| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To determine the efficacy, defined as overall response rate (ORR), of 9 cycles of ixazomib, daratumumab and low dose dexamethasone
(overall response will be defined as (stringent) complete response ((s)CR), very good partial (VGPR) response and partial response (PR))
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| E.2.2 | Secondary objectives of the trial |
To determine:
• the tolerability of 9 cycles of ixazomib, daratumumab and low dose dexamethasone
• AE of CTCAE grade 2-4
• CR and VGPR after 9 induction cycles
• CR and VGPR on protocol
• immunophenotypic CR after 9 induction cycles
• immunophenotypic CR on protocol
• the flow MRD negative CR
• the imaging plus flow MRD CR
• PFS
• OS
• efficacy of therapy
• the effect and the tolerability of maintenance therapy with ixazomib and daratumumab
• time to next treatment
• PFS2
• quality of life (QoL)
Exploratory :
To identify
♦ geriatric assessment outcomes that predict feasibility and the toxicity
♦ biomarkers; sarcopenia and senescence markers, that reflect biological age and predict feasibility and the toxicity
♦ immunological and molecular prognostic markers that predict outcome and toxicity
♦ biomarkers for response
♦ To investigate the prognostic value of MRD
♦ To investigate the prognostic value of FDG-PET-CT at diagnostics and in FU |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Previously untreated patients with a confirmed diagnosis of multiple myeloma according to IMWG criteria;
• Measurable disease according to the IMWG criteria ;
(If plasmacytoma is the only measurable parameter, the patient is not allowed to be included in the study, because of difficult response evaluation).
• 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 (with the understanding that consent may be withdrawn by the patient at any time without consequences to future medical care).
• 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 (see section 9.4 for details).
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| E.4 | Principal 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. Note that FEV1 testing is required for patients suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal;
• Moderate or severe persistent asthma within the past 2 years or currently uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study);
• 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Overall response rate (at least PR) on induction therapy. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Evaluation will take place when the data of all patients of induction therapy and evaluation are available |
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| E.5.2 | Secondary end point(s) |
• 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
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluation will take place when the data of all patients until 5 years after
registration are available |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Geriatric evaluation and Quality of Life |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 43 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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