| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| First relapsed or refractory multiple myeloma (including relapse after high dose chemotherapy followed by autologous stem cell transplantation) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the bone marrow, multiple myeloma (other designation: plasmacytoma) by relapse or non response of the 1st line theraphy |
| Krebserkrankung des Knochenmarks, Multiples Myelom (Andere Bezeichnung: Plasmozytom), bei Rückfall bzw. Nicht-Ansprechen nach der ersten verabreichten Therapie (Erstlinien-Therapie) |
|
| 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 | 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of the combination of bendamustine, lenalidomide and dexamethasone as 2nd-line therapy in patients with refractory/ relapsed multiple myeloma as defined by the combined CR-/VGPR-rate being achieved during the induction treatment phase or within four weeks after administration of the last induction cycle of the BRd regimen. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the
- Objective response rates (sCR, CR, VGPR, PR, MR) achieved during the induction treatment phase or within four weeks after the last administration of six induction cycles of the BRd-regimen.
- Best response (sCR, CR, VGPR, PR, MR) achieved during the whole study duration (i.e. including maintenance treatment phase)
- Time to progression (TTP)
- Overall survival (OS) at 18 months after the last evaluable patient has been enrolled into the study
- Safety and tolerability (type, frequency, severity, and relationship of adverse events to study therapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet the following inclusion criteria to be eligible for the study:
- Written informed consent to be obtained before any study specific procedure
- Patients with first relapsed or refractory multiple myeloma (including patients with relapse after high dose chemotherapy followed by autologous stem cell transplantation) who have received no more than one prior anti-myeloma treatment line. Refractory myeloma is defined as relapse or disease progression while on first line therapy, or progression within 60 days after completion of 1st-line therapy.
- Treatment with a lenalidomide/ dexamethasone-based 2nd-line regimen is indicated and intended
- Measurable disease as defined by at least one of the following 3 measurements:
*serum monoclonal protein level ≥ 1 g/dl (≥ 10 g/l) or
*urine M-protein level ≥ 200 mg/24hours or
*serum FLC assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/l) provided serum FLC ratio is abnormal
- ECOG performance status 0, 1, or 2
- Age ≥ 18 years
- All previous cancer therapy (except corticosteroid therapy), including radiation, cytostatic therapy and surgery, must have been discontinued at least 4 weeks prior to treatment in this study.
- No prior treatment with a bendamustine containing regimen
- Prior treatment with lenalidomid is allowed if the treatment is completed > 12 months prior to study entry and the patient responded to prior lenalidomid treatment
- Adequate hematological values
- Adequate hepatic function
- Adequate renal function
- Disease free of prior malignancies for > 5 years unless the patient
o has been treated with a curative intent and is considered to be in complete remission for ≥2 years prior to study enrolment
o or has a curatively-treated
o basal cell/ squamous cell carcinoma of the skin,
o carcinoma „in situ“of the cervix,
o ductal breast carcinoma in situ with complete surgical resection(i.e. negative margins),
o medullary or papillary thyroid tumor
o or low grade, early stage localized prostate cancer treated surgically with curative intent
- Patient has the capability to understand the information given by the investigator on the trial
- Patient‟s adherence to the protocol and geographic proximity to allow proper staging, treatment, and follow-up
- Female subjects of childbearing potential* must:
o understand that the study medication could have a potential teratogenic risk
o agree to fully comply with the mandatory pregnancy prevention programme as requested for the treatment with lenalidomide
o agree to use, and be able to comply with an effective, double-method contraception** without interruption, 4 weeks before starting study drug, throughout study drug therapy (including dose interruptions) and for 4 weeks after the end of study drug therapy, even if she has amenorrhoea. This applies also to females confirming abstinence to sexual intercourse.
o agree to have a medically supervised pregnancy test with a minimum sensitivity of 25 mIU/ml not more than 3 days prior to the start of study medication once the subject has been on effective contraception for at least 4 weeks. This requirement also applies to women of childbearing potential who practice complete and continued abstinence. The test should ensure that the subject is not pregnant at start of treatment
- Male subjects must
o agree to use condoms throughout study drug therapy, during any dose interruption and for at least 6 months after cessation of study therapy with bendamustine and for at least one week after cessation of study therapy with lenalidomide if their partner is of childbearing potential. In addition, their partner must also use a highly effective method of contraception as outlined above.
o agree not to donate semen during study drug therapy and for 6 months after end of study drug therapy with bendamustine and for one week after end of study therapy with lenalidomide.
