Overview

Myelodysplastic syndromes, primarily affecting older adults, are a heterogeneous group of clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis that manifest clinically as anemia, neutropenia, and/or thrombocytopenia of variable severity; these often result in RBC- transfusion dependent (TD) anemia, increased risk of infection, and/or hemorrhage, as well as a potential to progress to acute myeloid leukemia (AML).

Lenalidomide is approved for red blood cell transfusion-dependent (RBC TD) anemia due to low-risk myelodysplastic syndromes (MDS) with a chromosome 5q deletion (del5q) with or without additional cytogenetic abnormalities. About one third of patients are refractory/resistant/intolerant and will require further treatment options.

Luspatercept (ACE-536), an erythroid maturation agent, is a recombinant fusion protein consisting of a modified form of the extracellular domain (ECD) of the human activin receptor type IIB (ActRIIB) linked to the Fc portion of human immunoglobulin G1 (IgG1-Fc). Luspatercept acts on endogenous inhibitors of late-stage erythropoiesis (eg, growth differentiation factor 11, GDF11) to increase release of mature erythrocytes into circulation. Nonclinical data have demonstrated that luspatercept binds to negative regulators governing late-stage erythroid development to inhibit their action, thereby promoting the maturation of erythrocytes in the bone marrow.

Luspatercept is indicated for the treatment of adult patients with transfusion-dependent anaemia associated with beta-thalassaemia and due to very low, low and intermediate-risk MDS with ring sideroblasts, who had an unsatisfactory response to or are ineligible for erythropoietin-based-therapy. It is not indicated for other MDS subtypes. Unfortunately, patients with MDS with del5q refractory/resistant/intolerant to lenalidomide are excluded from clinical trials that evaluate novel treatments for the anemia of RBC TD lower risk MDS. Therefore, treatment of anemia in such patients is an unmet need.

QOL-ONE Phoenix is a Phase 2, multicenter, single arm, prospective study. The primary objective of the study is to evaluate the effect of luspatercept on RBC TI in subjects with MDS with del5q with IPSS-R very low, low, or intermediate risk and < 5% bone marrow blasts, resistant/refractory/intolerant to lenalidomide and who require RBC transfusions.

The study is divided into a Screening Period, a 2-year Treatment Period and a 3-year Follow-up Period.

Primary objective is to evaluate the effect of luspatercept on RBC TI (lack of transfusions for 8 consecutive weeks within the first 24 weeks) in subjects with MDS with del5q with IPSS-R very low, low, or intermediate risk and < 5% bone marrow blasts, resistant/refractory/intolerant to lenalidomide and RBC TD.

Eligibility

Inclusion Criteria:

1. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
2. Documented diagnosis of MDS with del5q according to 2018 WHO classification
3. IPSS-R classification (Greenberg, 2012) of very low, low, or intermediate risk disease, and:
   • < 5% blasts in bone marrow
   • Peripheral blood WBC count <13,000/μL
4. Refractory or intolerant to, or ineligible for, prior ESA treatment
5. If previously treated with ESAs or granulocyte colony-stimulating factor (G-CSF), both agents must have been discontinued ≥ 4 weeks prior to date of screening.
6. Refractory or intolerant to, or ineligible for, prior lenalidomide treatment, as defined by any one of the following:
   • Refractory to prior lenalidomide treatment for at least 4 cycles; - documentation of non-response or response that is no longer maintained (HI-E)
   • Intolerant to prior lenalidomide treatment - documentation of discontinuation of lenalidomide at any time after introduction due to intolerance or an adverse event
   • lenalidomide ineligible -platelet counts below 50000/mmc or absolute neutrophil count below 500/mmc at the start of treatment
   • lenalidomide must have been discontinued ≥ 4 weeks prior to date of screening.

Requires RBC transfusions, as documented by the following criteria:

• average transfusion requirement of ≥ 2 units/8 weeks of pRBCs confirmed for a minimum of 16 weeks immediately preceding enrolment.
• Hb levels at the time of or within 7 days prior to administration of a RBC transfusion must have been ≤ 10.0 g/dL in order for the transfusion to be counted towards meeting eligibility criteria. RBC transfusions administered when Hb levels were > 10.0 g/dL and/or RBC transfusions administered for elective surgery will not qualify as a required transfusion for the purpose of meeting eligibility criteria.
• no consecutive 56-day period that was RBC transfusion-free during the 16 weeks immediately preceding screening 7. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 8. Females of childbearing potential, defined as a sexually mature woman who: 1) has not

  undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months), must:

• Have two negative pregnancy tests as verified by the Investigator prior to starting study therapy (unless the screening pregnancy test was done within 72 hours of C1D1). Refer to Section 6.1 for additional details. She must agree to ongoing pregnancy testing during the course of the study, and after the end of study treatment.
• If sexually active, agree to use, and be able to comply with, highly effective contraception without interruption, 5 weeks prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks after discontinuation of study therapy. 9. Male subjects must:
• Agree to use a condom, defined as a male latex condom or non latex condom not made out of natural (animal) membrane (for example, polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks following investigational product discontinuation, even if he has undergone a successful vasectomy. 10. Subject is willing and able to adhere to the study visit schedule and other protocol

  requirements.

Exclusion Criteria:

1. P53 mutation at screening
2. Prior therapy with disease modifying agents for underlying MDS disease (hypomethylating agents)
   • subjects who previously received HMA may be enrolled at the investigator's discretion contingent that the subject received no more than 1 dose of HMA). The last dose must be ≥ 5 weeks from the date of screening.
3. Previously treated with either luspatercept (ACE-536) or sotatercept (ACE-011)
4. Secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases. 5 Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding
5. Prior allogeneic or autologous stem cell transplant 7. Known history of diagnosis of AML
6. Use of any of the following within 5 weeks prior to study entry:
   • anticancer cytotoxic chemotherapeutic agent or treatment
   • corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to study entry for medical conditions other than MDS
   • iron-chelating agents, except for subjects on a stable or decreasing dose for at least 8 weeks prior to screening
   • other RBC hematopoietic growth factors
   • investigational drug or device, or approved therapy for investigational use. If the half- life of the previous investigational product is known, use within 5 times the half- life prior to screening or within 5 weeks, whichever is longer is excluded. 9. Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment. 10. Estimated glomerular filtration rate (eGFR) or creatinine clearance < 40 mL/min. 11. Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase or alanine aminotransferase/serum glutamic pyruvic transaminase ≥ 3.0 x upper limit of normal (ULN) 12. Total bilirubin ≥ 2.0 x ULN.
   • higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis) or in the presence of known history of Gilbert Syndrome.
   • subjects are excluded if there is evidence of autoimmune hemolytic anemia 13. Prior history of malignancies, other than MDS, unless the subject has been free of the disease (including completion of any active or adjuvant treatment for prior malignancy) for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed:
   • Basal or squamous cell carcinoma of the skin
   • Carcinoma in situ of the cervix
   • Carcinoma in situ of the breast
   • Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)