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Cladribine, Idarubicin, Cytarabine, and Venetoclax in Treating Patients With Acute Myeloid Leukemia, High-Risk Myelodysplastic Syndrome, or Blastic Phase Chronic Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT02115295
Recruitment Status : Recruiting
First Posted : April 16, 2014
Last Update Posted : May 6, 2023
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Study Description
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Brief Summary:
This phase II trial studies how well cladribine, idarubicin, cytarabine, and venetoclax work in patients with acute myeloid leukemia, high-risk myelodysplastic syndrome, or blastic phase chronic myeloid leukemia. Drugs used in chemotherapy, such as cladribine, idarubicin, cytarabine, and venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Condition or disease Intervention/treatment Phase
Acute Biphenotypic Leukemia Acute Myeloid Leukemia Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Blasts 10 Percent or More of Bone Marrow Nucleated Cells Blasts 10 Percent or More of Peripheral Blood White Cells de Novo Myelodysplastic Syndrome Myelodysplastic Syndrome Previously Treated Myelodysplastic Syndrome Recurrent Acute Myeloid Leukemia Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive Refractory Acute Myeloid Leukemia Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive Secondary Acute Myeloid Leukemia Untreated Adult Acute Myeloid Leukemia Drug: Cladribine Drug: Cytarabine Drug: Gilteritinib Drug: Idarubicin Other: Laboratory Biomarker Analysis Drug: Midostaurin Drug: Venetoclax Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the complete response rate (CR) of cladribine in combination with idarubicin and cytarabine (araC) in patients with acute myeloid leukemia (AML), high risk (HR) myelodysplastic syndrome (MDS), or myeloid blast phase of chronic myeloid leukemia (CML).

SECONDARY OBJECTIVES:

I. To determine the overall response rate (ORR) of cladribine in combination with idarubicin and araC in patients with AML, HR MDS, or myeloid blast phase of CML.

II. To assess overall survival (OS) and event free survival (EFS) of patients treated with cladribine, idarubicin, and araC (cytarabine).

III. To assess the duration of response to the combination in patients with AML, HR MDS, or myeloid blast phase of CML.

IV. To determine the safety and tolerability of the combination in patients with AML, HR MDS, or myeloid blast phase of CML.

EXPLORATORY OBJECTIVES:

I. To study and describe the relationship between pretreatment patient/disease characteristics (including AML-associated molecular abnormalities) and outcome.

II. To identify molecular biomarkers predictive of response to therapy. III. To study and describe the relationship between patient/disease characteristics, use of intrathecal prophylaxis, and incidence of leptomeningeal disease.

IV. To study the trajectories of leukemia mutations and molecular minimal residual disease (MRD) during the therapy.

OUTLINE:

INDUCTION: Patients receive cladribine intravenously (IV) and cytarabine IV over 1-2 hours on days 1-5 and idarubicin IV over 30-60 minutes on days 1-3. Patients with untreated AML and MDS also receive venetoclax orally (PO) on days 2-8. AML patients with known FLT3-ITD or FLT3 kinase domain mutations may receive midostaurin PO twice daily (BID) on days 6-19 or gilteritinib PO once daily (QD) on days 1-14. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients receive cladribine IV and cytarabine IV over 1-2 hours on days 1-3 and idarubicin IV over 30-60 minutes on days 1-2. Patients with untreated AML and MDS also receive venetoclax PO on days 2-8. AML patients with known FLT3-ITD or FLT3 kinase domain mutations may receive midostaurin PO BID on days 6-19 or gilteritinib PO QD. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6-12 months.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 458 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Cladribine Plus Idarubicin Plus Cytarabine (ARAC) in Patients With AML, HR MDS, or Myeloid Blast Phase of CML
Actual Study Start Date : May 19, 2014
Estimated Primary Completion Date : May 31, 2025
Estimated Study Completion Date : May 31, 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Treatment (cladribine, cytarabine, idarubicin)

INDUCTION: Patients receive cladribine IV and cytarabine IV over 1-2 hours on days 1-5 and idarubicin IV over 30-60 minutes on days 1-3. Patients with untreated AML and MDS also receive venetoclax PO on days 2-8. AML patients with known FLT3-ITD or FLT3 kinase domain mutations may receive midostaurin PO BID on days 6-19 or gilteritinib PO QD on days 1-14. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients receive cladribine IV and cytarabine IV over 1-2 hours on days 1-3 and idarubicin IV over 30-60 minutes on days 1-2. Patients with untreated AML and MDS also receive venetoclax PO on days 2-8. AML patients with known FLT3-ITD or FLT3 kinase domain mutations may receive midostaurin PO BID on days 6-19 or gilteritinib PO QD. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.

