| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with newly diagnosed symptomatic multiple myeloma according to the International Myeloma Working Group Diagnostic Criteria (Kyle 2009) |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with newly diagnosed symptomatic multiple myeloma according to the International Myeloma Working Group Diagnostic Criteria (Kyle 2009) |
| Formålet med denne protokol er at teste effekten af at behandle patienter med nydiagnostiseret myelomatose med 5 forskellige lægemidler, som alle er aktive overfor myelomatose |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| 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 efficacy and safety of the combination therapy of doxorubicin, cyclophosphamide, bortezomib, dexamethasone and lenalidomide in newly diagnosed multiple myeloma patients |
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| E.2.2 | Secondary objectives of the trial |
Efficacy: To determine the clinical efficacy as measured by response rate (sCR plus CR plus VGPR) of the combination of doxorubicin, cyclophosphamide, bortezomib, dexamethasone and lenalidomide in patients with newly diagnosed multiple myeloma at 4-weeks after completion of 8 cycles of ACVDL, and 3 months after 4 cycles of ACVDL followed by high-dose melphalan.
Safety: To evaluate the safety profile of the combination of doxorubicin, cyclophosphamide, bortezomib, dexamethasone and lenalidomide in newly diagnosed multiple myeloma patients.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria:
1. Male or female subjects ³ 18 years at the time of signing informed consent.
2. Subject is diagnosed with symptomatic multiple myeloma based on the International Myeloma Working Group Diagnostic Criteria (Kyle 2009):
a. Monoclonal plasma cells in the bone marrow ≥10% and/or presence of a biopsy-proven plasmacytoma.
b. Monoclonal 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 is required.
c. Myeloma-related organ dysfunction (1 or more)*:
o [C] Calcium elevation in the blood (Ionized serum calcium > 0.25 mmol/l above the upper limit of normal)
o [R] Renal insufficiency (Serum creatinine > 173 µmol/l)
o [A] Anemia (Hemoglobin < 6.0 mmol/l)
o [B] Lytic bone lesions or osteoporosis#
* A variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy. Such dysfunction is sufficient to support classification as myeloma if proven to be myeloma related.
# If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) is the sole defining criteria, then ≥30% plasma cells are required in the bone marrow.
3. The myeloma disease burden must be measurable with at least one of the following criteria (Durie et al. 2006):
a. Serum M-protein ≥ 10 g/l
b. Urine M-protein ≥ 200 mg/24 h
c. Involved FLC ≥ 100 mg/l provided serum FLC ratio is abnormal
d. Bone marrow plasma cells > 30%
4. Subject has a Karnofsky performance status of ≥ 60 (Appendix 10).
5. 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.
6. Subject is willing and able to comply with the protocol as judged by the investigator.
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| E.4 | Principal exclusion criteria |
1. Any prior systemic therapy for multiple myeloma.
2. Other therapies such as biologic therapy and chemotherapy less than 3 months prior to screening.
3. Concurrent or recent (less than 2 weeks prior to Screening) radiotherapy or surgery.
4. Prior glucocorticoid treatment of multiple myeloma exceeding dexamethasone 20mg/day for a maximum of 7 days. Topical glucocorticosteroid therapy to treat non-malignant comorbid disorders is permitted.
5. More than or equal to grade 2 peripheral neuropathy according to the NCI-CTC criteria on clinical examination within 14 days before enrollment (Day 1 of Cycle 1).
6. Evidence of mucosal or internal bleeding and/or platelet counts < 50 x 109/l. Platelet transfusions may not be used to meet PLT eligibility criteria.
7. Absolute neutrophil count (ANC) < 1 x 109/l. Growth factors may not be used to meet ANC eligibility criteria.
8. Hemoglobin < 5.0 mmol/l. The subject may be included after correction of the hemoglobin level by transfusion or treatment with erythropoietin.
9. Alanine aminotransferase (ALAT) > 2 x ULN.
10. Myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class IV heart failure (see Appendix 15), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant.
11. Clinically relevant active infection or serious co-morbid medical conditions, such as chronic obstructive or chronic restrictive pulmonary disease, and cirrhosis.
12. Any 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.
13. Prior malignancy (within the last 3 years) except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, in situ breast cancer, in situ prostate cancer or other cancer for which the subject has been disease-free for at least 3 years.
14. Female subject is pregnant or breast-feeding. The first serum pregnancy test to be done within 10-14 days prior to the study treatment start and repeated serum pregnancy test to be done within 24 hours prior to the start of study treatment.
