| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed multiple myeloma. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Newly diagnosed multiple myeloma. |
|
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the stringent Complete Response (sCR) rate by the end of two cycles of induction treatment, defined as the proportion of patients who have achieved sCR, according to International Myeloma Working Group (IMWG) criteria (Kumar et al. 2016), by the end of two cycles of induction treatment. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate CR and sCR rate following induction, ASCT and maintenance treatment.
• To evaluate overall response rate and rate of very good partial response (VGPR) or better following induction, ASCT, and maintenance treatment.
• To evaluate best response during induction.
• To evaluate duration of and time to sCR and time to CR.
• To evaluate time to VGPR or better.
• To evaluate time to partial response (PR) or better.
• To assess negative minimal residual disease (MRD) rate following induction, ASCT and maintenance treatment.
• To evaluate clinical outcomes including:
o Time to progression (TTP)
o Progression-free survival (PFS)
o Overall survival (OS)
o Duration of response (DOR)
• To assess the safety and tolerability of Isa-RVD.
• To evaluate stem cell yield after mobilization.
Note:
Please refer to trial protocol for exploratory objectives and correlative objectives. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Previously diagnosed with MM based on standard IMWG criteria and currently requires treatment.
2. Provided voluntary written informed consent before performance of any study-related procedures not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
3. Age ≤ 75 years, with patients over the age of 70 requiring PI approval.
4. Measurable disease defined as at least one of the following:
• Serum M protein ≥ 0.5 g/dL (≥5 g/L)
• Urine M protein ≥200 mg/24 hours
• Serum free light chain (FLC) assay: Involved FLC assay ≥10 mg/dL (≥100 mg/L) and an abnormal Serum FLC ratio (<0.26 or >1.65)
5. Screening Laboratory evaluations within the following parameters:
• Absolute neutrophil count (ANC) ≥ 1,000 cells/dL (1.0 x 10^9/L) (Growth factors cannot be used within 14 days before first drug administration)
• Platelet count ≥ 75,000 cells/dL (75 x 10^9/L) if < 50% BM nucleated cells are plasma cells, ≥ 30,000 cells/dL if ≥ 50% of BM nucleated cells are plasma cells. (without transfusions required during the 3 days prior to the screening hematologic test)
• Total Bilirubin ≤ 2.0 X upper limit of normal (ULN) (except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
• AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN
• Hemoglobin ≥ 8g/dL
• Calculated creatinine clearance ≥ 30 mL/min
6. ECOG performance status ≤ 2.
7. Participant agrees to be registered into the mandatory Risk Management Programme for Lenalidomide and be willing and able to comply with the requirements of this programme.
8. Ability to understand and the willingness to sign a written informed consent document
9. Participant is considered eligible for ASCT by the treating physician. |
|
| E.4 | Principal exclusion criteria |
1. Prior therapy for multiple myeloma
2. Diagnosed or treated for another malignancy within 3 years prior to enrolment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in-situ malignancy, or low risk prostate cancer after curative therapy.
3. Central nervous system involvement.
4. Peripheral neuropathy ≥ Grade 3, or Grade 2 with pain on clinical examination during the screening period.
5. Any medical or psychiatric illness that in the Investigator’s opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study.
6. Concurrent uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, Grade 3 thromboembolic event or myocardial infarction within the past 6 months.
7. Prior major surgical procedure or radiation therapy within 4 weeks of initiation of therapy (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of therapy).
8. Daily requirement for corticosteroids (equivalent to > 10 mg/day prednisone for more than 7 days (except for inhalation corticosteroids).
9. Concurrent symptomatic amyloidosis or plasma cell leukaemia
10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)
11. Known active infection requiring parenteral or oral anti-infective treatment within 14 days of start of therapy.
12. Active hepatitis B or hepatitis C viral infection
13. Pregnant or breastfeeding female or female who intends to become pregnant during the participation in the study. Females of childbearing potential (FCBP) unwilling to prevent pregnancy by the use of a highly effective method of contraception for ≥4 weeks before the start of study treatment, during treatment (including dose interruptions), and up to 5 months following the last dose of study treatment and/or who are unwilling or unable to be tested for pregnancy before study treatment initiation (2 negative tests), weekly during 1st month
of treatment and then prior each treatment cycle administration or every 2 weeks in case or irregular menstrual cycles up to 5 months following the last dose of study treatment.
14. Male participants who disagree to practice true abstinence or disagree to use a condom during sexual contact with a pregnant female or a FCBP while participating in the study during dose interruptions and at least 3 months following study treatment discontinuation, even if has undergone a successful vasectomy.
Note 1: a FCBP is a female who: 1) has achieved menarche at some time point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).
Note 2: True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
15. Receiving any other investigational agents
16. Hypersensitivity to steroids, or H2 blockers that would prohibit further treatment with these agents.
17. Inability to tolerate thromboprophylaxis
18. Hypersensitivity (or contraindication) to dexamethasone, sucrose histidine (as base and hydrochloride salt), boron, mannitol, and polysorbate 80, or to any of the components of the study therapy.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Stringent Complete Response (sCR) rate by the end of two cycles of induction treatment, defined as the proportion of patients who have achieved sCR, according to International Myeloma Working Group (IMWG) criteria (Kumar et al. 2016), by the end of two cycles of induction treatment.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis will be performed on the response data after two cycles for all evaluable patients in the Full Analysis Set.
All efficacy analyses will be performed for the Full Analysis Set, which is the set of all eligible patients who start study medication and have some post-baseline assessment of efficacy.
Safety analyses will be performed for the Safety Data Set, which is the set of all patients excluding those who received no study medication.
After the study has been completed, the data cleaned, and the database closed out, the statistical analysis will be performed by Cancer Trials Ireland according to the Statistical Analysis Plan. |
|
| E.5.2 | Secondary end point(s) |
• CR and sCR rate following induction, ASCT and maintenance treatment.
• Overall response rate and rate of very good partial response (VGPR) or better following induction, ASCT, and maintenance treatment.
• Best response during induction
• Duration of and time to sCR and time to CR.
• Time to VGPR or better.
• Time to partial response (PR) or better.
• Negative minimal residual disease (MRD) rate following inductions, ASCT and maintenance treatment.
• Clinical outcomes including:
o Time to progression (TTP).
o Progression-free survival (PFS).
o Overall survival (OS).
o Duration of response (DOR).
• Safety and tolerability of Isa-RVD.
• Stem cell yield after mobilization. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary analysis will be performed on the response data after two cycles for all evaluable patients in the Full Analysis Set.
All efficacy analyses will be performed for the Full Analysis Set, which is the set of all eligible patients who start study medication and have some post-baseline assessment of efficacy.
Safety analyses will be performed for the Safety Data Set, which is the set of all patients excluding those who received no study medication.
After the study has been completed, the data cleaned, and the database closed out, the statistical analysis will be performed by Cancer Trials Ireland according to the Statistical Analysis Plan. |
|
| 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 | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
|
| 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 end of the study is defined as when all enrolled patients have completed treatment and follow up until either study withdrawal, death or for a maximum period of 3.5 years after the last patient enrolled. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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