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Integrating Geriatric Assessment and Genetic Profiling to Personalize Therapy Selection in Older Adults With Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT03226418
Recruitment Status : Recruiting
First Posted : July 21, 2017
Last Update Posted : July 23, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Vijaya Bhatt, University of Nebraska

Brief Summary:

This phase II trial of the impact of clinicogenetic risk-stratified management on outcomes of acute myeloid leukemia in older patients is to determine the rate of complete remission and mortality at 90 days in the entire cohort of older patients (≥60 years) with newly diagnosed acute myeloid leukemia, who receive clinicogenetic risk-stratified therapy allocation.

Subjects will receive standard of care intensive or low-intensity induction based on cytogenetic and geriatric assessment-based risk stratification.

Subjects will be evaluated for disease status, survival, quality of life and neurocognitive status for 90 days and then followed for a total of 2 years for survival data.


Condition or disease Intervention/treatment Phase
Adult Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Therapy-Related Acute Myeloid Leukemia Drug: Cytarabine Drug: Decitabine Drug: Idarubicin Other: Laboratory Biomarker Analysis Drug: Liposome-encapsulated Daunorubicin-Cytarabine Other: Quality-of-Life Assessment Other: Questionnaire Administration Drug: Azacitidine Drug: Venetoclax Drug: glasdegib Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 75 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of the Impact of Clinicogenetic Risk-Stratified Management on Outcomes of Acute Myeloid Leukemia in Older Patients
Actual Study Start Date : July 7, 2017
Estimated Primary Completion Date : July 7, 2022
Estimated Study Completion Date : July 7, 2023


Arm Intervention/treatment
Experimental: Group I

INTENSIVE INDUCTION THERAPY: Patients receive cytarabine intravenously (IV) on days 1-7 and idarubicin over 10-15 minutes on days 1-3 (7+3), or liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1, 3 and 5. Gemtuzumab or midostaurin are added to 7+3 as per the standard of care. Treatment continues for 1 course in the absence of unacceptable toxicity.

INTENSIVE CONSOLIDATION THERAPY: Patients who go into remission, receive cytarabine IV over 1-3 hours twice daily (BID) on days 1, 3, and 5. Treatment repeats every 4 weeks for 2-4 courses in the absence of disease progression or unacceptable toxicity. Patients treated with liposome-encapsulated daunorubicin-cytarabine receive liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1 and 3. Treatment repeats every 5-8 weeks for 2 courses in the absence of disease progression, unacceptable toxicity.

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

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Liposome-encapsulated Daunorubicin-Cytarabine
Given IV
Other Names:
  • CPX-351
  • Cytarabine-Daunorubicin Liposome for Injection
  • Liposomal AraC-Daunorubicin CPX-351
  • Liposomal Cytarabine-Daunorubicin
  • Liposome-encapsulated Combination of Daunorubicin and Cytarabine
  • Vyxeos

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Experimental: Group II

LOW-INTENSITY: Patients receive venetoclax in combination with azacitidine or decitabine or other standard of care low-intensity therapy such as azacitidine or decitabine alone or in combination with FLT3 inhibitor such as midostaurin, low-dose cytarabine in combination with glasdegib.

Venetoclax dose varies depending on drug interaction with antifungal agents. Given daily continuous for >= 3 months orally. Glasdegib dose is 100 mg oral daily.

Decitabine IV over 1-3 hours daily for 5-10 days. Treatment repeats every 4-5 weeks for >= 3 courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant. Azacitidine IV infusion over 10 to 40 minutes days 1 -7. Treatment repeats every 4-5 weeks for >= 3 courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant.

Drug: Decitabine
Given IV
Other Names:
  • 5-Aza-2'-deoxycytidine
  • Aza-TdC
  • Dacogen
  • Decitabine for Injection
  • Deoxyazacytidine
  • Dezocitidine

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Drug: Azacitidine
Given by infusion

Drug: Venetoclax
oral tablet

Drug: glasdegib
oral tablet




Primary Outcome Measures :
  1. Rate of complete remission and mortality in the entire cohort of older patients [ Time Frame: At 90 days ]
    All analyses will be performed based on intent-to-treat principle. The method of inversion will be used to generate an interval estimate for the proportion of 90-day mortality.


Secondary Outcome Measures :
  1. Rate of complete remission and mortality in subsets of older patients who receive intensive and low-intensity chemotherapy [ Time Frame: At 90 days ]
    All analyses will be performed based on intent-to-treat principle. The method of inversion will be used to generate an interval estimate for the proportion of 90-day mortality.

  2. Baseline functional status measure by geriatric assessment [ Time Frame: At 90 days ]
    Will assess the impact of baseline functional status on the rate of complete remission and mortality.

