Primary objective:To compare the effect of ixa+dex versus pom+dex on progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (RRMM) who have received at least 2 prior lines of therapy, including lenalidomide and…
ID
Source
Brief title
Condition
- Plasma cell neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Progression-free survival (PFS), defined as the time from randomization to the
first occurrence of confirmed progressive disease (PD), as evaluated by the
investigator, according to International Myeloma Working Group (IMWG) criteria,
or death from any cause, whichever occurs first.
Secondary outcome
The secondary endpoints are OS, measured as the time from randomization to
death from any cause; ORR (defined as complete response, very good partial
response (VGPR), or PR [per IMWG criteria]); duration of response; time to
response; time to progression (TTP); health-related QOL as measured by the
physical domain of the EORTC QLQ-C30; health-related QOL as measured by other
domains of the EORTC QLQ-C30, by the EORTC QLQ-MY20, and by the EQ-5D-5L;
health care utilization as measured by the number and duration of medical
encounters; and safety/tolerability.
After the primary endpoint of PFS has been met, all central efficacy and
investigator assessments of response for protocol purposes will be
discontinued; patients will be followed for survival and the appropriate data
collected.
Background summary
MM is a clonal disease of plasma cells that is characterized by the
accumulation of plasma cells in the bone marrow (and other organs) and
sometimes results in bone marrow failure, bone destruction, hypercalcemia,
anemia, infection, and renal failure. It is the second most common
hematological malignancy, constituting approximately 1% of all reported
neoplasms and approximately 13% of hematologic cancers worldwide [9]. The
incidence of MM is expected to increase over the next decade, which highlights
the need for more effective MM therapies. Moreover, to a greater extent in the
future than now, MM will be a disease that primarily affects older persons
(those aged 64 to 84 years), who generally have a worse prognosis
MM remains an incurable disease for most patients and development of RRMM is an
inevitable reality for almost all patients. While there is no widely accepted
standard of care for RRMM, patients typically receive several lines of therapy
with combinations of drugs over the course of their disease.
Ixazomib in combination with LenDex has been approved by the US FDA and other
agencies for the treatment of patients with MM who have received at least 1
prior therapy [3,4]. The exploration of ixazomib for other therapeutic areas is
ongoing. To date, activity in MM has been seen with single-agent ixazomib and
with ixazomib combined with established therapies. In addition, single-agent
activity has been observed in relapsed amyloidosis and indolent non-Hodgkin
lymphoma.
Overall, ixazomib shows signs of antitumor activity, as evidenced by at least
50% reduction in disease burden in some patients, including patients that have
been heavily pretreated as well as those with newly diagnosed MM, and prolongs
stabilization of the underlying disease in other patients across all ongoing
studies. Though additional data continue to be obtained to further establish
the clinical benefit of this drug, the emerging data support the continued
development of ixazomib for the treatment of patients with hematologic and
solid tumor malignancies as well as ixazomib as part of doublet therapy for
RRMM
Study objective
Primary objective:
To compare the effect of ixa+dex versus pom+dex on progression-free survival
(PFS) in patients with relapsed and/or refractory multiple myeloma (RRMM) who
have received at least 2 prior lines of therapy, including lenalidomide and a
proteasome inhibitor, and are refractory to lenalidomide but not refractory to
proteasome inhibitors.
Secondary objectives:
• To compare overall survival (OS) in patients treated with ixa+dex versus
pom+dex.
• To compare duration of response, overall response rate (ORR), time to
response, and time to progression with ixa+dex versus pom+dex.
• To obtain health-related QOL data related to physical functioning of patients
treated with ixa+dex versus pom+dex.
• To assess health-related QOL by additional function and symptom domains of
the EORTC QLQ-C30 instrument and by the EORTC QLQ-MY20
and 5-level classification system of the EuroQol 5-Dimensional Health
Questionnaire (EQ-5D-5L) instruments.
• To evaluate health care utilization by patients receiving ixa+dex versus
those receiving pom+dex.
• To collect plasma concentration-time data for ixazomib to contribute to
population pharmacokinetic characterization of ixazomib and to conduct
exposure-response analyses for patients receiving ixa+dex.
