Velcade (Bortezomib), Adriamycin Dexamethasone (PAD) or Vincristine Adriamycin Dexamethasone in Second Line Treatment of Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this research study is to test the safety and effectiveness of replacing vincristine with a drug called bortezomib (also known as Velcadeor PS341) in the standard therapy vincristine, doxorubicin (not limited to, but formerly referred to under the tradename Adriamycin) and dexamethasone (VAD) in patients with multiple myeloma. Multiple Myeloma is the second most common cancer of the blood. Bortezomib is the first approved cancer treatment in a new class of medicines called proteasome inhibitors. It disrupts the cell cycle of the cell, affecting numerous biologic pathways, including those related to growth and survival of cancer cells. The treatment will be used as second line treatment, which means either the disease has returned after a period of improvement (relapse) or the disease did not respond to the initial treatment (refractory). Patients will receive either bortezomib (PS341), doxorubicin (Adriamycin) and dexamethasone (PAD) or the VAD standard therapy.

Detailed Description
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Bortezomib, has been approved for use in patients with multiple myeloma, who have already received at least one prior treatment and whose disease is worsening on their last treatment and who have already undergone or are unsuitable for bone marrow transplantation. Bortezomib has significant activity in patients with relapsed multiple myeloma, its efficacy is increased with the addition of dexamethasone and it demonstrates synergy with doxorubicin. The VAD combination has been widely used in multiple myeloma and has demonstrated to be effective in relapsed patients. Based on previous trial results, it is hoped that bortezomib, in replacing vincristine in the VAD standard therapy, can improve the response to treatment of patients with multiple myeloma, with manageable side effects. This is an international, multicentre, randomised, open-label, parallel group study. About 212 patients will take part in the study. Patients will be treated with either bortezomib (PS-341), Adriamycin and Dexamethasone (PAD) or Vincristine, Adriamycin and Dexamethasone (VAD). There will be an initial 14 day screening period to evaluate if the patient is suitable for the study. After screening, eligible patients will be randomised to receive either PAD or VAD. Patients will receive therapy for up to 8 treatment cycles of 28 days each. After the treatment period, there will be a long-term follow-up period with monthly visits until disease progression or relapse. Thereafter follow-up will be continued by at least a phone call every other month. This long-term follow-up period will be performed for all patients until the last patient was treated and followed up for 1 year. Response to treatment will be assessed according to the European group for blood and marrow transplant criteria (EBMT). Disease burden will be monitored by measuring M-protein concentration in serum and in urine every 4 weeks until disease progression or relapse. Thereafter follow-up for survival will be continued every other month by at least a phone call. Safety will be assessed by monitoring of adverse events (AEs), vital signs, physical examination and clinical laboratory tests. Treatment with PAD or VAD will be for up to 8 cycles of 28 days each. Treatment beyond 6 cycles will be discussed on individual basis. Proposed dosages are: bortezomib 1.3 mg/m² intravenous (IV) bolus on Days 1, 4, 8, and 11; vincristine 0.4mg IV push on Days 1 to 4; doxorubicin 9mg/m² IV push on Days 1 to 4; dexamethasone in 1st cycle 40 mg daily on Days 1 to 4, 9 to 12 and 17 to 20, orally (or equivalent parenteral dose) and on subsequent cycles as 40 mg daily on Days 1 to 4 and 17 to 20 only.

Official Title
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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

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: adriamycin
* Drug: bortezomib
* Drug: dexamethasone
* Drug: vincristine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsed or refractory multiple myeloma following 1 previous line of therapy and, is scheduled by the investigator to be treated with vincristine, adriamycin and dexamethasone standard therapy measurable secretory multiple myeloma based on defined criteria Karnofsky performance status of >or = 60% fulfils defined laboratory requirements within 14 days before baseline if female, the patient is either postmenopausal or surgically sterilised or willing to use an acceptable method of birth control for defined period of time if male, the patient agrees to use an acceptable barrier method for contraception for a defined period of time. Exclusion Criteria: More than one previous line of therapy for multiple myeloma use of bortezomib in the previous line of therapy and/or received bortezomib in a previous trial known allergy or hypersensitivity to bortezomib, boron or mannitol peripheral neuropathy or neuropathic pain of grade 2 or higher myocardial infarction within 6 months of enrollment 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: VAD Treatment<br>vincristine in combination with adriamycin and dexamethasone | Drug: adriamycin<br>* adriamycin: 9mg/m² intravenous (IV) push on days 1 to 4<br>Drug: dexamethasone<br>* dexamethasone: 40 mg daily days 1- 4/9-12/17-20 - cycle 1 / days 1-4/17-20 - subsequent cycle<br>Drug: vincristine<br>* vincristine: 0.4mg IV push on days 1 to 4<br>|
| Experimental: PAD Treatment<br>bortezomib in combination with adriamycin and dexamethasone | Drug: adriamycin<br>* adriamycin: 9mg/m² intravenous (IV) push on days 1 to 4<br>Drug: bortezomib<br>* bortezomib: 1.3 mg/m² intravenous (IV) bolus on days 1, 4, 8, and 11<br>Drug: dexamethasone<br>* dexamethasone: 40 mg daily days 1- 4/9-12/17-20 - cycle 1 / days 1-4/17-20 - subsequent cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Confirmed Disease Response | The primary efficacy analysis was based on the best response obtained during the treatment period according to the European Group for Blood and Marrow Transplantation (EBMT) criteria as assessed by the investigator. The best confirmed response was defined as 2 separate and consecutive evaluations of response, at least 6 weeks apart (for progressive disease [PD], 1 to 3 weeks apart). The ordering of the responses was: complete response (CR), partial response (PR), minimal response (MR), no change (NC) and PD. CR was the best response and the poorest response was PD. | every 28 days during treatment period for up to 6 to 8 cycles | 
| Best Reported Disease Response | The primary efficacy analysis was based on the best response obtained during the treatment period according to the EBMT criteria as assessed by the investigator. The ordering of the responses was: CR, PR, MR, NC and PD. CR was the best response and the poorest response was PD. | every 28 days during treatment period for up to 6 to 8 cycles | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | DOR was defined as the duration from the date of the best confirmed response for subjects who achieved CR or PR to the date of first documented evidence of PD (or relapse for subjects who experienced CR) over the duration of the study. DOR = ([Date of PD or date of censoring - Date of best response]+1)/30.44. | every 28 days during treatment period for up to 6 to 8 cycles | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, bortezomib, Cancer, Hematology, bone marrow, immunoglobulin, relapse, refractory, plasma cell, Velcade, adriamycin, dexamethasone, vincristine