Study ObjectivesPrimary:• To determine the effect of ixazomib maintenance therapy on progression-free survival (PFS), compared to placebo, in patients with NDMM who have had a response (complete response [CR], very good partial response [VGPR], or…
ID
Source
Brief title
Condition
- Plasma cell neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is:
• PFS, defined as the time from the date of randomization to the date of first
documentation of disease progression, as evaluated by an independent review
committee (IRC) using IMWG (International Myeloma Working Group) criteria, or
death due to any cause, whichever occurs first
Secondary outcome
The key secondary endpoint is:
• OS, measured as the time from the date of randomization to the date of death
Background summary
Despite more therapeutic options, MM remains incurable, and there is a need for
new and better agents. When patients relapse after their initial therapy, they
demonstrate variable responses to subsequent treatments with decreasing
likelihood and duration of response (DOR). Patients become refractory to
approved therapies and ultimately are left with no alternative treatment
options. In an effort to expand the therapeutic armamentarium against MM with
agents that target the proteasome, Takeda Development Center Americas (Takeda)
has developed ixazomib (MLN9708), a small molecule 20S proteasome inhibitor.
Maintenance therapy is a long-duration, low-intensity therapy intended to
prolong the duration of a patient*s response to primary antineoplastic
treatment. Requirements for a successful maintenance therapy include good
long-term tolerability and adherence (low discontinuation rates due to toxicity
and convenience of administration), demonstration of clinical benefit either in
prolonging survival or improving quality of life without shortening survival,
and a favorable benefit:risk ratio. Although there is emerging evidence for
the clinical benefit of maintenance therapy following SCT, a positive
benefit:risk balance is yet to be established in existing therapies, no therapy
has been approved for this indication, and a true standard of care (SoC) has
not been adopted
Maintenance therapy has not yet been proven to be a superior treatment strategy
compared to the current paradigm of a post-ASCT treatment-free interval
followed by salvage therapy at relapse. Together with the lack of a universal
maintenance SoC and an evidence-based comparator with a demonstrated survival
benefit for maintenance therapy post-ASCT, a strong justification is provided
to conclude that a phase 3, placebo-controlled trial is an appropriate approach
for determining the efficacy of single-agent ixazomib maintenance therapy.
Study objective
Study Objectives
Primary:
• To determine the effect of ixazomib maintenance therapy on progression-free
survival (PFS), compared to placebo, in patients with NDMM who have had a
response (complete response [CR], very good partial response [VGPR], or partial
response [PR]) to induction therapy followed by high-dose therapy (HDT) and
ASCT
Key Secondary:
• To determine the effect of ixazomib maintenance therapy on overall survival
(OS) compared to placebo
Study design
This is a randomized, placebo-controlled, double-blind, phase 3 study in
patients with NDMM
Intervention
Patients will receive blinded study drug (ixazomib capsules or matching placebo
capsules) orally on Days 1, 8, and 15 of every 28 day cycle, for a duration of
approximately 24 months (26 cycles, to the nearest complete cycle), or until
documented disease progression (on the basis of the IMWG criteria) or
intolerable toxicities, whichever comes first. The initial dose of study drug
will be 3 mg of ixazomib or matching placebo, which will be increased to 4 mg
on Cycle 5, Day 1 if tolerated during the first 4 cycles.
Study burden and risks
Ixazomib can cause the following discomforts and risks. However, we might not
know all the risks of ixazomib at this moment. It is possible that ixazomib
can cause additional discomforts and risks other than those listed below:
- Swelling or fluid buildup in the arms or legs
- Flu-like symptoms and other upper respiratory tract infections
- Arthralgia or joint pain
- Lung infections including pneumonia or pneumonitis
- Herpes Zoster that can sometimes cause local pain that may last after
recovery from the skin rash and does not go away for some time
In earlier studies with ixazomib the risks listed below were reported.
However, we don*t know if they were caused by Ixazomib or by the patient*s
disease(s), other medications, patient related other factors or a combination
of these factors:
- Feeling short of breath or difficulty breathing
- Feeling tired or week
- Cough
- Fever
- Headache
- Feeling dizzy or dizziness
- Lowered red cells or anemia which may make you feel tired
- Lowered white blood cells called neutrophils that may increase your risk of
infection and may be associated with fever
- Constipation
- Distortion of the sense of taste i.e. an abnormal or impaired sense of taste
- Trouble falling asleep, staying asleep or both
Acute febrile neutrophilic dermatosis (Sweet*s syndrome) and pemphigus
vulgaris, have been reported in MLN9708 studies when given in combination with
other drugs. These rashes are disorders of the immune system, which differ from
regular skin rashes and are generally more severe.
Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenia purpura
(TTP) and hemolytic uremic syndrome (HUS), are rare, serious blood disorders
that cause low levels of platelets and red blood cells, and result in blood
clots in small vessels. Symptoms may include fatigue, fever, bruising, nose
bleeds, and decreased urination. These disorders can occasionally be fatal.
TMA, TTP, and HUS have been seen rarely (<0.1%) in patients treated with
ixazomib.
Overdose has been reported in patients taking ixazomib. Reports of accidental
overdose have been associated with risks such as nausea, lung infections
including aspiration pneumonia, multiple organ failure, and death. It is
important to take only one dose of ixazomib at a time, and only at the
prescribed interval.
Hayden Avenue, Lexington 95
Lexington, MA 02421
US
Hayden Avenue, Lexington 95
Lexington, MA 02421
US
Listed location countries
Age
Inclusion criteria
1. Adult male or female patients 18 years or older with a confirmed diagnosis
of symptomatic multiple myeloma according to standard criteria.
2. Documented results available for cytogenetics/ fluorescence in situ
hybridization (FISH) obtained at any time before transplant and for ISS staging
at the time of diagnosis.
3. Underwent standard of care induction therapy (induction therapy must include
PI and/or IMiD-based regimens as primary therapy for multiple myeloma),
followed by a single ASCT with a high-dose melphalan (200 mg/m2) conditioning
regimen, within 12 months of diagnosis. Vincristine, Adriamycin (doxorubicin),
and dexamethasone (VAD) is not an acceptable induction therapy for this trial.
4. Started screening no earlier than 75 days after transplant, completed
screening within 15 days, and randomized no later than 115 days after
transplant.
5. Patient must have not received post-ASCT consolidation therapy.
6. Documented response to ASCT (PR, VGPR, CR/stringent complete response [sCR])
according to IMWG criteria.
7. ECOG performance status of 0 to 2.
8. Female patients who:
* If they are of childbearing potential, agree to practice 2 effective methods
of contraception, at the same time, from the time of signing the informed
consent through 90 days after the last dose of study drug, AND
* Must also adhere to the guidelines of any treatment-specific pregnancy
prevention program, if applicable, OR
* Agree to practice true abstinence, when this is in line with the preferred
and usual lifestyle of the subject. (Periodic abstinence [eg, calendar,
ovulation, symptothermal, postovulation methods] and withdrawal are not
acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
* Agree to practice effective barrier contraception during the entire study
treatment period and through 90 days after the last dose of study drug, AND
* Must also adhere to the guidelines of any treatment-specific pregnancy
prevention program, if applicable, OR
* Agree to practice true abstinence, when this is in line with the preferred
and usual lifestyle of the subject. (Periodic abstinence [eg, calendar,
ovulation, symptothermal, postovulation methods for the female partner] and
withdrawal are not acceptable methods of contraception.)
9. Voluntary written consent must be given before performance of any
study-related procedure not part of standard medical care, with the
understanding that consent may be withdrawn by the patient at any time without
prejudice to future medical care.
10. Suitable venous access for the study-required blood sampling.
11. Patient is willing and able to adhere to the study visit schedule and other
protocol requirements.
12. Patients must meet the following clinical laboratory criteria at study
entry:
* Absolute neutrophil count (ANC) >= 1,000/mm3 and platelet count >= 75,000/mm3.
Platelet transfusions to help patients meet eligibility criteria are not
allowed within 3 days before randomization.
* Total bilirubin <= 1.5 x the upper limit of the normal range (ULN).
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
* 3 <= ULN.
* Calculated creatinine clearance >= 30 mL/min.
Exclusion criteria
1. Multiple myeloma that relapsed following primary therapy or is not
responsive to primary therapy. For this study, stable disease following ASCT
will be considered nonresponsive to primary therapy.
2. Double (tandem) ASCT.
3. Radiotherapy within 14 days before the first dose of study drug.
4. Diagnosed or treated for another malignancy within 5 years before
randomization or previously diagnosed with another malignancy with evidence of
residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of
any type are not excluded if they have undergone complete resection.
5. Female patients who are lactating and breastfeeding or have a positive serum
pregnancy test during the Screening period.
6. Major surgery within 14 days before randomization.
7. Central nervous system involvement.
8. Infection requiring IV antibiotic therapy or other serious infection within
14 days before randomization.
9. Diagnosis of Waldenstrom*s macroglobulinemia, POEMS (polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes)
syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome,
or myeloproliferative syndrome.
10. Evidence of current uncontrolled cardiovascular conditions, including
uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic
congestive heart failure, unstable angina, or myocardial infarction within the
past 6 months.
11. Systemic treatment with strong inhibitors of CYP3A (rifampin, rifapentine,
rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or
St. John*s wort within 14 days before randomization in the study.
12. Active hepatitis B or C virus infection, or known human immunodeficiency
virus (HIV) positive.
13. Comorbid systemic illnesses or other severe concurrent disease which, in
the judgment of the investigator, would make the patient inappropriate for
entry into this study or interfere significantly with the proper assessment of
safety and toxicity of the prescribed regimens (eg, PN that is Grade 1 with
pain or Grade 2 or higher of any cause).
14. Psychiatric illness/social situation that would limit compliance with study
requirements.
15. Known allergy to any of the study medications, their analogues, or
excipients in the various formulations of any agent.
16. Inability to swallow oral medication, inability or unwillingness to comply
with the drug administration requirements, or gastrointestinal (GI) procedure
that could interfere with the oral absorption or tolerance of treatment.
17. Treatment with any investigational products within 60 days before the first
dose of the study drug regimen.
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 | EUCTR2013-002076-41-NL |
| ClinicalTrials.gov | NCT02181413 |
| CCMO | NL47795.029.14 |