AML/MDS Drug Sensitization by in Vivo Chemotherapy Administration

Study Overview
=================
Brief Summary
-----------------
In this study, the investigators will explore the feasibility of ex vivo drug screening to predict sensitivity to chemotherapy resistance and to identify novel synergy between chemotherapies.

Official Title
-----------------
Identification of AML/MDS Drug Sensitization by in Vivo Chemotherapy Administration

Conditions
-----------------
Acute Myeloid Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Procedure: Peripheral blood draw
* Procedure: Bone marrow aspirate
* Procedure: Buccal swab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) Peripheral blood blasts > 1% Peripheral white blood cell count > 1,000/µl. Age ≥ 18 years Anticipated treatment with any of the following regimens (Cohort 0) or: Cohort 1: A standard induction protocol with infusional cytarabine Cohort 2: Decitabine (either 5-day or 10-day regimens) Cohort 3: Azacitidine (either intravenous or subcutaneous administration) Cohort 4: Decitabine (either 5-day or 10-day) + venetoclax Cohort 5: Azacitidine (either intravenous or subcutaneous administration on 7 day or 5+2+2 schedule) + venetoclax Patients may receive these therapies as part of other on-going clinical trials or as standard of care treatment. Patients in Cohort 1 may receive SOC midostaurin or gemtuzumab ozogamicin, provided these start after the Day 2 sample is collected. Patients in Cohort 1 may receive a standard combination of cytarabine/idarubicin, cytarabine/daunorubicin, or Vyxeos, a liposomal formulation of cytarabine and daunorubicin. ECOG performance status ≤ 3 Ability to understand and willingness to sign an IRB approved written informed consent document. Exclusion Criteria: Pregnant or currently nursing Prior chemotherapy with hypomethylating agents Known history of positive HIV serology. Known positive Hepatitis C serology. Patient must not have received any chemotherapy within 7 days of enrollment, and any acute treatment-related toxicities must have returned to baseline. Patients may have received hydrea as long as they fulfill peripheral blood blast and peripheral WBC inclusion criteria. Prior TKI therapy is allowed, but must be discontinued within 3 days of baseline blood collection. Currently receiving any other investigational agents.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort 0<br>-A technical run-in of 5 patients with any of the following: Standard cytarabine/idarubicin induction, includes cytarabine 200 mg/m2 CIVI in 0.9% normal saline over 24 hours for 7 consecutive days (Days 1-7) & idarubicin 12 mg/m2 per day for 3 consecutive days (Days 1-3). Other standard cytarabine-based induction protocols are allowed Decitabine 20 mg/m2/day as a 1-hour infusion on consecutive Days 1-5 or 1-10 of each 28-day cycle. Azacitidine 75 mg/m2/day as a subcutaneous injection on Days 1-7 or on day 1-5 and 8-9 of each 28-day cycle Decitabine 20 mg/m2/day as a 1-hour infusion on consecutive Days 1-5 or 1-10 of each 28-day cycle. Patients will receive venetoclax PO 100 mg on Day 1, 200 mg on Day 2, and 400 mg daily thereafter. Azacitidine 75 mg/m2/day as a 1-hour infusion or by subcutaneous injection on consecutive Days 1-7 or on day 1-5 and 8-9 of each 28-day cycle. Patients will receive venetoclax PO 100 mg on Day 1, 200 mg on Day 2, and 400 mg daily thereafter. | Procedure: Peripheral blood draw<br>* All cohorts will have peripheral blood drawn at baseline no more than 4 days prior to the first dose of chemotherapy and must also occur before the first dose of chemotherapy Cohort 0 or 1 - peripheral blood draw on Day 2 Cohorts 0, 2, 3, 4 and 5 - peripheral blood draw on Day 3 Cohort 0 or 1 - peripheral blood draw on Day 35 (at count recovery) Cohorts 0, 2, 3, 4, and 5 - peripheral blood draw on Cycles 2 or 3 and 4 or 5, Day 28<br>Procedure: Bone marrow aspirate<br>* Cohort 0 or 1 - bone marrow aspirate on Day 14 Cohort 0 or 1 - bone marrow aspirate on Day 35 (at count recovery) Cohorts 0, 2, 3, 4, and 5 - bone marrow aspirate on Cycles 2 or 3 and 4 or 5, Day 28<br>Procedure: Buccal swab<br>* Cohort 0 or 1 - buccal swab on Day 35 (at count recovery) Cohorts 0, 2, 3, 4, and 5 - buccal swab on Cycle 2 or 3 and 4 or 5, Day 28<br>|
