Pre-emptive Therapy With DEC-C to Improve Outcomes in MDS Patients With Measurable Residual Disease Post Allogeneic Hematopoietic Cell Transplant

Phase 1

Recruiting

• Conditions: Myelodysplastic Syndromes
• Interventions: Drug: DEC-C; Device: MyeloSeq-HD

• Registration Number: NCT04742634
• Lead Sponsor: Washington University School of Medicine

Brief Summary

The investigators hypothesize that early measurable residual disease (MRD)-guided pre-emptive therapy with decitabine + cedazaridine (DEC-C) will decrease the risk of progression in post-transplant myelodysplastic syndromes (MDS) patients with persistent mutations (molecular MRD). To detect molecular MRD, the investigators will perform ultra-deep, error-corrected panel-based sequencing (MyeloSeq-HD) at Day 30 in post-transplant MDS patients. The investigators will treat patients with detectable molecular MRD with DEC-C to determine if pre-emptive, MRD-guided therapy with DEC-C decreases relapse rates and improves progression-free survival.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-01-28
• Study First Submitted QC: 2021-02-03
• Study First Posted: 2021-02-08
• Study Start: 2022-05-12
• Status Verified: 2025-09
• Last Update Submitted: 2025-09-17
• Last Update Posted: 2025-09-23
• Primary Completion: 2033-11-30
• Study Completion: 2033-11-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 126

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase I Dose Level 1: DEC-C	DEC-C	* Bone marrow biopsy \& MyeloSeq-HD will be obtained on Day 30 post-transplant. MRD positivity is defined as the presence of at least one somatically acquired mutation detected prior to transplant that persists at Day 30 post-transplant with a variant allele frequency of ≥ 0.2%. MRD-positive patients will receive up to 5 cycles of DEC-C prior to the Day 180 bone marrow evaluation. If the Day 180 MyeloSeq-HD shows that MRD is still detectable in the opinion of the MGI board-certified molecular pathologist but below 0.5% and patient has tolerated initial treatment without toxicity, the patient may continue treatment. If it shows a lack of MRD, the patient will be moved to the post-treatment surveillance arm. If it shows any mutation detection prior to transplant that persists with a variant allele frequency of ≥ 0.2%VAF, the patient will receive up to an additional 6 cycles of DEC-C. * 35 mg decitabine/100 mg cedazuridine taken by mouth once daily on Days 1, 2, 3 of a 28 day cycle.
Phase I Dose Level 1: DEC-C	MyeloSeq-HD	* Bone marrow biopsy \& MyeloSeq-HD will be obtained on Day 30 post-transplant. MRD positivity is defined as the presence of at least one somatically acquired mutation detected prior to transplant that persists at Day 30 post-transplant with a variant allele frequency of ≥ 0.2%. MRD-positive patients will receive up to 5 cycles of DEC-C prior to the Day 180 bone marrow evaluation. If the Day 180 MyeloSeq-HD shows that MRD is still detectable in the opinion of the MGI board-certified molecular pathologist but below 0.5% and patient has tolerated initial treatment without toxicity, the patient may continue treatment. If it shows a lack of MRD, the patient will be moved to the post-treatment surveillance arm. If it shows any mutation detection prior to transplant that persists with a variant allele frequency of ≥ 0.2%VAF, the patient will receive up to an additional 6 cycles of DEC-C. * 35 mg decitabine/100 mg cedazuridine taken by mouth once daily on Days 1, 2, 3 of a 28 day cycle.
Phase I Dose Level 2: DEC-C	DEC-C	* Bone marrow biopsy \& MyeloSeq-HD will be obtained on Day 30 post-transplant. MRD positivity is defined as the presence of at least one somatically acquired mutation detected prior to transplant that persists at Day 30 post-transplant with a variant allele frequency of ≥ 0.2%. MRD-positive patients will receive up to 5 cycles of DEC-C prior to the Day 180 bone marrow evaluation. If the Day 180 MyeloSeq-HD shows that MRD is still detectable in the opinion of the MGI board-certified molecular pathologist but below 0.5% and patient has tolerated initial treatment without toxicity, the patient may continue treatment. If it shows a lack of MRD, the patient will be moved to the post-treatment surveillance arm. If it shows any mutation detection prior to transplant that persists with a variant allele frequency of ≥ 0.2%VAF, the patient will receive up to an additional 6 cycles of DEC-C. * 35 mg decitabine/100 mg cedazuridine taken by mouth once daily on Days 1-4 of a 28 day cycle.
Phase I Dose Level 2: DEC-C	MyeloSeq-HD	* Bone marrow biopsy \& MyeloSeq-HD will be obtained on Day 30 post-transplant. MRD positivity is defined as the presence of at least one somatically acquired mutation detected prior to transplant that persists at Day 30 post-transplant with a variant allele frequency of ≥ 0.2%. MRD-positive patients will receive up to 5 cycles of DEC-C prior to the Day 180 bone marrow evaluation. If the Day 180 MyeloSeq-HD shows that MRD is still detectable in the opinion of the MGI board-certified molecular pathologist but below 0.5% and patient has tolerated initial treatment without toxicity, the patient may continue treatment. If it shows a lack of MRD, the patient will be moved to the post-treatment surveillance arm. If it shows any mutation detection prior to transplant that persists with a variant allele frequency of ≥ 0.2%VAF, the patient will receive up to an additional 6 cycles of DEC-C. * 35 mg decitabine/100 mg cedazuridine taken by mouth once daily on Days 1-4 of a 28 day cycle.
Phase II MRD Positive: DEC-C	DEC-C	* 35 mg decitabine/100 mg cedazuridine taken by mouth once daily per the schedule determined in the Phase I portion of the study. Cycle 1 Day 1 may take place between Day 42 and Day 100 post-transplant. MRD-positive patients will receive up to 5 cycles of DEC-C prior to the Day 180 bone marrow evaluation. * Bone marrow biopsy with MyeloSeq-HD will be obtained on Day 180 post-transplant. If the Day 180 MyeloSeq-HD shows that MRD is still detectable in the opinion of the MGI board-certified molecular pathologist but below 0.5% and patient has tolerated initial treatment without toxicity, the patient may continue treatment. If it shows a lack of MRD, the patient will be moved to the post-treatment surveillance arm. If it shows any mutation detection prior to transplant that persists with a variant allele frequency of ≥ 0.2%VAF, the patient will receive up to an additional 6 cycles of DEC-C.
Phase II MRD Positive: DEC-C	MyeloSeq-HD	* 35 mg decitabine/100 mg cedazuridine taken by mouth once daily per the schedule determined in the Phase I portion of the study. Cycle 1 Day 1 may take place between Day 42 and Day 100 post-transplant. MRD-positive patients will receive up to 5 cycles of DEC-C prior to the Day 180 bone marrow evaluation. * Bone marrow biopsy with MyeloSeq-HD will be obtained on Day 180 post-transplant. If the Day 180 MyeloSeq-HD shows that MRD is still detectable in the opinion of the MGI board-certified molecular pathologist but below 0.5% and patient has tolerated initial treatment without toxicity, the patient may continue treatment. If it shows a lack of MRD, the patient will be moved to the post-treatment surveillance arm. If it shows any mutation detection prior to transplant that persists with a variant allele frequency of ≥ 0.2%VAF, the patient will receive up to an additional 6 cycles of DEC-C.
Phase II MRD Negative: Observation Arm	MyeloSeq-HD	* In phase II, up to 77 patients who do not have MRD positivity on Day 30 post-transplant (i.e., the absence of at least one somatically acquired mutation detected prior to transplant that persists at Day 30 post-transplant with a variant allele frequency of ≥ 0.2%) will be placed on the observation arm and treated with standard of care. * Patients on the observation arm will be followed every 3 months for 2 years and every 6 months for 3 years for progression and survival

