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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Janssen-Cilag Pty Ltd
ClinicalTrials.gov Identifier:
NCT00872521
First received: March 27, 2009
Last updated: March 25, 2013
Last verified: March 2013
  Purpose

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.


Condition Intervention Phase
Multiple Myeloma
Drug: PAD induction
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Trial of Bortezomib, Doxorubicin and Dexamethasone (PAD) Induction Therapy in Patients With Untreated Multiple Myeloma (MM), Stratified for Markers of Bortezomib Resistance

Resource links provided by NLM:


Further study details as provided by Janssen-Cilag Pty Ltd:

Primary Outcome Measures:
  • 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 [ Time Frame: 84 days ] [ Designated as safety issue: No ]
    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:
  • Disease Response After 4 Cycles of Bortezomib, Doxorubicin and Dexamethasone (PAD) Induction [ Time Frame: 84 days ] [ Designated as safety issue: No ]
    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 Response Rate (ORR) to Bortezomib, Doxorubicin and Dexamethasone (PAD) Induction 3-months Following Autologous Stem Cell Transplant (ASCT). [ Time Frame: 3-months following ASCT ] [ Designated as safety issue: No ]
    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.

  • Disease Response 3-months After Autologous Stem Cell Transplant (ASCT) [ Time Frame: 3-months after ASCT ] [ Designated as safety issue: No ]
    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.

  • Event Free Survival (EFS) [ Time Frame: 2 years after Day 1 Cycle 1 of PAD ] [ Designated as safety issue: No ]
    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).

  • Overall Survival [ Time Frame: 2 years after Day 1 Cycle 1 of PAD ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    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) [ Time Frame: 84 days ] [ Designated as safety issue: No ]
    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). [ Time Frame: 84 days ] [ Designated as safety issue: No ]
    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) Stratified by Protein Expression (Bcl-2) [ Time Frame: 84 days ] [ Designated as safety issue: No ]
    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) [ Time Frame: 84 days ] [ Designated as safety issue: No ]
    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). [ Time Frame: 2 years after Day 1 Cycle 1 of PAD ] [ Designated as safety issue: No ]
    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).

  • Overall Survival (OS) Stratified by Protein Expression (Cyclin D1) [ Time Frame: 2 years after Day 1 Cycle 1 of PAD ] [ Designated as safety issue: No ]
    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) [ Time Frame: 2 years after Day 1 Cycle 1 of PAD ] [ Designated as safety issue: No ]
    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) [ Time Frame: 2 years after Day 1 Cycle 1 of PAD ] [ Designated as safety issue: No ]
    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).


Enrollment: 107
Study Start Date: January 2009
Study Completion Date: November 2011
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: bortezomib; doxorubicin; dexamethasone
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)
Drug: 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)


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).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00872521

Locations
Australia
Adelaide, Australia
Box Hill, Australia
Brisbane, Australia
Camperdown, Australia
Geelong, Australia
Gosford, Australia
Greenslopes, Australia
Malvern, Australia
Melbourne, Australia
Parkville, Australia
Perth, Australia
Sydney, Australia
Westmead, Australia
Woden, Australia
Wollongong, Australia
Woolloongabba N/A, Australia
Sponsors and Collaborators
Janssen-Cilag Pty Ltd
Investigators
Study Director: Janssen-Cilag Pty Ltd Clinical Trial Janssen-Cilag Pty Ltd
  More Information

No publications provided

Responsible Party: Janssen-Cilag Pty Ltd
ClinicalTrials.gov Identifier: NCT00872521     History of Changes
Other Study ID Numbers: CR015640, 26866138MMY2059, PIMMS Trial
Study First Received: March 27, 2009
Results First Received: December 14, 2012
Last Updated: March 25, 2013
Health Authority: Australia: Department of Health
Australia: Department of Health and Ageing Therapeutic Goods Administration

Keywords provided by Janssen-Cilag Pty Ltd:
Multiple Myeloma
transplant eligible
doxorubicin
dexamethasone
bortezomib
bortezomib resistance
PAD induction
PIMMS Trial

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Bortezomib
Doxorubicin
BB 1101
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids

ClinicalTrials.gov processed this record on April 23, 2014