A Phase 2, Multicentre, Randomised, Open-Label, Parallel Group Study to Evaluate the Safety and Efficacy of Velcade® when added to Adriamycin-Dexamethasone Treatment versus Vincristine-Adriamycin-Dexamethasone Standard Treatment in Subjects with Multiple Myeloma who are Refractory to or Have Relapsed after Primary Therapy for Multiple Myeloma. - PAD versus VAD in 2nd line multiple myeloma

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2006-001709-27-LT
• Date of registration: 29/06/2006
• Prospective Registration: Yes
• Primary sponsor: Janssen-Cilag International N.V.
• Public title: A Phase 2, Multicentre, Randomised, Open-Label, Parallel Group Study to Evaluate the Safety and Efficacy of Velcade® when added to Adriamycin-Dexamethasone Treatment versus Vincristine-Adriamycin-Dexamethasone Standard Treatment in Subjects with Multiple Myeloma who are Refractory to or Have Relapsed after Primary Therapy for Multiple Myeloma. - PAD versus VAD in 2nd line multiple myeloma
• Scientific title: A Phase 2, Multicentre, Randomised, Open-Label, Parallel Group Study to Evaluate the Safety and Efficacy of Velcade® when added to Adriamycin-Dexamethasone Treatment versus Vincristine-Adriamycin-Dexamethasone Standard Treatment in Subjects with Multiple Myeloma who are Refractory to or Have Relapsed after Primary Therapy for Multiple Myeloma. - PAD versus VAD in 2nd line multiple myeloma
• Date of first enrolment: 25/09/2006
• Target sample size: 212
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-001709-27
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no

Countries of recruitment

Germany, Hungary, Lithuania

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female subject, aged >= 18 years.
2. The subject has given 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performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to his or her medical care.
3. Subject was previously diagnosed with multiple myeloma based on standard criteria and has measurable disease. Measurable disease for secretory multiple myeloma is defined as any quantifiable serum monoclonal protein value (generally, but not exclusively, greater than 1 g/dL of immunoglobulin G (IgG) M-Protein and greater than 0.5g/dL immunoglobulin A (IgA)) or urine light-chain excretion of e 200 mg/24 hours.
4. The subject has relapsed or is refractory for multiple myeloma following 1 previous line of therapy and is scheduled by the investigator to be treated with vincristine, adriamycin and dexamethasone (VAD) combination treatment. PD or relapse are defined as one or more of the following criteria:
Criteria for PD:
Criteria for PD for subjects not in CR
·>25% increase in either serum or urine M-protein;
·>25% increase in plasma cells on bone marrow;
·Definite increase in size of bone lesion or plasmacytoma;
·Development of new bone lesion or plasmacytoma; or
·Development of hypercalcemia (corrected serum calcium >11.5 mg/dl or 2.8 mmol/l) not attributable to other causes.
Criteria for relapse from CR
·reappearance of serum or urinary paraprotein on immunofixation or routine electrophoresis, confirmed by at least one further investigation and excluding oligoclonal immune reconstitution
·>5% plasma cells in bone marrow aspirate or on trephine bone biopsy
·Development of new lytic bone lesions or soft tissue plasmacytomas or definite increase in the size of residual bone lesions
·Development of hypercalcemia (corrected serum calcium >11,5 mg/dl or 2.8 mmol/l) not attributable to any other cause.
5.Subject has a Karnofsky performance status of >= 60 (see Attachment 1: Karnofsky Performance Status Scale).
6. Subject has a life expectancy estimated at screening of at least 6 months.
7. The subject meets the following pretreatment laboratory criteria at and within 14 days before baseline (Day 1 of Cycle 1, before study drug administration):
-platelet count >= 50x 109/L;
-haemoglobin >7.5 g/dl without transfusion support within 7 days before the test;
-creatinine clearance >= 20 mL/min (calculated or measured, see Attachment 2: Creatinine Clearance Calculation for formula).
-absolute neutrophil count (ANC) >= 0.75 x 10 9/L without the use of colony stimulating factors.

