Myelodysplastic Syndromes, MDS/MPN Crossover Syndromes
Conditions
Brief summary
Another term for myelodysplastic syndrome is bone marrow failure. The bone marrow is where components of blood such as red cells, platelets and white cells are made. In bone marrow failure, the ability for bone marrow to make these cells is decreased. In myelodysplastic syndrome, this decreased bone marrow function is believed to result from abnormalities that prevent the normal maturation process by which bone marrow cells develop into red blood cells, white blood cells and platelets. In myelodysplastic syndrome, these abnormal bone marrow cells occupy space in the bone marrow and prevent the function of remaining normal bone marrow cells. One approach to treating the abnormal growth of immature cells is to give chemotherapy which damages DNA within these cells and causes their death. Unfortunately, such therapy has side-effects, since even normal cells can be affected by the treatment. Both 5-azacitidine (5AZA) and decitabine (DEC) are FDA-approved to treat MDS. In this study, 5AZA and DEC will be administered using an alternating low doses schedule in an attempt to overcome the known mechanisms of resistance to the administration of 5AZA or DEC as single agents caused by automatic adaptive shifts in DNA metabolism.
Detailed description
This will be a single arm, open label pilot study of 5AZA-alt-DEC. Participants will be treated for a minimum of 24 weeks in the absence of clear evidence of progressive disease. Participants who have any response will be permitted to continue treatment until relapse or progression of disease that is not sensitive to protocol defined dose escalation. The primary objective of this study is to determine Overall Response Rate (ORR) of 5AZA-alt-DEC. The combined response endpoint will include complete response (CR), partial response (PR), and hematologic improvement (HI), with HI criteria specifically as defined by IWG criteria The secondary endpoints of this study include: * Cumulative incidence of response for both CR and overall response * Duration of response (DOR) * Safety evaluation by tabulation of adverse events of grade 3 and higher Correlative endpoints include: * Correlation of DNMT1 depletion with clinical response criteria * Correlation of clinical response with disease biological phenotype measured by morphology and cytogenetics * Exploratory measurements of pyrimidine metabolism pre-treatment and on-therapy
Interventions
DRUG5-azacytidine
5-azacytidine 50 mg/m\^2 Day 1 every week ± G-CSF \ 5 µg/kg (300µg vs 480µg)
DRUGDecitabine
Decitabine 5 mg/m\^2 Day 4 every week ± G-CSF \ 5 µg/kg (300µg vs 480µg)
Sponsors
Benjamin Tomlinson
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must have MDS or MDS/myeloproliferative overlap disorder with potential sensitivity to HMA therapy, defined as prior published evidence of response to HMA * Myelodysplastic Syndromes: * As classified by hematopathology review of WHO categories, myelodysplastic/myeloproliferative neoplasm unclassifiable, refractory anemia with ring sideroblasts and thrombocytosis, refractory cytopenia with unilineage dysplasia (RCUD), refractory anemia with ring sideroblasts (RARS), refractory cytopenia with multi-lineage dysplasia (RCMD), refractory anemia with excess blasts (RAEB), myelodysplastic syndrome with isolated del(5q), myelodysplastic syndrome unclassifiable (MDS-U). * Participant with MDS who are IPSS-R high and very high risk or IPSS intermediate 2 risk and higher are excluded given proven overall survival benefit in higher risk MDS from AZA-001 with this treatment * Myelodysplastic/myeloproliferative neoplasm overlap disorders ---MDS/MPN crossover syndromes with limited evidence of extramedullary hematopoiesis (may not have palpable splenomegaly) and reticulin fibrosis of grade 1 or less without evidence of progression to accelerated phase. These may include but may not be limited to RARS-T, CMML, Atypical CML (BCR-ABL negative), and MDS/MPN NOS * Indication for HMA therapy: Symptomatic anemia OR thrombocytopenia with a platelet count of \<100 x 109/L OR transfusion dependence for red-cells OR transfusion dependence for platelets OR absolute neutrophil count \< 1.0 x 109/L --Participants with lower risk MDS must have must have