  3. Baseline functional status [ Time Frame: Up to 90 days ]
    Will evaluate the influence of baseline functional status on the quality of life and neurocognitive status. The association between categories of functional status and quality of life will be explored using analysis of variance (ANOVA); if assumptions of ANOVA fail, Kruskal Wallis will be used. The association between functional status (fit or vulnerable) and neurocognitive status (< 25 or 26 or higher) will be explored using a chi-square test. A generalized linear mixed model will be utilized to evaluate changes in quality of life over time. The proportion (and associated 95% confidence interval) of patients with definitely or probably modifiable impairments will be presented.

  4. Functional status [ Time Frame: Up to 90 days ]
    The association between functional status and grade 3/4 toxicities will be explored using ANOVA; if assumptions of ANOVA fail, Kruskal Wallis will be used.

  5. Symptom burden [ Time Frame: Up to 90 days following initiation of chemotherapy ]
    Will determine the symptom burden at diagnosis and 10, 30 and 90 days following initiation of chemotherapy.

  6. Mortality [ Time Frame: From the time of diagnosis to death, assessed up to 90 days ]
    Mortality at 90 days will be calculated as the time from date of diagnosis to date of death due to any cause by 90 days from diagnosis.

  7. Quality of life as measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) version 3.0 [ Time Frame: Up to 4 years ]
    Composite scores, as determined by EORTC QLQ-C30 version 3.0, will be utilized to determine quality of life status. A generalized linear mixed model will be utilized to evaluate changes in quality of life over time.

  8. Neurocognitive status as measured by the Montreal Cognitive Assessment (MoCA) [ Time Frame: Up to 4 years ]
    Composite scores, as determined by MOCA test, will be utilized to determine neurocognitive status.



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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  1. A new diagnosis of de novo, secondary or treatment-related AML, other AML equivalent such as myeloid sarcoma, myelodysplastic syndrome in transformation to AML, or high-grade treatment-related myeloid neoplasm
  2. Patients aged ≥60 years
  3. Karnofsky Performance Status ≥60%
  4. Subjects must be able and willingly give signed informed consent

Exclusion criteria:

  1. Acute promyelocytic leukemia (APL). Patients with brief exposure to all-trans retinoic acid (ATRA), arsenic trioxide (ATO) or similar product for suspected APL, who later turn out not to have APL, are eligible for the study.
  2. Relapsed or refractory AML, who require salvage therapy
  3. Prior exposure to decitabine or azacitidine will be an exclusion criterion for the use of decitabine or azacitidine alone.
  4. Patients, who require urgent initiation of chemotherapy (other than debulking agent such as hydroxyurea or cyclophosphamide) due to leukemia-related emergencies such as leukostasis, or disseminated intravascular coagulopathy. Patients will not be excluded solely based on prior use of debulking agent. Prior or current use of leukapheresis will be allowed.
  5. Uncontrolled serious infection at the time of enrollment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of enrollment, patients do not have signs of infection progression. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection
  6. Uncontrolled clinically significant arrhythmia, myocardial ischemia or congestive heart failure within the past 2 weeks, that is considered by the treating physician as a contraindication for initiation of chemotherapy.
  7. Ejection fraction <45% will be an exclusion criteria for intensive chemotherapy. Such patients may receive low intensity therapy.
  8. Clinically significant kidney (e.g. GFR ≤45ml/minute or Creatinine of ≥2 mg/dl) or liver dysfunction (e.g. AST/ALT and/or bilirubin ≥2 times ULN) at the time of enrollment that may prevent from safely using chemotherapy. Such patients may be allowed to receive low-intensity chemotherapy. Patients with elevated bilirubin secondary to Gilbert syndrome will not be excluded.
  9. Any other condition that may not allow safe use of chemotherapy based on the clinical judgment of the treating oncologist.

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): NCT03226418


Contacts
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Contact: Rachal nurse coordinator 402-559-8155 rachal.brantley@unmc.edu

Locations
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United States, Nebraska
University of Nebraska Medical Center Recruiting
Omaha, Nebraska, United States, 68198
Contact: Vijaya R. Bhatt    402-559-8008    vijaya.bhatt@unmc.edu   
Principal Investigator: Vijaya R. Bhatt         
Sponsors and Collaborators
University of Nebraska
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Vijaya Bhatt University of Nebraska

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Responsible Party: Vijaya Bhatt, Principal Investigator, University of Nebraska
ClinicalTrials.gov Identifier: NCT03226418     History of Changes
Other Study ID Numbers: 179-17
NCI-2017-01285 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
179-17 ( Other Identifier: University of Nebraska Medical Center )
P30CA036727 ( U.S. NIH Grant/Contract )
First Posted: July 21, 2017    Key Record Dates
Last Update Posted: July 23, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Azacitidine
Decitabine
Venetoclax
Daunorubicin
Idarubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors