The primary objective is:* To evaluate RBC transfusion independence (RBC-TI) of luspatercept compared with placebo for the treatment of anemia due to IPSS-R very low, low, or intermediate risk MDS in subjects with ring sideroblasts (* 15%) who…
ID
Source
Brief title
Condition
- Anaemias nonhaemolytic and marrow depression
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint of transfusion independent response is defined as
the absence of any RBC transfusion during any consecutive 56 day period during
the Primary Phase of the Treatment Period.
Secondary outcome
The key secondary endpoint is the proportion of subjects achieving RBC-TI with
duration * 12 weeks.
Background summary
This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter
study to determine the efficacy and safety of luspatercept (ACE-536) versus
placebo for the treatment of anemia due to IPSS-R very low, low, or
intermediate risk MDS in subjects with ring sideroblasts (* 15%) who require
RBC transfusions.
Study objective
The primary objective is:
* To evaluate RBC transfusion independence (RBC-TI) of luspatercept compared
with placebo for the treatment of anemia due to IPSS-R very low, low, or
intermediate risk MDS in subjects with ring sideroblasts (* 15%) who require
RBC transfusions
The secondary objectives are:
* To assess the safety and tolerability of luspatercept compared with placebo
* To evaluate the effect of luspatercept on reduction in RBC transfusions,
increase in hemoglobin, duration of RBC-TI, improvement in health-related
quality of life (HRQoL) (ie, European Organization for Research and Treatment
of Cancer Quality of Life Questionnaire [EORTC QLQ-C30]), increase in
neutrophils, increase in platelets, decrease in serum ferritin, decrease in
iron chelation therapy use, and time to RBC-TI compared with placebo
* To evaluate population pharmacokinetics and exposure-response relationships
for luspatercept in MDS subjects
Study design
The study is divided into the Screening Period, a double-blind Treatment Period
(Primary Phase and Extension Phase) and a Posttreatment Follow-up Period.
Eligible subjects will be randomized at a 2:1 ratio to either:
* Experimental Arm - Luspatercept (ACE-536): Starting dose of 1.0 mg/kg
subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day
treatment cycle)
OR
* Control Arm: Placebo (volume equivalent to experimental arm) subcutaneous
injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle).
After randomization, no crossover between the treatment arms will be permitted
at any point during the study.
Best supportive care may be used in combination with study treatment in both
arms when clinically indicated per investigator discretion.
Stratification will be based on the following factors:
1. RBC Transfusion burden at baseline
* * 6 RBC units/8 weeks (mean of the two consecutive 8-week periods immediately
prior to randomization)
* < 6 RBC units/8 weeks (mean of the two consecutive 8-week periods immediately
prior to randomization)
2. IPSS-R at baseline
* Very low, low
* Intermediate
Primary Phase of the Treatment Period: Weeks 1-24
Subjects should receive investigational product (IP) through at least the first
24 calendar weeks unless the subject experiences unacceptable toxicities,
withdraws consent, or meets any other discontinuation criteria.
MDS Disease Assessment: Week 25 Visit
The Week 25 Visit should be completed 24 calendar weeks after the date of first
dose, regardless of dose delays. Because central laboratory results from bone
marrow and peripheral blood samples are required as part of the MDS Disease
Assessment, a 14-day window is allowed for the Week 25 Visit.
In order for subjects to remain on double-blind treatment beyond the first 24
calendar weeks, the following criteria must be confirmed upon the completion of
the MDS Disease Assessment by the investigator at the Week 25 Visit:
* Evidence of clinical benefit (eg, decrease in RBC transfusion requirement
compared to baseline requirement or hemoglobin increase compared to baseline)
AND
* Absence of progression to acute myeloid leukemia (AML) or high/very high risk
category MDS per IPSS-R based on morphological assessment of bone marrow and
peripheral blood and cytogenetics.
Based on the outcome of the Week 25 Visit MDS Disease Assessment, subjects will
either be discontinued from treatment with IP and enter the Posttreatment
Follow-up Period or continue double-blind treatment with IP in the Extension
Phase of the Treatment Period.
