 38043 | |
4 | Hôpital Dupuytren | Limoges | France | 87042 | |
5 | Hôpital Saint-Eloi | Montpellier | France | 34295 | |
6 | CHU Hôtel Dieu | Nantes | France | 44093 | |
7 | Hôpital l'Archet I | Nice | France | 06200 | |
8 | Hôpital Saint louis | Paris | France | 75010 | |
9 | CHU de Haut-Lévèque | Pessac | France | 33604 | |
10 | Centre Hospitalier Lyon-Sud | Pierre-Bénite | France | 69495 | |
11 | Centre Henri Becquerel | Rouen | France | 76038 | |
12 | Institut de Cancérologie de la Loire Lucien Neuwirth | Saint-Priest-en-Jarez | France | 42270 | |
13 | IUCT Oncopole | Toulouse | France | 31059 | |
14 | Hôpital Brabois | Vandœuvre-lès-Nancy | France | 54500 |
Sponsors and Collaborators
- Groupe Francophone des Myelodysplasies
- AbbVie
Investigators
- Principal Investigator: Thomas CLUZEAU, PHD, CHU de Nice - Hôpital l'Archet I
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- VENTOGRAFT
- 2021-000632-56