Primary objective* To determine the efficacy, defined as overall response rate (ORR; >= partial response (PR)), of 9 cycles of ixazomib, daratumumab and low dose dexamethasoneSecondary objectives* To determine the tolerability, defined as…
ID
Source
Brief title
Condition
- Plasma cell neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Overall response rate (at least PR) on induction therapy.
Secondary outcome
• Discontinuation rate due to toxicity of maintenance therapy with Ixazomib and
daratumumab.
• Safety and toxicity as defined by type, frequency and severity of adverse
events as defined by the National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE), version 4
• Complete Response and Very Good Partial Response rate after 9 induction
cycles and on protocol
• Immunophenotypic Complete Response after 9 induction cycles and on protocol
• Minimal Residual Disease negative flow cytometry of bone marrow on protocol
• PET-CT negative, defined as disappearance of increased tracer uptake at
entry, or decrease to less than mediastinal blood pool SUV or decrease to less
than surrounding normal tissue
• Progression free survival, defined as time from registration to progression
or death from any cause, whichever comes first
• Overall survival, measured from date of registration to death from any cause.
Patients alive at the date last contact, will be censored
• Time to (maximum) response
• Improvement in response from the start of maintenance therapy
• Discontinuation rate due to toxicity of 9 cycles of Ixazomib, daratumumab and
low-dose dexamethasone.
• Time to next treatment
• PFS2, defined as the time from registration to the date of objective disease
progression or death from any cause after second line therapy
• Quality of life as defined by the EORTC QLQ-C30, QLQ-MY20 and EQ-5D-5L
definitions
Exploratory endpoints
• Geriatric assessments (both questionnaires and physical assessments),
senescence markers in fibroblasts obtained by skin biopsy and sarcopenia as
determined by CT-scan that reflect biological age and predict feasibility and
the toxicity of treatment
• Identification of immunological and molecular prognostic markers that predict
feasibility and the toxicity of treatment
• Identification of biomarkers for response
Background summary
Data from both clinical trials and population based registries indicate that
elderly patients also benefit from novel therapies. The challenge is to
identify a relatively non-toxic strategy for unfit and frail patient enabling
effective treatment with novel agents. With the availability of the oral
proteasome inhibitor ixazomib, that does not induce grade 3 and 4 neuropathy,
the way is paved for oral proteasome-inhibitor based therapy, also in the
maintenance setting. The implementation of daratumumab in novel treatment
regimens for unfit and frail patients is obvious, being a novel class of drugs
with promising efficacy and mild and mainly infusion-related side effects,
which was manageable also in the elderly patients. Therefore, the efficacy and
feasibility of 9 cycles of ixazomib, daratumumab and low dose dexamethasone
followed by ixazomib and daratumumab maintenance until progression for a
maximum of 2 years will be investigated in unfit and frail newly diagnosed
multiple myeloma (NDMM) patients
Study objective
Primary objective
* To determine the efficacy, defined as overall response rate (ORR; >= partial
response (PR)), of 9 cycles of ixazomib, daratumumab and low
dose dexamethasone
Secondary objectives
* To determine the tolerability, defined as discontinuation rate due to
treatment related toxicity, of 9 cycles of ixazomib, daratumumab and low
dose dexamethasone
* To determine adverse events of CTCAE grade 2-4
* To determine complete response (CR) and very good partial response (VGPR)
after 9 induction cycles
* To determine complete response (CR) and very good partial response (VGPR) on
protocol
* To determine immunophenotypic complete response after 9 induction cycles
* To determine immunophenotypic complete response on protocol
* To determine the flow Minimal Residual Disease negative complete remission
* To determine the imaging plus flow MRD negative complete remission
* To determine progression free survival (PFS)
* To determine overall survival (OS)
* To determine efficacy of therapy determined as time to response and the time
to best response
* To determine the effect of maintenance therapy with ixazomib and daratumumab
in terms of improvement of response during maintenance
* To determine the tolerability of maintenance therapy, defined as
discontinuation rate due to treatment related toxicity of ixazomib and
daratumumab
* To determine time to next treatment
* To determine PFS2
* To evaluate quality of life (QoL)
Exploratory objectives
* To identify geriatric assessment outcomes that predict feasibility and the
toxicity of treatment
* To identify biological markers; sarcopenia and senescence markers, that
reflect biological age and that predict feasibility and the toxicity of
treatment
* To identify immunological and molecular prognostic markers that predict
outcome and toxicity
* To identify biomarkers for response
* To investigate the prognostic value of Minimal Residual Disease
* To investigate the prognostic value of FDG-PET-CT at diagnostics and in
follow up
Study design
Investigator-initiated, multicenter, non-randomized, open label, phase II
clinical trial
Intervention
Induction therapy with 9 cycles of ixazomib, daratumumab and dexamethasone,
followed by maintenance therapy with ixazomib and daratumumab until progression
for a maximum period of two years
Study burden and risks
The benefit will be that unfit and frail patients can be treated with an oral
proteasome inhibitor ixazomib instead of the currently available subcutaneous
proteasome inhibitor bortezomib, with considerably less polyneuropathy.
