| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Myeloma, Multiple Myeloma |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028566 |
| E.1.2 | Term | Myeloma |
|
| 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 compare progression-free survival (PFS) between Arm A and Arm B |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the response rates (RR) between the two arms
• To compare time to progression (TTP) between the two arms
• To compare the overall survival (OS) between the two arms
• To compare the toxicity between the two arms
• To define genetic prognostic groups evaluated by gene expression profiling (GEP)
• To examine the best treatment in each Gene Expression Profile-defined prognostic group
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Eligibility Criteria for registration
• Participants must have a diagnosis of MM, according to International Myeloma Foundation 2003 Diagnostic Criteria. According to these criteria, all three of the following must be met with labs peformed within 21 days of study entry:
Monoclonal plasma cells in the bone marrow > 10% and/or presence of a biopsy-proven plasmacytoma
Monoclonal protein (M-protein) present in the serum and/or urine. If no monoclonal protein is detected (non-secretory) disease, then > 30% monoclonal bone marrow plasma cells and/or a biopsy-proven plasmacytoma required
Myeloma-related organ dysfunction (1 or more) of the following. A variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy.
[C] Calcium elevation in the blood, defined as serum calcium > 10.5 mg/l or upper limit of normal
[R] Renal insufficiency, defined as serum creatinine > 2 mg/dl
[A] Anemia, defined as hemoglobin <10 g/dl or 2 g < normal
[B] Lytic bone lesions or osteoporosis. If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) are the sole defining criteria, then > 30% plasma cells are required in the bone marrow.
Note: These criteria identify Stage IB and Stages II and III A/B myeloma by Durie-Salmon stage. Stage IA becomes smoldering or indolent myeloma.
• Participants must have symptomatic myeloma with organ damage related to myeloma as defined in section 3.1.1 with labs done within 21 days of study entry.
• Participants must have myeloma that is measurable by either serum evaluation of the monoclonal component or by assay of free light chains (serum or urinary). Measurable disease is defined as one or more of the following: serum M-protein > 1 g/dl, urine M-protein > 200 mg/24 h, and/or serum FLC assay: involved FLC level > 10 mg/dl provided serum FLC ratio is abnormal.
• Age between 18 and 65 years at the time of signing the informed consent form.
• ECOG performance status <2 (Karnofsky >60%, see Appendix V).
• Negative HIV blood test within 21 days of study entry. HIV-positive individuals on combination antiretroviral therapy are ineligible because of the potential for PK interactions with lenalidomide, bortezomib and/or dexamethasone. In addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
o Criteria for women of non-childbearing potential
A female subject or a female partner of a male subject is considered to have childbearing potential unless she meets at least one of the following criteria:
• Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year*
• Premature ovarian failure confirmed by a specialist gynaecologist
• Previous bilateral salpingo-oophorectomy, or hysterectomy
• XY genotype, Turner syndrome, uterine agenesis.
*Amenorrhoea following cancer therapy does not rule out childbearing potential.
Female subjects of childbearing potential must follow the recommandations as precognized in the protocol.
Male subjects must
- Agree to use condoms throughout study drug therapy, during any dose interruption and for one week after cessation of study therapy if their partner is of childbearing potential and has no contraception.
- Agree not to donate semen during study drug therapy and for one week after end of study drug therapy.
All subjects must
- Agree to abstain from donating blood while taking study drug therapy and for one week following discontinuation of study drug therapy.
- Agree not to share study medication with another person and to return all unused study drug to the investigator.
• Ability to understand and the willingness to sign a written informed consent document. Voluntary written informed consent must be obtained before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
|
|
| E.4 | Principal exclusion criteria |
All labs should be done within 21 days of study entry.
• Participant must not have been treated with any prior systemic therapy. Treatment by localized radiotherapy is not an exclusion criterion if an interval of at least two weeks between the end of radiotherapy and entry in the study is observed. Similarly, the dose of corticosteroids received by the participant prior to study entry as part of any initial therapy should not exceed the equivalent of 160 mg of dexamethasone over a two-week period.
