| 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 |
| Type of cancer of the white blood cells |
|
| 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 | 17.0 |
| 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 |
Phase 1:
-To determine the safety, MTD, and RP2D of once weekly ixazomib on Days 1, 8, and 15 of a 28-day cycle when added to SOC MP on Days 1 through 4 of each cycle
-To determine the safety, MTD, and RP2D once weekly ixazomib on Days 1, 8, 15, 22, and 29 of a 42-day cycle when added to SOC MP on Days 1 through 4 of each cycle
-To determine the safety, MTD, and RP2D once weekly ixazomib on Days 1, 8, 22, and 29 of a 42-day cycle when added to SOC MP on Days 1 through 4 of each cycle
Phase 2:
To determine CR + VGPR during the induction therapy period following ixazomib administration once weekly on Days 1, 8, and 15 of a 28-day cycle when added to SOC MP on Days 1 through 4 of every cycle
To determine CR + VGPR during the induction therapy period following ixazomib administration once weekly on either Days 1, 8, 15, 22, and 29 or Days 1, 8, 22, and 29 of a 42-day cycle when added to SOC of MP on Days 1 through 4 of every cycle |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1
To characterize the PK in plasma of oral ixazomib when added to standard care MP
To evaluate the ORR, including CR; including stringent complete response [sCR]), very good partial response (VGPR) and partial response (PR), during the entire during the induction therapy period and throughout the entire treatment period
Phase 2
To determine the time to response during the induction therapy period
To evaluate the DOR for patients who responded during the induction therapy period
To determine ORR during the induction therapy period and through the entire treatment period
To assess the time to progression (TTP)
To evaluate time to next therapy and treatment-free interval
To evaluate the progression-free survival (PFS)
To evaluate the overall survival (including 1-year survival rate)
To determine the safety profile of ixazomib
To evaluate changes in QOL
-To assess pain response rate, as assessed by the BPI-SF and analgesic use |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patient for whom standard MP treatment is indicated and who is not a candidate for HDT-SCT for 1 of the following reasons:
The patient is 65 years of age or older.
The patient is less than 65 years of age but has significant comorbid condition(s) that are likely to have a negative impact on tolerability of HDT-SCT.
2. Symptomatic MM or asymptomatic myeloma with myeloma-related organ damage diagnosed according to standard criteria
3. Patients must have measurable disease defined by at least 1 of the following 3 measurements:
Serum M-protein ≥ 1 g/dL (≥ 10 g/L)
Urine M-protein ≥ 200 mg/24 hours
Serum free light chain assay: involved free light chain level ≥ 10 mg/dL (≥ 100 mg/L), provided that the serum free light chain ratio is abnormal
4. Patients must meet the following clinical laboratory criteria within 3 days before the first dose of study treatment to be enrolled in the study:
Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3.
platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days prior to study drug dosing.
Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN).
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN.
Calculated creatinine clearance ≥ 30 mL/min
5. ECOG performance status of 0 to 2
6. Female patients who:
If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, AND
Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
Agree to practice true abstinence when this is line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
7. Male patients, even if surgically sterilized (ie, status postvasectomy), who:
Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
Agree to practice true abstinence when this is line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
8. 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.
|
|
| E.4 | Principal exclusion criteria |
1. Peripheral neuropathy ≥ Grade 2 on clinical examination during the screening period.
2. Female patients who are lactating or pregnant.
3. Major surgery within 14 days before the first dose of study drug. (Note: kyphoplasty or vertebroplasty is not considered major surgery.)
4. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before the first dose of study drug.
5. Diarrhea >Grade 1, based on the NCI CTCAE grading, in the absence of antidiarrheals.
6. Prior systemic therapy for MM, including investigational drugs. Prior treatment with corticosteroids or localized radiation therapy does not disqualify the patient (the maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone, a total of which can be given in a 2-week period.
7. Radiotherapy within 14 days before the first dose of study treatment.
8. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), 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 within 14 days before the first dose of study treatment.
9. Central nervous system involvement.
10. Diagnosis of smoldering MM, Waldenström’s macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.
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. QTc > 470 msec on a 12-lead ECG obtained during the Screening period. If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG.
13. Known or suspected human immunodeficiency virus (HIV) positive.
14. Known or suspected hepatitis B surface antigen-positive status or known or suspected active hepatitis C infection.
15. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
16. Known allergy to any of the study medications, their analogues, or excipients in the various formulations.
17. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing.
18. Diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I:
DLT, MTD, and RP2D of oral ixazomib when added to a standard care regimen of MP
Phase 2:
Combined response rate of CR + VGPR in patients treated with ixazomib when added to a standard care regimen of MP during the induction period
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1
Only DLTs occurring in Cycle 1 in phase 1 will necessarily influence decisions regarding dose escalation, expansion of a dose level, or evaluation of intermediate dose levels. However, DLTs occurring in later cycles may be taken into consideration for dose-escalation decisions, at the discretion of the investigators/sponsor. The MTD or RP2D estimation will be made following evaluation of the available data from Phase 1. The RP2D will require first-cycle DLTs in not more than 1 in 6 DLT-evaluable patients enrolled in a single cohort.
Phase 2
Arm B Induction Period: End of each 28 day cycle.
Arm C&D Induction Period: End of each 42 day cycle |
|
| E.5.2 | Secondary end point(s) |
Phase 1 Secondary Endpoint:
Single and multiple-dose plasma PK
Whole blood 20S proteasome inhibition parameters
ORR during the entire study
Phase 2 Secondary Endpoint
To determine the time to response during the induction therapy period
To evaluate the duration of response (DOR) for patients who responded during the induction therapy period
To determine ORR during the induction therapy period and throughout the entire study
To assess the time to progression (TTP)
To evaluate time to next therapy and treatment-free interval
To evaluate the progression-free survival (PFS) rate
To evaluate the overall survival (including 1-year survival rate)
To determine the safety profile of ixazomib
To evaluate changes in quality of life (QoL)
Pain response rate, measured by the proportion of pain responders, as determined by the BPI-SF and analgesic use
Development of new or worsening of existing selected skeletal-related events |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1
PK and whole blood 20S proteasome Activity
Arm A; Cycle 1 (Day 1,2,4,8,11,12,15,16,17) Cycle 2 (Day 1), Cycle 3 (Day 1)
Arm B: Cycle 1 (Day 1,2,3,4,8,15,16,17,18,22) Cycle 2 (Day 1), Cycle 3 (Day 1)
PK only Arms C&D Cycle 1 (Day 1,2,3,5,8,29,30,31,33,36), Cycle 2 (Day 1)
Phase 2
PK
Arm B: Cycle 1&2 (Day 1,8,15,22-28)
Arm C&D: Cycle 1 to 32 (Day 1,8,15,22, 29, 35
Response:
Arm B Induction Period: End of each 28 day cycle.
Arm C & D Induction Period: End of each 42 day cycle
Response will be assessed every 2 cycles for all patients during maintenance therapy.
QoL and Pain Response:
Screening, Day 1 each cycle, EoT and PFS follow-up
Skeletal Assessment: Once annually or at investigator discretion
Safety evaluations - ongoing |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 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.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Canada |
| Czech Republic |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| Last patient, last visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 92 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 92 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
