| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed and/or Refractory Multiple Myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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 |
|
| E.2.2 | Secondary objectives of the trial |
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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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). |
|
| E.4 | Principal 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). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
During study treatment: weekly (Days 1 and 15) for 2 cycles and then once a cycle (on Day 1) for the remainder of the treatment period, until PD or discontinuation. In addition, in Arm B only, on Day 22 of Cycles 1 and 2, hematologic laboratory assessments will be performed.
During follow-up period: very 4 weeks until the occurrence of PD (if treatment discontinued for any reason other than PD) or every 12 weeks until death or termination of the study by the sponsor |
|
| E.5.2 | Secondary end point(s) |
The key secondary endpoint is OS, measured as the time from randomization to death from any cause.
Other secondary endpoints are:
- ORR, defined as PR, very good partial response (VGPR), or complete response (CR), as evaluated by the investigator according to IMWG criteria.
- Duration of response, defined as the time from the first documentation of PR or better to first documentation of PD.
- Time to response, defined as the time from randomization to the first documentation of PR or better.
- TTP, defined as the time from randomization to first documentation of PD.
- Health-related QOL as measured by the physical functioning 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.
- HU as measured by the number and duration of medical encounters.
The safety endpoint is the safety/tolerability of ixa+dex versus pom+dex. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| every 12 weeks until death or termination of the study by the sponsor |
|
| 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 | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 51 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Israel |
| Russian Federation |
| Turkey |
| United States |
| Belgium |
| Czechia |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Spain |
| Sweden |
| United Kingdom |
|
| 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
|
| The study will be considered complete after the study analysis (for PFS and all secondary endpoints) has been completed or the study has been terminated by the sponsor. The estimated time frame for study completion is approximately 28 months. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 20 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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