• Primary amyloidosis (AL) or myeloma complicated by amylosis.
• Participants may not be receiving any other study agents.
• Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• Poor tolerability or known allergy to any of the study drugs or compounds of similar chemical or biologic composition to lenalidomide, bortezomib and/or dexamethasone.
• Participants with platelet level <50,000/uL. Transfusion may not be used to meet platelet eligibility criteria
• Participants with an absolute neutrophil count (ANC) <1000/uL. Growth factor may not be used to meet ANC eligibility criteria.
• Participants with hemoglobin level < 8.0 g/dL. Transfusion may be used to meet hemoglobin eligibility criteria.
• Hepatic impairment, defined as bilirubin > 2mg/dL and AST (SGOT), ALT (SGPT), or alkaline phosphotase > 2x ULN
• Renal insufficiency, defined as serum creatinine > 2.5 mg/dL and/or creatinine clearance < 40 mL/min (either actual or calculated values may be used)
• Respiratory compromise, defined as ventilation tests and DLCO < 50% normal
• Participant must not demonstrate clinical signs of heart or coronary failure, or evidence of left ventricular ejection fraction (LVEF) < 40%. Participant must not have myocardial infarction within 6 months prior to enrollment or have New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conductive system abnormalities.
• Intercurrent illness including, but not limited to ongoing or active severe infection, known infection with hepatitis B or C virus, poorly controlled diabetes, or psychiatric illness/social situations that would limit compliance with study requirements.
• Participants may not have previous history of another malignant condition except for basal cell carcinoma and stage I cervical cancer.
• Female participants must not be pregnant or breast-feeding. Pregnant women are excluded from this study because lenalidomide is an immunomodulatory agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with lenalidomide, breastfeeding should be discontinued if the mother is treated with lenalidomide. These potential risks may also apply to other agents used in this study.
• Inability to comply with an anti-thrombotic treatment regimen (e.g., aspirin, Lovenox administration)
• Peripheral neuropathy > Grade 2 on clinical examination.
• Mental illness likely to interfere with participation in the study and adults under juridical protection
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objective of this randomized phase III study is to compare the progression-free survival (PFS) of Arms A (conventional dose arm) and Arm B (high dose therapy arm) in newly diagnosed myeloma patients who have completed 1 cycle of RVD. PFS is defined as the time from randomization until progression or death from any cause. Patients alive without confirmed progression will be censored at the time of the last disease evaluation. Deaths without progression are counted as failures even if they occur long after the last disease evaluation. Patients are stratified by county (US vs. IFM), poor vs. standard cytogenetic risk factors and ISS (Stage I vs. II vs. III). Patients will be randomized equally to the two arms using permuted blocks within stratification combinations.
Endpoint definitions
Duration of overall response: The duration of overall response is measured as the time from initiation of first response to first documentation of disease progression or death. Patients who have not progressed or died are censored at the date last known progression-free.
Duration of overall complete response: The duration of overall CR is measured as the time from initiation of CR to first documentation of disease progression or death. Patients who have not progressed or died are censored at the date last known progression-free .
Progression-Free Survival (PFS): the primary endpoint in this study. PFS is defined as the time from initiation of the first cycle of RVD to the disease progression or death from any cause. Patients who have not progressed or died are censored at the date last known progression-free.
Time to progression is defined as the time time from initiation of the first cycle of RVD until progression. Patients who have died without evidence of progression are censored in the TTP analysis at the time of death and patients who are alive without progression are censored at the last disease assessment.
Overall survival (OS): OS is defined as the time initiation of the first cycle of RVD to death. Alive patients are censored at the date last known alive.
|
|
| 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 | No |
| 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Strategy of the study : VRD +/- AG : Arm A and B |
|
| 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 | 81 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
| Last visit of last subject. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
