| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients diagnosed with smoldering multiple myeloma (SMM) or active multiple myeloma (MM) will be invited to participate in the study. |
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| E.1.1.1 | Medical condition in easily understood language |
| Individuals diagnosed with multiple myeloma or it's precursor, smoldering multiple myeloma, will be invited to participate in the study. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| 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 |
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| 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 | 10075894 |
| E.1.2 | Term | Smoldering myeloma |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 |
| This is a phase II study to assess the safety and efficacy of treating patients with intermediate-risk SMM with combinational therapy with dexamethasone and lenalidomide and treating patients with high risk SMM or active MM with combinational therapy with dexamethasone, lenalidomide, and carfilzomib. The primary objective is to determine the persistent MRD negativity rate one year following the completion of 2-year treatment. |
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| E.2.2 | Secondary objectives of the trial |
To determine the MRD negativity rate at the end of 6 months, 12 months, 24 months and at two years after the completion of treatment.
To determine the progression free survival and overall survival.
To determine duration of response.
To determine rate of adverse events
To determine the toxicities associated with this treatment approach in subjects with SMM.
To evaluate the incidence of myeloma after population-based treatment of SMM.
Various correlative work and relation to clinical outcome.
To describe quality of life of patients.
To describe the safety of the combination therapy.
Exploratory objective to treat active MM identified through screening.
|
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants that are diagnosed with MM, high- or intermediate-risk SMM in the iStopMM study will be invited to participate in this study. Each patient must meet all the following inclusion criteria to be enrolled in the study:
1) At least 18 years of age, with at least 6 months of expected survival
2) Active MM or SMM (defined as measurable M spike OR pathological FLC ratio AND bone marrow PC% > 10%) which is untreated
3) The following laboratory values obtained ≤ 30 days prior to registration.
o Calculated creatinine clearance* >=30 mL/min
o Absolute neutrophil count (ANC) >1000/mm3
o Platelet count >75000/mm3
o Hemoglobin ≥8.0 g/dL
o Total bilirubin ≤ 1.5 x ULN
o ALT and AST ≤ 3 x ULN
4) Prior therapy for the treatment of solitary plasmacytoma is permitted, but >7 days should have elapsed from the last day of radiation. NOTE: Prior therapy with clarithromycin, DHEA, anakinra, pamidronate or zoledronic acid is permitted. Any additional agents not listed must be approved by the Principal Investigator.
5) Measurable disease as defined by at least ONE of the following:
o Serum monoclonal protein >1.0 g/L
o >200 mg of monoclonal protein in the urine on 24 hour electrophoresis
o Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio.
6) ECOG performance status (PS) 0, 1 or 2
7) Provide informed written consent.
8) Negative pregnancy test done ≤7 days prior to entry, for women of childbearing potential only.
9) Willing to follow strict birth control measures as outlined in the protocol.
10) Female subjects: If they are of childbearing potential, agree to one of the following:
o Practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of trial drug, AND must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable
o Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
11) Male subjects: even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following:
o Agree to practice effective barrier contraception during the entire trial treatment period and through 90 days after the last dose of trial drug
o Must adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable
o Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception). Willing to return to enrolling institution for follow-up during the Active Treatment Phase of the trial.
o Agree not to donate sperm for at least 90 days after the last dose of carfilzomib
12) Patients must be willing and able to adhere to the study schedule and other protocol requirement
* According to the CKD-EPI equation
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| E.4 | Principal exclusion criteria |
1) MGUS or low-risk SMM.
2) Diagnosed or treated for another malignancy ≤ 2 years before trial enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. NOTE: Subjects with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
3) If any of the following exist at screening, subject will not be eligible for trial because this trial involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
o Pregnant women
o Nursing women
o Men or women of childbearing potential who are unwilling to employ adequate contraception (per protocol)
4) Other co-morbidity which would interfere with subject's ability to participate in trial, e.g. uncontrolled infection, uncompensated heart or lung disease.
5) Other concurrent chemotherapy, or any ancillary therapy considered investigational. NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment.
6) Peripheral neuropathy > Grade 3 on clinical examination or grade 2 with pain within 30 days prior to entry.
7) Major surgery ≤14 days prior to entry.
8) Evidence of current uncontrolled cardiovascular conditions, including hypertension, cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial infarction within the past 6 months. Note: Prior to trial entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
9) Known human immunodeficiency virus (HIV) positive.
Known hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection.
10) Any medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
11) Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure), or known sensitivity to mammalian-derived products. Known allergies, hypersensitivity, or intolerance to trial drugs.
12) LVEF < 40% for patients treated with carfilzomib.
13) Inability to comply with protocol/procedures.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| One year after 2-year treatment |
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| E.5.2 | Secondary end point(s) |
- Progression free survival
- Overall survival
- Duration of response
- Incidence of adverse events
- Patient reported outcome regarding quality of life |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| On a regular follow-up during 2-year treatment and five year clinical 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 | 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 | 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) | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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