| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed multiple myeloma and 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 | 19.1 |
| 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 |
NDMM:
To determine the combined response rate of CR (including stringent CR [sCR]) + VGPR following treatment with oral ixazomib when added to a regimen of cyclophosphamide and low-dose dexamethasone (Cd) during the induction phase
RRMM:
To determine overall response rate (ORR; CR + VGPR +partial response [PR]), following treatment with oral ixazomib when added to a regimen of Cd |
|
| E.2.2 | Secondary objectives of the trial |
NDMM:
* To evaluate the tolerability and toxicity of the combination of oral ixazomib with Cd
* To characterize the PK in plasma of oral ixazomib in combination with Cd
* To determine ORR (CR + VGPR + PR), CR, VGPR, and PR during the induction phase and the ORR (CR + VGPR + PR), CR + VGPR, CR, VGPR, and PR throughout the entire treatment period
* To determine time to response for patients who respond during the induction phase
* For other secondary objectives see Protocol
RRMM:
* To evaluate the tolerability and toxicity of the combination of oral ixazomib with Cd
* To characterize the PK in plasma of oral ixazomib in combination with Cd
* To determine CR + VGPR, CR, VGPR, and PR
* To determine time to response for patients who respond
* For other secondary objectives see Protocol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
NDMM:
1. Adult male or female patients 18 years of age or older with a confirmed diagnosis of symptomatic MM according to standard criteria
2. Patients for whom cyclophosphamide and dexamethasone treatment is appropriate and who are considered not eligible for HDT-SCT for 1 or more 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, in the opinion of the investigator, likely to have a negative impact on tolerability of HDT-SCT.
RRMM:
3. Adult male or female patients 18 years or older with a confirmed diagnosis of symptomatic MM either currently or at the time of initial diagnosis, according to standard criteria, and relapsed and/or refractory disease after 1 to 3 lines of prior therapy. A patient is considered to have refractory disease if disease progression occurred during the treatment period or within 60 days of receiving the last dose of a given therapy. A line of therapy is defined as 1 or more cycles of a single-agent or combination therapy or a sequence of planned treatments such as induction therapy followed by autologous stem cell transplantation (ASCT) and then maintenance therapy.
4. No evidence of graft-versus-host disease for patients who have undergone prior allogeneic stem cell transplantation.
NDMM and RRM:
5. 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.
6. Patients must meet all of the following clinical laboratory criteria:
* Absolute neutrophil count (ANC) ≥ 1000/mm3 and platelet count ≥ 75,000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days prior to administration of the study drug
* 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 (CrCL) ≥ 30 mL/min
7. Eastern Cooperative Oncology Group performance status of 0, 1, or 2
8. Female patients who:
* Are 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 the time of signing the informed consent through 90 days after the last dose of study drug, or
* Agree to practice true abstinence over the period previously described, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.), and
* Adhere to any treatment-specific pregnancy prevention guidelines for Cyclophosphamide and dexamethasone
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
* Agree to practice true abstinence over the period previously described, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.), and
* Adhere to any treatment-specific pregnancy prevention guidelines for cyclophosphamide and dexamethasone
9. 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.
10. Suitable venous access for the study-required blood sampling.
11. Patient is willing and able to adhere to the study visit schedule and other protocol requirements. |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment for multiple myeloma with either standard of care treatment or investigational regimen (for patients with NDMM only).
NOTE: Prior treatment with corticosteroids (maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone over 14 days. Localized radiation is permitted as long as it is below a therapeutic level and administered at least 14 days prior to the first dose of study treatment.
2. 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.
3. Central nervous system involvement.
4. 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.
5. Peripheral neuropathy Grade 1 with pain or Grade 2 or higher peripheral neuropathy of any cause on clinical examination during the Screening period.
6. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing.
7. Infection requiring IV antibiotic therapy or other serious infection within 14 days before the first dose of study drug.
8. Ongoing or active infection, known human immunodeficiency virus (HIV) positive, active hepatitis B or C infection
9. Systemic treatment 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 within 14 days before the first dose of study treatment.
10. Known allergy to any of the study medications, their analogues, or excipients in the various formulations.
11. Major surgery within 14 days before the first dose of study drug. (Note: kyphoplasty or vertebroplasty is not considered major surgery.)
12. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period.
13. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
14. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
15. Treatment with any investigational products for reasons other than MM within 30 days before the first dose of study drug. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
NDMM:
Combined response rate of CR (including sCR) + VGPR during the induction phase in patients treated with ixazomib when added to a regimen of Cd
RRMM:
ORR (CR + VGPR +PR) in patients treated with ixazomib when added to a regimen of Cd |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
NDMM:
SPEP, UPEP, immunofixation of blood and urine, and serum free light chain at screening, on D1 of each cycle, at EOT, and every 8 weeks during PFS follow-up. For suspected CRs, one bone-marrow aspirate assessment required. To determine a response of sCR, bone marrow, immunohistochemistry or immunofluorescence for kappa/lambda ratio, and serum free light chain required for all patients suspected to be in CR to meet this requirement of this response category.
RRMM:
SPEP, UPEP, immunofixation of blood and urine, and serum free light chain at screening, on D1 of each cycle, at EOT, and every 8 weeks during PFS follow-up. For suspected CRs, one bone-marrow aspirate required. |
|
| E.5.2 | Secondary end point(s) |
NDMM:
* All AEs, Grade 3 or higher AEs, AEs resulting in discontinuation, AEs resulting in dose reduction, serious adverse events (SAEs), and assessments of clinical laboratory values
* PK parameters including, but not limited to single-dose maximum (peak) concentration (Cmax), Tmax, and AUC
* ORR (CR + VGPR + PR), CR, VGPR, PR, stable disease (SD), progressive disease (PD) during the induction phase; ORR, CR + VGPR, CR, VGPR, PR, SD and PD and throughout the entire study
* Time to response, defined as the time interval from the date of enrollment to the date of first documented response during the induction phase
* DOR, defined for responders as the time interval from the date of first response to the date of disease progression
* TTP, defined as the time interval from the date of enrollment to the date of first documented disease progression
* PFS, defined as the time interval from the date of enrollment to the date of first documented disease progression or death
* AEs, SAEs, AEs resulting in discontinuation, AEs resulting in dose reduction in patients remaining on treatment after 13 cycles, ORR, CR, VGPR, and PR of single-agent ixazomib as maintenance therapy in patients remaining on treatment after 13 cycles
* Comparison of change in global health status between baseline and each postbaseline assessment, as measured by the global health scale, functioning, and symptoms of the EORTC QLQ-C30.
RRMM:
* All AEs, Grade 3 or higher AEs, AEs resulting in discontinuation, AEs resulting in dose reduction, serious adverse events (SAEs), and assessments of clinical laboratory values
* PK parameters including but not limited to single-dose maximum (peak) concentration (Cmax), Tmax, and AUC
* CR + VGPR, CR, VGPR, PR, SD, PD
* Time to response
* DOR
* TTP
* PFS
* Comparison of change in global health status between baseline and each postbaseline assessment, as measured by the global health scale, functioning, and symptoms of the EORTC QLQ-C30. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Continuous.
2. On D1-3, 5, 8, 15, 16, 17, 19 and 22 of C1, and D1 of C2 (safety lead-in). On D1, 8, 15 and 22 of C1-3 (other patients).
3. SPEP, UPEP, immunofixation of blood and urine, and serum free light chain at screening, on D1 of each cycle, at EOT, and every 8 weeks during PFS follow-up. For suspected CRs, one bone-marrow aspirate required.
4. See 3.
5. SPEP and UPEP on D1 of each cycle, at EOT, and every 8 weeks during PFS follow-up. Chemistry laboratory at screening, on D1, 8, 15 and 22 of C1-3, then D1 of each cycle, and at EOT. Skeletal survey at screening and once annually. Additional skeletal surveys possible. See also 3.
6. See 5.
7. See 5.
8 NDMM. See 1 and 3.
8 RRMM/9 NDMM. At screening, on D1 of each cycle, at EOT, and every 8 weeks during PFS follow-up. |
|
| 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 | 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 | 3 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| Greece |
| Poland |
| Sweden |
| 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
|
| The trial will end with an approximately 36-month (3-year) treatment and/or progression-free survival (PFS) follow-up period of 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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