A Study of Efficacy of Treatment With Bortezomib (in Combination With Doxorubicin and Dexamethasone) in Previously Untreated Patients With Multiple Myeloma

Phase 2

Completed

• Conditions: Multiple Myeloma
• Interventions: Drug: PAD induction

• Registration Number: NCT00872521
• Lead Sponsor: Janssen-Cilag Pty Ltd

Brief Summary

The purpose of this study is to determine efficacy of treatment with bortezomib (in combination with doxorubicin and dexamethasone) in previously untreated patients with Multiple Myeloma.

Detailed Description

This is an open-label, single-arm, multicentre study which will enroll approximately 105 patients. Open-label means all people involved in the study know the identity of the intervention. Single-arm means there is one group of patients, all receiving the same treatment. Four 21-day cycles of a combination of bortezomib i.v. (intravenous) 1.3 mg/m2 (Days 1, 4, 8 and 11), doxorubicin i.v. 20 mg/m2 (days 1 and 4) and dexamethasone p.o. (by mouth) (days 1, 2, 4, 5, 8, 9, 11 and 12) (PAD) will be given. Patients will be discontinued if disease progresses, or unacceptable treatment-related toxicity occurs. Following PAD treatment, patients will have peripheral blood stem cells (PBSC) collected, and an autologous stem cell transplant (ASCT) will be performed. Patients will then make monthly visits to the Study Doctor until 1 year after start of treatment, and attend a final follow-up visit at 2 years. Efficacy assessment of response to PAD will be made using the International Myeloma Working Group (IMWG) criteria. The primary outcome is to compare the overall response rate following 4 cycles of PAD induction therapy between patients with and without extra copies of the long arm of the first chromosome (1q21) measured by fluorescent in situ hybridisation (FISH) in their marrow at baseline. Patient reported outcomes will be assessed using the AQoL (Assessment of Quality of Life). Safety will be evaluated throughout the study by assessment of adverse events including changes in physical examination, concomitant medication, ECOG (Eastern Cooperative Oncology Group) scores, vital signs and clinical laboratory findings. A sample size of 105 provides 80% power (a=0.05) to detect a difference in overall response rate of 28% at the end of 4 cycles of PAD. This is based on the assumptions that 44% of patients have amplification of 1q21 1, 2, the overall response rate with PAD combination therapy is 80%; the overall response rate with PAD if PAD therapy does not overcome 1q21 amplification is assumed to be 64%, while without 1q21 amplification it is assumed to be 92%. That is: Overall Response Rate (ORR) = P1q21 amplified x ORRamplified + P1q21 not amplified x ORRnot amplified i.e. 80% = 44% x 64% + 56% x 92%. The sample size of 105 allows for a 20% drop-out rate. Four 21-day cycles of PAD: a combination of bortezomib i.v. (intravenous) 1.3 mg/m2 (Days 1, 4, 8 and 11), doxorubicin i.v. 20 mg/m2 (days 1 and 4) and dexamethasone p.o. (by mouth) (days 1, 2, 4, 5, 8, 9, 11 and 12).

Study Timeline

• Study Start: 2009-01
• Study First Submitted: 2009-03-27
• Study First Submitted QC: 2009-03-27
• Study First Posted: 2009-03-31
• Primary Completion: 2011-03
• Study Completion: 2011-11
• Results First Submitted: 2012-12-14
• Results First Submitted QC: 2013-03-25
• Results First Posted: 2013-05-07
• Status Verified: 2014-05
• Last Update Submitted: 2014-05-07
• Last Update Posted: 2014-05-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 107

Inclusion Criteria

• Previously diagnosed with multiple myeloma
• eligible for autologous stem cell transplantation
• meets pre-treatment lab criteria (as defined within protocol).

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Exclusion Criteria

• Previously received treatment for multiple myeloma (including prior therapy with radiation or pulsed dexamethasone), except localised radiation to a solitary lesion or plasmacytomas or 4 days of corticosteroid therapy
• have a current diagnosis of smoldering multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), or Waldenström Macroglobulinemia
• have a history of any other malignancy within 5 years before enrolment
• have other significant comorbidities.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
bortezomib; doxorubicin; dexamethasone	PAD induction	PAD induction Open Label Treatment: Four 21-day Treatment Cycles Bortezomib 1.3 mg/m2 i.v. (D1 4 8 \& 11) Doxorubicin 20 mg/m2 i.v. (D1 \& 4) Dexamethasone 20 mg p.o. (D1 2 4 5 8 9 11 \& 12)

