| 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 |
| The primary objective of this study is to determine the overall response rate (ORR) with the combination of ixazomib, daratumumab and dexamethasone: an ORR inferior to 60% is considered not promising and an 80% as important. |
|
| E.2.2 | Secondary objectives of the trial |
• The hematologic and non-hematologic toxicity profile of the combination
• Duration of response (DOR)
• Time to progression (TTP)
• Progression-free survival (PFS)
• Overall survival (OS, for the duration of the study)
• Time to next therapy (TNT)
• MRD negativity using NGFC
• Serum bone markers levels (NTX, CTX, bALP, RANKL, OPG, Dkk-1 and SOST) and serum angiogenic cytokines levels (angiogenin, VEGF, angiopoietin-1 and -2) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males and females at least 18 years of age.
2. Voluntary written informed consent before performance of any study-related procedure.
3. Relapsed patients with measurable disease parameters according to the IMWG:
• IgG multiple myeloma: Serum M protein level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours, or
• IgA, IgD, IgE, IgM multiple myeloma: Serum M-protein level ≥0.5 g/dL or urine M-protein level ≥200 mg/24 hours; or
• Light chain multiple myeloma, for patients without measurable disease in the serum or urine: Serum immunoglobulin FLC ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio.
4. Patients who have received one prior regimen for MM based on lenalidomide (induction followed by any planned high dose therapy or consolidation or maintenance would be considered as one regimen, see Attachment 1 for the definition of one line of therapy).
5. Patients must have documented evidence of PD based on the investigator’s determination of response as defined by the modified IMWG criteria.
6. Willingness and ability to participate in study procedures.
7. Patient has a Karnofsky Performance Status ≥70.
8. For patients experiencing toxicities resulting from previous therapy, the toxicities must be resolved or stabilized to ≤Grade 1.
9. Patients with adequate bone marrow reserve, as evidenced by:
a. Absolute neutrophil count (ANC) ≥1.0x109/L.
b. Platelet count ≥75x109/L for patients in whom <50% of bone marrow nucleated cells are plasma cells and ≥50x109/L for patients in whom ≥50% of bone marrow nucleated cells are plasma cells (transfusions are not permitted to reach this level).
10. All of the following results during Screening:
a. Hemoglobin level ≥8 g/dL (≥4.65 mmol/L) (transfusions are not permitted to reach this level).
b. Creatinine clearance ≥30 mL/min by Cockcroft-Gault formula.
c. Alanine aminotransferase (ALT) level ≤2.5 times the upper limit of normal (ULN).
d. Aspartate aminotransferase (AST) level ≤2.5 x ULN.
e. Total bilirubin level ≤1.5 x ULN, (except for Gilbert Syndrome: direct bilirubin ≤1.5 × ULN).
f. Serum calcium corrected for albumin ≤14.0 mg/dL (≤3.5 mmol/L), or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L). |
|
| E.4 | Principal exclusion criteria |
1. Previous exposure to anti-CD38 antibodies or ixazomib.
2. Systemic treatment with or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort within 14 days before C1D1.
3. Patient has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, prior to C1D1. The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum of 4 days) for palliative treatment before C1D1.
4. Previous allogenic stem cell transplant; or autologous stem cell transplantation (ASCT) within 12 weeks before C1D1.
5. Patient has received radiotherapy within 14 days of C1D1. Urgent localized radiotherapy for Spinal Cord Compression is allowed.
6. History of malignancy (other than MM) within 3 years before C1D1 (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that in the opinion of the investigator, with concurrence with the Sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years).
7. Clinical signs of meningeal involvement of MM.
8. Patient has clinically significant cardiac disease, including: unstable angina or myocardial infarction within 6 months to C1D1, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless patient has a pacemaker, or ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF)>470 mesc.
9. Any of the following:
a. Known active hepatitis A
b. Patient is seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects 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.
c. Known to be 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).
10. Known to be seropositive for human immunodeficiency virus (HIV).
11. Patient has a history of significant neurological, endocrine, gastrointestinal, respiratory, or inflammatory illness or stroke; or COPD requiring >2 hospitalizations in the preceding 12 months from C1D1.
12. Patient has plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard differential) or Waldenström’s macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis.
13. Patient has uncontrolled hypertension or hypertension requiring >2 medications for adequate control within 14 days to C1D1.
14. Patient has uncontrolled diabetes within 14 days to C1D1 or diabetes mellitus with >2 episodes of ketoacidosis in the preceding 12 months from C1D1.
15. Patient has ongoing ≥Grade 2 peripheral neuropathy.
16. Patient had ≥Grade 3 rash during prior therapy.
17. Patient has had major surgery within 14 days prior to C1D1, or has not fully recovered from an earlier surgery, or has surgery planned during the time the patient is expected to participate in the study or within 2 weeks after the last dose of study drug administration. Note: patients with planned surgical procedures to be conducted under local anesthesia may participate. Kyphoplasty or vertebroplasty are not considered major surgery.
18. Pregnant or nursing women.
19. Any other clinically significant medical disease or condition that, in the Investigator’s opinion, may interfere with protocol adherence
20. 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.
21. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.
22. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
23. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is ORR, which is defined as the percentage of patients that achieve PR or better according to the IMWG criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Evaluation of the toxicity profile of the combination, hematologic and non-hematologic.
• Progression free survival (PFS), which is defined as the duration from C1D1 to either PD, according to the IMWG criteria [3, 40], or death, whichever occurs first. For patients who have not progressed and are alive, data will be censored at the last disease evaluation before the start of any subsequent anti-myeloma therapy. Relapse from CR by positive immunofixation or trace amount of M-protein is not considered to be PD and is not included in the PFS calculation
• Time to disease progression (TTP), defined as the time from C1D1 to the date of first documented evidence of PD, as defined in the IMWG criteria.
• Time to next therapy (TNT) defined as the time, in months, from C1D1 to the date to next anti-neoplastic therapy or death from any cause, whichever comes first. For patients who neither start a new anti-neoplastic therapy nor die, survival time will be censored at the date of their last available follow-up date. For a patient who does not have any post-baseline follow-up assessments and who has not died, survival time will be censored at C1D1.
• Duration of response will be calculated from the date of initial documentation of a response (CR, VGPR or PR) to the date of first documented evidence of PD, as defined in the IMWG criteria. For patients who have not progressed, data will be censored at the last disease evaluation before the start of any subsequent anti-myeloma therapy.
• Overall survival (OS) is measured from C1D1 to the date of the patient’s death. If the patient is alive or the vital status is unknown at the time of the analysis, then the patient’s data will be censored at the date the patient was last known to be alive.
• Minimal residual disease (MRD) negativity rate, defined as the proportion of patients who achieve a negative result of MRD. Patients without MRD assessment will be considered as having MRD-positive results.
• Levels of serum bone markers (NTX, CTX, bALP, RANKL, OPG, Dkk-1 and SOST) and angiogenic cytokines (angiogenin, VEGF, angiopoietin-1 and -2) will be evaluated on C1D1 and then every 3 months until PD. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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