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Myeloid Leukemia

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Anti-Infective Agents

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All Drugs and Chemicals

Amino Acids

Cytarabine

Idarubicin

Quizartinib

Cladribine

2-chloro-3'-deoxyadenosine

2'-deoxyadenosine

Cordycepin

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Enzyme Inhibitors

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

INDUCTION: Patients receive idarubicin Intravenous over 1 hours on days 1-3, cladribine intravenous over 1-2 hours on days 1-5, cytarabine Intravenous over 3 hours on days 1-5 (or days 1-3 for patients over age 60), and quizartinib by mouth daily on days 6-19. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients who achieve CR or CRp after Induction receive idarubicin Intravenous over 1 hours on days 1-2, cladribine Intravenous over 1-2 hours on days 1-3, cytarabine Intravenous over 3 hours on days 1-3, and quizartinib by mouth daily on days 4-28. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients who achieve CR or CRi/CRh after Consolidation receive quizartinib by mouth daily on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Musa Yilmaz

This phase I/II trial studies the side effects and how well cladribine, idarubicin, cytarabine, and quizartinib work in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndrome that is newly diagnosed, has come back (relapsed), or does not respond to treatment (refractory). Drugs used in chemotherapy, such as cladribine, idarubicin, and cytarabine, 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. Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving quizartinib with cladribine, idarubicin, and cytarabine may help to control acute myeloid leukemia or high-risk myelodysplastic syndrome.

PRIMARY OBJECTIVES:

I. To determine the efficacy of quizartinib (AC220) in combination with cladribine, idarubicin and cytarabine (ara-C) induction chemotherapy in newly diagnosed or relapsed/refractory patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

II. To determine the safety of the combination.

SECONDARY OBJECTIVES:

I. To determine the overall survival and disease-free survival of patients treated with this combination.

II. To investigate correlations of response to this combination with a 81-gene panel of gene mutations both in patients with and without FLT3 mutations.

III. To identify individual treatment-resistant cell populations and their signaling state that may relate to clinical outcomes using CyTOF (cytometry by time of flight) and single cell sequencing.

OUTLINE:

INDUCTION: Patients receive idarubicin intravenously (IV) over 1 hour on days 1-3, cladribine IV over 1-2 hours on days 1-5, cytarabine IV over 2 hours on days 1-5 (or days 1-3 for patients over age 60), and quizartinib orally (PO) once daily (QD) on days 6-19. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients who achieve complete response (CR) or CR with incomplete platelet recovery (CRp) after Induction receive idarubicin IV over 1 hour on days 1-2, cladribine IV over 1-2 hours on days 1-3, cytarabine IV over 2 hours on days 1-3, and quizartinib PO QD on days 4-28. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients who achieve CR or CR with incomplete bone marrow recovery (CRi)/CR with partial hematologic recovery (CRh) after Consolidation receive quizartinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

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

Cladribine, Idarubicin, Cytarabine, and Quizartinib in Treating Patients With Newly Diagnosed, Relapsed, or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

A Combination of Cladribine, Idarubicin, Cytarabine (CLIA) and Quizartinib for the Treatment of Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (MDS))

Will be estimate using the Kaplan-Meier method for each patient cohort. In addition, efficacy EFS will be analyzed in the intent to treat (ITT) population per cohort.

Defined as any clinically significant treatment-related grade 3 or greater non-hematologic toxicity. Patient toxicity data will be summarized using frequency and percentages, by type, grade and relationship to the study drugs.

Will be estimate using the Kaplan-Meier method for each patient cohort. In addition, efficacy OS will be analyzed in the ITT population per cohort.

Will be estimate using the Kaplan-Meier method for each patient cohort. In addition, efficacy DFS will be analyzed in the ITT population per cohort.

The rate of response will be estimated for each 28-gene panel of gene mutations for each patient cohort.

Will also explore the change of FLT3 ligand level before and after treatment using summary statistics, by patient cohort and by other subgroups (i.e. age).

Will also explore the change in the presence of other gene mutations before and after treatment using summary statistics, by patient cohort and by other subgroups (i.e. age).

