AML/MDS Drug Sensitization by in Vivo Chemotherapy Administration

Recruiting

Conditions: Myelodysplastic Syndromes
Acute Myeloid Leukemia

Interventions: Procedure: Peripheral blood draw
Procedure: Bone marrow aspirate
Procedure: Buccal swab

Registration Number: NCT04263181

Lead Sponsor: Washington University School of Medicine

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: RECRUITING

Sex: All

Target Recruitment: 165

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.

Study Type: OBSERVATIONAL

Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Cohort 0	Bone marrow aspirate	-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.
Cohort 1	Peripheral blood draw	* 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).
Cohort 1	Buccal swab	* 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).
Cohort 0	Peripheral blood draw	-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.
Cohort 1	Bone marrow aspirate	* 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).
Cohort 2	Buccal swab	* 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.
Cohort 3	Peripheral blood draw	* 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
Cohort 3	Buccal swab	* 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
Cohort 0	Buccal swab	-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.
Cohort 4	Peripheral blood draw	* 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.
Cohort 4	Bone marrow aspirate	* 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.
Cohort 2	Peripheral blood draw	* 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.
Cohort 2	Bone marrow aspirate	* 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.
Cohort 3	Bone marrow aspirate	* 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
Cohort 4	Buccal swab	* 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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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 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
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 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 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 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 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

Trial Locations

Locations (1): Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States

AML/MDS Drug Sensitization by in Vivo Chemotherapy Administration

Recruitment & Eligibility

Study & Design

Trial Locations

Instant Trial Alerts

Instant Trial Alerts