Clinical trial NCT00048230: PS-341 (VELCADE™) Versus High-Dose Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma
Official title: An International, Multi-Center, Randomized, Open-Label Study of PS-341 (VELCADE™) Versus High-Dose Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Myeloma
Keywords: Relapsed Multiple Myeloma
Refractory Multiple Myeloma
Lead sponsor: Millennium Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2002-10-30
Enrollment: 620
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study will compare the efficacy of PS-341 versus high dose dexamethasone.


Eligibility criteria: Inclusion Criteria

* Patient is of a legally consenting age, as defined by local regulations.
* Patient is, in the investigator's opinion, willing and able to comply with the protocol requirements.
* Patient 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performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
* Female patient is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.
* Male patient agrees to use an acceptable method for contraception for the duration of the study.
* Patient was previously diagnosed with multiple myeloma based on standard criteria and currently requires second-, third-, or fourth-line therapy because of PD, defined as a 25% increase in M-protein, development of new or worsening of existing lytic bone lesions or soft tissue plasmacytomas, or hypercalcemia (serum calcium \>11.5 mg/dL), or relapse from CR.
* Patient has measurable disease, defined as follows:
* For secretory multiple myeloma, measurable disease is defined as any quantifiable serum monoclonal protein value (generally, but not exclusively, greater than 1 g/dL of IgG M-Protein and greater than 0.5g/dL IgA) and, where applicable, urine light-chain excretion of ≥200 mg/24 hours.
* For oligo- or non-secretory multiple myeloma, measurable disease is defined by the presence of soft tissue (not bone) plasmacytomas as determined by clinical examination or applicable radiographs (i.e. MRI, CT-Scan). In patients with oligosecretory multiple myeloma, the serum and/or urine M-protein measurements are very low and difficult to follow for response assessments. Therefore, other disease sites (bone marrow; extramedullary mass) must be assessed and followed. In patients with non-secretory multiple myeloma, there is no M-protein in serum or urine by immunofixation.
* Patient has a Karnofsky performance status ≥60%.
* Patient has a life-expectancy \>3 months.
* Patient has the following laboratory values at and within 14 days before Baseline (Day 1 of Cycle 1, before study drug administration):
* Platelet count ≥50 x 10E+9/L without transfusion support within 7 days before the laboratory test.
* Hemoglobin ≥7.5 g/dL, without transfusion support within 7 days before the laboratory test.
* Absolute neutrophil count (ANC) ≥0.75 x 10E+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 the ULN.
* Total bilirubin: ≤1.5 x the ULN.
* Calculated or measured creatinine clearance: ≥20 mL/minute.

Exclusion Criteria

* Patient previously received treatment with VELCADE.
* Patient previously was refractory to treatment with high-dose dexamethasone, as experiencing less than a partial response to or PD within 6 months after discontinuing dexamethasone, or discontinued dexamethasone because of ≥Grade 3 dexamethasone-related toxicity.
* Previous high-dose dexamethasone therapy is defined as \>500 mg dexamethasone or equivalent over a 10-week period, whether administered alone or as part of the VAD regimen.
* Patient received nitrosoureas within 6 weeks or any other chemotherapy, including thalidomide or clarithromycin, or radiation therapy within 3 weeks before enrollment.
* Patient received corticosteroids (\>10 mg/day prednisone or equivalent) within 3 weeks before enrollment.
* Patient received immunotherapy or antibody therapy within 8 weeks before enrollment.
* Patient received plasmapheresis within 4 weeks before enrollment.
* Patient had major surgery within 4 weeks before enrollment. (Kyphoplasty is not considered major surgery.)
* Patient has a history of allergic reaction attributable to compounds containing boron or mannitol.
* Patient has peripheral neuropathy of Grade 2 or greater intensity, as defined by the NCI Common Toxicity Criteria (NCI CTC):
* Grade 2: Objective sensory loss or paresthesia (including tingling), interfering with function, but not interfering with activities of daily living (ADLs).
* Grade 3: Sensory loss or paresthesia interfering with ADLs.
* Grade 4: Permanent sensory loss that interferes with function.
* Patient had 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.
* Patient was treated for a cancer other than multiple myeloma within 5 years before enrollment, with the exception of basal cell carcinoma or cervical cancer in situ.
* Patient has cardiac amyloidosis.
* Patient 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.
* Patient is known to be human immunodeficiency virus (HIV)-positive. (Patients assessed by the investigator to be at risk for HIV infection should be tested in accordance with local regulations.)
* Patient is known to be hepatitis B surface antigen-positive or has known active hepatitis C infection.
* Patient has an active systemic infection requiring treatment.
* Female patient is pregnant or breast-feeding.