| Cohort 1<br>Patients treated with cytarabine/idarubicin induction therapy Patients will receive a standard cytarabine/idarubicin induction, which includes cytarabine 200 mg/m2 CIVI in 0.9% normal saline over 24 hours for 7 consecutive days (Days 1-7) and idarubicin 12 mg/m2 per day in 0.9% normal saline over 15-30 minutes for 3 consecutive days (Days 1-3). Other standard cytarabine-based induction protocols are allowed (e.g. cytarabine/daunorubicin or Vyxeos). | Procedure: Peripheral blood draw<br>* All cohorts will have peripheral blood drawn at baseline no more than 4 days prior to the first dose of chemotherapy and must also occur before the first dose of chemotherapy Cohort 0 or 1 - peripheral blood draw on Day 2 Cohorts 0, 2, 3, 4 and 5 - peripheral blood draw on Day 3 Cohort 0 or 1 - peripheral blood draw on Day 35 (at count recovery) Cohorts 0, 2, 3, 4, and 5 - peripheral blood draw on Cycles 2 or 3 and 4 or 5, Day 28<br>Procedure: Bone marrow aspirate<br>* Cohort 0 or 1 - bone marrow aspirate on Day 14 Cohort 0 or 1 - bone marrow aspirate on Day 35 (at count recovery) Cohorts 0, 2, 3, 4, and 5 - bone marrow aspirate on Cycles 2 or 3 and 4 or 5, Day 28<br>Procedure: Buccal swab<br>* Cohort 0 or 1 - buccal swab on Day 35 (at count recovery) Cohorts 0, 2, 3, 4, and 5 - buccal swab on Cycle 2 or 3 and 4 or 5, Day 28<br>|
| Cohort 2<br>Patients treated with decitabine Patients will receive decitabine 20 mg/m2/day as a 1-hour infusion on consecutive Days 1-5 or 1-10 (per treating physician discretion) of each 28-day cycle. | Procedure: Peripheral blood draw<br>* All cohorts will have peripheral blood drawn at baseline no more than 4 days prior to the first dose of chemotherapy and must also occur before the first dose of chemotherapy Cohort 0 or 1 - peripheral blood draw on Day 2 Cohorts 0, 2, 3, 4 and 5 - peripheral blood draw on Day 3 Cohort 0 or 1 - peripheral blood draw on Day 35 (at count recovery) Cohorts 0, 2, 3, 4, and 5 - peripheral blood draw on Cycles 2 or 3 and 4 or 5, Day 28<br>Procedure: Bone marrow aspirate<br>* Cohort 0 or 1 - bone marrow aspirate on Day 14 Cohort 0 or 1 - bone marrow aspirate on Day 35 (at count recovery) Cohorts 0, 2, 3, 4, and 5 - bone marrow aspirate on Cycles 2 or 3 and 4 or 5, Day 28<br>Procedure: Buccal swab<br>* Cohort 0 or 1 - buccal swab on Day 35 (at count recovery) Cohorts 0, 2, 3, 4, and 5 - buccal swab on Cycle 2 or 3 and 4 or 5, Day 28<br>|
| Cohort 3<br>Patients treated with azacitidine Patients will receive azacitidine 75 mg/m2/day as a subcutaneous injection on Days 1-7 or on day 1-5 and 8-9 (per treating physician discretion) of each 28-day cycle | Procedure: Peripheral blood draw<br>* All cohorts will have peripheral blood drawn at baseline no more than 4 days prior to the first dose of chemotherapy and must also occur before the first dose of chemotherapy Cohort 0 or 1 - peripheral blood draw on Day 2 Cohorts 0, 2, 3, 4 and 5 - peripheral blood draw on Day 3 Cohort 0 or 1 - peripheral blood draw on Day 35 (at count recovery) Cohorts 0, 2, 3, 4, and 5 - peripheral blood draw on Cycles 2 or 3 and 4 or 5, Day 28<br>Procedure: Bone marrow aspirate<br>* Cohort 0 or 1 - bone marrow aspirate on Day 14 Cohort 0 or 1 - bone marrow aspirate on Day 35 (at count recovery) Cohorts 0, 2, 3, 4, and 5 - bone marrow aspirate on Cycles 2 or 3 and 4 or 5, Day 28<br>Procedure: Buccal swab<br>* Cohort 0 or 1 - buccal swab on Day 35 (at count recovery) Cohorts 0, 2, 3, 4, and 5 - buccal swab on Cycle 2 or 3 and 4 or 5, Day 28<br>|
| Cohort 4<br>Patients treated with decitabine + venetoclax Patients will receive decitabine 20 mg/m2/day as a 1-hour infusion on consecutive Days 1-5 or 1-10 (per treating physician discretion) of each 28-day cycle. Patients will receive venetoclax PO 100 mg on Day 1, 200 mg on Day 2, and 400 mg daily thereafter. | Procedure: Peripheral blood draw<br>* All cohorts will have peripheral blood drawn at baseline no more than 4 days prior to the first dose of chemotherapy and must also occur before the first dose of chemotherapy Cohort 0 or 1 - peripheral blood draw on Day 2 Cohorts 0, 2, 3, 4 and 5 - peripheral blood draw on Day 3 Cohort 0 or 1 - peripheral blood draw on Day 35 (at count recovery) Cohorts 0, 2, 3, 4, and 5 - peripheral blood draw on Cycles 2 or 3 and 4 or 5, Day 28<br>Procedure: Bone marrow aspirate<br>* Cohort 0 or 1 - bone marrow aspirate on Day 14 Cohort 0 or 1 - bone marrow aspirate on Day 35 (at count recovery) Cohorts 0, 2, 3, 4, and 5 - bone marrow aspirate on Cycles 2 or 3 and 4 or 5, Day 28<br>Procedure: Buccal swab<br>* Cohort 0 or 1 - buccal swab on Day 35 (at count recovery) Cohorts 0, 2, 3, 4, and 5 - buccal swab on Cycle 2 or 3 and 4 or 5, Day 28<br>|
| Cohort 5<br>Patients treated with azacitidine + venetoclax Patients will receive azacitidine 75 mg/m2/day as a 1-hour infusion or by subcutaneous injection on consecutive Days 1-7 or on day 1-5 and 8-9 (per treating physician discretion) of each 28-day cycle. Patients will receive venetoclax PO 100 mg on Day 1, 200 mg on Day 2, and 400 mg daily thereafter. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine whether ex vivo drug sensitivity obtained for Day 0 ex vivo treatments for all cohorts as measured by a 384 well high throughput flow-based viability assay correlates with clinical assay |  | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ex vivo drug sensitivity obtained for Day 0 ex vivo treatments as measured by a 384 well high throughput flow-based viability assay correlates with molecular responses as measured by founding clone mutation reduction <2% and exome sequencing |  | 90 days | 
| Determine whether an increase in ex vivo drug resistance on day 2 (cohorts 0 or 1) or day 3 (cohorts 2, 3, 4 and 5), as measured by a 384 well high-throughput flow-based viability assay, correlates with reduced clinical responses |  | 90 days | 
| Determine whether reduced ex vivo drug sensitivity on day 2 (cohorts 0 or 1) or day 3 (cohorts 2, 3, 4, and 5), as measured by a 384 well high throughput flow-based viability assay, correlates with reduced molecular responses |  | 90 days | 
| Determine whether reduced drug ex vivo drug sensitivity on day 2 (cohorts 0 or 1) or 3 (cohorts 2, 3, 4, and 5), as measured by a 384 well high throughput flow-based viability assay, correlates with reduced disease-free survival |  | 1 year | 
| Determine whether reduced ex vivo drug sensitivity, as measured by a 384 well high throughput flow-based viability assay, correlates with reduced survival |  | 1 year | 
| Determine whether in vivo chemotherapy leads to increased ex vivo sensitivity to any class of drugs in more than 20% of patients treated on any study arm as measured by a 384 well high throughput flow-based viability assay |  | Day 3 | 
| Determine whether decitabine and azacitidine are associated with overlapping or unique profiles in drug sensitivity changes as measured by a 384 well high throughput flow-based viability assay |  | Day 3 | 
| Determine whether ex vivo drug sensitivity, as measured by a 384 well high throughput flow-based viability assay, correlates with the presence of clinically available mutations, as measured by exome sequencing |  | 90 days | 
| Determine whether MDS and AML have overlapping or unique profiles in ex vivo drug sensitivity, as measured by a 384 well high throughput flow-based viability assay |  | Day 0 | 
| Determine whether MDS and AML have overlapping or unique profiles in ex vivo drug sensitivity as measured by a 384 well high throughput flow-based viability assay |  | Day 3 |