• To compare safety/tolerability of ixa+dex to that of pom+dex.
Study design
Study C16029 is a randomized, open-label, phase 2 study. The 3 stratification
factors are International Staging System stage (I or II vs III at study entry),
prior lines of therapy (2 vs 3 or more), and age (<65 vs >=65 years). Patients
will be randomized in a 3:2 ratio to receive ixazomib+dexamethasone (ixa+dex;
Arm A) or pomalidomide+dexamethasone (pom+dex; Arm B), until first confirmed
progressive disease (PD) or unacceptable toxicities.
Intervention
Arm A
Ixazomib will be administered at a 4 mg starting dose, with escalation to 5.5
mg at Cycle 2 for patients who tolerate the 4 mg dose in Cycle 1 (specifically,
patients who do not experience any new Grade 1 peripheral neuropathy with pain
or other ixazomib-related >=Grade 2 nonhematologic or >=Grade 3 neutropenia or
thrombocytopenia in Cycle 1). Patients who have had any dose reductions, holds,
or delays because of ixazomib toxicities will not dose escalate. Dose
escalation beyond the start of Cycle 2 is permitted only when dose escalation
was inadvertently missed at Cycle 2.
Ixazomib will be administered orally on Days 1, 8, and 15 of each 28-day cycle,
combined with dexamethasone 20 mg (or 10 mg if patient is aged >=75 years)
orally on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until PD. In
cases where only 4 mg tablets for dexamethasone are available (eg, 4 mg
dexamethasone is the only dosage available), the following dexamethasone
schedule is recommended for patients aged >=75 years: 12 mg dexamethasone will
be given on Days 1, 8, 15, and 22 of every 28-day cycle; and 8 mg dexamethasone
will be given on Days 2, 9, 16, and 23 of every 28-day cycle.
Arm B
Pomalidomide will be administered at 4 mg orally on Days 1 to 21 of each 28-day
cycle, combined with dexamethasone 40 mg (or 20 mg if patient is aged >=75
years) orally on Days 1, 8, 15, and 22 of each 28-day cycle until PD.
Study burden and risks
The more commonly occurring discomforts and risks are listed below:
• Low platelet count which may increase the chance of bleeding
• Skin rash which may range from some red areas, small flat spots, or small
raised bumps that may or may not be itchy in a few areas or all over the body
• Feeling tired or weak
• Nausea
• Vomiting
• Diarrhea
• Numbness or tingling or pain feelings in hands and feet
• Constipation
• 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
STUDY PROCEDURAL RISKS
In addition to the risks of all study medications, routine needle sticks for
blood samples may cause pain, bruising and rarely, infection at the site where
blood is drawn.
Possible side effects of bone marrow aspirate/biopsy include bleeding,
infection, bruising, discomfort and/or pain at the aspirate site and possible
side effects from the local anesthetic (pain or bruising at the injection site).
The X-ray, skeletal x-ray, MRI or CT scans associated with this study are
typically the same number of times as if you were not in a clinical trial.
There are some side-effects or risks associated with these scans. Often
subjects who have an MRI or CT scan experience feelings of claustrophobia (fear
of being confined in any space). Also, the risk of radiation exposure from
these scans is uncertain and has not been definitively determined.
Refer for an overview of the other Ixazomib side effects to section 8.8.1 of
the Protocol
Refer for an overview of the Pomalidomide side effects to section 8.8.2 of the
Protocol
Benefit:
It can increase the amount of time the patients live without worsening of the
patients disease
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Age
Inclusion criteria
• Adult patients (aged >=18 years) who have been diagnosed with multiple myeloma
(MM) according to standard criteria.
• All patients must have had a relapse or PD after having received 2 or more
prior lines of systemic therapy. (A line of therapy is defined as 1 or more
cycles of a planned treatment program; this may consist of 1 or more planned
cycles of single-agent therapy or combination therapy, as well as a sequence of
treatments administered in a planned manner. For example, a planned treatment
approach of induction therapy followed by autologous stem-cell transplantation,
followed by maintenance is considered 1 line of therapy. Typically each line of
therapy is separated by PD.)
