| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Anemia and low or intermediate-1 risk myelodysplastic syndromes, or non-proliferative chronic myelomonocytic leukemia (CMML). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Anemia and a low level of myelodysplastic syndrome (when bone marrow does not make enough healthy blood cells) and non-proliferative chronic myelomonocytic leukemia (high level of white blood cells) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054350 |
| E.1.2 | Term | Chronic myelomonocytic leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10002272 |
| E.1.2 | Term | Anemia |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028533 |
| E.1.2 | Term | Myelodysplastic syndrome |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to determine a safe, tolerable and effective dose of sotatercept that results in the greatest frequency of erythroid hematological improvement (HI-E) in patients with anemia and low- or intermediate-1 risk MDS. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to evaluate the:
1. Safety of sotatercept
2. Rate of RBC transfusion independence in transfusion-dependent subjects
3. Time to HI-E
4. Duration of HI-E
5. Time to progression to acute myeloid leukemia (AML)
6. Time to progression to events of higher risk MDS (ie, int-2 or high risk IPSS)
7. Progression-free survival (PFS)
8. Overall survival (OS)
9. Pharmacokinetics (PK) of sotatercept |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provide written informed consent prior to the conduct of any study-related assessment or procedure.
2. Age ≥18 years at the time of signing the informed consent form.
3. Able to adhere to the study visit schedule and other requirements of the protocol.
4. Documented diagnosis of MDS or non-proliferative chronic myelomonocytic leukemia (CMML, WBC ≤13,000 /mm3,World Health organization, Vardiman, 2009) that meets International Prognostic Scoring System (IPSS, Appendix B) criteria for low or intermediate-1 risk disease.
5. Anemia defined as requiring transfusion ≥ 2 units of RBCs within 84 days of enrollment for Hgb ≤ 9.0 g/dL.
6. No response to prior treatment with epoetin alpha (≥40,000 U/wk x 8), or darbepoetin alpha (≥500 mcg q3W x 4), or low chance of response to erythroid stimulating factors reflected by endogenous serum erythropoietin (EPO) concentration >500 mU/ml.
7. All previous therapy, including erythropoiesis-stimulating agents, granulocyte colonystimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GMCSF), must have been discontinued ≥28 days before enrollment
8. Eastern Cooperative Group (ECOG) performance status (Appendix D) ≤2.
9. Creatinine <1.5 X ULN.
10. Total bilirubin ≤3.0 mg/dL, except if associated with primary shunt hyperbilirubinemia (idiopathic dyserythropoietic jaundice).
11. AST (SGOT) and ALT (SGPT) ≤3.0 x upper limit of normal (ULN).
12. Females of childbearing potential participating in the study are to use highly effective methods of birth control during study participation and for 112 days (approximately five times the mean terminal half-life of sotatercept [23 days] based on multiple-dose PK data) following the last dose of sotatercept. Females of childbearing potential must have a negative serum beta-human chorionic gonadotropin (β-HCG) pregnancy test within three days of sotatercept dosing (Day 1). Subjects must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of sotatercept. A females of childbearing potential is a sexually mature woman who has not
undergone a hysterectomy or bilateral oophorectomy or who has not been
postmenopausal for at least 24 consecutive months (ie, who has had menses at some time in the preceding 24 months).
13. Males must agree to use a latex condom during any sexual contact with females of child bearing potential while participating in the study and for 112 days following the last dose of sotatercept, even if he has undergone a successful vasectomy. Subjects must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of sotatercept.
14. Free of metastatic malignancy (other than MDS) for ≥2 years. |
|
| E.4 | Principal exclusion criteria |
1. Patients with MDS with chromosome 5q deletion.
2. Women who are pregnant or breast feeding (Women who are lactating must agree not to breast feed) or planning to become pregnant or breast feed during the period of treatment and for 112 days following the last dose of sotatercept.
3. Males who do not agree to use a latex condom or non-latex condom NOT made of natural (animal) membrane during sexual contact with females of childbearing potential or a pregnant female while participating in the study and for at least 112 days following the last dose of sotatercept, even if he has undergone successful vasectomy.
4. Major surgery within 30 days prior to Day 1
5. Incomplete recovery or incomplete healing of wounds from previous surgery.
6. Subjects with classification of 3 or higher heart failure as classified by the New York Heart Association (NYHA) (Appendix E).
7. History of thrombosis, deep vein thrombosis, pulmonary emboli, or embolic stroke if not stable on anticoagulants and/or occurring within the past 6 months. Local central line thrombosis is allowed.
8. History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients in the investigational product (Refer to the Investigator’s Brochure for further information).
9. A condition, including laboratory abnormality, that, as determined by the Investigator, places the subject at unacceptable risk if he/she were to participate in the study or that potentially confounds interpretation of data from the study.