* 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 (amenorrhoea following cancer therapy does not rule out childbearing potential), premature ovarian failure confirmed by a specialist gynaecologist, previous bilateral salpingo-oophorectomy or hysterectomy, XY genotype, Turner‟s syndrome or uterine agenesis.
** An effective, double method contraception must include a highly effective method of contraception, such as:
- Implant Levonorgestrel-releasing intrauterine system (IUS)
- Medroxyprogesterone acetate depot
- Tubal sterilization
- Sexual intercourse with a vasectomised male partner only; vasectomy confirmed by two negative semen analyses
- Ovulation inhibitory progesterone-only pills (i.e., desogestrel)
and an additional effective contraceptive method such as:
- Condom / femidom
- Diaphragm
- Cervical cap
- Abstinence |
|
| E.4 | Principal exclusion criteria |
- Pregnant or breast feeding females
- Any prior use of bendamustine
- Patients who are unable or unwillingly to undergo antithrombotic therapy
- Any serious underlying medical condition (at the judgment of the investigator) which impairs the ability of the patient to participate in the trial (e.g. active autoimmune disease, uncontrolled diabetes, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric disorder)
- Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she would participate in the study or any condition significantly confounding the ability to interpret data from the study, based on the local investigator‟s judgment
- Severe cardiovascular disease, including myocardial infarction within 6 months before study entry, New York Heart Association Class III or IV heart failure, uncontrolled angina or severe uncontrolled ventricular arrhythmias (≥ Lown 3)
- Use of any other experimental drug or therapy /treatment in a clinical trial 30 days prior to trial entry
- Known hypersensitivity to study drug(s) or hypersensitivity to any other component of the study drugs
- Any major surgical procedure within 30 days prior to study therapy
- Any concurrent antineoplastic therapy with chemotherapeutic agents or biologic agents or radiation therapy
- Known chronic hepatitis B or C, known HIV infection
- Jaundice or any other severe damage of the liver parenchyma
- Any contraindication for the treatment with bendamustine, lenalidomide, dexamethasone and / or pegfilgrastim in accordance with the appropriate SmPCs
- Any other concomitant drugs contraindicated for the use together with the study drugs according to the national health authorities. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is defined as the combined CR (complete remission) and VGPR (very good partial remission) rate achieved during the induction treatment phase or within 4 weeks after the last administration of the six induction cycles. The best response achieved within this time period will be used to assess the proportion of patients achieving the primary endpoint. CR and VGPR will be assessed according to the International uniform response criteria for multiple myeloma:
CR is therefore defined as
- Negative immunofixation in serum and urine and
- Disappearance of any soft tissue plasmacytomas and
- ≤ 5% plasma cells in bone marrow (confirmation with repeat bone marrow biopsy not needed)
VGPR is defined as
- Serum and urine M-protein detectable by immunofixation but not on electrophoresis or
- 90% or greater reduction in serum M-protein plus urine M-protein level < 100 mg per 24 h |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| An interim analysis will be performed for efficacy (allowing for determination of the primary endpoint) 4 weeks after the 13th evaluable patients will have completed the induction phase. The final analysis will take place once all patients have terminated trial therapy. |
|
| E.5.2 | Secondary end point(s) |
- Objective response rates (sCR, CR, VGPR, PR, MR; achieved within four weeks after the last administration of six induction cycles of the BRd regimen)
- Best response (sCR, CR, VGPR, PR, MR) achieved during the whole study duration (i.e. including maintenance phase)
- Time to progression (TTP)
- Overall survival (OS) at 18 months after the last evaluable patient has been enrolled into the study
- Safety and tolerability (type, frequency, severity, and relationship of adverse events to study therapy) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| An interim analysis will be performed for efficacy 4 weeks after the 13th evaluable patients will have completed the induction phase. A safety interim analysis will also take place 4 weeks after the 13th patient will have completed the induction phase. The final analysis will take place once all patients have terminated trial therapy. |
|
| 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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.8.3 |
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 | 8 |
| 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 | 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 |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
End of trial treatment is the last visit of the last patient undergoing the trial.
The trial may be stopped early based on the results of the efficacy and safety interim analysis or if new scientific data become available which change the risk/ benefit ratio. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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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