Clinical Trials Register

Summary
EudraCT Number:	2017-000322-35
Sponsor's Protocol Code Number:	ACE-536-MF-001
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2017-06-28
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2017-000322-35

A.3

Full title of the trial

A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Luspatercept (ACE-536) in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis and Anemia With and Without Red Blood Cell-Transfusion Dependence

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study to evaluate the benefit and safety of Luspatercept (ACE-536) in adults with myeloproliferative neoplasm-associated myelofibrosis and anemia with and without red blood cell-transfusion dependence

A.4.1

Sponsor's protocol code number

ACE-536-MF-001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03194542

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1197-1202

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Celgene Corporation
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Celgene Corporation
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Celgene Corporation
B.5.2	Functional name of contact point	Clinical Trial Disclosure
B.5.3	Address:
B.5.3.1	Street Address	86 Morris Avenue
B.5.3.2	Town/ city	Summit, New Jersey
B.5.3.3	Post code	07901
B.5.3.4	Country	United States
B.5.4	Telephone number	+19137096862
B.5.6	E-mail	ClinicalTrialDisclosure@bms.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Reblozyl
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Luspatercept
D.3.2	Product code	ACE-536
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Luspatercept
D.3.9.1	CAS number	1373715-00-4
D.3.9.2	Current sponsor code	ACE-536
D.3.9.3	Other descriptive name	LUSPATERCEPT
D.3.9.4	EV Substance Code	SUB179621
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	37.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Reblozyl
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Luspatercept
D.3.2	Product code	ACE-536
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Luspatercept
D.3.9.1	CAS number	1373715-00-4
D.3.9.2	Current sponsor code	ACE-536
D.3.9.3	Other descriptive name	LUSPATERCEPT
D.3.9.4	EV Substance Code	SUB179621
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	87.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Anemia associated with myeloproliferative neoplasm (MPN)-associated
myelofibrosis

E.1.1.1

Medical condition in easily understood language

Anemia due to a bone marrow disorder resulting in abnormal production of 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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10077161
E.1.2	Term	Primary myelofibrosis
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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10074689
E.1.2	Term	Post polycythemia vera myelofibrosis
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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10074690
E.1.2	Term	Post essential thrombocythemia myelofibrosis
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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10074692
E.1.2	Term	Post essential thrombocythaemia myelofibrosis
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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10074691
E.1.2	Term	Post polycythaemia vera myelofibrosis
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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10028537
E.1.2	Term	Myelofibrosis
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

To evaluate the efficacy and safety of luspatercept for the treatment of anemia in subjects
with MPN-associated myelofibrosis with and without RBC-transfusion dependence.

E.2.2

Secondary objectives of the trial

- To evaluate the safety of luspatercept in MPN-associated myelofibrosis
- To evaluate the effect of luspatercept in MPN-associated myelofibrosis:
-- on the time to and duration of anemia response
-- on frequency of RBC transfusions and transfusion dependence
-- on symptom response improvement via the Myeloproliferative Neoplasms Symptom Assessment Form (Total Symptom Score (MPN-SAF TSS)
-- on health-related quality of life (HRQoL) via the EQ-5D-5L and Functional Assessment of Cancer Therapy – Anemia (FACT-An) questionnaires
--on the changes in hemoglobin and mean hemoglobin increase
-- To evaluate population pharmacokinetics of luspatercept in subjects with MPN-associated myelofibrosis with and without RBC-transfusion dependence

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject is ≥18 years of age at the time of signing the informed consent form (ICF).
2. Subject has MPN-associated myelofibrosis (PMF, post-PV MF, and/or post-ET MF) as confirmed from the most recent local bone marrow biopsy report according to the World Health organization 2016 criteria (Arber, 2016).
3. Subject has anemia defined as:
a. Cohorts 1 and 3A
i. Obtain ≥ 3 Hgb levels of ≤ 9.5 g/dL recorded on ≥ 3 different days, including the day of dosing, in the 84-day period immediately up to the C1D1 date. There must be ≥ 14 days in between each Hgb measurement. No subjects with an interval ≥ 42 days between hemoglobin measurements will be enrolled.
ii. There must not be any RBC transfusions within the 84-day period immediately up to the C1D1 date.
b. Cohorts 2 and 3B
i. Average RBC-transfusion frequency: 4 to 12 RBC units/84 days immediately up to the C1D1 date. There must be no interval > 56 days without ≥ 1 RBC transfusion.
ii. Subjects must have a Hgb value of < 13 g/dL on C1D1 prior to luspatercept administration.
iii. Only RBC transfusions given when the Hgb ≤ 9.5 g/dL are scored in determining eligibility.
iv. RBC transfusions given because of bleeding, infection, or chemotherapy-induced anemia are not scored in determining eligibility.
4. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
5. Subject is not anticipated during the 6 months from the C1D1 date to receive a hematopoietic cell transplant.
6. A female of childbearing potential (FCBP) for this study is defined as a female who: 1)
has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) 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). FCBP participating in the study must:
a. Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.
b. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal halflife of luspatercept based on multiple-dose pharmacokinetics [PK] data) after discontinuation of study therapy.
7. Male subjects must:
a. Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom 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 (approximately 5 times the mean terminal half-life of luspatercept based on multiple-dose PK data) following investigational product discontinuation, even if he has undergone a successful vasectomy
8. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
9. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.