* Patient currently is enrolled in another clinical research study and/or is receiving an investigational agent for any reason.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Berkeley
country: United States
facility: Alta Bates Comprehensive Cancer Center
state: California
city: Duarte
country: United States
facility: City of Hope
state: California
city: La Jolla
country: United States
facility: Scripps Clinic
state: California
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Vallejo
country: United States
facility: Kaiser Permanente Oncology Clinical Trials
state: California
city: Washington
country: United States
facility: Lombardi Cancer Center, Georgetown University Medical Center
state: District of Columbia
city: Washington
country: United States
facility: Med Star Institute, Washington Cancer Center
state: District of Columbia
city: Jacksonville
country: United States
facility: Hematology/Oncology Associates, PA
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center, University of S. Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University Medical School
state: Illinois
city: Maywood,
country: United States
facility: Loyola University Medical Center: Cardinal Bernardin Cancer Center
state: Illinois
city: Shreveport
country: United States
facility: LSU HC
state: Louisiana
city: Boston
country: United States
facility: Tufts New England Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center, Kirstein Room 135
state: Massachusetts
city: Ann Arbor
country: United States
facility: Department of Internal Medicine, Univ. of Michigan Comp. Cancer Center
state: Michigan
city: Minneapolis
country: United States
facility: VA Medical Center, Sections of Hematology/Oncology
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: St. Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center, David Jurist Research Building
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New Hyde Park
country: United States
facility: Long Island Jewish Medical Center, Division of Hematology/Oncology
state: New York
city: New York
country: United States
facility: St. Vincent's Comprehensive Cancer Center, Research Department
state: New York
city: New York
country: United States
facility: NY Presbyterian Hospital
state: New York
city: Rochester
country: United States
facility: Rochester General Hospital, Lipson Cancer Blood Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center, James P. Wilmot Cancer Center
state: New York
city: Charlotte
country: United States
facility: Carolinas Hematology-Oncology Associates
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Western Pennsylvania Hospital, Dept. of Human Oncology
state: Pennsylvania
city: Charleston
country: United States
facility: Trident Palmetto Hematology/Oncology
state: South Carolina
city: Nashville
country: United States
facility: Division of Hematology/Stem Cell Transplant
state: Tennessee
city: Dallas
country: United States
facility: Texas Oncology at Medical City Dallas Hospital
state: Texas
city: Dallas
country: United States
facility: Baylor Institute for Immunology Research
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Wien
country: Austria
facility: Wilhelminenspital Wien, Abt. Fur Med. und Medizinische Onkologie
city: Antwerpen
country: Belgium
facility: ACZA, Campus Stuivenberg
city: Brussels
country: Belgium
facility: CHU Erasme / ULB University, Hematology 7th Floor
city: Bruxelles
country: Belgium
facility: Institut Jules Bordet, Unite Sterile
city: Charleroi
country: Belgium
facility: C.H. Notre Dame-Reine Fabiola
city: Leuven
country: Belgium
facility: UZ Gasthuisberg, Department of Hematology
city: Rugge
country: Belgium
facility: AZ St. Jan, Dept. of Haematology
city: Yvoir
country: Belgium
facility: Cliniques Universitaires U.C.L de Mont Godinne, Hopital de Jour
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: London
country: Canada
facility: London Health Sciences Center
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Research Institute, Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: Royal Victoria Hospital
state: Quebec
city: Lile
country: France
facility: Hospital Claude Huriez, Service des Maladies du Sang
state: Cedex
city: Nantes
country: France
facility: Nantes Hotel Dieu Hospital
state: Cedex
city: Toulouse
country: France
facility: Hopital Purpan, Pavillon Dieulafoy, Service d'Hematologie Clinique
state: Cedex
city: Villejuif
country: France
facility: Institut Gustave-Roussy, Service d'Hematologie
state: Cedex
city: Clamart
country: France
facility: Hopital Antoine Beclere, Hopital de Jour de Medecine Interne
city: Paris
country: France
facility: Hopital Hotel Dieu, Service d'hematologie et oncologie medicale
city: Paris
country: France
facility: Hopital Saint-Louis, Direction Financiere
city: Paris
country: France
