Compare efficacy and safety ofpomalidomide versus placebo in reversing RBC-transfusiondependence in subjects with MPN-associated myelofibrosis and RBC-transfusion-dependence. Investigate variables correlated with RBC-transfusion-independence and/or…
ID
Source
Brief title
Condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Proportion of subjects achieving >= 84 consecutive days of
RBC-transfusionindependence..
Secondary outcome
* Duration ofRBC-transfusion-independence
* Time to becoming RBC-transfusion-independent
* Survival
* Frequency of AEs
* Healthcare resource utilization
* EQ-5D Health Outcome Assessment
* FACT-An Quality ofLife (QoL) Assessment
Pre-study subject-, disease- and therapy-related variables correlated with
response
and response-duration.
Background summary
Patients that take part in this study suffer from myeloproliferative neoplasm
(MPN)*associated myelofibrosis with severe anemia. Myeloproliferative neoplasm
(MPN)-associated myelofibrosis is characterized by ineffective erythropoiesis,
megakaryocyte hyperplasia, and reactive bone marrow fibrosis with increased
micro-vessel density and extramedullary hematopoiesis.
Severe anemia unresponsive to therapy can be fatal. Infection-risk is increased
because of decreased numbers of and/or dysfunctional granulocytes. There may be
evidence of bleeding from decreased numbers of and/or dysfunctional platelets.
Extra-medullary hematopoiesis typical of MPN associated myelofibrosis results
in spleen and liver enlargement (splenomegaly and hepatomegaly) in about 20% of
affected persons at diagnosis resulting in early satiety and substantial weight
loss. MPN-associated myelofibrosis is a progressive disorder such that many of
the signs and symptoms discussed above will develop with time even in persons
in whom they are absent at diagnosis. For example, although anemia is present
at diagnosis in about 30% of affected persons, it develops at some point in the
disease in most if not all affected persons.
Two types oftherapies are used in myelofibrosis: (1) targeted towards the
cancer clone; and (2)those directed towards signs and symptoms of the disease.
No anti-cancer drug is FDA approved for therapy of myelofibrosis. Therapy of
anemia in MPN-associated myelofibrosis is problematic. Pomalidomide is a novel
drug in the class of immunomodulatory drugs known as IMiDs compounds. However,
pomalidomide had fewer adverse events and is more active in modulating levels
of inflammatory-cytokines and growthfactors. Data from experimental models and
a Celgene-sponsored trial indicate pomalidomide increased erythropoiesis in
mice with sickle cell disease and humans with MPN-associated myelofibrosis.
Study objective
Compare efficacy and safety ofpomalidomide versus placebo in reversing
RBC-transfusiondependence in subjects with MPN-associated myelofibrosis and
RBC-transfusion-dependence. Investigate variables correlated with
RBC-transfusion-independence and/or duration of RBC transfusion independence
and to explore the pharmacokinetics of pomalidomide in subjects with MPN
associated myelofibrosis with RBC transfusion-dependence, and to explore the
pharmacokinetics of pomalidomide in subjects with MPN associated myelofibrosis
with RBC transfusion-dependence.
Study design
There will be 3 study phases: screening, treatment and post-treatment
follow-up. The treatment phase is comprised of a blinded interval for all
subjects and an open-label interval for subjects who had been randomized to
receive pomalidomide and remain transfusion-independent at the completion of
the blinded treatment interval. Treatment phase begins on the day of
randomization.
Subjects will provide informed consent prior to undergoing any study-related
procedures. The screening period may be up to 28 days during which the site
must receive approval from the sponsor before randomizing the subject. Once
approval is received to randomize the subject, an
effort should be made to randomize the subject as soon as possible and before
the next RBCtransfusion is needed. Subjects should be randomized within 28 days
of signing informed consent. In the event that the planned randomization
exceeds 28 days post informed consent signature, written approval to proceed
should be obtained from the Medical Monitor to ensure eligibility criteria
continue to be satisfied. Hemoglobin (Hgb) must not exceed 130 gIL on the day
the subject is randomized. Subjects will be randomized 2:1 in a blinded manner
to receive pomalidomide capsule, 0.5 mg/day or matching placebo capsule /day.