National Cancer Institute (NCI)

M.D. Anderson Cancer Center

Venetoclax

Homoharringtonine

Patients receive omacetaxine SC BID on days 2-3 or 2-4, and venetoclax PO on days 1-7, 1-10 or 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Omacetaxine Mepesuccinate

Courtney DiNardo, MD

This phase Ib/II trial best dose, possible benefits and/or side effects of omacetaxine and venetoclax in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has come back (recurrent) or does not respond to treatment (refractory) and have a genetic change RUNX1. Drugs used in chemotherapy, such as omacetaxine, 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. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving omacetaxine and venetoclax may help to control the disease.

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability and recommended phase 2 dose (RP2D) of omacetaxine in combination with venetoclax for patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome harboring a RUNX1 mutation. (Phase 1b) II. To determine the efficacy of omacetaxine in combination with venetoclax for patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome harboring a RUNX1 mutation. (Phase II)

SECONDARY OBJECTIVES:

I. To determine duration of response (DOR), event-free survival (EFS), and overall survival (OS).

II. To evaluate occurrence of minimal residual disease (MRD) negative status by multiparameter flow cytometry and molecular evaluation.

EXPLORATORY OBJECTIVE:

I. To investigate global gene expression profiles, deoxyribonucleic acid (DNA) methylation profiles, BH3 profiling and other potential prognostic markers to explore predictors of antitumor activity and/or resistance to treatment.

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

Patients receive omacetaxine subcutaneously (SC) twice daily (BID) on days 2-3 or 2-4, and venetoclax orally (PO) on days 1-7, 1-10 or 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days, then every 3 months for 3 years.

Omacetaxine and Venetoclax for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Harboring Mutant RUNX1

Phase Ib/II Study of Omacetaxine and Venetoclax for Patients With Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Harboring Mutant RUNX1

MRD negative status and exploratory biomarkers will be summarized graphically and with descriptive statistics. The association between molecular and cellular markers and overall response and/or resistance will be assessed through logistic regression analyses. Paired t-test or Wilcoxon signed rank test will be used to assess the marker change over time.

Safety data will be summarized using frequency and percentage, by category and severity.

Defined as the proportion of patients who had complete remission, complete remission with incomplete hematologic recovery, complete remission with incomplete count recovery, partial response or marrow clearance of blasts within 3 months of treatment initiation among adult patients with acute myeloid leukemia. Analyses will be performed for enrolled subjects, with laboratory response assessment occurring +/- 7 days from bone marrow evaluations. The depth of remission such as with exploratory analyses of minimal residual disease negativity by flow cytometry and/or concomitant molecular analysis will also be performed.

The Kaplan-Meier method will be used to estimate the probabilities. Log-rank tests will be used to compare among subgroups of patients in terms of EFS.

The Kaplan-Meier method will be used to estimate the probabilities. Log-rank tests will be used to compare among subgroups of patients in terms of OS.

The Kaplan-Meier method will be used to estimate the probabilities.

Leukemia, Myelomonocytic, Chronic

Leukemia, Myelomonocytic, Juvenile

Leukemia, Myelomonocytic, Acute

Acute Disease

Myeloproliferative Disorders

Myelodysplastic-Myeloproliferative Diseases

Chronic Disease

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Chronic Graft Versus Host Disease

Dendritic Cell Tumor

Blastic Plasmacytoid Dendritic Cell

Chronic Myeloproliferative Disorders

Myelodysplastic/myeloproliferative Disease

Azacitidine

Decitabine

Participants receive decitabine IV over 1 hour on days 1-10 and may also receive decitabine on days 1-5 after achieving complete remission/complete remission with incomplete count recovery during consolidation/maintenance. Participants also receive venetoclax PO daily on days 1-28 of cycle 1 and on days 1-21 of subsequent cycles. Treatment repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Abhishek Maiti, MBBS

This phase II trial studies how well venetoclax and decitabine work in treating participants with acute myeloid leukemia that has come back or does not respond to treatment, or with high-risk myelodysplastic syndrome that has come back. Drugs used in chemotherapy, such as venetoclax and decitabine, 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.

PRIMARY OBJECTIVE:

I. To determine the overall response rate (ORR) of venetoclax in combination with 10-day decitabine in patients with refractory/relapsed acute myeloid leukemia (AML); elderly (\> 60 year old) patients with newly diagnosed AML not eligible for intensive chemotherapy; patients with high-risk myelodysplastic syndrome (MDS) with bone marrow blasts between 10% and 20%, relapsed or refractory to prior hypomethylating agent (HMA) therapy, or chronic myelomonocytic leukemia (CMML) with bone marrow blasts \>= 10% regardless of prior therapy; AML patients with prior history of MDS or CMML who received therapy for the MDS or CMML and progressed to AML, and younger patients with newly diagnosed AML with poor risk complex karyotype and/or TP53 deletions/mutations and patients with blastic plasmacytoid dentritic cell neoplasm (BPDCN).