E.4

Principal exclusion criteria

1. Subject (sbj) use of hydroxyurea or other drugs with potential effects on hematopoiesis (refer to Section 8.2 for prohibited medications) or ongoing AEs from previous treatment ≤ 112 days immediately up to the enrollment date
a. Systemic corticosteroids are permitted for nonhematological conditions providing the sbjt is receiving a stable or decreasing dose for ≥ 84 days immediately up to enrollment and is receiving a constant dose equivalent to ≤ 10 mg prednisone for the 28 days immediately up to enrollment
2. Cohort 1 and 2 only: sbjs treated with JAK2 inhibitors ≤ 112 days immediately up to the enrollment date or if anticipated/substantial likelihood for sbj to receive ruxolitinib within the first 168 days on the study
3. Cohort 3 only: subjects not receiving ruxolitinib: a.for at least 280 days (40 weeks) without interruptions exceeding 2 consecutive weeks; b. on a stable daily dose for at least 112 days (16 weeks) immediately up to the enrollment date as part of their standard-of-care therapy;
4. Sbj use of ESAs or androgenic steroids ≤ 112 days immediately up to the enrollment date
5. Starting iron chelation therapy (ICT) or changing the ICT dose within ≤ 112 days up to the enrollment date
6. Sbj with anemia from iron deficiency, B12 and folate deficiencies, hemolytic anemia, infection, or bleeding
7. Pregnant or breastfeeding females
8. Sbj with blood myeloblasts ≥ 5%
9. Sbj with major surgery within 8 weeks up to the enrollment date. Sbj must have completely recovered from any previous surgery immediately up to the enrollment date
10. Sbj with prior history of malignancies, other than disease under study, unless the sbj has been free of the disease for ≥ 5 years. However, sbj with the following history/concurrent conditions is 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)
11. Sbj with prior therapy of luspatercept or sotatercept
12. Sbj participation in any other clinical protocol or investigational trial that involves administration of experimental therapy and/or therapeutic devices within 30 days immediately up to the enrollment date
13. Sbj with prior hematopoietic cell transplant
14. Sbj with any of the following lab. abnormalities at screening: - Neutrophils < 1 x 10^9/L;- White blood count (WBC) > 100 x 10^9/L;
- Platelets
i. Cohorts 1 and 2: < 25 x 10^9/L
ii. Cohort 3A and 3B: < 50 x 10^9/L
iii. All Cohorts: > 1000 x 10^9/L
- Estimated glomerular filtration rate < 45 mL/min/1.73 m2 (via the 4-variable modification of diet in renal disease MDRD formula)
- Aspartate aminotransferase (AST) or alanine transaminase (ALT) > 3.0 x upper limit of normal (ULN)
- Direct bilirubin ≥ 2 x ULN
i.higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis)
- Uncontrolled hyperthyroidism or hypothyroidism
15. Sbj with stroke, deep venous thrombosis, pulmonary or arterial embolism within 6 months immediately up to the enrollment date.
16. Sbj with diastolic blood pressure ≥ 90 mmHg or systolic blood pressure ≥ 140 mHg measured during the Screening Period despite appropriate treatment.
17. Sbj with inadequately controlled heart disease and/or have a known left ventricular ejection fraction <35%.
18. Sbj with history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product (see IB).
19. Sbj with uncontrolled systemic fungal, bacterial, or viral infection (ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).
20. Sbj with human immunodeficiency virus (HIV), evidence of active infectious Hepatitis B (HepB), and/or evidence of active HepC.
21. Sbj with any significant medical condition, laboratory abnormality, psychiatric illness, or is considered vulnerable by local regulations that would prevent the subject from participating in the study.
22. Sbj with any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
23. Sbj with any condition or concomitant medication that confounds the ability to interpret data from the study.
24. Subject on anticoagulant therapy not under appropriate control or subject not on a stable dose of anticoagulant therapy for ≥ 8 weeks up to the enrollment date.
25. Subject on anagrelide within 28 days immediately up to the enrollment date
26. Subject with a major bleeding event (defined as symptomatic bleeding in a critical area or organ and/or bleeding causing a decrease in Hgb of ≥ 2 g/dL or leading to transfusion of ≥ 2 units of packed red cells) in the last 6 months prior to enrollment.

E.5 End points

E.5.1

Primary end point(s)

1) Anemia response as it relates to hemoglobin (Hgb) increase
2) Anemia response as it relates to increased red blood cell (RBC) – transfusion independence

E.5.1.1

Timepoint(s) of evaluation of this end point

1.) Cohorts 1 and 3A: Any consecutive “rolling” 84-day period from Day 1 through
and including Day 168

2.) Cohorts 2 and 3B: Any consecutive “rolling” 84-day period from Day 1 through
and including Day 168

E.5.2

Secondary end point(s)

1. Time to anemia response
2. Duration of anemia response
3. Frequency of RBC transfusions
4. Frequency of RBC-transfusion dependence
5. Proportion of subjects who achieve ≥ 50% reduction in fatigue symptom as measured by the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)
6. The proportion of subjects who achieve ≥ 50% reduction in total symptom score (TSS)
7. Health-related quality of life (HRQoL)
8. Functional Assessment of Cancer Therapy – Anemia (FACTAn)
9. EQ-5D-5L questionnaires
10. Adverse Events (AEs)
11. Antidrug antibodies (ADA)
12. Pharmacokinetic - AUC
13. Pharmacokinetic - Cmax
14. Changes in hemoglobin in the absence of RBC transfusions (Cohorts 1 and 3A)
15 Mean hemoglobin increase

E.5.2.1

Timepoint(s) of evaluation of this end point

1. from Day 1 through and including Day 168
2. Day 1 through end of treatment.
3, 4, 5, 6, 7, 8, 9, 14 Day 1 through and including Day 168 and Day 1 through end of treatment
10. Screening through 42 days post last dose
11. Day 1 up to 1 year for ADA-negative subjects; Day 1 up to 2 years for ADA-positive subjects
12, 13. Up to 1 year
15. Any consecutive “rolling” 84-day period from Day 1 through and including Day 168; Day 1 through end of treatment

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Biomarkers

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind