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

Myelodysplastic Syndromes Clinical Trial

Official title:

A Phase I/II Trial of Pre-emptive Therapy With DEC-C to Improve Outcomes in MDS Patients With Measurable Residual Disease Post Allogeneic Hematopoietic Cell Transplant

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04742634
• Other study ID #: 202103255
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: May 12, 2022
• Est. completion date: November 30, 2033

Study information

• Verified date: September 2023
• Source: Washington University School of Medicine
• Contact: Meagan Jacoby, M.D., Ph.D.
• Phone: 314-747-8465
• Email: mjacoby[@]wustl.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 126
• Est. completion date: November 30, 2033
• Est. primary completion date: November 30, 2033
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

This study uses a two-stage eligibility process. Step 1 assesses eligibility prior to the MyeloSeq-HD assay being performed, while Step 2 assesses eligibility of MRD-positive patients for the intervention arm and MRD-negative patients for the observation arm. Patients who are MRD-positive who are determined to be ineligible to continue into the intervention arm must satisfy the eligibility criteria for the observation arm in order to be enrolled in that arm.

Eligibility Criteria for MyeloSeq-HD Assay (Step 1)

• Diagnosis of myelodysplastic syndromes (MDS) based on World Health Organization classification (2016 revision) who have received an allogeneic hematopoietic cell transplant. Any stem cell source, conditioning regimen, and immunosuppression regimen as determined by the treating physician, per institutional guidelines, is permitted. Patients may have received any therapy, or no therapy, prior to transplant.

• 18 to 75 years of age.

• Must have undergone gene panel testing prior to the start of transplant conditioning and must have at least one somatically acquired mutation that is interrogated by the MyeloSeq-HD panel. If the patient has a variant that is known to be a germline/inherited myeloid predisposition gene in that patient, this variant cannot and will not be used as evidence of MRD positivity. If the pre-transplant gene panel testing is a next-generation sequencing panel other than the MyeloSeq platform, the outside report will be reviewed by the PI and the molecular pathologists at the McDonnell Genome Institute to ensure eligibility.

• Willing to comply with the treatment assignment:

• Intent to proceed with DEC-C therapy if one or more variants detected prior to transplant persists at Day 30 post-transplant with a variant allele frequency of = 0.5%.

• Intent to proceed with standard of care as determined by the treating physician on the observation arm (no DEC-C intervention) if no variants detected prior to transplant persist at Day 30 post-transplant with a variant allele frequency of = 0.5%, or if the other inclusion criteria are not met.

• Not currently receiving any investigational agents.

• Ability to understand and willingness to sign an IRB-approved written informed consent document (or that of legally authorized representative, if applicable).

Eligibility Criteria for Step 2 Step 2A Inclusion Criteria (DEC-C Intervention Arm)

• One or more somatically acquired variants that were present prior to transplant detected by the MyeloSeq-HD panel at Day 30 post-transplant, with a variant allele frequency of = 0.5%

• Within Days 42-100 post-transplant.

• = 5 % bone marrow myeloblasts on the Day 30 post-transplant biopsy.

• Absolute neutrophil count (ANC) = 1.0 X 109/L and platelets = 50 X 109/L.

• Only patients with adequately controlled GVHD = Grade 2 are eligible for the DEC-C intervention arm. Patients with active grade 3 or higher GVHD are ineligible for the DEC-C intervention arm.

• ECOG performance status = 2

• Adequate renal and hepatic function as described below:

• Total bilirubin = 1.5 x IULN

• AST(SGOT)/ALT(SGPT) = 3.0 IULN

• Creatinine clearance = 30 mL/min using Cockcroft-Gault Formula below:

CrCl = [(140-age) x body weight in kg]/(serum creatinine in mg/dL x 72) x 0.85 if female

*NOTE: If, in the opinion of the treating physician, bilirubin is elevated secondary to hemolysis or Gilbert's disease, the patient may be eligible after discussion with the Washington University PI

• Decitabine has been shown to be teratogenic in animal studies and use of IV decitabine in the first trimester of pregnancy has been associated with major birth defects. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men and women treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and 6 months after completion of the study.

Step 2B Inclusion Criteria (Observation Arm)

• EITHER = 5 % bone marrow myeloblasts on the Day 30 post-transplant biopsy OR enrolled in the study with > 5% bone marrow myeloblasts on the Day 30 post-transplant biopsy but not meeting eligibility criteria for the intervention arm.

• Not receiving any investigational agents.

Step 2A Exclusion Criteria

• Currently receiving any other investigational agents.

• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to DEC-C or other agents used in the study.

• Concomitant administration of drugs metabolized by cytidine deaminase

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.

• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum/urine pregnancy test no more than 10 days prior of the start of the first cycle of DEC-C.

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Neoplasm, Residual

Intervention

Drug:
• DEC-C
DEC-C will be provided by Taiho Pharmaceuticals. Cycle 1 Day 1 may take place between Day 42 & Day 100 post-transplant.

Device:
• MyeloSeq-HD
-Laboratory test developed at Washington University School of Medicine

Locations

Country	Name	City	State
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Washington University School of Medicine	Taiho Oncology, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of patients with dose-limiting toxicities (Phase I only)	-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	Completion of cycle 1 (each cycle is 28 days) for all phase I participants (estimated to be 13 months)
Primary	Maximum tolerated dose (MTD) (Phase I only)	-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.	Completion of cycle 1 (each cycle is 28 days) for all phase I participants (estimated to be 13 months)
Primary	Recommended phase II dose (Phase I only)	-The recommended phase II dose will be less than or equal to the maximum tolerated dose	Completion of cycle 1 (each cycle is 28 days) for all phase I participants (estimated to be 13 months)
Primary	Progression-free survival (PFS) (Phase II recommended dose only)	-Progression-free survival: Defined as the interval from the date of transplant to disease progression or death, whichever is first.	1 year post-transplant
Primary	Rate of relapse (Phase II recommended dose only)	-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.	1 year post-transplant
Secondary	Overall survival (OS)	-Overall survival: Defined as the date of transplant to the date of death from any cause.	1 year post-transplant
Secondary	Percentage of patients requiring DEC-C dose adjustment/delay		Through completion of treatment (estimated to be 168 days)
Secondary	Percentage of cycles given on time/at dose		Through completion of treatment (estimated to be 168 days)
Secondary	Change in mutational MRD disease burden as measured by variant allele frequency (VAF) cycles	-In patients who have at least 1 cycle of treatment	Day 180

External Links

•   Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine