The primary objective of this study is:* The primary objective of this clinical trial will be to determine the efficacy of MMB compared with ruxolitinib as measured by splenic response rate at Week 24 (SRR24).The secondary objectives of this study…
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Brief title
Condition
- Bone disorders (excl congenital and fractures)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
For the primary efficacy analysis, non-inferiority of MMB will be evaluated by
comparing the SRR24 in the MMB group to 60% of that
in the ruxolitinib group at Week 24 with a 2-sided 0.05 level, using the
Cochran-Mantel-Haenszel approach to adjust for the stratification
factors. If non-inferiority is concluded, then superiority of MMB relative to
ruxolitinib will also be evaluated.
Secondary outcome
Secondary endpoints will be response rate of total symptom score at Week 24,
rate of RBC transfusion through Week 24, rate of RBC
transfusion independence at Week 24, rate of RBC transfusion dependence at Week
24. The primary efficacy hypothesis relating to
splenic response rate must be rejected at the 2-sided 0.05 significance level
before the efficacy hypotheses for these secondary efficacy
endpoints are tested. These 4 secondary endpoints will be tested sequentially
in the order listed, at the 2-sided 0.05 significance level.
If a null hypothesis is not rejected, formal sequential testing will be stopped
and only nominal significance will be cited for the remaining
secondary endpoints. For the first secondary endpoint, response rate in TSS at
Week 24, non-inferiority of MMB will be evaluated by
comparing the response rate in the MMB group to 67% of that in the ruxolitinib
group with a 2-sided 0.05 level, using the CMH approach
to adjust for the stratification factors. Superiority of MMB to ruxolitinib of
the remaining 3 secondary endpoints will be evaluated subsequently.
Efficacy endpoints will be analyzed based on the ITT and PP analysis sets, with
ITT analysis as primary. Categorical variables will be
compared using Cochran-Mantel-Haenszel approach to adjust for the
stratification factors. Continuous endpoints will be assessed using
analysis of covariance (ANCOVA) with baseline values and stratification factors
as covariates. Rate of event occurrences will be
analyzed using negative binomial model. Time-to-event efficacy endpoints will
be assessed using Kaplan-Meier methods and stratified
log-rank tests. Overall survival (OS) will be assessed as a safety endpoint.
Based on the safety analysis set, information regarding IP administration, IP
compliance, and safety variables will be described
and summarized.
Using data from the PK and pharmacodynamic analysis sets, MMB plasma
concentrations and pharmacodynamic markers will also be
described and summarized.
Background summary
See Page 17 of the protocol, section 1.1 Background
Study objective
The primary objective of this study is:
* The primary objective of this clinical trial will be to determine the
efficacy of MMB compared with ruxolitinib as measured by splenic response rate
at Week 24 (SRR24).
The secondary objectives of this study are:
* To determine the effect of MMB compared with ruxolitinib on the improvement
of total symptom score (TSS) at Week 24
* To determine the effect of MMB compared with ruxolitinib on rate of RBC
transfusions through Week 24.
* To determine the effect of MMB compared with ruxolitinib on RBC transfusion
independence rate at Week 24.
* To determine the effect of MMB compared with ruxolitinib on transfusion
dependence rate at Week 24.
Study design
This is a randomized, double-blind, active-controlled study. After the
screening period, this study begins with a 24 week double-blind treatment
phase. Subjects will be randomized on a 1:1 basis to receive MMB or ruxolitinib
as described in protocol Section 5.1. Treatment assignment will be stratified
by the following factors:
* Transfusion dependence (yes or no)
* Platelet count (< 100 x 109/L, * 100 x 109/L and * 200 x 109/L, or >200 x
109/L)
The investigational products (IPs) in this study will be MMB or its matching
placebo (MMB IP) and ruxolitinib or its matching placebo
(ruxolitinib IP). After completion of the double-blind treatment phase,
subjects will be eligible to receive open-label MMB in the open-label
phase.
Intervention
Patients will randomly be assigned to one of the following treatment arms;
* Group A: About 210 patients (50%) will receive momelotinib once daily
together with ruxolitinib placebo twice daily for 24 weeks during the double
blinded treatment phase with the option to receive momelotinib treatment for up
to three and a half years in open-label afterwards.
* Group B: About 210 patients (50%) will receive ruxolitinib twice daily and
momelotinib placebo once daily for 24 weeks during the double blinded treatment
phase with the option to receive momelotinib treatment for up to three and a
half years in open-label afterwards.
Study burden and risks
For a detailed overview, see Main ICF Netherlands - Section 5: 'What risks or
discomforts can be expected?'
POSSIBLE MOMELOTINIB SIDE EFFECTS
In a randomized study of people with myelofibrosis taking momelotinib up to 6
months, the most common adverse (bad or harmful) events in at least 5 out of
100 people were:
* Some patients have reported a feeling of light-headedness and flushing
(reddening of the face), low blood pressure, nausea and headache when they take
the very first dose of momelotinib (7%). This effect typically lasts for
between 30 minutes to 3 hours in most patients and often resolves by the second
day of treatment.