SECONDARY OBJECTIVES:

I. To determine the duration of response, disease-free survival (DFS), and overall survival (OS) of patients with refractory/relapsed AML treated with this combination.

II. To determine the number of patients who achieve a hematologic improvement (HI) in platelets, hemoglobin, or absolute neutrophil count (ANC) and the number of patients who achieve \> 50% reduction in blasts on therapy with venetoclax/10-day decitabine.

III. To determine the safety of venetoclax in combination with 10-day decitabine in patients with refractory/relapsed AML.

IV. To determine the number of patients who transition towards stem cell transplantation upon achieving response with the combination venetoclax/10-day decitabine regimen.

V. To determine the incidence of infectious complications per cycle with venetoclax in combination with 10-day decitabine.

EXPLORATORY OBJECTIVES:

I. To investigate possible relationships between baseline protein and gene expression signatures/mutation profile and BH3 profiling in predicting clinical response to the combination.

II. To characterize the pharmacokinetic (PK) profiles of venetoclax in combination with decitabine and antifungals in plasma samples.

OUTLINE:

Participants receive decitabine intravenously (IV) over 1 hour on days 1-10 and may also receive decitabine on days 1-5 after achieving complete remission/complete remission with incomplete count recovery during consolidation/maintenance. Participants also receive venetoclax orally (PO) daily on days 1-28 of cycle 1 and on days 1-21 of subsequent cycles. Treatment repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up every 3 to 6 months for up to 5 years.

Venetoclax and Decitabine in Treating Participants With Relapsed/Refractory Acute Myeloid Leukemia or Relapsed High-Risk Myelodysplastic Syndrome

A Phase II Study of Venetoclax in Combination With 10-Day Decitabine in Newly Diagnosed Elderly or Relapsed/Refractory Acute Myeloid Leukemia and Relapsed High-Risk Myelodysplastic Syndrome and Blastic Plasmacytoid Dendritic Cell Neoplasm

Baseline protein, gene expression signatures/mutation profile and BH3 profiling will be summarized with descriptive statistics. The correlation with endpoints of anti tumor activity will be explored where possible.

Will be defined as the proportion of patients who had CR (complete remission), CRp (complete remission with incomplete platelet recovery), CRi (complete remission with incomplete count recovery), PR (partial response) or marrow clearance of blasts within 3 months of treatment initiation among adult patients with acute myeloid leukemia (AML); and complete remission (CR), partial remission (PR) or marrow CR (mCR) lasting at least 4 weeks for patients with myelodysplastic syndrome (MDS). Descriptive statistics including plots, mean, median and standard deviations will be used to summarize data. Will estimate the ORR for the combination treatment, along with the 95% confidence interval. The association between ORR and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.

Toxicity type, severity and attribution will be summarized for each patient using frequency tables.

Will be estimated using the method of Kaplan-Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log rank tests.

Decitabine and cedazuridine drug combination

Patients receive decitabine and cedazuridine PO QD on days 1-10. Patients who achieve CR/CRi during consolidation/maintenance may receive decitabine and cedazuridine PO QD on days 1-5. Patients also receive venetoclax PO QD on days 1-28 of cycle 1 and days 1-21 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Decitabine and Cedazuridine

Abhishek Maiti

This phase II trial studies the effects of venetoxlax in combination with decitabine and cedazuridine in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). Chemotherapy drugs, such as venetoclax and decitabine, 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. Cedazuridine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving venetoxlax in combination with decitabine and cedazuridine may help to control acute myeloid leukemia.

PRIMARY OBJECTIVE:

I. To determine the overall response rate (complete remission \[CR\], complete remission with incomplete count recovery \[CRi\], MLFS and partial response \[PR\]) of 10-days decitabine and cedazuridine (oral decitabine) and venetoclax in patients with refractory/relapsed acute myeloid leukemia (AML).

SECONDARY OBJECTIVES:

I. To determine the duration of response, event-free survival (EFS), and overall survival (OS) of patients with refractory/relapsed AML treated with this combination.