15. Female subjects who are of childbearing potential (biologically capable of becoming pregnant) or men with partners of childbearing potential, who are unwilling or unable to use effective means of contraception. The means of contraception must either commit to continued abstinence from sexual intercourse or begin TWO acceptable methods of birth control, one highly effective method (hormonal contraceptives pills, injections or implants, tubal ligation, partner’s vasectomy) and one additional effective method (condom, diaphragm, cervical cap) AT THE SAME TIME, at least 28 days before she starts ACVDL and for at least 28 days after the last dose of ACVDL.
16. Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
17. Uncontrolled diabetes mellitus at the discretion of the investigator.
18. Hypersensitivity and/or contraindication to any one of the Investigational Medicinal Products (IMP), acyclovir or similar anti-viral drug.
19. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes).
20. Known HIV infection.
21. Known active hepatitis B or C viral infection.
22. Known intolerance to steroid therapy.
23. Current or recent (within 30 days prior to Screening) treatment with another investigational drug.
24. Unable to comply with the administration of the study treatment.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy
The response rate of stringent complete response (sCR) or complete response (CR) or very good partial response (VGPR) at 4-weeks after completion of 8-cycle ACVDL, and 3 months post 4-cycle ACVDL followed by high-dose melphalan and stem cell transplantation. The response rate is defined as the percentage of patients who achieve either a sCR or CR or VGPR using International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma (Durie et al. 2006).
Safety
The following parameters will be used to evaluate the safety of the ACVDL therapy
1. Vital signs
2. Physical examination
3. Peripheral neuropathy assessment
4. FACT/GOG-Neurotoxicity Questionnaire
5. ECG & Echocardiography
6. Serum haematology, biochemistry and immunology
7. Urinalysis for protein and glucose
8. Adverse events (NCI Common Terminology Criteria for Adverse Events, Version 4.0)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety: Patients are evaluable for safety when they have received at least one dose of study treatment.
Efficacy: The response rate of stringent complete response (sCR) or complete response (CR) or very good partial response (VGPR) at 4-weeks after completion of 8-cycle ACVDL, and 3 months post 4-cycle ACVDL followed by high-dose melphalan and stem cell transplantation. The response rate is defined as the percentage of patients who achieve either a sCR or CR or VGPR using International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma (Durie et al. 2006).
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| E.5.2 | Secondary end point(s) |
1. The percentage of patients who achieve either a sCR or a CR using IMWG Response Criteria 2006 after completion of 4-cycle ACVDL, 4 weeks after completion of the 8-cycle ACVDL (non-SCT patients), and 3 months post 4-cycle ACVDL followed by high-dose melphalan and stem cell transplantation (SCT patients). The endpoint will also be evaluated by baseline stage of myeloma according to ISS 2005 when allowed by sample size.
2. The percentage of patients who achieve a VGPR using IMWG Response Criteria 2006 after completion of 4-cycle ACVDL, 4 weeks after completion of the 8-cycle ACVDL (non-SCT patients), and 3 months post 4-cycle ACVDL followed by high-dose melphalan and stem cell transplantation (SCT patients). The endpoint will also be evaluated by baseline stage of myeloma according to ISS 2005 when allowed by sample size.
3. Time to progression (TTP) measured from date of first dose of the ACVDL therapy until documentation of disease progression according to IMWG Response Criteria 2006. The TTP will be stratified by the baseline stage of myeloma according to ISS 2005. Death due to cause other than progression will be censored. Patient without an event will be censored at date last known progression-free.
4. Progression-free survival (PFS) defined as the start of the ACVDL therapy until documentation of disease progression according to IMWG Response Criteria 2006 or death due to any cause. The PFS will be stratified by the baseline stage of myeloma according to ISS 2005. Patients without an event will be censored at date last known progression-free.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. The percentage of patients who achieve either a sCR or a CR or a VGPR using IMWG Response Criteria 2006 after completion of 4-cycle ACVDL, 4 weeks after completion of the 8-cycle ACVDL (non-SCT patients), and 3 months post 4-cycle ACVDL followed by high-dose melphalan and stem cell transplantation (SCT patients).
2. Time to progression (TTP) measured from date of first dose of the ACVDL therapy until documentation of disease progression (truncated).
3. Progression-free survival (PFS) defined as the start of the ACVDL therapy until documentation of disease progression (truncated). |
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| 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 | No |
| 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
| 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 | 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
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| End of trial is with the last visit of the last patient |
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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 | 7 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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