 Drug: Cladribine
Given IV
Other Names:
  • 2-CdA
  • 2CDA
  • CdA
  • Cladribina
  • Leustat
  • Leustatin
  • Leustatine
  • RWJ-26251

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

Drug: Gilteritinib
Given PO
Other Names:
  • ASP-2215
  • ASP2215
  • Xospata

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

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Midostaurin
Given PO
Other Names:
  • CGP 41251
  • CGP41251
  • N-Benzoyl-Staurosporine
  • N-Benzoylstaurosporine
  • PKC-412
  • PKC412
  • Rydapt

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


Outcome Measures
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Primary Outcome Measures :
  1. Complete response (CR) rate [ Time Frame: Up to 12 months ]
    CR rate will be determined.


Secondary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Up to 12 months ]
    ORR will be determined.

  2. Overall survival (OS) [ Time Frame: Up to 12 months ]
    OS will be assessed.

  3. Event-free survival (EFS) [ Time Frame: Up to 12 months ]
    EFS will be assessed.

  4. Duration of response [ Time Frame: Up to 12 months ]
    Duration of response will be assessed.

  5. Incidence of toxicities [ Time Frame: Up to 12 months ]
    Safety and tolerability of cladribine in combination with idarubicin and cytarabine will be determined.


Other Outcome Measures:
  1. Use of intrathecal prophylaxis [ Time Frame: Up to 12 months ]
    The relationship between patient/disease characteristics and use of intrathecal prophylaxis will be studied and described.

  2. Incidence of leptomeningeal disease [ Time Frame: Up to 12 months ]
    The relationship between patient/disease characteristics and incidence of leptomeningeal disease will be studied and described.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with a diagnosis of AML, acute biphenotypic leukemia, or high risk MDS (>= 10% blasts or International Prognostic Scoring System [IPSS] >= intermediate-2) will be eligible; patients with CML in myeloid blast phase are also eligible
  • For frontline cohorts (1 or 4): no prior potentially curative therapy for leukemia; prior therapy with hydroxyurea, hematopoietic growth factors, azacytidine, decitabine, tretinoin (ATRA), or a total dose of cytarabine up to 2 g (for emergency use for stabilization) is allowed; patients deemed able to receive venetoclax (ie. insurance clearance) will be assigned to frontline cohort 4; patients with secondary AML who have been treated for their antecedent myeloid neoplasm will be enrolled into the separate secondary AML cohort
  • For salvage cohort: patients with previously treated, relapsed or refractory AML, acute biphenotypic leukemia, or CML in myeloid blast phase are eligible
  • Bilirubin =< 2 mg/dL
  • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN) or < 5 x ULN if related to leukemic involvement
  • Creatinine =<1.5 x ULN
  • Known cardiac ejection fraction of >= 45% within the past 6 months
  • Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
  • A negative urine pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling on this trial
  • Patient must have the ability to understand the requirements of the study and signed informed consent a signed informed consent by the patient or his legally authorized representative is required prior to their enrollment on the protocol

Exclusion Criteria:

  • Pregnant women are excluded from this study because the agents used in this study have the potential for teratogenic or abortifacient effects; because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with the chemotherapy agents, breastfeeding should also be avoided
  • Uncontrolled intercurrent illness including, but not limited to active uncontrolled infection, symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Patient with documented hypersensitivity to any of the components of the chemotherapy program
  • Men and women of childbearing potential who do not practice contraception; women of childbearing potential and men must agree to use contraception prior to study entry and for the duration of study participation
Contacts and Locations
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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): NCT02115295


Contacts
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Contact: Tapan Kadia 713-792-7305 tkadia@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Tapan M. Kadia    713-792-7305      
Principal Investigator: Tapan M. Kadia         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Tapan M Kadia M.D. Anderson Cancer Center
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02115295    
Other Study ID Numbers: 2012-0648
NCI-2014-01103 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2012-0648 ( Other Identifier: M D Anderson Cancer Center )
First Posted: April 16, 2014    Key Record Dates
Last Update Posted: May 6, 2023
Last Verified: May 2023

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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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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Blast Crisis
Leukemia, Biphenotypic, Acute
Myelodysplastic Syndromes
Syndrome
Recurrence
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Disease Attributes
 Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myeloproliferative Disorders
Chronic Disease
Cell Transformation, Neoplastic
Carcinogenesis
Neoplastic Processes
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cytarabine
2-chloro-3'-deoxyadenosine