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR): Number of Participants Who Are Responders (Had Stringent Complete Response [sCR], CR, Very Good Partial Response [VGPR] or Partial Response [PR]) After 4 Cycles of Bortezomib, Doxorubicin and Dexamethasone (PAD) Induction	84 days	International Myeloma Working Group (IMWG) criteria - CR: negative immunofixation on the serum and urine, no soft tissue plasmacytomas and \<5% plasma cells in the bone marrow; sCR: CR+normal free light chain ratio, no clonal cells in bone marrow by immunohistochemistry or immunofluorescence; VGPR: serum and urine M-protein detected by immunofixation but not electrophoresis, \>90% in serum M-protein+urine, M-protein level \<100 mg/24hour; PR: ≥50% decrease of serum and M-protein, 24 hour urinary M-protein decrease by ≥90% or \<200 mg/24hour

Secondary Outcome Measures

Name	Time	Method
Disease Response 3-months After Autologous Stem Cell Transplant (ASCT)	3-months after ASCT	Number of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD) and relapse as per IMWG criteria.
Overall Survival (OS) Stratified by Protein Expression (Cyclin D1)	2 years after Day 1 Cycle 1 of PAD	Percentage of participants who had no event of death 2 years after Day 1 Cycle 1 of bortezomib, doxorubicin and dexamethasone (PAD) stratified by protein expression (Cyclin D1).
Overall Survival (OS) Stratified by Protein Expression (Bcl-2)	2 years after Day 1 Cycle 1 of PAD	Percentage of participants who had no event of death 2 years after Day 1 Cycle 1 of bortezomib, doxorubicin and dexamethasone (PAD) stratified by protein expression (bcl-2).
Overall Survival (OS) Stratified by Protein Expression (FGFR3)	2 years after Day 1 Cycle 1 of PAD	Percentage of participants who had no event of death 2 years after Day 1 Cycle 1 of bortezomib, doxorubicin and dexamethasone (PAD) stratified by protein expression (FGFR3).
Overall Response Rate (ORR) Stratified by Protein Expression (Bcl-2)	84 days	Number of participants who are responders and nonresponders after 4 cycles of bortezomib, doxorubicin and dexamethasone (PAD) induction stratified by protein expression (bcl-2)
Overall Response Rate (ORR) Stratified by Protein Expression (FGFR3)	84 days	Number of participants who are responders and nonresponders after 4 cycles of bortezomib, doxorubicin and dexamethasone (PAD) induction stratified by protein expression (FGFR3)
Overall Survival (OS) Stratified by Protein Expression (p53).	2 years after Day 1 Cycle 1 of PAD	Percentage of participants who had no event of death 2 years after Day 1 Cycle 1 of bortezomib, doxorubicin and dexamethasone (PAD) stratified by protein expression (p53).
Disease Response After 4 Cycles of Bortezomib, Doxorubicin and Dexamethasone (PAD) Induction	84 days	Number of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR) and stable disease (SD).
Overall Survival	2 years after Day 1 Cycle 1 of PAD	Percentage of participants who had no event of death 2 years after Day 1 Cycle 1 of bortezomib, doxorubicin and dexamethasone (PAD).
Assessment of Quality of Life (AQoL) Scores	Up to 2 years	The AQoL is a multi-attribute utility health-related quality of life (HRQoL) instrument. It combines the 4 dimensions of independent living, relationships, senses and mental health into a single utility score. The AQoL instrument scores between 1 (best HRQoL) and -0.04 (worst possible HRQoL).
Overall Response Rate (ORR) Stratified by Protein Expression (p53)	84 days	Number of participants who are responders and nonresponders after 4 cycles of bortezomib, doxorubicin and dexamethasone (PAD) induction stratified by protein expression (p53).
Overall Response Rate (ORR) Stratified by Protein Expression (Cyclin D1).	84 days	Number of participants who are responders and nonresponders after 4 cycles of bortezomib, doxorubicin and dexamethasone (PAD) induction stratified by protein expression (Cyclin D1).
Overall Response Rate (ORR) to Bortezomib, Doxorubicin and Dexamethasone (PAD) Induction 3-months Following Autologous Stem Cell Transplant (ASCT).	3-months following ASCT	Responders are the number of participants who achieved stringent complete response (sCR)/ complete response (CR), very good partial response (VGPR) or partial response (PR) following PAD induction.
Event Free Survival (EFS)	2 years after Day 1 Cycle 1 of PAD	Percentage of participants who did not have any of the following events: Death, Disease progression, Relapse, Cardiovascular accidents, Deep vein thrombosis, Pulmonary embolism, Fracture, Acute renal failure, Nervous system disorders 2 years after Day 1 Cycle 1 of bortezomib, doxorubicin and dexamethasone (PAD).