| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed multiple myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 evaluate the overall response rate after 4 cycles and the best response to induction therapy with combination of lenalidomide, subcutaneous bortezomib, and dexamethasone (RsqVD) in patients with newly diagnosed multiple myeloma. |
|
| E.2.2 | Secondary objectives of the trial |
i. To evaluate the rate and severity of Peripheral Neuropathy (PN) of SQ bortezomib in combination with lenalidomide, and dexamethasone after the 4th and after the final cycle of induction therapy
ii. To evaluate safety of induction therapy
iii. To evaluate safety of maintenance therapy
iv. To evaluate Time To Progression (TTP)
v. To evaluate Progression-Free Survival (PFS)
vi. To evaluate duration of response
vii. To evaluate Overall Survival (OS).
Exploratory Objectives:
For patients who elect to go on to stem cell transplant, exploratory endpoints will also be stem cell yield (number of CD34+ cells and days of harvesting) and engraftment parameters.
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Primary Objectives
Identification and validation of protein biomarkers to predict response to RsqVD induction therapy.
i) List of differentially expressed proteins from a discovery proteomic comparison of two patient groups, non-responders to RsqVD therapy and responders to RsqVD therapy
ii) Validation of predictive biomarkers of response to RsqVD induction therapy in a cohort of patients enrolled in the RsqVD trial.
Secondary Objectives
Validation of biomarkers of bone disease in multiple myeloma patients enrolled on the RsqVD study in order to evaluate their potential to predict relapse in patients and monitor bone disease progression from baseline pre-treatment to disease progression and/or withdrawal from the RsqVD study.
Discover and validate biomarkers that can detect sub-clinical bone lesions by monitoring relapse to RsqVD therapy and bone disease progression in patients. |
|
| E.3 | Principal inclusion criteria |
1. Participants must have a diagnosis of MM according Revised International Myeloma Working Group diagnostic criteria (Rajkumar 2014):
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma and
any one or more of the following myeloma defining events:
•End organ damage that can be attributed to the underlying plasma cell proliferative disorder,
specifically:
- Hypercalcaemia: serum calcium >0·25 mmol/L (>1 mg/dL) higher than the upper limit of
normal or >2·75 mmol/L (>11 mg/dL)
- Renal insufficiency: creatinine clearance <40 mL per min† or serumcreatinine >177 μmol/L
(>2 mg/dL)
- Anemia: hemoglobin value of >20 g/L below the lower limit of normal,or a hemoglobin
value <100 g/L
- Bone lesions: one or more osteolytic lesions on skeletal radiography,CT, or PET-CT
•One or more of the following biomarkers of malignancy:
- Clonal bone marrow plasma cell percentage ≥60%
- Involved: uninvolved serum free light chain ratio§ ≥100
- >1 focal lesions on MRI studies
2. Patient has received no prior treatment with any systemic therapy for the treatment of multiple myeloma.
a. Prior treatment of hypercalcaemia or spinal cord compression with corticosteroids does not disqualify the patient (the dose should not exceed the equivalent of 160 mg of dexamethasone in a 2 week period)
b. Bisphosphonates are permitted
c. Patients treated with local radiotherapy with or without concomitant exposure to steroids, for pain control or management of cord/nerve root compression, are eligible. Two weeks must have lapsed since last date of radiotherapy, which is recommended to be a limited field. Patients who require concurrent radiotherapy should have entry to the protocol deferred until the radiotherapy is completed and 2 weeks have passed since the last date of therapy.
3. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
4. Age ≥ 18 years at the time of signing Informed Consent.
5. Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Lenalidomide Pregnancy Prevention Risk Management Plan. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mlU/mL 10 to14 days prior to therapy and repeated again within 24 hours prior to prescribing lenalidomide for induction Cycle 1 (prescriptions must be filled within 7 days as required by Lenalidomide Pregnancy Prevention Risk Management Plan) and must either commit to complete abstinence from
heterosexual contact or begin TWO acceptable methods of birth control, one highly effective method and one additional effective (barrier) method, AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must practice complete abstinence or agree to use a condom during sexual contact with a FCBP even if they have had a successful vasectomy. All study participants must be registered into the mandatory Lenalidomide Pregnancy Prevention Risk Management Plan, and be willing and able to comply with the requirements of the Lenalidomide Pregnancy Prevention Risk Management Plan.
