Study to Evaluate Optimized Retreatment and Prolonged Therapy With Bortezomib

Study Overview
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Brief Summary
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The objective of this study is to describe the effect of optimized retreatment with bortezomib in combination with dexamethasone followed by prolonged therapy with bortezomib, versus standard retreatment with bortezomib in combination with dexamethasone on progression free survival (PFS).

Detailed Description
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This is an interventional, randomized (assignment to a group is happening by chance, like flipping a coin), open-label, parallel-group, event-driven, international, multicenter, Phase 3 study. This study has different phases: a pre-treatment phase, a treatment phase (which consists of an optimized retreatment period followed by a prolonged therapy period, or a standard retreatment period followed by a posttreatment period), and a long-term follow-up phase for survival up to the end of the study. Before the premature stopping of enrollment, the end of the study was event-driven, defined as 1 year after 186 events (an 'event' being defined as disease progression or death). Following the premature stopping of enrollment, effective 20 June 2014, the end of the study is defined as a maximum of 18 months after enrollment of the last patient in the study. After providing written informed consent, patients will be evaluated for eligibility during a 14-day pre-treatment period. The study doctor will carry out tests to see if the patient is suitable for this study, within the two weeks before receipt of the first dose of the study drugs. Once it has been determined that the patient is able to participate, he/she will be randomly assigned to 1 of 2 different bortezomib retreatment schedules. In this first randomization, patients will receive optimized retreatment or standard retreatment in a 2:1 ratio. Group A: optimized retreatment followed by prolonged therapy. Patients will start therapy with retreatment with 6 cycles of bortezomib and dexamethasone (two 21-day cycles followed by four 35-day cycles) followed by a second randomization in a 1:1 ratio to 1 of 2 prolonged therapy schedules with bortezomib alone (Group A1: once weekly for the first 4 weeks in 35-day cycles; or Group A2: once every other week). Group B: standard retreatment with eight 21-day bortezomib and dexamethasone cycles, followed by posttreatment follow-up every 6 weeks. During the retreatment phase, a series of tests will be done at the first day of each cycle. For patients in Group A the doctor will assess if the patient has responded to the treatment or not. Only if the patient responded, will he/she be able to continue in the prolonged therapy part of the study. At this time the patient will be randomized to one of the two groups (Group A1 or Group A2) in the prolonged therapy phase. During the prolonged therapy phase the disease status and the response to therapy will be evaluated every 6 weeks. This phase will continue until the disease progresses, in case there are unacceptable toxicities despite dose modifications. During the posttreatment period patients in group B will continue to be evaluated for disease status every 6 weeks until confirmed disease progression, when they start alternative multiple myeloma treatment, are withdrawn from the study, death or at the end of the study (a maximum of 18 months after the last patient is enrolled in the study), whichever occurs first. In case the patient discontinues bortezomib before disease progression during the treatment phase, he/she will be asked to complete the End of Study Visit procedures and will be evaluated every 6 weeks until confirmed disease progression, when they start alternative multiple myeloma treatment, are withdrawn from the study, death or at the end of the study (a maximum of 18 months after the last patient is enrolled in the study), whichever occurs first. All patients will have an End of Trial Visit performed 30 to 35 days after the last administration of bortezomib, or as soon as possible after bortezomib treatment is discontinued for patients receiving alternative multiple myeloma therapy. After confirmed disease progression or start of the first alternative multiple myeloma therapy, patients will enter the long-term follow-up phase for up to a maximum of 18 months after the last patient is enrolled in the study. During this phase, the patients will be contacted by at least a telephone call every other month to be followed up for the first alternative multiple myeloma therapy and survival. From the end of the study in countries where bortezomib is not commercially available for prolonged therapy or is not accessible (via a national program or access program) at that time, patients who in the opinion of the investigator would continue to benefit from prolonged therapy with bortezomib, will continue to be supplied with bortezomib until it is accessible in that particular country or for a period of 2 years, whichever occurs first. Before the premature stopping of enrollment, it was planned to enroll a target of 240 patients in this study.

Official Title
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A Randomized, Controlled Phase 3 Study to Evaluate Optimized Retreatment and Prolonged Therapy With Bortezomib (Velcade) in Patients With Multiple Myeloma in First or Second Relapse.

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: bortezomib (optimized retreatment)
* Drug: dexamethasone (optimized retreatment)
* Drug: bortezomib (standard retreatment)
* Drug: dexamethasone (standard retreatment)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have received a bortezomib containing regimen in one of the previous line(s) of therapy and have shown at least PR to the previous bortezomib therapy. Have relapsed / progressed multiple myeloma following 1 or 2 previous lines of therapy as defined in the protocol. Have measurable secretory multiple myeloma: measurable disease for secretory multiple myeloma is defined by at least one of the following measurements: serum M protein greater than or equal to 1 g/dL (≥10g/L], urine M-protein of ≥200 mg/24 hours. Have an ECOG performance status of ≤2. Have a life expectancy estimated at screening of ≥6 months. Exclusion Criteria: Has received more than 2 previous lines of therapy for multiple myeloma or has received no previous bortezomib-containing regimen. Has been refractory to bortezomib, defined as either having progressed during bortezomib therapy or relapsed/progressed within 6 months after the last dose of bortezomib. Has oligosecretory or nonsecretory multiple myeloma. Has a history of a myocardial infarction within 6 months of enrollment or has 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. 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 4.0.

