This is a multicenter, Phase Ib/II study that combines Luspatercept and Lenalidomide in
people with lower-risk, non-del(5q) MDS for whom ESAs were ineffective or who are unlikely to
respond to ESAs, with a baseline serum EPO level >200.
Lenalidomide, also known as Revlimid® is an FDA approved drug for some types of lymphoma and
for those who have a different type of MDS than what is being looked at in this study.
Lenalidomide is considered investigational (experimental) in this study because it is being
used in a different setting than the FDA approval. Lenalidomide blocks the development of
abnormal cells, prevents the growth of blood vessels within tumors, and also stimulates
specialized cells of the immune system to attack the abnormal cells.
Luspatercept, also known as Reblozyl, has been recently approved by the FDA for those with
lower-risk MDS. Luspatercept works by helping red blood cells grow and mature.
There are 2 parts to this study: part 1 is referred to as phase I and part 2 is referred to
as phase II.
- The goal of phase I is to find the safest dosing schedule of Luspatercept in combination
with Lenalidomide
- The goal of phase II is to use the safest dosing schedule (found in phase I) to assess
the independence a patient can have from receiving red blood cell transfusions.
Inclusion Criteria:
- Participant must understand and voluntarily sign an ICF prior to any study related
assessments/procedures being conducted.
- Documented diagnosis of MDS according to WHO/FAB classification that meets IPSS-R
classification (Greenberg, 2012; Appendix D) of very low, low, or intermediate risk
disease
- 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that is no longer maintained to prior ESA-containing regimen, either as single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:
- recombinant human erythropoietin (rHu EPO) ≥ 40,000 IU/wk for at least 8
doses or equivalent; OR
- darbepoetin alpha ≥ 200-500 μg Q1-3W for at least 4 doses or equivalent;
- Intolerant to prior ESA treatment - documentation of discontinuation of prior
ESA-containing regimen, either as single agent or combination (eg, with GCSF), 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
- 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.
- 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.
- Hemoglobin levels at the time of or within 7 days prior to administration of a
RBC transfusion must have been ≤ 10.0 g/dL for the transfusion to be counted
towards meeting eligibility criteria. Red blood cell transfusions administered
when Hgb 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 randomization
- Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2
- 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:
- 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.
- 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.
- Male subjects must:
--Agree to use a condom, defined as a male latex condom or nonlatex 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.
- Subject is willing and able to adhere to the study visit schedule and other protocol
requirements.
Exclusion Criteria:
- Prior therapy with Lenalidomide.
- Previously treated with either luspatercept (ACE-536) or sotatercept (ACE011)
- MDS associated with del 5q cytogenetic abnormality
- Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies,
or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding
--iron deficiency to be determined by serum ferritin ≤ 15 μg/L and additional testing
if clinically indicated (eg, calculated transferrin saturation [iron/total iron
binding capacity ≤ 20%] or bone marrow aspirate stain for iron).
- Prior allogeneic stem cell transplant
- Known history of diagnosis of AML
- Use of any of the following within 4 weeks prior to randomization:
- Anticancer cytotoxic chemotherapeutic agent or treatment
- Other RBC hematopoietic growth factors (eg, Interleukin-3)
- 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 randomization or within 5 weeks, whichever is longer
is excluded.
- Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure
(DBP) ≥ 100 mmHg despite adequate treatment.
- 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 ≥ 1 year. However, subjects with the following history/concurrent
conditions involving in situ cancer (or similar) 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)
- Major surgery within 4 weeks prior to randomization. Subjects must have completely
recovered from any previous surgery prior to randomization
- History of stroke, deep venous thrombosis (DVT), pulmonary or arterial embolism within
6 months prior to randomization
- Pregnant or breastfeeding females
- Subject has any significant medical condition, laboratory abnormality, psychiatric
illness, or is considered vulnerable by local regulations (eg, imprisoned or
institutionalized) that would prevent the subject from participating in the study.