facility: Hopital Cochin, Service de Hematologie
city: Pierre Benite Cedex
country: France
facility: Centre Hospitalier Lyon Sud
city: Vandoeuvre
country: France
facility: Hopital de Brabois, Service Hematologie et Medecine Interne
city: Berlin
country: Germany
facility: Universitatsklinikum Charite, Abt. Fuer Haematologie/Onkologie
city: Bonn
country: Germany
facility: Medizinische Klinik und Poliklinik 1
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carus
city: Erlangen
country: Germany
facility: University of Erlangen-Nurenberg, Division of Hematology/Oncology
city: Freiburg
country: Germany
facility: Freiburg University Medical Center, Dept. of Hemayology/Oncology
city: Hamburg
country: Germany
facility: Medical University Clinic (Oncology/Haematology)
city: Hamm
country: Germany
facility: St. Marien Hospital, Klinik fur Hamatologie und Onkologie
city: Heidelberg
country: Germany
facility: Universitatsklinikum Heidelberg, Abt. Fur Haematologie und Onkologie
city: Hufelandstr
country: Germany
facility: University of Essen Medical School, Dept. of Internal Medicine
city: Mainz
country: Germany
facility: Johannes Gutenberg-Universitat Mainz, III. Med Klinik und Poliknik
city: Muenster
country: Germany
facility: Uniklinikum Muenster
city: Tubingen
country: Germany
facility: Eberhard-Karls Universitat, Medizinische Klinik
city: Belfast
country: Ireland
facility: Belfast City Hospital
city: Haifa
country: Israel
facility: RAMBAM Medical Center, Department of Hematology and Bone
city: Jerusalem
country: Israel
facility: Hadassah University Hospital
city: Bergamo
country: Italy
facility: Dipartmento Clinico esperimentale Di Oncologia et Ematolgia
city: Bologna
country: Italy
facility: Instituto di Ematologia e Oncologia Medica, Lorenzo e Ariosto Seragnoli
city: Roma
country: Italy
facility: Dipartimento di Biotecnologie Cellulari ed Ematologia
city: Torino
country: Italy
facility: Azienda Ospedaliera, S. Giovanni Battista
city: Amsterdam
country: Netherlands
facility: Dept. of Clinical Hematology, Academic Medical Center
city: Rotterdam
country: Netherlands
facility: Department of Hematology, Erasmus MC, 1a, Daniel Den Hoed
city: Utrecht
country: Netherlands
facility: Dept. Hematology, University Medical Centre
city: Barcelona
country: Spain
facility: Hospital Clinico Universitario de Barcelona, Haematology Department
city: Salamanca
country: Spain
facility: University Hospital of Salamanca
city: Stockholm
country: Sweden
facility: Department of Haematology, Huddinge University Hospital M54
city: Stockholm
country: Sweden
facility: Karolinska Hospital, Dept. of Hematology
city: Withington
country: United Kingdom
facility: Adult Leukaemia Unit, Christie Hospital
state: Manchester
city: Birmingham
country: United Kingdom
facility: Department of Haematology, Queen Elizabeth Hospital
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary
city: London
country: United Kingdom
facility: Department of Haematology, St. Bartholomew's Hospital
city: London
country: United Kingdom
facility: Department of Haematology, ICSM, Hammersmith Hospital
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital, Leukaemia and Myeloma Units
Study officials:
References:
citation: Dimopoulos MA, Orlowski RZ, Facon T, Sonneveld P, Anderson KC, Beksac M, Benboubker L, Roddie H, Potamianou A, Couturier C, Feng H, Ataman O, van de Velde H, Richardson PG. Retrospective matched-pairs analysis of bortezomib plus dexamethasone versus bortezomib monotherapy in relapsed multiple myeloma. Haematologica. 2015 Jan;100(1):100-6. doi: 10.3324/haematol.2014.112037. Epub 2014 Sep 26.
citation: Lichter DI, Danaee H, Pickard MD, Tayber O, Sintchak M, Shi H, Richardson PG, Cavenagh J, Blade J, Facon T, Niesvizky R, Alsina M, Dalton W, Sonneveld P, Lonial S, van de Velde H, Ricci D, Esseltine DL, Trepicchio WL, Mulligan G, Anderson KC. Sequence analysis of beta-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone. Blood. 2012 Nov 29;120(23):4513-6. doi: 10.1182/blood-2012-05-426924. Epub 2012 Sep 27.
citation: van Duin M, Broyl A, de Knegt Y, Goldschmidt H, Richardson PG, Hop WC, van der Holt B, Joseph-Pietras D, Mulligan G, Neuwirth R, Sahota SS, Sonneveld P. Cancer testis antigens in newly diagnosed and relapse multiple myeloma: prognostic markers and potential targets for immunotherapy. Haematologica. 2011 Nov;96(11):1662-9. doi: 10.3324/haematol.2010.037978. Epub 2011 Jul 26.
citation: Vogl DT, Stadtmauer EA, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Facon T, Harousseau JL, Boral A, Neuwirth R, Anderson KC. Impact of prior therapies on the relative efficacy of bortezomib compared with dexamethasone in patients with relapsed/refractory multiple myeloma. Br J Haematol. 2009 Nov;147(4):531-4. doi: 10.1111/j.1365-2141.2009.07875.x. Epub 2009 Sep 1.