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Venetoclax With Combination Chemotherapy in Treating Patients With Newly Diagnosed or Relapsed or Refractory Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT03214562
Recruitment Status : Recruiting
First Posted : July 11, 2017
Last Update Posted : June 11, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase Ib/II trial studies the best dose and side effects of venetoclax and how well it works when given with combination chemotherapy in treating patients with newly diagnosed acute myeloid leukemia or acute myeloid leukemia that has come back or does not respond to treatment. Venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate, cytarabine, filgrastim and idarubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax together with combination chemotherapy may work better in treating patients with acute myeloid leukemia.

Condition or disease Intervention/treatment Phase
High Risk Myelodysplastic Syndrome Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Drug: Cytarabine Biological: Filgrastim Drug: Fludarabine Drug: Fludarabine Phosphate Drug: Idarubicin Drug: Idarubicin Hydrochloride Biological: Pegfilgrastim Drug: Venetoclax Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability and to determine the dose-limiting toxicity and the maximum tolerated dose MTD of the combination of fludarabine phosphate (fludarabine), cytarabine, filgrastim (GCSF), idarubicin hydrochloride (idarubicin) (FLAG-IDA) + venetoclax for patients with acute myeloid leukemia (AML) (Phase 1b).

II. To determine the overall activity of this combination in patients newly diagnosed or relapsed/refractory (AML) (Phase 2).

SECONDARY OBJECTIVES:

I. Determine the preliminary assessment of efficacy by response to revised International Working Group (IWG) criteria and time to response variables including overall survival (OS), event-free survival (EFS) and duration of response (DOR).

II. Determine biomarkers that may be predictive of venetoclax activity.

OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study.

INDUCTION THERAPY: Patients receive venetoclax orally (PO) on days 1-14, fludarabine phosphate intravenously (IV) over 30 minutes on days 2-6, cytarabine IV over 4 hours on days 2-6, idarubicin hydrochloride IV over 15-30 minutes on days 4 and 5, filgrastim subcutaneously (SC) on days 1-7, or pegfilgrastim SC after day 5. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY: Patients receive venetoclax PO on days 1-7, fludarabine phosphate IV over 30 minutes on days 2-4, cytarabine IV over 4 hours on days 2-4, filgrastim SC on days 1-7, or pegfilgrastim SC after days 3. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may also receive idarubicin hydrochloride as in Induction Therapy during 1 cycle of Consolidation Therapy per the treating physician.

MAINTENANCE THERAPY: Patients receive venetoclax PO on days 1-28. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 56 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Study of the BCL-2 Inhibitor Venetoclax in Combination With Standard Intensive AML Induction/Consolidation Therapy With FLAG-IDA in Patients With Newly Diagnosed or Relapsed/Refractory AML
Actual Study Start Date : September 26, 2017
Estimated Primary Completion Date : September 30, 2023
Estimated Study Completion Date : September 30, 2023


Arm Intervention/treatment
Experimental: Treatment (venetoclax, FLAG-IDA)
See detailed description.
Drug: Cytarabine
Given IV
Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453

Biological: Filgrastim
Given SC
Other Names:
  • G-CSF
  • Neupogen
  • r-metHuG-CSF
  • Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
  • rG-CSF
  • Tevagrastim

Drug: Fludarabine
Given IV
Other Name: Fluradosa

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586

Drug: Idarubicin
Given IV
Other Names:
  • 4-Demethoxydaunomycin
  • 4-demethoxydaunorubicin
  • 4-DMDR

Drug: Idarubicin Hydrochloride
Given IV
Other Names:
  • Idamycin
  • Idamycin PFS
  • Idarubicin HCl
  • IMI-30
  • SC-33428
  • Zavedos

Biological: Pegfilgrastim
Given SC
Other Names:
  • Filgrastim SD-01
  • filgrastim-SD/01
  • Fulphila
  • HSP-130
  • Jinyouli
  • Neulasta
  • Neulastim
  • Pegfilgrastim Biosimilar HSP-130
  • Pegfilgrastim Biosimilar Pegcyte
  • SD-01
  • SD-01 sustained duration G-CSF

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto




Primary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Up to 6 years ]
    Defined as complete response (CR) + CR with incomplete blood count recovery (CRi) + partial response (PR). Will be estimated along with the 95% credible interval.