-corrected serum calcium < 14 mg/dL (3.5 mmol/L).
-aspartate transaminase (AST): <= 2.5 x the upper limit of normal (ULN).
-alanine transaminase (ALT): <= 2.5 x ULN.
-total bilirubin: <= 1.5 x ULN.
8. The subject is, in the investigators opinion, willing and able to comply with the protocol requirements.
9. If female, the subject is either postmenopausal or surgically sterilised or willing to use an acceptable method of birth control (i.e., total abstinence periodic abstinence can not be allowed-, a hormonal contraceptive, intrauterine device, diaphragm with spermicide, or condom with spermicide) from screening through at least 30 days after completion of the last treatment cycle.
10. If male, the subject agrees to use an acceptable barrier method for contraception from screening through at least 30 days after completion of the last treatment cycle.
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Exclusion criteria:
1. Subject received more than one previous line of therapy for multiple myeloma.
2. Subject has known allergy or hypersensitivity to bortezomib, boron or mannitol.
3. Use of Velcade® in the previous line of therapy and/or the subject received Velcade® in a previous trial.
4. Subject has oligosecretory or non-secretory multiple myeloma.
5. Subject received nitrosoureas or any other chemotherapy (including thalidomide), clarithromycin, interferon within 6 weeks.
6. Subject received corticosteroids (> 10 mg/day prednisone or equivalent) within 3 weeks before enrolment.
7. Subject received immunotherapy or antibody therapy within 8 weeks before enrolment.
8. Subject received plasmapheresis within 4 weeks before enrolment.
9. Subject had major surgery within 4 weeks before enrolment (kyphoplasty was not considered major surgery).
10. Subject has peripheral neuropathy or neuropathic pain of grade 2 or greater intensity, as defined by the National Cancer Institute Common Terminology Criteria of Adverse Events (NCI CTCAE), version 3.0 (see Attachment 6 for link).
11. Subject had a myocardial infarction within 6 months of enrolment or had 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 conduction system abnormalities.
12. Subject has poorly controlled hypertension, diabetes mellitus, or other serious medical or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol.
13. Subject was treated for a cancer other than multiple myeloma within 5 years before enrolment, with the exception of basal cell carcinoma or cervical cancer in situ.
14. Subject is known to be human immunodeficiency virus (HIV)-positive. Subjects assessed by the investigator to be at risk for HIV infection should be tested in accordance with local policies.
15. Subject was known to be hepatitis B surface antigen-positive or had known active hepatitis C infection. (Subjects assessed by the investigator to be at risk for hepatitis B or C infection are to be tested in accordance with local regulations.)
16. Subject had an active systemic infection requiring treatment.
17. Subject uses disallowed medication (see section 8.2).
18. Subject has received an experimental drug or used an experimental medical device within 4 weeks before enrolment.
19. If female, the subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum pregnancy test at screening. Pregnancy testing is not required for postmenopausal or surgically sterilised women.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Multiple Myeloma
MedDRA version: 9.0 Level: LLT Classification code 10028228

Intervention(s)

Trade Name: VELCADE
Product Name: VELCADE 3.5 mg powder for solution for injection
Product Code: PS-341, 26866138-AAA-PB-001
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: bortezomib
CAS Number: 179324-69-7
Current Sponsor code: 26866138
Other descriptive name: Boronic Acid: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2[(pyrazinylcarbonyl)amino]propyl]amino]butyl
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 3.5-

Primary Outcome(s)

Main Objective: To assess the safety and efficacy of replacing vincristine with Velcade® (bortezomib, also named PS341) in the standard therapy vincristine, adriamycin and dexamethasone (VAD) in subjects with multiple myeloma who are refractory to or have relapsed after their primary therapy for multiple myeloma. The efficacy response will be measured by the response rate of the disease.

Primary end point(s): Primary endpoint is Response Rate as defined by the combination of subjects with CR and PR according to the EBMT (European Group for Blood and Marrow Transplantation) criteria. It will be analysed by a stratified Mantel-Hanszel test at a 2-sided level where a = 5%. The stratification variables will be primary therapy (high dose versus conventional dose therapy and whether or not stem cells were transplanted), age groups and country.
The primary analysis will be based on the best response obtained during the treatment period.
Subjects who discontinue the treatment period without reaching a PR or CR will be analysed as non-responders.

Secondary Objective: To assess the duration of response, event free survival, the time to progression, the one year survival and the overall survival of the subjects treated with Velcade® in combination with the adriamycin and dexamethasone (PAD) therapy versus the VAD standard therapy.

Secondary ID(s)

26866138MMY2038