Primary Outcome Measures

Name	Time	Method
Number of patients with dose-limiting toxicities (Phase I only)	Completion of cycle 1 (each cycle is 28 days) for all phase I participants (estimated to be 13 months)	-Dose-limiting toxicities (DLTs) are defined as any of the following adverse events that occur during the DLT observation period (Cycle 1) during the phase I portion of the study, determined to be possibly, probably, or definitely related to the study drug: * Grade 4 neutropenia or grade 4 thrombocytopenia in the absence of increased blasts and/or evidence of persistent MDS at the end of Cycle 1.; * Any grade 3 or higher non-hematologic toxicity except for grade 3 vomiting or diarrhea not requiring tube feeding, total parenteral nutrition, or requiring or prolonging hospitalization, or grade 3 or 4 isolated electrolyte abnormalities that last \<72 hours.; * Any other non-hematologic toxicity that is clinically significant and/or unacceptable that does not respond to supportive care, results in disruption of dosing schedule more than 28 days, or is judged to be a DLT by the Investigator.; * Confirmed Hy's law cases will be considered a DLT
Maximum tolerated dose (MTD) (Phase I only)	Completion of cycle 1 (each cycle is 28 days) for all phase I participants (estimated to be 13 months)	-The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which ≥ 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity during the first cycle.
Recommended phase II dose (Phase I only)	Completion of cycle 1 (each cycle is 28 days) for all phase I participants (estimated to be 13 months)	-The recommended phase II dose will be less than or equal to the maximum tolerated dose
Progression-free survival (PFS) (Phase II recommended dose only)	1 year post-transplant	-Progression-free survival: Defined as the interval from the date of transplant to disease progression or death, whichever is first. Patients without documented disease progression or death at the time of analysis will be censored at the date of last adequate tumor assessment.
Rate of relapse (Phase II recommended dose only)	1 year post-transplant	-Disease progression/relapse post-transplant is defined as \>5% myeloblasts in the bone marrow, evidence of extramedullary disease, reemergence of pre-transplant cytogenetic abnormalities, or intervention by the treating physician (such as withdrawal of immunosuppression) for reemergence of pre-transplantation morphologic abnormalities that are likely relapsed disease in the opinion of the treating physician. Censoring rules for the Relapse endpoint include: Patients who do not relapse will be censored at the date of last disease assessment where no relapse was documented; Patients who die without relapse will be censored at the date of death if no relapse was observed prior to death. Patients who withdraw consent or are lost to follow-up will be censored at the date of last disease assessment showing no evidence of relapse; Patients who start a new anti-cancer therapy before documented relapse will be censored at the date of last disease assessment before the start of the new therapy.

Secondary Outcome Measures

Name	Time	Method
Overall survival (OS)	1 year post-transplant	-Overall survival: Defined as the date of transplant to the date of death from any cause. Patients still alive at the time of analysis will be censored at the date they were last known to be alive.
Percentage of patients requiring DEC-C dose adjustment/delay	Through completion of treatment (estimated to be 168 days)
Percentage of cycles given on time/at dose	Through completion of treatment (estimated to be 168 days)
Change in mutational MRD disease burden as measured by variant allele frequency (VAF) cycles	Day 180	-In patients who have at least 1 cycle of treatment

Trial Locations

Locations (1)

Washington University School of Medicine; 🇺🇸 St Louis, Missouri, United States