II. To determine the number of patients who achieve a hematologic improvement (HI) in platelets, hemoglobin, or ANC and the number of patients who achieve \> 50% reduction in blasts on therapy with venetoclax/10-day oral decitabine.

III. To determine the safety of venetoclax in combination with 10-day oral decitabine in patients with refractory/ relapsed AML.

IV. To determine the number of patients who transition towards stem cell transplantation upon achieving response with the combination venetoclax/10-day oral decitabine regimen.

V. To determine the incidence of infectious complications per cycle with venetoclax in combination with 10-day oral decitabine.

EXPLORATORY OBJECTIVE:

I. To investigate global gene expression profiles, cytometry by time of flight (CyTOF), BH3 profiling and other potential prognostic markers to explore predictors of antitumor activity and/or resistance to treatment.

OUTLINE:

Patients receive decitabine and cedazuridine orally (PO) once daily (QD) on days 1-10. Patients who achieve CR/CRi during consolidation/maintenance may receive decitabine and cedazuridine PO QD on days 1-5. Patients also receive venetoclax PO QD on days 1-28 of cycle 1 and days 1-21 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Venetoclax in Combination With Decitabine and Cedazuridine for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

A Phase II Study of Venetoclax in Combination With 10-day Oral Decitabine in Relapsed/Refractory Acute Myeloid Leukemia

Defined as the proportion of patients who had complete remission (CR), complete remission with incomplete count recovery (CRi), partial response (PR) or MLFS. Will estimate the ORR for the combination treatment, along with the Bayesian 95% credible interval.

The overall incidence and severity of all adverse events using Common Toxicity Criteria version 5.0. Safety data will be summarized using frequency and percentage, by category and severity.

Will estimate for the combination treatment, along with the Bayesian 95% credible interval.

The Kaplan-Meier method will be used to estimate the survival probabilities of time-to-event variables such as EFS. Log-rank tests will be used to compare among subgroups of patients in terms of the time-to-event variables.

The Kaplan-Meier method will be used to estimate the survival probabilities of time-to-event variables such as OS. Log-rank tests will be used to compare among subgroups of patients in terms of the time-to-event variables.

Will examine the association between gene expression profiles and prognostic markers and overall response and/or resistance will be assessed through logistic regression analyses. Paired t-test or Wilcoxon signed rank test will be used to assess the marker change over time.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cladribine, Idarubicin, Cytarabine, and Quizartinib in Treating Patients With Newly Diagnosed, Relapsed, or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome	NCT04047641	Acute Myeloid L... Blasts 20 Perce... High Risk Myelo... Recurrent Acute... Recurrent Acute... Recurrent High ... Refractory Acut... Refractory High...	Cladribine Cytarabine Idarubicin Quizartinib	18 Years -	M.D. Anderson Cancer Center
Omacetaxine and Venetoclax for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Harboring Mutant RUNX1	NCT04874194	Hematopoietic a... Recurrent Acute... Recurrent Acute... Recurrent Myelo... Refractory Acut... Refractory Acut... Refractory Myel...	Omacetaxine Mep... Venetoclax	18 Years -	M.D. Anderson Cancer Center
Omacetaxine and Venetoclax for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Harboring Mutant RUNX1	NCT04874194	Hematopoietic a... Recurrent Acute... Recurrent Acute... Recurrent Myelo... Refractory Acut... Refractory Acut... Refractory Myel...	Omacetaxine Mep... Venetoclax	18 Years -	M.D. Anderson Cancer Center
Venetoclax and Decitabine in Treating Participants With Relapsed/Refractory Acute Myeloid Leukemia or Relapsed High-Risk Myelodysplastic Syndrome	NCT03404193	Acute Myeloid L... Acute Myeloid L... Blastic Plasmac... Chronic Myelomo... Mixed Phenotype... Myelodysplastic... Recurrent Acute... Recurrent Acute... Recurrent Blast... Recurrent Chron... Recurrent Mixed... Refractory Acut... Refractory Blas... Refractory Chro... Refractory Mixe...	Decitabine Laboratory Biom... Venetoclax	18 Years -	M.D. Anderson Cancer Center
Venetoclax in Combination With Decitabine and Cedazuridine for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia	NCT04975919	Recurrent Acute... Recurrent Acute... Refractory Acut... Refractory Acut...	Decitabine and ... Venetoclax	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for recurrent acute biphenotypic leukemia