*A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy (the
urgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) 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. has had menses at any time during the preceding 24 consecutive months)
6. All necessary baseline studies for determining eligibility must be obtained within 21 days prior to enrolment
7. Subject has an ECOG performance status of < 2 or Karnofsky performance status of ≥ 60 (Appendix E).
8. Subject must be able to adhere to the study visit schedule and other protocol requirements.
9. Participants must also have measurable disease according to the Standard Diagnostic Criteria
(Rajkumar 2009):
• Serum IgG, IgA, or IgM M-protein ≥ 0.5 g/dL, or
• Serum IgD M-protein ≥ 0.05 g/dL, or
• Urinary M-protein excretion of more than 200 mg/24 hours, or
• Serum free light chains of at least 100 mg/L with an abnormal FLC ratio |
|
| E.4 | Principal exclusion criteria |
1. Patient has ≥ Grade 2 peripheral neuropathy on clinical examination within 14 days before enrolment
2. Renal insufficiency (serum creatinine levels > 2.5 mg/dL/221µmol/L, calculated creatinine clearance with Cockcroft-Gault formula (see Appendix G) < 45 ml/min)
3. Subjects with evidence of mucosal or internal bleeding and/or platelet refractory (i.e. unable to maintain a platelet count 50,000 cells/mm3)
4. Subjects with an absolute neutrophil count (ANC) < 1000 cells/mm3. Growth factors may not be used to meet ANC eligibility criteria
5. Subjects with a haemoglobin < 8.0 g/dL
6. AST (SGOT) and ALT (SGPT) > 2 x ULN, bilirubin levels 1.5 ULN
7. Concomitant therapy medications that include corticosteroids (except as indicated in inclusion criteria)
8. Myocardial infarction within 6 months prior to enrolment or has New York Heart Association (NYHA) Class III or IV heart failure (Appendix G), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
9. Clinically relevant active infection requiring treatment (antibiotics, antivirals, antifungals)
10. Any serious co-morbid condition, including laboratory abnormalities, that in the opinion of the Investigator places the subject at unacceptable risk if he/she were to participate in the study.
11. Female subject is pregnant or breast-feeding
12. Serious psychiatric illness or addiction likely to interfere with participation in this clinical study
13. Uncontrolled diabetes mellitus
14. Contraindication to any required concomitant drugs or supportive therapies including hypersensitivity to all anticoagulation and antiplatelet options or hypersensitivity to acyclovir or similar anti-viral drug. History of allergic reaction/hypersensitivity attributed to compounds containing boron, mannitol, polysorbate 80 or sodium citrate dehydrate
15. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes)
16. Known seropositive for or active HIV infection active hepatitis B or C viral infection. Patients who are seropositive because of hepatitis B virus vaccine are eligible
17. Known intolerance to steroid therapy
18. Patient has hypersensitivity to bortezomib, boron, or mannitol
19. Diagnosed or treated for another malignancy within 2 years of enrolment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy
20. Participation in clinical trials with other anti-myeloma investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial
21. Radiation therapy within 2 weeks before randomization. Enrolment of subjects who require concurrent radiotherapy
(which must be localized in its field size) should be deferred until the radiotherapy is completed and 2 weeks have elapsed since the last date of therapy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The most clinically relevant endpoint for this multiple myeloma population is overall response rate (ORR). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 4 cycles of treatment. |
|
| E.5.2 | Secondary end point(s) |
i. Peripheral neuropathy (PN).
ii. Safety.
iii. Time to progression (TTP).
iv. Progression-free survival (PFS).
v. Duration of response.
vi. Overall survival (OS).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
i. PN: after 4th and after final induction treatment cycle.
ii. Safety: end of each treatment cycle and up to 30 days post last dose of study drug.
iii. TTP: time from registration to progression, censored at date last known to be progression-free or at time of death.
iv. PFS: time from registration to disease progression or death from any cause, censored at date last known to be progression-free for those who have not progressed or died.
v. Duration of response: time from first response after treatment to date of disease progression or death from any cause, or date last known progression-free and alive.
vi. OS: time from registration to death from any cause or date last known alive for those who have not died. |
|
| 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 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 | 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
|
| All patients on maintenance treatment will complete an end of treatment/study withdrawal visit by 31 October 2019 and continue with treatment as per standard of care. Patients will be asked if they wish to provide informed consent to be followed up annually for overall survival outcomes through monitoring by the National Cancer Registry of Ireland (NCRI) for a maximum of 5 years. The trial will be considered fully closed by 2025. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 11 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
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