Subjects should take their first dose on the day they are randomized.
During treatment, subjects with disease-progression (Tefferi 2006a, Section
4.1.1.4), unacceptable toxicities, or other criteria for treatment
discontinuation (Section 11.1) at any time will discontinue treatment unless
there is evidence of clinical benefit. Otherwise, subjects will remain on
blinded treatment until at least Day 168. At the Day 169 visit subjects with a
RBC-transfusion-ffee period less than or equal to 28 days and/or without
demonstrating clinical benefit must discontinue from blinded treatment.
Otherwise, subjects may remain on blinded treatment until meeting criteria for
treatment discontinuation (Section 11.1), or until completion of the blinded
treatment interval ofthe study. The blinded treatment interval of the study
will be completed 141-225 days after the last subject is randomized or earlier
if the last subject(s) discontinue treatment prior to 141-225 days post
randomization.
Subjects who were randomized to receive pomalidomide and remain RBC
transfusion-independent or continue to experience clinical benefit at the
completion of the blinded treatment interval may continue toreceive
pomalidomide in the open-label treatment interval of this study. Subjects who
discontinue from treatment for any reason will be followed via telephone
contact by the site for collection of data on survival, cause(s) of death,
disease progression (with or
without transformation to blastic phase) and post-treatment therapy(ies) and
new cancers every 4 months for the first two years after treatment
discontinuation and every 6 months thereafter for a minimum of 5 years
post-randomization, or until death, lost to follow-up or withdrawal of consent
from the study. Withdrawal of consent from treatment is separate from
withdrawal of consent from the study.
Intervention
Subjects must have had bone marrow histology within 6 months before signing
informed consent and site must have assurance that slides meeting defined
criteria for central histological review are available and will be submitted to
the central reviewer. Cytogenetic analysis is not
mandatory, but if a cytogenetic analysis was performed, the cytogenetics report
must be submitted to the sponsor during screening. Otherwise a bone marrow
aspirate and biopsy for histology (and cytogenetics if feasible) should be done
during the screening-phase.
Study burden and risks
The patient needs to visit the hospital as described at E2. The following study
procedures will be done as described in the schedule on page 30 of the protocol:
- bone marrow biopsy or asprate (screening)
- ECG (screening)
- Physical examination
- Pregnancy test
- Blood sample
- Completion of questionaires (Health Care Resource Utilization, EQ-5D en
FACT-An)
- RBC transfusion assessment
Risks of the study are described in appendix 3 of the informed consent.
Morris Avenue 86
Summit, NJ 07901
US
Morris Avenue 86
Summit, NJ 07901
US
Listed location countries
Age
Inclusion criteria
1. Age *18 years of age at the time of signing the informed consent document.
2. MPN-associated myelofibrosis (primary myelofibrosis (PMF), post-polycythemia vera
myelofibrosis (post-PV MF) and/or post-essential thrombocythemia myelofibrosis (post-ET MF)
3. RBC-transfusion-dependence:
- Average RBC-transfusion frequency of *2 U/28 days over at least the 84 days
immediately prior to randomization. There must be no interval >42 days without
*1 RBC-transfusion.
- Only RBC-transfusions given when the hemoglobin *90 g/L^3 are scored in
determining eligibility.
- RBC-transfusions due to bleeding are not scored in determining eligibility
- RBC-transfusions due to chemotherapy-induced anemia are not scored in
determining eligibility.
4. Hemoglobin *130 g/L at randomization.
5. Bone marrow slides that meet defined criteria for central histological review will be
submitted to a central reviewer.
