| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Multiple Myeloma |
| Multiples Myelom |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10035226 |
| E.1.2 | Term | Plasma cell myeloma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| The primary objective of the trial is to determine MRD negativity (8 color flow, Euro-Flow plus Black Swan Panel) after consolidation (10 I-KRd cycles including intensification in transplant-eligible and 12 I-KRd cycles in transplant-ineligible patients) with a sensitivity of 10-5 |
|
| E.2.2 | Secondary objectives of the trial |
•To determine progression-free survival (PFS) - defined as time from
study treatment initiation to progression or death from any cause
whichever occurs first.
•To determine Overall Response Rate (ORR)
•To assess duration of minimal residual disease state
•To evaluate overall survival
•To assess time to subsequent therapy
•To evaluate progression-free survival on next line therapy (PFS2)
•To assess time to myeloma response
•Quality of life assessment of patients at baseline, during induction treatment, consolidation and maintenance treatment. Assessment of quality of life is performed using patient self-report questionnaires of the European Organization for Research and Treatment of Cancer Quality
of Life Questionnaire (EORTC-QLQC30) including the multiple myeloma module (EORTC-QLQMY20) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Subjects must have newly diagnosed, untreated, symptomatic (according to the revised CRAB criteria 2014), documented myeloma and have measurable disease (serum M-protein ≥ 1 g/dL (for IgA ≥ 0.5g/dL) or urine M-protein ≥ 200 mg/24 hours) or in case of oligosecretory myeloma: involved FLC level ≥ 10 mg/dl, provided sFLCratio is abnormal or in case of asecretory myeloma: > 1 focal lesions
measurable by MRI
Subjects must have high-risk myeloma defined as followed:
•Presence of one or more of the following cytogenetic abnormalities
(determined by FISH):
-□Del(17p) in ≥ 10% of purified cells
-□t(4;14)
-□> 3 copies +1q21
-□t(14;16)
•ISS Stage II or III (all patients)
FISH analysis of external laboratories other than Heidelberg is accepted, a list of laboratories will be filed in the study central.
2.Must be ≥ 18 years at the time of signing the informed consent form.
3.Must be able to adhere to the study visit schedule and other protocol requirements in the investigators opinion.
4. WHO performance status 0-3 (WHO=3 is allowed only if caused by MM and not by co-morbid conditions)
5. Females of childbearing potential (FCBP) (1) must agree to refrain from becoming pregnant for 28 days prior to initiation of study drug, while on study drug and for 30 -150 days* after discontinuation from the study drug by using 2 reliable methods of contraception and must agree to regular pregnancy testing during this timeframe.
(1) A female of childbearing potential is a sexually mature woman who:
1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., who has had menses at any time in the preceding 24 consecutive months) 3) has achieved menarche at some point.
6. Females must agree to abstain from breastfeeding during study participation and 30 150 days* after study drug discontinuation.
7. Males must agree to use a latex condom during any sexual contact with FCBP while participating in the study and for 90 150 days* following discontinuation from this study, even if he has undergone a successful vasectomy.
8. Males must also agree to refrain from donating semen or sperm while on treatment with any study drug and for 90 150 days* after discontinuation from this study treatment.
9. All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.
10. All subjects must agree not to share medication.
11. All participating subjects have to follow the requirements of the Lenalidomide Pregnancy Prevention Plan (please refer to section 4) *28 days after last dose of Lenalidomide, 30 days after last dose of Carfilzomib and 150 days (5 Months) after last dose of Isatuximab, for details number of days differ for Lenalidomide and Carfilzomib |
|
| E.4 | Principal exclusion criteria |
1. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize Carfilzomib), mannitol, sucrose, histidine (as base and hydrochloride salt) and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents.
2. Patients with known systemic amyloidosis (except for AL amyloidosis of the skin or the bone marrow)
3. Administration of systemic chemotherapy, biological, immunotherapy or any investigational agent (therapeutic or diagnostic) for multiple myeloma except bisphosphonate therapy. Emergency treatment with dexamethasone is allowed when the cumulative dexamethasone dose is less or equal 160 mg. It is allowed to include patients in the trial after 1 cycle (4 weeks) of any anti-myeloma first-line treatment.
4. Any of the following laboratory abnormalities:
oAbsolute neutrophil count (ANC) < 1,000/μL, unless related to myeloma
oPlatelet count < 30,000/ μL (in case of platelets < 50.000 /μl and ≥ 30.000 /μl myeloma bone marrow infiltration should be ≥ 50%)
o Corrected serum calcium > 14 mg/dL (> 3.5 mmol/L); or free ionized calcium > 6.5 mg/dL (> 1.6 mmol/L)
oSerum GOT/AST or SGPT/ALT > 3.0 x upper limit of normal (ULN) or serum total bilirubin > 2.0 mg/dL if not due to hereditary abnormalities as Gilbert's disease or hereditary hemolysis (Note: if the mentioned limits for bilirubin or ASAT/ALAT are exceeded, but there is no significant hepatic dysfunction at investigator's discretion, the study office has to be consulted prior to inclusion)
oPatients with severe renal impairment (eGFR < 30 ml/min/1.73 m², MDRD formula or CDK-EPI or Creatinine Clearance < 30 ml/min)
5.Active congestive heart failure (NYHA Class III to IV), symptomatic cardiac ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within four months prior study entry.
6. Known HIV seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B sAg and core antibody receiving and responding to antiviral therapy directed at hepatitis B: these patients are allowed). Patients with a history of hepatitis B infection have to be monitored repetively during treatment. In case of signs of hepatitis B reactivation, antiviral treatment has to be initiated and patients have to be referred to a specialist for treatment and monitoring of hepatitis infection.
7. Acute active, uncontrolled infection
8. Significant neuropathy (Grades 3 to 4, or Grade 2 with pain according CTC V4.03)
9. Second malignancy within the past 5 years except:
- adequately treated basal cell or squamous cell skin cancer
- carcinoma in situ of the cervix
- prostate cancer Gleason Score ≤ 6 with stable PSA over the past 12 months
- breast carcinoma in situ with full surgical resection
- treated medullary or papillary thyroid cancer
10. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to study entry.
11. Major surgery within 4 weeks prior to cycle 1 day 1 (kyphoplasty is not considered major surgery); subjects should have been fully recovered from any surgical related toxicities. 12. Female patients who are pregnant or lactating
13. Any other clinically significant medical disease or psychiatric condition that, in the Investigator's opinion, may interfere with protocol adherence or a patient's ability to give informed consent.
14. Participation in any other clinical trial (with the exclusion of observational, non-interventional studies)) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective of the trial is to determine MRD negativity (8 color flow, Euro-Flow plus Black Swan Panel) after induction and consolidation (10 I-KRd cycles including intensification in transplant-eligible and 12 IKRd cycles in transplant-ineligible patients) with a sensitivity of 10-5 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| after induction and consolidation (10 I-KRd cycles including intensification in transplant-eligible and 12 I-KRd cycles in transplantineligible patients) with a sensitivity of 10-5 |
|
| E.5.2 | Secondary end point(s) |
| To determine progression-free survival (PFS) - defined as time from study treatment initiation to progression or death from any cause whichever occurs first. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| to determine progression-free survival (PFS) - defined as time from study treatment initiation to progression or death from any cause whichever occurs first. |
|
| 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 | 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| 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
|
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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