Refer to Protocol Section 6.2.2 for additional details related to
procedures/assessments.
Extension Phase of the Treatment Period: After Week 25 Visit
Subjects who meet the criteria for remaining on double-blind treatment with IP
in the Extension Phase may continue dosing on Day 1 of each 21-day treatment
cycle until the subject experiences unacceptable toxicities, progression to AML
or high/very high risk MDS per IPSS-R or withdraws consent, or meets any other
discontinuation criteria.
MDS Disease Assessment will be repeated by the investigator at Extension Cycle
8, Day 1 and Day 1 of every eighth Extension cycle thereafter (ie, Extension
Cycle 8, 16, 24+, or every 24 weeks in the event of dose delays) until the
subject is discontinued from IP.
Posttreatment Follow-up Period:
All subjects discontinued from protocol-prescribed therapy for any reason will
be followed for adverse event (AE)/serious adverse event (SAE) reporting for a
period of 42 days after the last dose of IP, as well as for SAEs made known to
the Investigator at any time thereafter that are suspected of being related to
IP.
Continuation of monitoring for progression to AML will occur in the
Posttreatment Follow-up Period along with collection of information related to
subsequent MDS therapies, and overall survival for at least 3 years from the
date of last dose of IP unless the subject withdraws consent from the study,
dies, or is lost to follow-up.
Intervention
Eligible subjects will be randomized at a 2:1 ratio to either:
* Experimental Arm - Luspatercept (ACE-536): Starting dose of 1.0 mg/kg
subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day
treatment cycle)
OR
* Control Arm: Placebo (volume equivalent to experimental arm) subcutaneous
injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle).
Study burden and risks
Burden
- Subcutaneous administration of study medication: every cycle
- ECG: 3x
- Blood sampling: every visit
- Bone Marrow Biopsy/Aspirate: +/- 4 x
- Questionnaires: every other cycle
See also Protocol section 5 (Table of Events) of Protocol d.d. 25Sep2015
Luspatercept may cause the following very common side effects:
- Increases in red blood cell count, hemoglobin and hematocrit is expected with
treatment of ACE-536. This may result in an increase in blood pressure. Both
your red blood cell count and your blood pressure will be monitored by your
study doctor during the study. You may have a delay or reduction in study drug
dosing to minimize this risk.
- The study drug will be given as an injection (shot) under the skin. As with
any solution given this way, there may be redness, bruising, or slight swelling
where the injection was given. In the healthy volunteers, bleeding and /or a
darker colored skin mark at the injection site (injection site hemorrhage,
injection site macule) was commonly reported. You may feel some pain when the
needle is inserted or afterwards. Although it does not happen often, it is
possible that people you could faint or get an infection at the place the
needle is inserted.
Very common (> 10 % ) reported side effects in subjects:
Infection of the nose and throat (viral upper respiratory tract infection),
Headache, Fatigue, Cough, Diarrhea, Shortness of breath (dyspnoea), Increased
blood pressure (hypertension), Joint pain (arthralgia), Swelling of the arms
and legs (peripheral edema), Lung infection (pneumonia), Infection of the
bladder (urinary tract infection).
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Listed location countries
Age
Inclusion criteria
1. Subject is * 18 years of age the time of signing the informed consent form
(ICF).
2. Subject must understand and voluntarily sign an ICF prior to any
study-related assessments/procedures being conducted.