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 |
| --- | --- |
| Experimental: optimized retreatment, prolonged therapy<br>Patients will start therapy with retreatment with 6 cycles of bortezomib and dexamethasone (two 21-day cycles followed by four 35-day cycles) followed by a second randomization in a 1:1 ratio to 1 of 2 prolonged therapy schedules with bortezomib alone (Group A1: once weekly for the first 4 weeks in 35-day cycles; or Group A2: once every other week) | Drug: bortezomib (optimized retreatment)<br>* Type= exact number, unit = mg/m2 body surface area, number = 1.3, form = powder for solution for injection, route = subcutaneous, injection on Days 1, 4, 8 and 11, every 21 days of cycle 1 and 2; injection on Days 1, 8, 15, 22, every 35 days for cycles 3 to 6; followed by injections on Days 1, 8, 15, 22 every 35 days (Group A1) or injections every other week (Group A2). Treatment will be stopped at confirmed disease progression<br>Drug: dexamethasone (optimized retreatment)<br>* Type= exact number, unit = mg, number = 20, form = tablet, route = oral, intake on Days 1, 2, 4, 5, 8, 9, 11 and 12, every 21 days of cycle 1 and 2; intake on Days 1, 2, 8, 9, 15, 16, 22 and 23 every 35 days for cycles 3 to 6<br>|
| Other: standard retreatment<br>Current Standard of Care: Patients will start retreatment with eight 21-day bortezomib and dexamethasone cycles, followed by posttreatment follow-up every 6 weeks. | Drug: bortezomib (standard retreatment)<br>* Type= exact number, unit = mg/m2 body surface area, number = 1.3, form = powder for solution for injection, route = subcutaneous, injection on Days 1,4,8,11, every 21 days for cycles 1 to 8 or until confirmed disease progression<br>Drug: dexamethasone (standard retreatment)<br>* Type = exact number, unit = mg, number = 20, form = tablet, route= oral, intake on Days 1, 2, 4, 5, 8, 9, 11, 12, every 21 days for cycles 1 to 8 or until confirmed disease progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of optimized retreatment followed by prolonged therapy versus standard retreatment on Progression Free Survival (PFS) | Time from randomization to therapy to time of diagnosis of PD or death due to any cause | follow up to disease progression or death or to a maximum of 18 months after the last patient is enrolled in the study, whichever occurs first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Overall response rate as defined by the combination of patients with complete response, very good partial response and partial response according to the International Myeloma Working Group 2011 criteria (IMWG) | at end of treatment (defined as a maximum of 6 months in group B and an expected average of 17 months in group A) | 
| Time to Progression (TTP) | Time to Progression is defined as the time from baseline to PD, discontinuation/withdrawal or death. | at end of treatment (defined as a maximum of 6 months in group B and an expected average of 17 months in group A) | 
| Duration of Response (DOR) | DOR is defined as the duration from the date of the best confirmed response for patients who achieved Complete Response (CR) or Partial Response (PR) to the date of first documented evidence of PD over the duration of the study. | at end of treatment (defined as a maximum of 6 months in group B and an expected average of 17 months in group A) | 
| Time to Next Myeloma Therapy (TTNT) |  | at end of treatment (defined as a maximum of 6 months in group B and an expected average of 17 months in group A) | 
| Overall Survival (OS) |  | at end of treatment (defined as a maximum of 6 months in group B and an expected average of 17 months in group A) | 
| Eastern Cooperative Oncology Group (ECOG) Performance Status | The ECOG Performance Status is used to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis. The score ranges from 0 fully active, able to carry on all pre-disease performance without restriction to 5 dead. | at end of treatment (defined as a maximum of 6 months in group B and an expected average of 17 months in group A) | 
| European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - C30 (EORTC QLQ-C30) | The EORTC QLQ-C30 incorporates 5 functional scales (physical, role, emotional, cognitive and social functioning), 1 global health and quality of life scale, 3 symptom scales (fatigue, nausea/vomiting and pain), and 6 single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The recall period is 1 week (the past week). It is a 30-item questionnaire with responses ranging for the functional scales from not at all to very much and the global health/QOL ranging from very poor to excellent. Scores are transformed to 0-100 scale. | at end of treatment (defined as a maximum of 6 months in group B and an expected average of 17 months in group A) | 
| European Quality of Life-5 Dimensions Questionnaire (EQ-5D) | The EQ-5D is a 5-item questionnaire and a thermometer visual analogue scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state) | at end of treatment (defined as a maximum of 6 months in group B and an expected average of 17 months in group A) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, bortezomib, Velcade, First or Second Relapse, retreatment, Prolonged therapy