About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Participants must have MDS or MDS/myeloproliferative overlap disorder with potential sensitivity to HMA therapy, defined as prior published evidence of response to HMA

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

Disqualifiers

Subjects must have the ability to understand and the willingness to sign a written informed consent document and complete study related procedures.

MDS with IPSS-R high or very high risk, or IPSS intermediate-2 or high risk disease

Prior Treatment with azacitidine, decitabine or investigational HMA therapy with overlapping mechanism of action (e.g. guadecitibine)

No other disease directed therapy, save for hydroxyurea, including experimental or investigational drug therapy for 14 days prior to study entry.

Trial design

Design model

Single group

Treatments tested in this trial

5-azacytidine
Drug
5-azacytidine 50 mg/m\^2 Day 1 every week ± G-CSF \~5 µg/kg (300µg vs 480µg)
Decitabine
Drug
Decitabine 5 mg/m\^2 Day 4 every week ± G-CSF \~5 µg/kg (300µg vs 480µg)

Treatment groups

20 Participants

are divided into 1 treatment group

Group A: 5AZA-alt-DECExperimental treatment 2 interventions

Trial outcomes

Primary outcomes

1

Overall response rate (ORR) of 5AZA-alt-DEC

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

Time frame

Up to 6 months from end of treatment

Secondary outcomes

1

Cumulative incidence of response for both CR and overall response

Time frame

Up to 6 months from end of treatment

2

Duration of response (DOR)

Time frame

Up to 2 years from end of treatment

3

Safety evaluation by tabulation of all AEs and SAEs per CTACE version 5.0

Time frame

through 30 days after the final dose of study drug

Other outcomes

1

Correlation of clinical response IWG criteria with disease biological phenotype

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)

Time frame

Up to 2 years from end of treatment

2

Correlation of predicted DNMT1 depletion with clinically assessed DNMT1 depletion as evaluated by quantitative immunofluorescence

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

Time frame

Up to 2 years from end of treatment

3

Correlation of predicted DNMT1 depletion with clinically assessed DNMT1 depletion as evaluated by flow cytometry

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

Time frame

Up to 2 years from end of treatment

4

Correlation of predicted DNMT1 depletion with clinically assessed DNMT1 depletion as evaluated by standard pathologic interpretation of IHC

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

Time frame

Up to 2 years from end of treatment

5-Azacitidine and Decitabine Epigenetic Therapy for Myeloid Malignancies

About this trial

Eligibility criteria

Qualifiers

Disqualifiers

Trial design

Treatments tested in this trial

Treatment groups

Trial outcomes

Primary outcomes

Secondary outcomes

Other outcomes

Sponsors and contacts