• All patients must be refractory to lenalidomide, defined as having received
at least 2 consecutive cycles of lenalidomide as a single agent or within a
lenalidomide-containing regimen and having had PD during treatment with or
within 60 days after the last dose of lenalidomide. The starting dose of
lenalidomide should have been 25 mg (or as low as 10 mg in the case of renal
function impairment or other safety concern), and the final dose should have
been a minimum of 10 mg.
• All patients must have received at least 2 consecutive cycles of a
bortezomib- or carfilzomib-containing regimen, and either:
- Achieved at least a partial response (PR) and did not have PD during
treatment with or within 60 days after the last dose of bortezomib or
carfilzomib,
OR
- Had bortezomib and/or carfilzomib intolerance (defined as discontinuation
because of drug-related adverse events (AEs) before completion of the planned
treatment course) without PD upon the start of the next regimen.
• All patients must have an Eastern Cooperative Oncology Group score of 0 to 2.
• All patients must have measurable disease defined by serum M-protein >= 1 g/dL
(>=10 g/L) or urine M-protein >=200 mg/24 hours and must have documented MM
isotype by immunofixation (central laboratory).
Exclusion criteria
Patients meeting any of the following exclusion criteria are not to be enrolled
in the study:
- Patients must not have received prior ixazomib or pomalidomide and must not
have been a participant in a previous ixazomib clinical study.
- Prior allogenic bone marrow transplantation in any prior line of therapy or
prior autologous SCT in the last prior line of therapy*unless the autologous
SCT was
performed a year or more before disease progression.
- Female patients who are lactating and breastfeeding or have a positive serum
pregnancy test during the Screening period.
- Any serious medical or psychiatric illness that could, in the investigator's
opinion, potentially interfere with the completion of treatment according to
this protocol,
such as life-threatening illness unrelated to cancer.
- Diagnosed with or treated for another malignancy within 2 years before
randomization, or previously diagnosed with another malignancy and
have any evidence of residual, persistent, or recurrent disease. Patients with
nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if
they have
undergone complete resection.
- Diagnosis of smoldering MM (see Appendix D), Waldenström's macroglobulinemia,
POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and
skin changes) syndrome, plasma cell leukemia, primary amyloidosis,
myelodysplastic syndrome, or myeloproliferative syndrome.
- Known allergy to any of the study medications or their analogues, or
excipients in the various formulations.
- Peripheral neuropathy Grade 1 with pain or Grade 2 or higher peripheral
neuropathy of any cause on clinical examination during the Screening period.
- Treatment with any investigational products or with chimeric or fully human
monoclonal antibodies within 30 days before randomization, systemic anticancer
therapy or radiotherapy within 14 days before randomization (Note: "spot"
radiation for areas of pain is permitted), and major surgery within 14 days
before
randomization.
- Known gastrointestinal disease or gastrointestinal procedure that could
interfere with the oral absorption or tolerance of study therapy, including
difficulty swallowing.
- Serious infection requiring parenteral antibiotic therapy or any other
serious infection within 14 days before randomization.
- Central nervous system involvement with MM (by clinical symptoms and signs).
- Ongoing or active systemic infection, known human immunodeficiency virus-RNA
positive, known hepatitis B surface antigen seropositive, or known hepatitis C
virus-RNA positive.
Note: Patients who have positive hepatitis B core antibody can be enrolled but
must have hepatitis B virus-DNA negative. Patients who have positive hepatitis C
antibody can be enrolled but must have hepatitis C virus-RNA negative.
- Systemic treatment with strong cytochrome P-450 3A inducers (rifampin,
rifapentine,rifabutin, carbamazepine, phenytoin, phenobarbital) or use of St.
John's
wort within 14 days before randomization.
- Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
- History of severe cutaneous reactions, including hypersensitivity reactions
such as Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), in the context
of treatment with lenalidomide or thalidomide (see Section 8.7 of protocol
for more information).
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 | EUCTR2016-004742-28-NL |
| CCMO | NL62127.028.17 |