| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Myeloma, Multiple Myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Myeloma, Multiple Myeloma |
|
| 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 | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028566 |
| E.1.2 | Term | Myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| 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 |
| 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
• To compare quality of life (QOL) between the two arms |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•All laboratory assessments should be performed within 21 days of
initiation of protocol therapy:
• 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 screening tests
performed within 21 days of initiation of protocol therapy:
Monoclonal plasma cells in the bone marrow > 10% (or proven
plasmocytic infiltration in bone marrow biopsy)and/or presence of a
biopsy-proven plasmacytoma
Monoclonal protein (M-protein) present in the serum and/or urine.
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/dl or upper limit of normal
[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 or proven plasmocytic infiltration in bone marrow biopsy..
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 documented symptomatic myeloma with
organ damage related to myeloma as defined above with laboratory
assessments performed within 21 days of initiation of protocol therapy.
• Participants must have myeloma that is measurable by either serum
or urine evaluation of the monoclonal component or by assay of serum
free light chains. 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 with abnormal
serum FLC ratio.
• Age between 18 and 65 years at the time of signing the informed
consent form.
• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix IV).
• Negative HIV blood test within 21 days of initiation of protocol
therapy. HIV-positive individuals on combination antiretroviral therapy
are ineligible because of the potential for pharmacokinetic (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.
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 pregnant or of 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 laboratory assessments should be performed within 21 days of initiation of protocol therapy:
• Participant 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 initiation of protocol therapy is
observed. Similarly, the dose of corticosteroids received by the participant as part of any initial therapy should
not exceed the equivalent of 160 mg of dexamethasone over a two-week period before initiation of protocol
therapy (see Appendix V for equivalence table).
• Primary amyloidosis (AL) or myeloma complicated by amylosis.
• Participants receiving any other investigational 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/mm3. Transfusion within 7 days of screening is not allowed to meet
platelet eligibility criteria
• Participants with an absolute neutrophil count (ANC) <1000/uL. Growth factor within 7 days of screening is
not allowed 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 > 1.5 ? Institutionnal ULN Total Bilirubin (Patients with benign
hyperbilirubinemia (e.g., Gilbert’s syndrome) are eligible ) or AST (SGOT), or ALT (SGPT), or alkaline
phosphatase ≥ 2x ULN
• Renal insufficiency, defined as serum creatinine > 170 µmol and/or creatinine clearance < 50 mL/min (either
actual or calculated values may be used). The Cockgroft-Gault formula should be used for calculating creatinine
clearance values:
(140-age) x Body mass (kg) x 0.85 (female) or 1.0 (male)
serum creat (mg/dL) x 72
• Respiratory compromise, defined as ventilation tests with DLCO < 50%
• Participant with clinical signs of heart or coronary failure, or evidence of left ventricular ejection fraction
(LVEF) < 40%. Participant with myocardial infarction within 6 months prior to enrollment or have New York
Heart Association (NYHA Appendix VII) Class III or IV heart failure, uncontrolled angina, severe uncontrolled
ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conductive system
abnormalities. Prior to study entry, any ECG abnormality at screening has to be documented by the investigator
as not medically relevant
• Intercurrent illness including, but not limited to ongoing or active severe infection, known (active or not)
infection with hepatitis B or C virus, poorly controlled diabetes, or severe uncontrolled psychiatric disorder or
psychiatric illness/social situations that would limit compliance with study requirements.
• Participants with previous history of another malignant condition. If malignancy was experienced more tha 10 years an confirmed as cured, these participants may be considered for the study on cse by case basis with PI discussion.
• Female participants 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. Lactating females must agree not to breast feed
while taking lenalidomide
• Inability to comply with an anti-thrombotic treatment regimen (e.g., administration of low weight heparin type
innohep® or equivalent)
• Peripheral neuropathy ≥ Grade 2 on clinical examination within 21 days of initiation of protocol therapy.
• 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
Arm 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 after the last disease
evaluation. Patients are stratified by county (US vs. IFM), cytogenetics risk factors (standard, high risk, FISH
failures) and ISS (Stage I vs. II vs. III). Patients will be randomized equally to the two arms using permuted
blocks within stratification combinations.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| progression Free Survival [Time frame : up to 4 years or until progression ] |
|
| E.5.2 | Secondary end point(s) |
The secondary objectives of the study are to compare the following outcomes between the two arms: the response
rates (CR, at least VGPR), time to progression, overall survival, toxicity, and quality of life. The reasons
that participants who received 1 cycle of therapy did not proceed to the randomization will be collected and
reported. Prognostic groups defined by gene expression profiling will be defined in correlative studies. Time to
progression (TTP) is defined as the time from randomization until progression. Patients who have died without
evidence of progression are censored in the TTP analysis and patients who are alive without progression are
censored at the last disease assessment. Overall survival is defined as the time of randomization to death.
Patients are censored at the time last known alive. The planned sample size is 1000 eligible patients over 36
months for accrual rate of 27-28 patients/month |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Response Rates [ Time Frame: up to 4 years or until progression ]
Time To Progression [ Time Frame: up to 4 years or until progression ]
Toxicity comparison [ Time Frame: from randomization up to 4 years or
until progression ]
Genetic prognostic groups definition [ Time Frame: from randomization
up to 4 years or until progression ]
Best treatment examination in each GEP-defined prognostic group. [
Time Frame: from randomization up to 4 years or until progression ] |
|
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 81 |
| 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 |
| Belgium |
| France |
| Switzerland |
|
| 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 |
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