| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed multiple myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| a cancer that affects some of your immune cells and affects how your normal 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 | 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 |
| -Estimate the overall response rate (ORR). |
|
| E.2.2 | Secondary objectives of the trial |
-Estimate the rate of minimal residual disease negative complete
response (MRD[-]CR) at 12 months landmark.
-Describe the safety and tolerability of carfilzomib combined with
dexamethasone and pomalidomide.
-Estimate the frequency of best MRD[-] response in KPd.
-Estimate the frequency of sustained MRD[-]CR.
- Estimate the frequency of sustained MRD[-]CR at landmark 24 months.
- Estimate duration of response, time to response, progression-free
survival (PFS), and overall survival (OS).
- Estimate rate of CR or better. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Subjects are eligible to be included in the study only if all of the following criteria apply:
-Male or female subjects age ≥ 18 years
-First or second relapse of multiple myeloma
-Must be Refractory to lenalidomide
-Measurable disease with at least 1 of the following assessed within 28 days prior to enrollment:
•IgG multiple myeloma: serum monoclonal protein (M-protein) level ≥ 1.0 g/dL
•IgA, IgD, IgE multiple myeloma: serum M-protein level ≥ 0.5 g/dL
•urine M-protein ≥ 200 mg per 24 hours
•in subjects without measurable serum or urine M-protein, serum-free light
•chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio
-Must have at least a partial response (PR) to at least 1 line of prior therapy
-Prior therapy with PI is allowed. Subjects receiving prior carfilzomib therapy must have achieved at least a PR, was not removed due to toxicity, did not relapse within 60 days from discontinuation of carfilzomib, and must have at least a 6 month carfilzomib treatment-free interval from their last dose of carfilzomib
-Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2
|
|
| E.4 | Principal exclusion criteria |
Subjects are excluded from the study if any of the following criteria apply:
Disease Related
- Primary refractory multiple myeloma
-Waldenström macroglobulinemia
- Multiple myeloma of IgM subtype
-POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
-Plasma cell leukemia
-Primary amyloidosis
-Previous diagnosis of amyloidosis associated with myeloma
-Myelodysplastic syndrome
-Toxicity requiring discontinuation of lenalidomide therapy
-Prior treatment with pomalidomide
Other Medical Conditions
- History of other malignancy within the past 3 years,
- Active HBV infection.
-HIV infection, hepatitis C infection
-Presence of graft-versus-host disease including continuation of immunosuppressive therapy despite resolution of graft-versus-host disease
-Known cirrhosis
- Uncontrolled hypertension, defined as an average systolic blood pressure
- Active congestive heart failure
-Intolerance to hydration due to pre-existing pulmonary or cardiac impairment
-History of interstitial lung disease or ongoing interstitial lung disease
-Active infection within 14 days prior to enrollment requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents.
- Significant neuropathy (grades 3 to 4, or grade 2 with pain) within 14 days prior to enrollment
-Known pulmonary hypertension
-Pleural effusions requiring thoracentesis or ascites requiring paracentesis within14 days prior to enrollment
Prior/Concomitant Therapy
-Immunotherapy with potential antimyeloma activity within 21 days prior to enrollment
-Monoclonal antibody therapy within 21 days prior to enrollment
-Chemotherapy with approved anticancer therapeutic within 21 days prior to enrollment
-Plasmapheresis within 21 days prior to enrollment
-Glucocorticoid therapy within 14 days prior to enrollment that exceeds a
cumulative dose of 160 mg of dexamethasone or equivalent dose of other corticosteroids
-Focal radiation therapy within 7 days prior to enrollment.
-Major surgery (except kyphoplasty) within 28 days prior to enrollment
-Autologous or allogeneic stem cell transplant within 90 days prior to enrollment
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Objective response defined as the best overall confirmed response of
partial response (PR), very good partial response (VGPR), complete
response (CR), or stringent complete response (sCR) by Independent
Review Committee (IRC) per International Myeloma Working Group
Uniform Response Criteria. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis will be triggered 12 months after the last subject
enrollment. |
|
| E.5.2 | Secondary end point(s) |
• MRD[-]CR at a sensitivity of 10-5 using next generation sequencing (NGS)-based method in the bone marrow at 12 months ± 4 weeks from start of treatment.
• subject incidence of treatment-emergent adverse events.
• MRD[-] response at a sensitivity of 10-5 using NGS-based method in the bone marrow at any time during therapy.
• sustained MRD[-]CR at a sensitivity of 10-5 using NGS based method in the bone marrow defined as subjects that maintain MRD[-]CR 12 months or more after achieving MRD[-]CR status, disregarding when the first MRD[-]CR was reached.
• sustained MRD[-]CR at a sensitivity of 10-5 using NGS based method in the bone marrow at 24 months ± 4 weeks from start of treatment and calculated only within the subjects who reached MRD[-]CR in the time window for primary endpoint assessment.
• landmark overall response by 12 months, defined as the best overall confirmed response of PR, VGPR, CR or sCR by 12 months from start of treatment.
• duration of response, defined as time from first date of PR or better to date of disease progression or death due to any cause.
• time to response, defined as time from start of treatment to first date of PR or better.
• PFS defined as time from start of treatment until progression or death from any cause.
• OS, defined as time from start of treatment until death from any cause.
• best overall confirmed response of CR or better. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-The secondary analysis MRD[-]CR will be triggered at 12 months at a sensitivity of 10-5 using NGS[-] based method in the bone marrow.
-MRD[-]CR rate at 12 months landmark is defined as the proportion of subjects who reach MRD[-]CR at 12 months landmark assessment among all subjects who received at least 1 dose of carfilzomib.
-The final analysis is planned after all subjects in have had the opportunity to complete their end of study visit. |
|
| 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 | No |
| 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 | 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
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
| United States |
| Estonia |
| France |
| Spain |
| Germany |
| Greece |
| Italy |
| Denmark |
|
| 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 end of study date is defined as the date when the last subject across all sites is assessed or receives an intervention. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| 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 | 6 |
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