Geriatric Assessment & Genetic Profiling to Personalize Therapy in Older Adults With Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVES: I. 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 (AML) who receive clinicogenetic risk-stratified therapy allocation. SECONDARY OBJECTIVES: I. To determine the rate of complete remission and mortality at 90 days in subsets of older patients who receive intensive and low-intensity chemotherapy. II. To assess the impact of baseline functional status (measured by geriatric assessment) on the rate of complete remission and mortality at 90 days in older patients, who receive clinicogenetic risk-stratified therapy allocation. III. To evaluate the influence of baseline functional status on the quality of life, grades 3 and 4 toxicities (Common Terminology Criteria for Adverse Events [CTCAE] version 4.03 grades) and neurocognitive status at baseline and at 90 days in older patients. IV. To determine the symptom burden at diagnosis and 10, 30 and 90 days following initiation of chemotherapy. V. To determine proportion of patients with impairments detected by geriatric assessment. OUTLINE: Patients are assigned to 1 or 2 groups based on cytogenetic and geriatric assessment-based risk stratification. 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 disease progression or 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 or unacceptable toxicity. GROUP II: LOW-INTENSITY INDUCTION: Patients receive oral venetoclax and azacitidine IV on days 1-7 or decitabine IV on days 1-5. Alternate standard of care low-intensity therapies are allowed at the discretion of treating physician. Treatment repeats every 4 weeks for 1-4 courses in the absence of disease progression or unacceptable toxicity. LOW-INTENSITY CONSOLIDATION: Patients who achieve complete remission, receive oral venetoclax and azacitidine IV on days 1-7 or decitabine IV on days 1-5 or other standard of care low-intensity chemotherapy. Treatment repeats every 4 weeks for 3 or more courses in the absence of disease progression, unacceptable toxicity or receipt of allogeneic stem cell transplant. After completion of study treatment, patients are followed up for up to 2 years.

Official Title
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A Phase II Study of the Impact of Clinicogenetic Risk-Stratified Management on Outcomes of Acute Myeloid Leukemia in Older Patients

Conditions
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Adult Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Therapy-Related Acute Myeloid Leukemia

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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 Patients aged ≥60 years Karnofsky Performance Status ≥60% Subjects must be able and willingly give signed informed consent Exclusion criteria: 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. Relapsed or refractory AML, who require salvage therapy Prior exposure to decitabine or azacitidine will be an exclusion criterion for the use of decitabine or azacitidine alone. 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. 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 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. Ejection fraction <45% will be an exclusion criteria for intensive chemotherapy. Such patients may receive low intensity therapy. 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. Any other condition that may not allow safe use of chemotherapy based on the clinical judgment of the treating oncologist.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I<br>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<br>* Given IV<br>* Other names: WR-28453;Drug: Idarubicin<br>* Given IV<br>* Other names: 4-DMDR;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Liposome-encapsulated Daunorubicin-Cytarabine<br>* Given IV<br>* Other names: Vyxeos;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Group II<br>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<br>* Given IV<br>* Other names: Dezocitidine;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Azacitidine<br>* Given by infusion<br>* Other names: VIDAZA;Drug: Venetoclax<br>* oral tablet<br>* Other names: Venclexta, Venclyxto;Drug: glasdegib<br>* oral tablet<br>* Other names: Daurismo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of complete remission and mortality in the entire cohort of older patients | 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. | At 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of complete remission and mortality in subsets of older patients who receive intensive and low-intensity chemotherapy | 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. | At 90 days | 
| Baseline functional status measure by geriatric assessment | Will assess the impact of baseline functional status on the rate of complete remission and mortality. | At 90 days | 
| Baseline functional status | 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. | Up to 90 days | 
| Functional status | 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. | Up to 90 days | 
| Symptom burden | Will determine the symptom burden at diagnosis and 10, 30 and 90 days following initiation of chemotherapy. | Up to 90 days following initiation of chemotherapy | 
| Mortality | 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. | From the time of diagnosis to death, assessed up to 90 days | 
| 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 | 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. | Up to 4 years | 
| Neurocognitive status as measured by the Montreal Cognitive Assessment (MoCA) | Composite scores, as determined by MOCA test, will be utilized to determine neurocognitive status. | Up to 4 years |