* Infections (36%)
o Low levels of white blood cells can increase the risk of infections, such as
pneumonia, upper respiratory tract infections, urinary tract infections,
infectious colitis (inflammation in your intestine that leads to diarrhea), and
localized infections. Tell your study doctor if you develop symptoms such as
chills, nausea, vomiting, aches, weakness, or fever. If you develop a fever
when your white blood count is low you may need to be hospitalized to receive
treatment.
* Kidney problems (i.e. elevation of uric acid [27%] and creatinine [13%]).
Elevated kidney tests can indicate kidney damage.
* Liver problems (i.e., elevation of liver enzymes [22 to 25%]). Elevated liver
tests can indicate liver damage. Your laboratory values will be monitored
closely.
* Low levels of certain blood cells, such as:
o Platelets (cells that help your blood to clot) leading to an increased risk
of bleeding or bruising. (19%)
o Red blood cells (cells that carry oxygen to all parts of the body) leading to
fatigue, shortness of breath, lightheadedness, an increase in your heart rate
and palpitations. You may also experience headaches and chest pain. (14%)
o Transfusions may be required to counteract the effects of a low platelet
count or low red blood cell counts.
* Diarrhea (18%), nausea (16%), constipation (10%), abdominal pain (10%), and
vomiting (9%).
* Headache (17%)
* Lightheadedness (16%)
* Fatigue (tired feeling) (15%)
* Sensory Neuropathy in the feet and hands (a condition affecting the nerves
supplying the arms and legs). You may experience numbness and tingling in these
areas (10%)
* Low blood pressure (9%)
* Bruising (8%)
* Shortness of breath (8%)
* Cough (8%)
* Arm or leg pain (7%) and joint pain (6%)
* Fever (7%)
* Flushing (6%)
* Weakness (6%)
Other uncommon, but potentially serious or life-threatening events seen in
patients taking momelotinib:
* High blood pressure (4%)
* Heart failure (i.e., the pumping chambers of the heart can*t pump blood
efficiently throughout your body) (<1%).
* Jaundice (yellowing of the skin and eyes) or if you contract viral hepatitis
infection. In patients who have ever been infected with hepatitis B virus,
there is a risk that the virus can flare up during treatment with drugs that
affect your immune system, such as momelotinib. This could lead to liver
failure or even death. You will be tested for viral hepatitis infection before
you are allowed to participate in this study (<1%)
* Adrenal insufficiency. Inability of the adrenal glands (glands located on top
of the kidneys) to produce a normal quantity of hormones (<1%).
* Pleural effusion (build-up of fluid between the layers of tissue that line
the lungs and chest cavity) (<1%).
* Awkward, uncoordinated walking, double vision, and/or confusion (<1%)
Other Possible Momelotinib Side Effects
In studies with animals given momelotinib for 9 months with about twice the
amount of momelotinib in the blood compared to the amount in the human studies,
cataracts were observed. Cataracts were not observed at lower doses. In human
studies, increased rates of cataracts have not been observed; however, you
should tell your Study Doctor if you notice any changes in your vision.
Possibility of interaction with other medications
Momelotinib may affect your body*s reaction to other medicines. In particular,
momelotinib may block the ability of a protein called BCRP to transport other
medicines into and out of cells.
Other drugs may affect your body*s reaction to momelotinib. In particular,
medicines that are called CYP3A inducers could lead to lower blood levels of
momelotinib, and this can decrease the potential benefit to you.
Your study doctor will inform you of any medications that you should not be
taking while you are participating in this study.
POSSIBLE RUXOLITINIB SIDE EFFECTS
The medical problems listed below have been observed in people with
myelofibrosis who have taken ruxolitinib. These are not all of the possible
medical problems seen with ruxolitinib. You will be given a Patient Information
leaflet.
* Low levels of certain blood cells, such as:
o red blood cells (cells that carry oxygen to all parts of the body) leading to
fatigue, shortness of breath, lightheadedness, an increase in your heart rate
and palpitations. You may also experience headaches and chest pain. (82,4%)
o white blood cells (cells that protect you against infection) leading to an
increased risk of infection. If you should develop a fever when your white
blood count is low, you may need to be hospitalized to receive treatment.
(16,6%)
o platelets (cells that help your blood to clot) leading to an increased risk
of bleeding or bruising. (69,8%)
o Transfusions may be required to counteract the effects of a low platelet
count or low red blood cell count.