  2. CR/CRi rate [ Time Frame: Up to 6 years ]
    Will be estimated along with the 95% credible interval.

  3. Hematologic response [ Time Frame: Up to 6 years ]
    Will be estimated along with the 95% credible interval.

  4. Duration of response [ Time Frame: From the date of initial response, assessed up to 6 years ]
    Defined as the number of days from the date of initial response (PR or better) to the date of first documented disease progression/relapse or death, whichever occurs first. Will be calculated for all patients.

  5. Event-free survival [ Time Frame: From the date of treatment initiation, assessed up to 6 years ]
    Defined as the number of days from the date of treatment initiation (i.e., course 1 day 1) to the date of documented treatment failure, relapses from CR, or death from any cause, whichever occurs first. Will be calculated for all patients. Estimated using Kaplan-Meier method. Log-rank tests will be used to compare among subgroups of patients.

  6. Overall survival [ Time Frame: Up to 6 years ]
    Estimated using Kaplan-Meier method. Log-rank tests will be used to compare among subgroups of patients.

  7. Anti-tumor activity [ Time Frame: Up to 6 years ]
    Will be summarized graphically and with descriptive statistics.

  8. Pharmacodynamic markers [ Time Frame: Up to 6 years ]
    Two samples t-test /Wilcoxon rank sum tests will be used to compare pharmacodynamics/pharmacokinetics (PD/PK) parameters between responder and non-responders, and logistic regression analysis will also be used to evaluate the association of PD/PK parameters with response.

  9. Drug exposure levels [ Time Frame: Up to 6 years ]
    Will be summarized graphically and with descriptive statistics.

  10. Overall incidence and severity of all adverse events [ Time Frame: Up to 6 years ]
    Graded using Common Toxicity Criteria version 4.0. Safety data will be summarized using frequency and percentage, by category and severity.


Secondary Outcome Measures :
  1. Morphologic leukemia-free state [ Time Frame: Up to 6 years ]
    Will be estimated along with the 95% credible interval.


Other Outcome Measures:
  1. Exploratory biomarkers [ Time Frame: Up to 6 years ]
    Will be summarized graphically and with descriptive statistics. Peripheral blood and bone marrow aspirate samples will be obtained at study specified time points. Biomarker assays may include, but are not limited to, BH3 profiling and characterization of BCL-2 and related proteins, and assessment of the depth of response and monitoring of disease recurrence by assessment of minimal residual disease (MRD) in the bone marrow.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of AML by World Health Organization (WHO) criteria. Patients with high risk myelodysplastic syndrome (MDS) as defined by the presence of >= 10% blasts are also eligible at the discretion of the principal investigator
  • Patients older than 65 who are deemed fit to receive intensive chemotherapy by the treating physician will be eligible after discussion with the principal investigator (PI).
  • Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
  • Creatinine clearance >= 30 mL/min based on the Cockcroft-Gault equation
  • Total bilirubin < 1.5 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement
  • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN unless considered due to leukemic involvement
  • Ability to understand and provide signed informed consent
  • Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug
  • Only patients who are relapsed, refractory, or intolerant of standard AML therapy will be eligible for Part 1 (minimum of 1 prior line of AML-directed therapy)

Exclusion Criteria:

  • Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML)
  • Patients having received any prior BCL2 inhibitor therapy
  • Subject has known active central nervous system (CNS) involvement with AML
  • Patients with New York Heart Association (NYHA) class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 40% by echocardiogram or multi-gated acquisition (MUGA) scan
  • Patients with a history of myocardial infarction within the last 6 months or unstable / uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias
  • Patients with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C
  • Patients with known dysphagia, short-gut syndrome, or other conditions that would affect the ingestion or gastrointestinal absorption of drugs administered orally
  • Subject has any other significant medical or psychiatric history that in the opinion of the investigator would adversely affect participation in this study
  • Subject has a white blood cell count > 25 x 10{9}/L. (Note: hydroxyurea is permitted to meet this criterion)
  • Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception (a) appropriate method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03214562


Contacts
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Contact: Courtney DiNardo, MD 713-794-1141 cdinardo@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Courtney DiNardo    713-794-1141      
Principal Investigator: Courtney DiNardo         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Courtney DiNardo M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03214562     History of Changes
Other Study ID Numbers: 2016-0979
NCI-2018-01119 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2016-0979 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: July 11, 2017    Key Record Dates
Last Update Posted: June 11, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Bone Marrow Diseases
Venetoclax
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Hematologic Diseases
Vidarabine
Cytarabine
Fludarabine
Fludarabine phosphate
Idarubicin
Lenograstim
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents
Adjuvants, Immunologic
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors