| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Transplant ineligible patients with newly diagnosed multiple myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Transplant ineligible patients with 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 | 16.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10028229 |
| E.1.2 | Term | Multiple myelomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| 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 show non-inferiority with respect to response rates between KTd and KRd: Overall response rate (ORR) will be assessed according to International Myeloma Working Group (IMWG) criteria to determine the ORR in patients NDMM after receiving 9 cycles induction therapy with either carfilzomib in combination with thalidomide and dexamethasone or carfilzomib in combination with lenalidomide and dexamethasone |
|
| E.2.2 | Secondary objectives of the trial |
• Feasibility, safety and efficacy of a K monotherapy maintenance strategy over 12 months
• Response (the updated IMWG response criteria will be applied for response evaluation in all patients; this also includes MRD evaluation which will be performed in all patients achieving CR and in patients which are in a CR at the end of maintenance)
• Overall Survival (OS) in patients with NDMM ineligible for transplantation receiving either KTd versus KRd induction therapy and sub-sequent being randomized either to maintenance arm with carfilzomib or to control only for a maximum period of 12 months.
• Progression free survival (PFS) of both induction arms.
• Safety and tolerability of KTd and KRd followed by randomization to carfilzomib maintenance for a maximum period of 12 months or observation only.
• Changes in quality of life (QoL) in patients treated by either KTd or KRd followed by maintenance with carfilzomib for a maximum period of 12 months or observation only. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Age ≥ 18 years
• Able to provide written informed consent in accordance with federal, local, and institutional guidelines
• newly diagnosed, symptomatic multiple myeloma
• Transplant-ineligibility (age > 65 years or patients not eligible due to comorbidities determined by investigator or patients not willing to undergo ASCT on personal preference)
• Measurable disease, as defined by one or more of the following (assessed within 21 days prior to randomization):
o Serum M-protein ≥ 0.5 g/dL, or
o Urine M-protein ≥ 200 mg/24 hours, or
o In subjects without detectable serum or urine M-protein, serum-free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal κ/λ ratio
• No prior treatment for multiple myeloma
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1
• Patients at cardiac risk (NYHA >II or pre-existing coronary heart disease or any other relevant cardiac complication) should be scheduled for a baseline ECHO and can only be included if the LVEF is ≥40%); independent of cardiac risk ECG has to be done for inclusion of Asian patients and patients > 75 years of age
• Adequate organ and bone marrow function within the 21 days prior to randomization defined by:
o Bilirubin < 2 times the upper limit of normal (ULN), Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times the ULN
o absolute neutrophil count (ANC) ≥ 1000/mm3 (growth factor support for max 3 days allowed to achieve this value)
o Hemoglobin ≥ 7.0 g/dL (Use of erythropoietic stimulating factors and red blood cell [RBC] transfusion per institutional guidelines is allowed, however the most recent RBC transfusion may not have been done within 7 days prior to obtaining screening hemoglobin.)
o Platelet count ≥ 30,000/mm3
• Calculated or measured creatinine clearance (CrCl) of > 30 mL/min. Calculation should be based on the Cockcroft and Gault formula: [(140 – Age) ∙ Mass (kg) / (72 ∙ Creatinine mg/dL)]; multiply result by 0.85 if female
• Females of childbearing potential (FCBP) must have a confirmed negative serum pregnancy test within the 21 days prior to randomization
• Females of childbearing potential and male subjects who are sexually active with FCBP must agree to use effective concomitant method(s) of contraception during the study and for 30 days (women) and 90 days (men) following the last study drug treatment administration.
|
|
| E.4 | Principal exclusion criteria |
• ECOG ≥2
• Frail patients
• Waldenström macroglobulinemia
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard differential)
• Myelodysplastic syndrome
• Smoldering Myelom and MGUS
• Second malignancy within the past 5 years except:
o Adequately treated basal cell or squamous cell skin cancer
o Carcinoma in situ of the cervix
o Prostate cancer Gleason score ≤ 6 with stable prostate-specific antigen (PSA over 12 months
o Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins)
o Treated medullary or papillary thyroid cancer
o Similar condition with an expectation of > 95% five-year disease-free survival
• History of or current amyloidosis
• Immunotherapy within the 21 days prior to randomization
• Glucocorticoid therapy within the 14 days prior to randomization that exceeds accumulative dose of 160 mg dexamethasone or 1000 mg prednisone
• Extended field radio therapy (more than 3 fields) within the 21 days prior to randomization
• Known history of allergy to Carfilzomib, Captisol (a cyclodextrin derivative used to solubilize carfilzomib) or any other component of formulation
• Contraindication to dexamethasone, thalidomide or lenalidomide or any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs
• Active congestive heart failure (New York Heart Association [NYHA] Class III or IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, acute diffuse infiltrative pulmonary disease, pericardial disease, or myocardial infarction within 4 months prior to enrollment
• Active infection within the 14 days prior to randomization requiring systemic antibiotics and/or antiviral therapy
• Pleural effusions requiring thoracentesis within the 14 days prior to randomization
• Ascites requiring paracentesis within the 14 days prior to randomization
• Uncontrolled hypertension or uncontrolled diabetes despite medication
• Significant neuropathy (Grade 2 with pain or Grade 3 or higher) within the 14 days prior to randomization
• Known cirrhosis
• Known human immunodeficiency virus (HIV) seropositivity or active hepatitis C or hepatitis B infection (subjects with past hepatitis B virus [HBV] infection or resolved HBV infection defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti HBc] antibody test are eligible; subjects positive for hepatitis C virus [HCV] antibody are eligible only if polymerase chain reaction [PCR] is negative for HCV RNA.)
• Participation in another interventional study within the 28 days prior to randomization
• Major surgery (except kyphoplasty) within the 28 days prior to randomization
• Female subjects who are pregnant or lactating
• Any other clinically significant medical disease or social condition that, in the investigator’s opinion, may interfere with protocol adherence or a subject’s ability to give informed consent, be compliant with study procedures, or provide accurate information. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response rate after 9 cycles induction will be the primary endpoint, which is statistically powered to show non-inferiority. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After end of induction therapy |
|
| E.5.2 | Secondary end point(s) |
1. Feasibility, safety and efficacy of a K monotherapy maintenance strategy over 12 months
2. Response (the updated IMWG response criteria will be applied for response evaluation in all patients; this also includes MRD evaluation which will be performed in all patients achieving CR and in patients which are in a CR at the end of maintenance)
3. Overall Survival (OS) in patients with NDMM ineligible for transplantation receiving either KTd versus KRd induction therapy and sub-sequent being randomized either to maintenance arm with carfilzomib or to control only for a maximum period of 12 months.
4. Progression free survival (PFS) of both induction arms.
5. Safety and tolerability of KTd and KRd followed by randomization to carfilzomib maintenance for a maximum period of 12 months or observation only.
6. Changes in quality of life (QoL) in patients treated by either KTd or KRd followed by maintenance with carfilzomib for a maximum period of 12 months or observation only. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. End of maintenance therapy (12 months)
2. -4. End of induction therapy (9 months), end of maintenance therapy (12 months), during Follow-up (every 3 months until end of study)
5. Between start and end of maintance therapy (12 months)
6. Between start of induction therapy and end of maintenance therapy (21 months) |
|
| 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 | 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 | No |
| 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 | 17 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 | 7 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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