Bortezomib is currently standard of care. Secondly, patients will be treated
with daratumumab, a novel class drug, with pronounced effectivity in heavily
pretreated patients with limited toxicity only. In this heavily pretreated
patients not only response rate was high; 39%, in addition 65% of patients who
responded were still in remission after one year. Moreover, the data of the
addition of daratumumab to bortezomib/dexamethasone, after 1 to 3 prior lines
of therapy resulted in a 61% reduction of progression, which has not been
reached with other novel drugs. Therefore, this regimen is expected to result
in efficacy. Secondly, less side effects as compared to the standard of care
*Melphalan, Bortezomib, Prednisone - MPV* is expected, which we recently
investigated in the HOVON 123 study. Preliminary data showed that 49% of frail
patients and 29% of unfit patients had to discontinue therapy because of
toxicity.
The burden will be that 1. Patients will receive intranvenous daratumumab
instead of a combined oral/sc regimen of MPV or an oral regimen with
lenalidomide/dexamethasone. 2. Following induction therapy, maintenance therapy
will be given until progression for a maximum of two years. Although a benefit
with respect to prolongation of PFS is expected, the extent is currently
unknown. Patients may suffer from side effects, although these are generally
mild with ixazomib and daratumumab and also the combination of a proteasome
inhibitor with daratumamab was found to be safe with limited additional side
effects to a proteasome inhibitor only.
There are additional procedures required as compared to standard care because
of biological assessment of frailty, such as a CT scan to determine the
presence of sarcopenia, geriatric assessments and a skin biopsy for senescence
markers. Patients have to participate in QoL studies, and in case of complete
response undergo a PET-CT scan and an additional BM aspirate
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Listed location countries
Age
Inclusion criteria
• Previously untreated patients with a confirmed diagnosis of multiple myeloma
according to IMWG criteria;
• Measurable disease according to the IMWG criteria;
• Patients who are either unfit or frail according to the IMWG criteria;
• Age 18 years or older.
• Absolute neutrophil count (ANC) >= 1.0 x109/l and platelet count >= 75x109/l.
Platelet transfusions and G-CSF to help patients meet eligibility criteria are
not allowed;
• Written informed consent, including consent for additional bone marrow and
blood sampling and a skin biopsy
• Patient is capable of giving informed consent.
• Negative pregnancy test at study entry (only for women of childbearing
potential);
• Male patients and female patients of childbearing potential must agree to use
adequate contraception from the time of signing the informed consent form
through 90 days after the last dose of study drug.
Exclusion criteria
• Non-secretory MM;
• Plasma cell leukemia;
• Systemic Amyloid Light-chain (AL) amyloidosis;
• Central nervous system involvement;
• Known allergy to any of the study medications, their analogues, or excipients
in the various formulations of any agent;
• Neuropathy, grade 1 with pain or grade >= 2;
• Severe cardiac dysfunction (NYHA classification III-IV);
• Screening 12-lead ECG showing a baseline QT interval as corrected by
Fridericia*s formula (QTcF) >470 msec;
• Chronic obstructive pulmonary disease (COPD) with an Forced Expiratory Volume
in 1 second (FEV1) < 50% of predicted normal. ;
• Moderate or severe persistent asthma within the past 2 years or currently
uncontrolled asthma of any classification..
• Significant hepatic dysfunction (total bilirubin >= 3 x ULN or transaminases >=
5 times normal level) except patients with Gilbert*s syndrome as defined by >
80% unconjugated bilirubin
• Creatinine clearance <20 ml/min or Calculated Glomerular Filtration Rate
[ml/min/1.73m2] <20;
• Patients with active, uncontrolled infections;
• Patients known to be Human Immunodeficiency Virus (HIV)-positive;
• Patients seropositive for hepatitis B, defined by a positive test for
hepatitis B surface antigen [HBsAg]. Patients with resolved infection (ie,
subjects who are HBsAg negative but positive for antibodies to hepatitis B core
antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs])
must be screened using real-time polymerase chain reaction (PCR) measurement of
hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be
excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV
vaccination (anti-HBs positivity as the only serologic marker) AND a known
history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
• Patients seropositive for hepatitis C (except in the setting of a sustained
virologic response [SVR], defined as aviremia at least 12 weeks after
completion of antiviral therapy).
• Known GI disease or GI procedure that could interfere with the oral
absorption or tolerance of ixazomib including difficulty swallowing;
• Active malignancy other than MM requiring treatment or a malignancy that has
been treated with chemotherapy currently affecting bone marrow capacity;
• Systemic treatment, within 14 days before the first dose of ixazomib, with
strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine,
phenytoin, phenobarbital), or use of St. John*s wort;
• Pre-treatment with cytostatic drug, immunomodulatory drugs (IMiDs) or
proteasome inhibitors. Radiotherapy (provided the involved field is small and
there are >= 7 days between radiotherapy and administration of ixazomib) or a
short course of steroids (e.g. 4 day treatment of dexamethasone 40 mg/day or
equivalent) are allowed;
• Major surgery within 14 days before enrollment;
• Any serious medical or psychiatric illness, or familial, sociological and
geographical condition potentially hampering compliance with the study protocol
and follow-up schedule;
• Participation in other clinical trials, including those with other
investigational agents not included in this trial, within 30 days of the start
of this trial and throughout the duration of this trial;
• Female patients who are lactating.
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 | EUCTR2016-002600-90-NL |
| CCMO | NL59458.029.16 |
| Other | NTR (TC = 6297) |