Treatment of higher-risk (intermediate, high and very high) Myelodysplastic Syndromes (MDS) according to the revised International Prognostic Scoring System (IPSS-R) who obtained a stable hematological response ( CR, PR) after subcutaneous azacitidine treatment.

Azacitidine is administered in hospital in a day care regimen, in Italy only by subcutaneous injection. The long duration of therapy obliges patients to travel to the hospital regularly, with evident worsening quality of life, both for patients and caregivers, although balanced by prolongation of survival and hematological improvement. Many patients stop therapy or are reluctant to continue because of the dependence from caregivers and hospital care.

This clinical study will evaluate the efficacy and safety of oral azacitidine (CC-486) plus best supportive care in subjects with higher-risk (intermediate, high and very high) Myelodysplastic Syndrome (MDS) according to the revised International Prognostic Scoring System (IPSS-R) and (high and INT-2) according to IPSS who obtained a stable hematological response (CR, PR, SD with HI) after at least 4-6 cycles of subcutaneous azacitidine treatment and maintained for 2 additional cycles.

Azacitidine therapy is effective in prolonging survival in higher risk MDS patients provided therapy is administered at 28 day-cycles until progression or loss of response.

A study conducted several years ago shows that although most responses to azacitidine occurred within 6 cycles, continued azacitidine therapy led to a further improvement in response category in almost half (48%) of all responders with a median of 3 additional cycles, and that 92% of patients achieved their best response by Cycle 12. In a randomized phase 3 trial conducted by the US Cancer and Leukemia Group B, which compared azacitidine with best supportive care, most responses occurred during the third or fourth month of azacitidine therapy. The phase 3 Cancer and Leukemia Group B study also showed that 90% of responses occurred within the first 6 cycles of treatment and that best response generally occurred 2 cycles after the first response-all of which is consistent with the current findings. Taken together, these data suggest that although some effects of azacitidine manifest promptly, additional courses are usually necessary before best response is achieved. Therefore, continuing azacitidine therapy offers the best chance of enhanced benefit if treatment is tolerated and there is no evidence of disease progression.

Azacitidine may affect the differentiation and growth of the MDS clone without necessarily eradicating it, suggesting that repetitive and prolonged exposure to azacitidine may be necessary for both the initial effects and the subsequent augmentation of response. Discontinuation of azacitidine therapy is in fact invariably followed by loss of response, disease progression and short survival. Treatment should be optimized to deliver at least 6 cycles, and in responsive patients until progression. In clinical practice, however, AZA is often discontinued after few cycles. Prematurely interrupted therapy could be the cause of inferior outcomes registered in "real life" studies. This inconsistency may be due to differences in adherence to dose, schedule, and minimum number of cycles, as well as to the management of patients with severe comorbidities. Proper management of first-line azacitidine therapy, with appropriate doses and prolonged treatment, may partially reduce primary resistance. This is why it is extremely important to maintain treatment until progression, despite scarce compliance of the patients to subcutaneous injections. Anyhow, it is clear that the azacitidine effect is transient, with responses maintained for 6 to 24 months.

Survival of the patients with refractory/relapsed disease is extremely short. A premature arrest of treatment may thus provoke loss of response and accelerate progression. In order to improve the compliance to treatment of MDS patients who have shown optimal responses to azacitidine, an oral formulation of the drug could indeed be advantageous. Oral therapy with CC 486 could free patients from hospital and caregiver dependence, as well as from injection site reactions, consequently improving quality of life, without altering the necessary continuation of treatment. During the present Covid-19 outbreak it has became even clearer that treatment with medications in oral formulation, under strict control of treating physicians, may indeed, beyond improving quality of life, decrease the risk of exposure to infections derived by in hospital administered therapy for MDS patients.

An oral formulation of azacitidine like cc486 provides an opportunity to deliver the drug at lower systemic doses over a more prolonged schedule that can be practically achieved with parenteral therapy. In addition, an oral formulation that can be taken at home rather than in the hospital/clinic setting represents an opportunity for patients with MDS to have a more convenient route of administration, thus alleviating the morbidity of injection and avoiding the inconvenience and resource utilization costs associated with frequent hospital/clinic visits. In addition, intervention with azacitidine in patients with MDS that have obtained a response after sc azacitidine may offer better quality of life and possibly a survival advantage.

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

1. Male or female subjects ≥ 65 years of age at the time of signing the ICD;

2. Diagnosed, histologically confirmed at inclusion,

   • Int-2 or High according to IPSS, or
   • Very High, High or Intermediate according to IPSS-R, or
   • Hypoplastic AML (20-30% BM blasts, previosuly considered MDS RAEB-T)
   • myelodysplastic CMML (included in IPSS scoring, WBC < 13.x 109/L);

3. Should have undergone therapy with subcutaneous azacitidine for at least 4-6 cycles ( + 2 cycles)

4. Must have achieved CR/CRi, PR or SD with HI status, as evidenced by IWG Criteria 2006 ( APPENDIX E):

5. ECOG performance status of 0, 1, 2 (Appendix C);

6. Adequate bone marrow function based on ANCs ≥ 1.0 x 109/L and platelet counts ≥ 70 x 109/L.

7. Adequate organ function, defined as:

Serum bilirubin ≤1.5 times the upper limit of normal (ULN); Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times the ULN; Serum creatinine ≤ 2.5 times the ULN; 8.Male subjects with a female partner of childbearing potential must agree to practice abstinence or to the use of a physician-approved contraceptive method throughout the course of the study and avoid fathering a child during the course of the study and for 3 months following the last dose of azacitidine; 10. Understand and voluntarily sign an ICD prior to any study related assessments/procedures are conducted; 11. Able to adhere to the study visit schedule and other protocol requirements; 12. Ability to swallow study medication.

Exclusion Criteria:

• Absence of confirmed hematological response ( IWG HI/PR/CR) after at least 4 to 6 months of azacitidine sc and maintenance of response for 2 additional cycles.
• Inability to provide a valid informed consent.
• Eligibility for HSCT
• Active infection
• Serum creatinine > 2 x ULN at screening.
• ECOG performance status > 2
• Left ventricular ejection fraction < 50% by echocardiography
• A history of repeated hospitalization for severe infections Systemic diseases that would prevent study treatment (e.g. uncontrolled hypertension, cardiovascular, renal, hepatic, metabolic, etc.)
• Clinical or laboratory evidence of chronic Hepatitis B or Hepatitis C (definition of
• chronic hepatitis follows EASL 2017 criteria).
• History of HIV positive test result (ELISA or Western blot).
• ALT or AST over 3 times superior to ULN at screening.
• Total bilirubin over 1.5 times superior to ULN at screening (patients with Gilbert syndrome are allowed to enter the study)
• Patients participating in another clinical trial other than an observational registry study.
• Patients with a history of another malignancy within the past 3 years, with the exception of basal skin carcinoma or cervical carcinoma in situ or completely resected colonic polyps carcinoma in situ.
• History of non-compliance to medical regimens, or patients who are considered potentially unreliable and/or not cooperative.
• Presence of a surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of study drug.
• History of drug or alcohol abuse within the 12 months prior to enrollment.