3. Documented diagnosis of MDS according to WHO 2008 classification (Appendix
B) that meets IPSS-R classification (Greenberg, 2012; Appendix D) of very low,
low, or intermediate risk disease, and: Ring sideroblast * 15% of erythroid
precursors in bone marrow, and < 5% blasts in bone marrow
4. Refractory or intolerant to, or ineligible for, prior ESA treatment, as
defined by any one of the following:
- Refractory to prior ESA treatment - documentation of non-response or
response that is no longer maintained to prior ESA-containing regimen, either
as single agent or combination (eg, with G-CSF); ESA regimen must have been
either:
a) recombinant human erythropoietin (rHu EPO) * 40,000 IU/wk for at least 8
doses or equivalent;
OR
b) darbepoetin alpha * 500 *g Q3W for at least 4 doses or equivalent;
- Intolerant to prior ESA treatment - documentation of discontinuation of prior
ESAcontaining regimen, either as single agent or combination (eg, with G-CSF),
at any time after introduction due to intolerance or an adverse event
- ESA ineligible - Low chance of response to ESA based on endogenous serum
erythropoietin level > 200 U/L for subjects not previously treated with ESAs
5. If previously treated with ESAs or granulocyte colony-stimulating factor
(G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), both agents
must have been discontinued * 4 weeks prior to date of randomization.
6. 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 randomization.
- no consecutive 56-day period that was RBC transfusion-free during the 16
weeks immediately preceding randomization
7. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2
8. Females of childbearing potential (FCBP) 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:
a) 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). She must agree to ongoing pregnancy testing during the course
of the study, and after end of study treatment.
b) If sexually active, agree to use, and be able to comply with, 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 practice true abstinence* (which must be reviewed prior
to each IP administration or on a monthly basis [eg, in the event of dose
delays]) 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 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. Prior therapy with disease modifying agents or experimental agents for
underlying MDS disease
2. Previously treated with either luspatercept (ACE-536) or sotatercept
(ACE-011)
3. MDS associated with del 5q cytogenetic abnormality
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
6. Prior allogeneic or autologous stem cell transplant
7. Known history of diagnosis of AML
8. Use of any of the following within 5 weeks prior to randomization:
- Anticancer cytotoxic chemotherapeutic agent or treatment
- Corticosteroid, except for subjects on a stable or decreasing dose for * 1
week prior to randomization 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 randomization
- Other RBC hematopoietic growth factors (eg, Interleukin-3)
9. Uncontrolled hypertension, defined as repeated elevations of diastolic blood
pressure (DBP) * 100 mmHg despite adequate treatment.
10. Absolute neutrophil count (ANC) < 500/*L (0.5 x 10^9/L)
11. Platelet count < 50,000/*L (50 x 10^9/L)
12. Estimated glomerular filtration rate (eGFR) or creatinine clearance < 40
mL/min
13. Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase
(AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase
(ALT/SGPT) * 3.0 x upper limit of normal (ULN)
14. 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).
- Subjects are excluded if there is evidence of autoimmune hemolytic anemia
manifested as a corrected reticulocyte count of > 2% with either a positive
Coombs* test or over 50% indirect bilirubin
15. Prior history of malignancies, other than MDS, unless the subject has been
free of the disease 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)
16. Major surgery within 8 weeks prior to randomization. Subjects must have
completely recovered from any previous surgery prior to randomization
17. History of stroke, deep venous thrombosis (DVT), pulmonary or arterial
embolism within 6 months prior to randomization
18. Pregnant or breastfeeding females
19. Myocardial infarction, uncontrolled angina, uncontrolled heart failure, or
uncontrolled cardiac arrhythmia as determined by the investigator within 6
months prior to randomization
20. Uncontrolled systemic fungal, bacterial, or viral infection (defined as
ongoing signs/symptoms related to the infection without improvement despite
appropriate antibiotics, antiviral therapy, and/or other treatment), known
Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV) infection,
and/or Hepatitis C (HCV) infection.
21. History of severe allergic or anaphylactic reactions or hypersensitivity to
recombinant proteins or excipients in the investigational product.
22. Subject has any significant medical condition, laboratory abnormality, or
psychiatric illness that would prevent the subject from participating in the
study.
23. Subject has any condition including the presence of laboratory
abnormalities, which places the subject at unacceptable risk if he/she were to
participate in the study.
24. Subject has any condition or concomitant medication that confounds the
ability to interpret data from the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-003454-41-NL |
| ClinicalTrials.gov | NCT02631070 |
| CCMO | NL55975.028.16 |