10. Concurrent use of anti-cancer cytotoxic chemotherapeutic agent or treatment.
11. Known positive for human immunovirus (HIV) or infectious hepatitis type C or active infectious hepatitis type B.
12. Clinically significant anemia unrelated to myelodysplastic disease (eg, iron, B12 or folate deficiencies, autoimmune or hereditary hemolysis, active gastrointestinal bleeding, and chronic renal insufficiency).
13. Thrombocytopenia (platelet count <30,000/uL).
14. Uncontrolled hypertension (systolic blood pressure [SBP] ≥140 or diastolic blood pressure [DBP] ≥90). Controlled hypertension for this protocol is considered ≤ Grade 1 according to NCI CTCAE version 4.0 (current active minor version) (Appendix F).
15. Treatment with another investigational drug or device within 28 days prior to Day 1, or if the half life of the previous product is known, within 5 times the half life prior to dosing, whichever is longer.
16. Prior exposure to sotatercept (ACE-011).
17. Any significant medical condition, laboratory abnormality, or psychiatric illness that, as determined by the Investigator, would prevent the subject from participating in the study or providing written informed consent.
18. Any condition including the presence of laboratory abnormality that, as determined by the Investigator, places the subject at unacceptable risk if he/she were to participate in the study.
19. Any condition that, as determined by the Investigator, confounds the interpretation of data from the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of this study is the rate of HI-E (Appendix C) starting before the completion of 5 cycles (Day 106) of treatment. Subjects who have sustained Hgb increase by Day 106 but for a period less than 8 weeks (potential late responders) may continue treatment for up to an additional 3 cycles (9 weeks) beyond Cycle 5 (Day 106) for the purpose of meeting response criteria.
- HI-E [(for subjects that require a transfusion of <4 units of RBCs) in the eight weeks prior to randomization (Part 1) or start of therapy (Part 2)]is an increase ≥1.5 g/dL Hgb sustained over a period ≥8 weeks in the absence of RBC transfusion; or
- HI-E [(for subjects that require a transfusion of ≥4 units of RBCs) in the eight weeks prior to randomization (Part 1) or start of therapy (Part 2)]is a decrease ≥4 units of RBCs transfused over a period of 8 weeks, relative to the number of units of RBCs transfused in the 8 weeks immediately prior to Day 1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Assessed via hematological analysis conducted weekly throughout the Treatment Period, at the end of the Treatment Period, before administration of each treatment during the Extension Period, and at the end of the Extension Period. |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints of this study are:
1. Safety of sotatercept - based upon assessments listed in Section 10.7. [Adverse events, dose limiting toxicities, vital signs, clinical laboratory information, and administration of concomitant medications will be assessed at various times throughout the study. ECG will be conducted at Screening evaluation.]
2. RBC transfusion-independence in transfusion-dependent subjects (Appendix C). [Assessed via record of transfusions; conducted before administration of each treatment during the Treatment and Extension Periods, at the end of the Treatment Period, and at the end of the Extension Period]
3. Time to HI-E (Appendix C). [Assessed via hematological analysis
conducted weekly throughout the Treatment Period, at the end of the Treatment Period, before administration of each treatment during the Extension Period, and at the end of the Extension Period.]
4. Duration of HI-E (Appendix C). [Assessed via hematological analysis conducted weekly throughout the Treatment Period, at the end of the Treatment Period, before administration of each treatment during the Extension Period, and at the end of the Extension Period.]
5. Time to progression to AML; the time between randomization (Part 1) or start of therapy (Part 2) and the date of progression to AML (Appendix C). [Assessed after 6 weeks of treatment, at the end of the Treatment Period, at the end of the
Extension Period, and to include only transformation to AML and overall survival assessed every 6 months up to 2 years following the first administration of sotatercept during Follow-up Period.]
6. Time to progression to events of higher risk MDS; the time between randomization (Part 1) or start of therapy (Part 2) and date of progression to events of higher risk MDS (eg, int-2 or high risk IPSS, Appendix B). [Assessed after 6 weeks of treatment, at the end of the Treatment Period, at the end of the
Extension Period, and to include only transformation to AML and overall
survival assessed every 6 months up to 2 years following the first administration of sotatercept during Follow-up Period.]
7. Progression-free survival (PFS) - the time between randomization (Part 1) or start of therapy (Part 2) and disease progression (PD) (Appendix C) or death. [Assessed after 6 weeks of treatment, at the end of the Treatment Period, at the end of the Extension Period, and to include only transformation to AML and overall survival assessed every 6 months up to 2 years following the first
administration of sotatercept during Follow-up Period.]
8. Overall survival (OS) - the time between randomization (Part 1) or start of therapy (Part 2) and death. [Assessed at each visit during the Treatment Period, the Extension Period, and every 6 months up to 2 years following the first
administration of sotatercept.]
9. Concentration of sotatercept in serum. [Conducted weekly for the first
6 weeks of the Treatment Period, before administration of each treatment during the Treatment Period, at the end of the Treatment Period, before administration of every other treatment during the Extension Period, at the end of the Extension Period, and approximately 3 months after the last treatment.] |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of the patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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