Decitabine and Cedazuridine for the Improvement of Outcomes in Myelodysplastic Syndrome Patients with Measurable Residual Disease after Donor Stem Cell Transplantation
This is a phase I/II finds the best dose, possible benefits and/or side effects of decitabine and cedazuridine (DEC-C) in treating patients with myelodysplastic syndrome when given after stem cell transplant. DEC-C is a fixed-dose combination of the drugs decitabine and cedazuridine in a single tablet. DEC-C may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving DEC-C to patients who have an early measurable residual disease (meaning that a few malignant cells remain in the bone marrow after transplant) may decrease the risk of disease progression.
Inclusion Criteria
- 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 principal investigator (PI) and the molecular pathologists at the McDonnell Genome Institute to ensure eligibility.
- =< 5 % bone marrow myeloblasts on the Day 30 post-transplant biopsy.
- 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 >= 0.2%. * 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 >= 0.2%.
- Not currently receiving any investigational agents
- Ability to understand and willingness to sign an Institutional Review Board (IRB) approved written informed consent document (or that of a legally authorized representative, if applicable).
- DEC-C INTERVENTION ARM (STEP 2A)
- 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 >= 0.2%.
- Within Days 42-100 post-transplant.
- ≤ 5 % bone marrow myeloblasts on the day 30 post-transplant biopsy
- Absolute neutrophil count (ANC) >= 1.0 X 10^9/L.
- Platelets >= 50 X 10^9/L.
- Only patients with adequately controlled graft versus host disease (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.
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2.
- Total bilirubin =< 1.5 x institutional upper limit of the normal (IULN). * 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.
- Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3.0 IULN.
- Creatinine clearance >= 30 mL/min using Cockcroft-Gault formula.
- Decitabine has been shown to be teratogenic in animal studies and the use of intravenous (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 in 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.
- OBSERVATION ARM (STEP 2B)
- 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.
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 to the start of the first cycle of DEC-C.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04742634.
Locations matching your search criteria
United States
Missouri
Saint Louis
PRIMARY OBJECTIVES:
I. To determine the safety and tolerability of DEC-C in the post-allogeneic stem cell transplant setting. (Phase I)
II. To determine if pre-emptive therapy with DEC-C improves progression-free survival post-transplant in myelodysplastic syndrome (MDS) patients with molecular measurable residual disease at Day 30 post-transplant. (Phase II)
III. To determine if pre-emptive therapy with DEC-C decreases the rate of relapse post-transplant in MDS patients with molecular measurable residual disease at Day 30 post-transplant. (Phase II)
SECONDARY OBJECTIVES:
I. To determine overall survival at 1-year post-transplant in MDS patients with molecular minimal residual disease (MRD) at Day 30 post-transplant treated with DEC-C.
II. To establish the tolerability of DEC-C in the post-transplant setting.
III. To determine if treatment with DEC-C decreases molecular MRD burden in MRD-positive patients.
EXPLORATORY OBJECTIVES:
I. To prospectively bank serial bone marrow specimens for future studies of genetic biomarkers of disease relapse post-transplant.
II. To measure the level of disease burden in post-transplant samples using standard of care and novel markers of response, including multiparameter flow cytometry (hematologics, standard-of-care) and next-generation sequencing to identify mutations and mutational burden, and to correlate with outcomes.
III. To correlate post-transplant donor chimerism studies (short tandem repeat [STR] and/or fluorescence in situ hybridization [FISH]) and post-transplant cytogenetic and/or FISH abnormalities with the presence and level of mutations, and correlate with outcome.
IV. To determine if sequencing buccal swab and/or skin deoxyribonucleic acid (DNA) is necessary to identify somatic variants.
V. To determine the incidences and grades of graft-vs-host disease in patients treated DEC-C.
VI. To prospectively describe outcomes (relapse rate, progression-free survival, and overall survival) in MDS patients without molecular MRD at Day 30 (observation arm).
OUTLINE: This is a phase I, dose-escalation study of DEC-C followed by a phase II dose expansion study. Patients are assigned to 1 of 2 arms.
ARM I (OBSERVATION): Patients undergo bone marrow biopsy and those who are MRD-negative (variant allele frequency [VAF] < 0.2) or MRD positive patients who are not eligible to receive DEC-C on day 30 post-transplant receive standard of care.
ARM II (DEC-C): Patients undergo biopsy on day 30. Beginning between 42 and 100 days post-transplant, MRD-positive patients (VAF >= 0.2%) receive DEC-C orally (PO) once daily (QD) on days 1, 3 and 5, or days 1-3, or days 1-4 depending on dose level. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. At day 180, patients undergo bone marrow biopsy. Patients who are MRD-negative receive treatment as in Arm I. Patients who show that MRD is still detectable but below 0.2%, and patients who are MRD-positive (VAF >= 0.2%) continue DEC-C for 6 additional cycles in the absence of disease progression or unacceptable toxicity. Patients undergo buccal swab or skin punch biopsy on the trial. Patients also undergo bone marrow aspiration or blood sample collection on the trial.
After completion of study treatment, patients are followed up at 30 days, every 3 months for 2 years, then every 6 months for 3 years.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationSiteman Cancer Center at Washington University
Principal InvestigatorMeagan Jacoby
- Primary ID202103255
- Secondary IDsNCI-2021-05877
- ClinicalTrials.gov IDNCT04742634