Acute Myeloid Leukemia, Myelodysplastic Syndromes
Conditions
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.
Interventions
PROCEDUREPeripheral blood draw
* 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
PROCEDUREBone marrow aspirate
* 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
PROCEDUREBuccal swab
* 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
Sponsors
Washington University School of Medicine
Notable Labs
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | 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
| Measure | 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 |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMeagan Jacoby, M.D.
Washington University School of Medicine
Outcome results
None listed