| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| refractory and/or relapsed multiple myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| refractory and/or relapsed multiple myeloma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 progression-free survival in patients with relapsed/refractory multiple myeloma receiving ixazomib in combination with thalidomide and dexamethasone for 8 cycles followed by an ixazomib maintenance phase of a maximum period of 12 months. |
|
| E.2.2 | Secondary objectives of the trial |
To determine overall response rate (ORR) in patients with relapsed/refractory multiple myeloma (rrMM) receiving ixazomib in combination with thalidomide and dexamethasone followed by an ixazomib maintenance phase of a maximum period of 12 months.
To determine Overall Survival (OS) in patients with rrMM receiving ixazomib in combination with thalidomide and dexamethasone followed by an ixazomib maintenance phase of a maximum period of 12 months.
To determine Renal Response in a subgroup of patients with baseline GFR 15-30ml/min
To assess safety and toxicity of this combination regimen
To assess prognostic value of risk factors at diagnosis, including clinical assessments, lab values and cytogenetic abnormalities
To assess change of quality of life (QoL)
To evaluate possible correlations between altered expressions of specifically selected genes and their response to the treatment regimen. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients 18 years or older.
2. 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of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
3. Patients in need of therapy with a diagnosis of relapsed or refractory multiple myeloma who had at least one prior treatment line (induction + autologous SCT + consolidation + maintenance therapy = 1 therapy line)
4. Patients must have measurable disease defined by at least 1 of the following criteria:
• Serum M-protein ≥ 10g/l
• Urine M-protein ≥ 200mg/24h
• Serum free light chain assay: involved serum light chain ≥ 10mg/dl provided that free light chain ration is abnormal
5. Life expectancy > 3 months
6. ECOG ≤ 2
7. Patients must meet the following clinical laboratory criteria:
• Absolute neutrophil count (ANC) ≥ 1.000/mm3 and platelet count ≥ 50.000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.
• Total bilirubin ≤ 2 x ULN
• ALT and AST ≤ 3 x ULN
• GFR ≥ 15ml/min as calculated by Cockroft-Gault equation (see Appendix 13.2)
8. Female patients who:
• Are older than 50 years and postmenopausal for at least 1 year before the screening visit, OR
• Are surgically sterile, OR
• If they are of childbearing potential, agree to practice 2 effective methods of contraception at the same time, from 4 weeks before starting study therapy through 90 days after the last dose of study drug, OR
• Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
• Are informed and understand the possible consequences of the teratogenic potential of thalidomide
• All pregnancy prevention measurements for thalidomide described in the thalidomide prescribing information and thalidomide patient information leaflet need to be respected
9. Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following:
• Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
• Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
• Are informed and understand the possible consequences of the teratogenic potential of thalidomide
• All pregnancy prevention measurements for thalidomide described in the thalidomide prescribing information and thalidomide patient information leaflet need to be respected
10. Disease free of prior malignancies for ≥ 2 years with exception of curatively treated basal cell, squamous cell carcinoma of the skin, or carcinoma “in situ” of the cervix or breast if they have undergone complete resection.
|
|
| E.4 | Principal exclusion criteria |
1. Female patients who are lactating or have a positive serum pregnancy test during the screening period
2. Failure to have fully recovered (i.e., ≤ Grade 1 toxicity) from the reversible effects of prior chemotherapy
3. Previous treatment with ixazomib
4. Previous treatment with bortezomib or thalidomide within the last 3 months prior to baseline visit (cycle 1/day 1)
5. Primary refractory to, or relapsing during, or within ≤ 6 weeks after end of treatment with a proteasome inhibitor and/or thalidomide
6. Previous anti-cancer treatment within the last 21 days prior to baseline visit (cycle 1 / day 1), except corticosteroid therapy (40 - 160mg dexamethasone or corticosteroid dose equivalent per month)
7. Major surgery within 14 days before enrollment
8. Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the ixazomib.
9. Central nervous system involvement
10. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment
11. 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
12. Systemic treatment, within 14 days before the first dose of ixazomib, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort
13. Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive
14. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol
15. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
16. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing
17. Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with basal cell, squamous cell carcinoma of the skin, or carcinoma “in situ” of the cervix or breast with are not excluded if they have undergone complete resection
18. Patient has ≥ Grade 3 peripheral neuropathy or Grade 2 with pain on clinical examination during the screening period
19. Participation in other interventional 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
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| progression free survival (PFS), defined as the time from day 1 of cycle 1 to the date of first documentation of disease progression based on IMWG criteria or death due to any cause, whichever occurs first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 1 of every cycle, EOT, monthly during maintenance period |
|
| E.5.2 | Secondary end point(s) |
- Overall response rates being described as
o CR + VGPR/nCR + PR and
o CR + VGPR/nCR + PR + MR
- Time to first response, time to best response
- Renal Response in a subgroup of patients with baseline GFR 15-30ml/min, defined as follows:
CRrenal = GFR ≥ 60 ml/min
PRrenal = GFR increase >100%, i.e.: from stage V (GFR < 15ml/min) to stage III (GFR 30 – <60 ml/min)
MRrenal = GFR increase >50%, and
from stage V (GFR < 15ml/min) to stage IV (GFR 15 - <30 ml/min) or
from stage IV (GFR 15 - <30ml/min) to stage III (GFR 30 - <60 ml/min)
- Overall Survival (OS), defined as the time from day 1 / cycle 1 to death due to any cause
- Recording of AE´s, SAE´s, ECOG performance status, assessment of clinical laboratory values
- Association of PFS, OS, ORR with risk factors at diagnosis, including clinical assessments, lab values and cytogenetic abnormalities such as translocations t(4;14), t(14;16), ampl1q, del17, del13
- Change of baseline quality of life (QoL) to post-baseline QoL by use of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EORTC QLQ C30 and MY-20 module.
- Association of possible correlations between altered expressions of specifically selected genes including methylation status of key genes (tumor suppressor, oncogenes, DNA repair, cell cycle control and other) and their response to the treatment regimen detected by gene expression profiling and methylation assays obtained at screening.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 1 of every cycle, EOT, monthly during maintenance period (if applicable) |
|
| 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 | No |
| 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 | Yes |
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
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