| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10067095 |
| E.1.2 | Term | Multiple myeloma progression |
| 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 |
To investigate the safety and feasibility of carfilzomib + elotuzumab +
dexamethasone combination and initial efficacy in relapsed or progressed multiple myeloma patients. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients at the age of 18 to below 75 years with the life
expectancy of at least three months.
2. Prior confirmed diagnosis of multiple myeloma and measurable disease in
blood or urine with at least one of the following: Serum M-protein ≥ 5g/l,
Urine M-protein ≥ 200 mg/24 hours, In subjects without detectable serum
or urine M-component, serum free light chain (S-FLC) > 100 ml/l
(involved light chain) and an abnormal serum kappa/lambda ratio
3. Relapse or progression after 1 to 3 prior treatment lines, which have
included proteasome inhibitors (PI, bortezomib and/or ixazomib) and/or
lenalidomide. Refractoriness to PI´s and/or lenalidomide is allowed in the
preceding cycle. Patients must be carfilzomib naíve. Patients with
previous autologous transplantation can be included.
4. Need of treatment of relapse or progression: IMWG criteria for
relapse/progression (paraprotein or CRAB criteria or both). (Appendix 5)
5. Voluntary written consent must be given before performance of any study
related procedure not part of standard medical care, with the
understanding that the patient may withdraw consent at any time without
prejudice to future medical care.
6. Females of childbearing potential (FCBP) must have a confirmed negative
serum pregnancy test within the 7 days prior to inclusion
7. Females of childbearing potential must use one effective method of
contraception and their partners condom during the study and for 120 days
following the last study drug treatment dose and male subjects who are
sexually active with FCBP must agree to use condom during the study and
for 180 days following the last study drug treatment dose.
8. Eastern Cooperative Oncology Group (ECOG) performance status 0-2, or
Karnofsky at least 60. (Appendix 1)
9. Patients must meet the following adequate organ and bone marrow
function within 21 days prior to inclusion:
• Absolute neutrophil count (ANC) 1,000/mm3 (≥ 1.0 x 109/L) and
platelet count 75 x 109/L. Platelet transfusions to help patients
meet eligibility criteria are not allowed within 3 days before study
enrollment. Granulocyte growth factors are allowed to meet the
inclusion criteria?
• Hemoglobin (Hb) ≥ 80 g/l (use of erythropoietin and red blood cell
transfusions allowed by institutional guidelines, however the most
recent RBC may not have given within 7 days prior to obtaining
screening Hb
• Total bilirubin < 1.5 times the upper limit of the normal range (ULN).
• Alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) < 3 times the ULN.
• Calculated creatinine clearance ≥ 40 mL/min (Cockcroft-Gault
estimation of creatinine clearance (CRcl): CRcl (mL/min) = (140 -
age) x (weight [kg]) / 72 x (serum creatinine [mg/dL]); for females,
multiply by 0.85 (Cockcroft DW. 1976, Luke DR. 1990)(Appendix 2).
10. Patient must be willing and able to adhere to the study protocol visit
schedule and other protocol requirements.
11. Negative pregnancy test at inclusion if applicable |
|
| E.4 | Principal exclusion criteria |
1. Female patients who are lactating or have a positive serum pregnancy
test during the screening period.
2. Major surgery within 28 days before enrollment.
3. Radiotherapy within 14 days before enrollment, but if the involved field
is small, 7 days will be considered a sufficient interval before onset of
the treatment.
4. Glucocorticoid therapy within the 14 days prior to inclusion that
exceeds a cumulative dose of 160 mg dexamethasone or 1000 mg
prednisone.
5. Central nervous system involvement.
6. Infection requiring systemic antibiotic therapy or other serious infection
within 14 days before study enrollment.
7. Active congestive heart failure (NYHA III-IV) (Appendix 3),
symptomatic ischemia, conduction abnormalities uncontrolled by
conventional intervention, acute diffuse infiltrative pulmonary disease,
pericardial disease or myocardial infarction within 6 months prior to
enrollment or left ventricular ejection fraction (LVEF) <40% within one
month before randomization.
8. Ongoing or active systemic infection, active hepatitis A, B or C virus
infection, or known human immunodeficiency virus (HIV) positivity.
9. Any other serious medical or psychiatric illness that could, in the
investigator’s opinion, potentially interfere with the completion of
treatment according to this protocol.
10. Known allergy to Captisol (a cyclodextrin derivative used to solubilize
carfilzomib) or to any of the study medications, their analogues, or
excipients in the various formulations of any agent.
11. Contraindication to dexamethasone or any of the required concomitant
drugs or supportive treatments, including hypersensitivity to antiviral
drugs, or intolerance to hydration due to pre-existing pulmonary or
cardiac impairment.
12. Diagnosed or treated for another malignancy within 5 years before study
enrollment 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.
13. Patient has ≥ Grade 3 peripheral neuropathy, or Grade 2 with pain on
clinical examination within the 14 days prior to inclusion.
14. Participation in another interventional study within the 28 days before
this study inclusion.
15. Patients that have been previously treated with elotuzumab or
carfilzomib.
16. Primary plasma cell leukemia, systemic AL amyloidosis, Waldenström
macroglobulinemia, rare IgM multiple myeloma, POEMS syndrome,
myelodysplasia
17. Allogeneic or autologous stem cell transplantation planned
18. Participants receiving any other investigational agents or received
within 60 days
19. Pleural effusions requiring thoracocentesis within the 14 days prior the
inclusion.
20. Ascites requiring ascitespunction within the 14 days prior to inclusion.
21. Previous allogeneic transplantation
22. Uncontrolled hypertension or uncontrolled diabetes despite medication
23. Known hepatic cirrhosis
24. Severe autoimmune disease
25. Positive direct antiglobulin test (DAT), Coombs test |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response rate (ORR) with carfilzomib + elotuzumab + dexamethasone |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary endpoint (ORR) together with the relevant secondary
endpoints will be assessed after the minimum follow-up of one year
has been reached with the last included patient. |
|
| E.5.2 | Secondary end point(s) |
• Complete response rate (CR)
• Quality of response (proportion of minimal residual disease (MRD) negativity in patients
with at least VGPR response)
• Duration of responses
• Progression-free survival (PFS)
• Time to next treatment (TTNT)
• Safety (Adverse events) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Primary endpoint (ORR) together with the relevant secondary
endpoints will be assessed after the minimum follow-up of one year
has been reached with the last included patient.
To assess PFS and TTNT all patients will be followed until 4 years
after first dose. |
|
| 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 | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 | Yes |
| 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 patients are followed (PFS and TTNT) are followed until 4 years after first dose (two years after LPFV). All patients are followed 2 years after end of treatment. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
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