failed or have contraindications to available therapies (e.g. lenalidomide, epoetin if indicated for symptomatic anemia and/or transfusion dependence of red cells) known to be effective for treatment of their disease * Participants must have performance status of 60% or greater by Karnofsky Performance Status (KPS) * Must have adequate end organ function defined as: * AST and ALT \< 3× the upper limit of normal (ULN) * Bilirubin ≤ 1.5× the ULN. If elevated bilirubin is due to impaired conjugation (e.g Gilbert's disease or concomitant medication) or disease related hemolysis, then direct bilirubin ≤ 1.5× the ULN * As azacitidine and decitabine have little renal metabolism, and have proven safety even in dialysis participants, renal function is not an inclusion or
Exclusion criteria
* Subjects must have the ability to understand and the willingness to sign a written informed consent document and complete study related procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR) of 5AZA-alt-DEC | Up to 6 months from end of treatment | Overall response rate (ORR) of 5AZA-alt-DEC including: Complete Response (CR) Partial Response (PR) Hematologic improvement (HI), with HI criteria specifically as defined by IWG criteria Therefore, the overall response rate (ORR) = CR + PR + HI |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative incidence of response for both CR and overall response | Up to 6 months from end of treatment | Cumulative incidence of response for both CR and overall response |
| Duration of response (DOR) | Up to 2 years from end of treatment | Duration of response (DOR) |
| Safety evaluation by tabulation of all AEs and SAEs per CTACE version 5.0 | through 30 days after the final dose of study drug | Safety evaluation by tabulation of all AEs and SAEs per CTACE version 5.0 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Enzyme expression important in DEC metabolism: DCK, UCK2, and CDA by QRT-PCR. | At baseline, 12 weeks, 24 weeks and up to 2 years from end of treatment | Measurement of pyrimidine metabolism pre-treatment and on-therapy in marrow samples through Measurement of enzyme expression important in DEC metabolism: DCK, UCK2, and CDA by QRT-PCR. |
| Correlation of clinical response IWG criteria with disease biological phenotype | Up to 2 years from end of treatment | Correlation of clinical response (by IWG criteria for myelodysplastic syndrome and myelodysplastic/myeloproliferative overlaps syndromes depending on the underlying disease) with disease biological phenotype (morphologyand cytogenetics) |
| Surface expression of markers of monocytic and granulocytic differentiation by flow cytometry: CD11b, CD14 and CD15 | At baseline, 12 weeks, 24 weeks and up to 2 years from end of treatment | Measurement of pyrimidine metabolism pre-treatment and on-therapy in marrow samples through measurement of surface expression of markers of monocytic and granulocytic differentiation by flow cytometry: CD11b, CD14 and CD15 |
| Correlation of predicted DNMT1 depletion with clinically assessed DNMT1 depletion as evaluated by quantitative immunofluorescence | Up to 2 years from end of treatment | Evaluation of a primary mechanism of 5AZA-alt-DEC to maintain the depletion of DNMT1 as predicted by preclinical models. This will be evaluated by bone marrow analysis of DNTM1 depletion, measured through quantitative immunofluorescence |
| Correlation of predicted DNMT1 depletion with clinically assessed DNMT1 depletion as evaluated by flow cytometry | Up to 2 years from end of treatment | Evaluation of a primary mechanism of 5AZA-alt-DEC to maintain the depletion of DNMT1 as predicted by preclinical models. This will be evaluated by bone marrow analysis of DNTM1 depletion, measured through flow cytometry |
| Correlation of predicted DNMT1 depletion with clinically assessed DNMT1 depletion as evaluated by standard pathologic interpretation of IHC | Up to 2 years from end of treatment | Evaluation of a primary mechanism of 5AZA-alt-DEC to maintain the depletion of DNMT1 as predicted by preclinical models. This will be evaluated by bone marrow analysis of DNTM1 depletion, measured through standard pathologic interpretation of IHC |
Countries
United States
Contacts
Primary ContactBenjamin Tomlinson, MD
Outcome results
None listed