6. A blood cell or bone marrow allo-transplant should not be an appropriate therapy at this time.
7. Erythropoietin should not be an appropriate therapy at this time.
8. Androgenic steroids should not be an appropriate therapy at this time.
9. Treatment with systemic corticosteroids is permitted for non-hematological conditions providing the subject
is receiving a stable or decreasing dose for *84 days immediately prior to randomization and are receiving a
constant dose equivalent to *10 mg prednisone for the 28 days immediately prior to randomization.
10. Eastern Cooperative Oncology Group (ECOG) performance score *2.
11. Females of childbearing potential (FCBP) must undergo pregnancy testing based on the frequency outlined in
protocol Appendix 18.1 and pregnancy results must be negative.
12. Unless practicing complete abstinence from heterosexual intercourse, sexually active FCBP must agree to use
adequate contraceptive methods as specified in protocol Appendix 18.1.
13. Males (including those who have had a vasectomy) must use barrier contraception (condoms) when engaging
in sexual activity with FCBP as specified in Appendix 18.1.
14. Males must agree not to donate semen or sperm during the duration specified in Appendix 18.1.
15. All subjects must:
- Understand that the investigational product could have a potential teratogenic risk.
- Agree to abstain from donating blood while taking investigational product and
following discontinuation of investigational product
- Agree not to share study medication with another person.
- Be counseled about pregnancy precautions and risks of fetal exposure.
16. Understand and voluntarily sign an informed consent document before any study related assessments/
procedures are conducted.
17. Able to adhere to the study visit schedule and other protocol requirements.
Exclusion criteria
1. Prior bone marrow or blood cell transplant.
2. Use of drugs to treat MPN-associated myelofibrosis *30 days pre-randomization(42 days for hydroxyurea) or
ongoing adverse events from previous treatment.
3. Use of an erythropoietin or androgenic steroids *84 days pre- randomization.
4. Anemia from other proved causes other than MPN-associated myelofibrosis.
5. Pregnant or lactating females.
6. More than 10% blasts by bone marrow examination or more than 10% blasts in blood in censecutive measurements spanning at least 8 weeks.
7. Prior history of malignancies, other than the disease being studied unless the subject has been free of the malignancy for *5 years with the following exceptions:
-Basal cell carcinoma of the skin,
-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 TNM [tumor, nodes, metastasis] clinical staging system)
8. Proved human immunodeficiency virus-1 (HIV-1) infection
9. Active hepatitis B virus (HBV) or active hepatitis C Virus (HCV) infection.
10. Prior therapy with pomalidomide.
11. Any of the following adverse reactions to prior therapy with thalidomide or lenalidomide:
- Prior *grade-2 National Cancer Institute (NCI) Common Terminology Criteria
for Adverse Events (CTCAE) allergic reaction to thalidomide and/or lenalidomide
- Prior desquamating (blistering) rash while taking thalidomide and/or lenalidomide
- Hypersensitivity to thalidomide and/ or lenalidomide
12. Any of the following laboratory abnormalities:
-Neutrophils <0.5x10e9/L
- Platelets <25 x 10e9/L
- Estimated glomerular filtration rate <30 mL/min/1.73m²
- Aspartate aminotransferase (AST),and alanine transaminase (ALT) >3.0 x upper limit of normal (ULN)
- Total bilirubin *4 x ULN;
- Uncontrolled hyperthyroidism or hypothyroidism.
13. Deep venous thrombosis (DVT) or pulmonary embolus (PE) <6 months pre-randomization.
14. Heart disease *6 months pre-randomization including:
- New York Heart Association class >II, congestive heart failure
- Unstable angina
- Myocardial infarction within 6 months
15. Any significant medical condition, laboratory abnormality or psychiatric illness that
would prevent the subject from participating in the study.
16. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable
risk if he/she were to participate in the study.
17. Any condition 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 | EUCTR2010-018965-42-NL |
| CCMO | NL33360.029.10 |