* Bruising and/or bleeding (32,6%)
* High blood pressure (31,5%)
* Abnormal liver function test results (27,2%)
* High cholesterol (16,9%)
* Dizziness (15,3%)
* Headache (14,0%)
* Constipation (8,2%)
* Weight gain (7,1%)
* Shingles (Herpes Zoster 6,4*)
* Flatulence (5,2%)
* Infections. You may be at risk for developing a serious infection while
taking ruxolitinib. Urinary tract infections, tuberculosis, and higher
hepatitis B viral loads have been reported in patients who are receiving
ruxolitinib
* A rare disease that causes progressive damage of the brain and skin cancer
(non-melanoma) have also been reported in patients who are receiving ruxolitinib
* Tell your study doctor if you develop symptoms such as; chills, nausea,
vomiting, aches, numbness, tingling, weakness, paralysis, fever, painful skin
rash, unusual pale skin, blisters, difficulty walking, confusion, decline in
mental function, or problems with vision.
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Listed location countries
Age
Inclusion criteria
1. Age * 18 years old
2. Palpable splenomegaly at least 5 cm below left costal margin
3. Confirmed diagnosis of PMF or post-PV/ET MF in accordance with the World Health Organization (WHO) or International
Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria (Appendix 3)
4. Requires myelofibrosis therapy, in the opinion of the investigator
5. High risk OR intermediate-2 risk as defined by the International Prognostic Scoring System (IPSS) for Primary Myelofibrosis (Appendix 6); OR intermediate-1 risk as defined by IPSS and
associated with symptomatic splenomegaly, hepatomegaly, anemia (Hgb < 10.0 g/dL), and/or unresponsive to available therapy
6. Acceptable laboratory assessments obtained within 14 days prior to the first dose of IP: Absolute neutrophil count (ANC) > 0.75 x 109/L in the absence of growth factor in the prior 7 days, Platelet count > 50 x 109/L (> 100 x 109/L if AST/SGOT or ALT/SGPT > 2 x ULN) in the absence of platelet transfusion(s) or thrombopoietin mimetics in the prior 7 days, > Peripheral blood blast count < 10%, AST/SGOT and ALT/SGPT * 3 x ULN (* 5 x ULN if liver is
involved by extramedullary hematopoiesis as judged by the investigator or if related to iron chelator therapy that was started within the prior 60 days), Calculated creatinine clearance of * 45 mL/min, Direct bilirubin * 2.0 x ULN
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
8. Life expectancy of > 24 weeks
9. Negative serum pregnancy test for female subjects (unless surgically sterile or greater than 2 years post-menopausal)
10. Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix 5
11. Females who are nursing must agree to discontinue nursing before the first dose of IP
12. Able to understand and willing to sign the informed consent form
Exclusion criteria
1. Prior splenectomy
2. Splenic irradiation within 3 months prior to the first dose of IP
3. Eligible for allogeneic bone marrow or stem cell transplantation
4. Uncontrolled intercurrent illness including, but not limited to:
active uncontrolled infection (subjects receiving outpatient
antibacterial treatments and/or antiviral treatments for infection
that is under control or as infection prophylaxis may be included
in the study); active or chronic bleeding within 4 weeks prior to
the first dose of IP; symptomatic congestive heart failure; unstable
angina pectoris; uncontrolled cardiac arrhythmia; or psychiatric
illness/social situation that would limit compliance with study
requirements as judged by treating physician
5. QTc interval > 450 msec, unless attributed to bundle branch block
6. History of a concurrent or second malignancy except for
adequately treated local basal cell or squamous cell carcinoma of
the skin, cervical carcinoma in situ, superficial bladder cancer,
asymptomatic prostate cancer without known metastatic disease
and with no requirement for therapy or requiring only hormonal
therapy and with normal prostate-specific antigen for * 1 year
prior to randomization, adequately treated Stage 1 or 2 cancer
currently in complete remission, or any other cancer that has been
in complete remission for * 5 years
7. Criterion Removed
8. Known positive status for human immunodeficiency virus (HIV)
9. Chronic active or acute viral hepatitis A, B, or C infection (testing
required for hepatitis B and C), or hepatitis B or C carrier
10. Prior use of a JAK1 or JAK2 inhibitor
11. Use of strong CYP3A4 inhibitors or strong CYP3A4 inducers or dual inhibitors of CYP3A4 and CYP2C9 within 1 week prior to the first dose of IP
12. Use of chemotherapy, immunomodulating therapy, biologic
therapy, radiation therapy, or investigational therapy within
4 weeks of the first dose of IP
13. Changes to dose of iron chelator therapy within 14 days of the
first dose of IP
14. Unresolved non-hematologic toxicities from prior therapies that
are > CTCAE Grade 1
15. Presence of peripheral neuropathy * CTCAE Grade 2
16. Unwilling or unable to undergo a MRI or CT Scan per
requirements in Section 6.2.9.2
17. Known hypersensitivity to the IPs, the metabolites, or formulation
excipients
Design
Recruitment
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 | EUCTR2013-002707-33-NL |
| ClinicalTrials.gov | NCT01969838 |
| CCMO | NL46619.091.14 |