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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 : August 16, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE April 14, 2014
First Posted Date  ICMJE April 16, 2014
Last Update Posted Date August 16, 2019
Actual Study Start Date  ICMJE May 19, 2014
Estimated Primary Completion Date May 19, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 1, 2019)
Complete response (CR) rate [ Time Frame: Up to 12 months ]
CR rate will be determined.
Original Primary Outcome Measures  ICMJE
 (submitted: April 14, 2014)
Complete Response Rate (CR) [ Time Frame: 21 days ]
Patient's classified as achieving a complete response if they have complete remission (CR) or complete remission without platelet recovery (CRp). Patients who do not have evidence of a complete response considered not to have a complete response, regardless of the reason, including early withdrawals for any reason. Complete response rate (CR) defined as disappearance of all clinical and/or radiologic evidence of disease, including extramedullary leukemia. Neutrophil count ≥ 1.0 x 109/L and platelet count ≥ 100 x 109/L, and bone marrow differential showing ≤ 5% blasts. Response Criteria according to revised recommendations of the International Working Group Response Criteria (IWGRC) in acute myeloid leukemia.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 1, 2019)
  • Overall response rate (ORR) [ Time Frame: Up to 12 months ]
    ORR will be determined.
  • Overall survival (OS) [ Time Frame: Up to 12 months ]
    OS will be assessed.
  • Event-free survival (EFS) [ Time Frame: Up to 12 months ]
    EFS will be assessed.
  • Duration of response [ Time Frame: Up to 12 months ]
    Duration of response will be assessed.
  • Incidence of toxicities [ Time Frame: Up to 12 months ]
    Safety and tolerability of cladribine in combination with idarubicin and cytarabine will be determined.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 14, 2014)
Overall response rate (ORR) [ Time Frame: 21 days ]
Overall response defined as complete remission (CR), complete remission without platelet recovery (CRi), or partial remission (PR). Patients who do not have evidence of overall response considered to not have an overall response, regardless of the reason. Complete remission without platelet recovery (CRi) defined as participants meeting all criteria for CR, except for either residual neutropenia (ANC < 1.0 x 109/L) or thrombocytopenia (platelet count < 100 x 109/L). Partial remission (PR) defined as blood count recovery as for CR, but with a decrease in marrow blasts of at least 50% and not more than 6 to 25% abnormal cells in the bone marrow. Complete remission (CR) defined as disappearance of all clinical and/or radiologic evidence of disease, including extramedullary leukemia. Neutrophil count ≥ 1.0 x 109/L and platelet count ≥ 100 x 109/L, and bone marrow differential showing ≤ 5% blasts.
Current Other Pre-specified Outcome Measures
 (submitted: August 1, 2019)
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Cladribine, Idarubicin, Cytarabine, and Venetoclax in Treating Patients With Acute Myeloid Leukemia, High-Risk Myelodysplastic Syndrome, or Blastic Phase Chronic Myeloid Leukemia
Official Title  ICMJE Phase II Study of Cladribine Plus Idarubicin Plus Cytarabine (ARAC) in Patients With AML, HR MDS, or Myeloid Blast Phase of CML
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.
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.

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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.

Interventions:
  • Drug: Cladribine
  • Drug: Cytarabine
  • Drug: Gilteritinib
  • Drug: Idarubicin
  • Other: Laboratory Biomarker Analysis
  • Drug: Midostaurin
  • Drug: Venetoclax
Publications * Morita K, Kantarjian HM, Wang F, Yan Y, Bueso-Ramos C, Sasaki K, Issa GC, Wang S, Jorgensen J, Song X, Zhang J, Tippen S, Thornton R, Coyle M, Little L, Gumbs C, Pemmaraju N, Daver N, DiNardo CD, Konopleva M, Andreeff M, Ravandi F, Cortes JE, Kadia T, Jabbour E, Garcia-Manero G, Patel KP, Futreal PA, Takahashi K. Clearance of Somatic Mutations at Remission and the Risk of Relapse in Acute Myeloid Leukemia. J Clin Oncol. 2018 Jun 20;36(18):1788-1797. doi: 10.1200/JCO.2017.77.6757. Epub 2018 Apr 27.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 1, 2019)
408
Original Estimated Enrollment  ICMJE
 (submitted: April 14, 2014)
100
Estimated Study Completion Date  ICMJE May 19, 2022
Estimated Primary Completion Date May 19, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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; 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Tapan Kadia 713-792-7305 tkadia@mdanderson.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02115295
Other Study ID Numbers  ICMJE 2012-0648
NCI-2014-01103 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2012-0648 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Tapan M Kadia M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP