Clinical trial NCT00452569: Efficacy and Safety Study of 3 Thalidomide Doses for the Treatment of Relapsed Refractory Multiple Myeloma
Official title: Randomised, Controlled, Open-labelled, Multi-centre Comparison of Thalidomide Versus High-dose Dexamethasone for the Treatment of Relapsed Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Myeloma
Keywords: Relapsed Refractory Multiple Myeloma
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2007-03-27
Enrollment: 499
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective is to compare the time to progression (TTP) of three daily doses of thalidomide (100, 200 and 400 mg) with high-dose dexamethasone in relapsed refractory multiple myeloma (MM) patients and to subsequently select the optimum thalidomide dose in terms of median TPP and toxicity.


Eligibility criteria: Inclusion Criteria:

* Male or female patients, aged ≥ 18 years at the time of signing the informed consent form
* Patients who have been previously diagnosed with MM who have received between 1 \& 3 prior lines of treatment for their disease, and who require therapy because of disease progression
* Secretory MM with measurable levels of monoclonal protein in serum (\> 10 g/L of IgG M-protein or \> 5 g/L of IgA M-protein) or urine (≥ 200 mg/ 24hours); Patient with the following rare subclasses of the immunoglobulin: IgD, IgE, IgM can be included in the study if the level of monoclonal protein in serum is \> 5g/L or ≥ 200 mg/24hours in urine. As IgM immunoglobulin isotype can be related to Waldenstrom's macroglobulinemia, it is important to distinguish and not include in the study patients with Waldenstrom's macroglobulinemia.
* ECOG performance status of 0, 1, or 2
* Life expectancy \>3months
* Able to adhere to the study visit schedule \& other protocol requirements
* Women of child-bearing potential must agree to use 2 methods of contraception for at least 4weeks before starting the therapy, during the Treatment Period, \& for 4 weeks after the last dose
* Males must agree to use barrier contraception (latex condoms) when engaging in reproductive activity during the Treatment Period \& for 4 weeks after the last dose
* Written, informed consent

Exclusion Criteria:

* Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the Informed Consent Form
* Pregnant or lactating women. A serum β-hCG pregnancy test must be performed at the Screening visit for female patients of child-bearing potential. If the test is positive, the patient must be excluded from the study. Confirmation that the patient is not pregnant must be established by a negative serum or urinary pregnancy test with the result obtained 1day prior to the Baseline visit (or the day of the visit if results are available before drug delivery). A pregnancy test is not required for naturally post-menopausal women (who have not had menses at any time in the preceding 24 consecutive months) or surgically sterilized women (hysterectomy, bilateral ovariectomy, bilateral salpingectomy)
* Non-secretory MM
* Any of the following laboratory abnormalities: Absolute neutrophil count (ANC) \<500 cells/mm3 (0.5 x 109/L); Platelet count \<30,000/mm3 (30.0 x 109L) without transfusion support within 7 days before the test; Serum creatinine \>3.0mg/dL (265μmol/L); Serum aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) \>3.0 x upper limit of normal (ULN); Serum total bilirubin \>2.0mg/dL (34μmol/L)
* Any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable risk if s/he were to participate in the study, or which confounds the ability to interpret data from the study
* Severe cardiac dysfunction (according to the New York Heart Association \[NYHA\] classification III-IV)
* Severe bradycardia (\<50bpm)
* Peripheral neuropathy ≥Grade 2 in severity (according to the NCI CTC Version 3.0)
* Prior history of malignancy (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless the patient has been free of disease for ≥5years
* Patient received any chemotherapy, corticosteroids (\> 10 mg/day prednisone or equivalent as a continuous dose) within 4 weeks before randomization
* Previously treated with thalidomide or thalidomide derivatives
* Patients refractory to high-dose dexamethasone (defined as experiencing less than a PR to dexamethasone, or PD within 6months after discontinuing dexamethasone, or discontinued dexamethasone because of ≥Grade 3 dexamethasone-related toxicity. Previous high-dose dexamethasone therapy is defined as \>500mg dexamethasone or equivalent over a 10week period, whether administered alone or as part of the VAD regimen)
* Contraindications for high-dose dexamethasone
* Active or chronic gastrointestinal ulcers, active viral infections (herpes, varicella, HIV, hepatitis B, hepatitis C), glaucoma, uncontrolled hypertension, or diabetes mellitus, unless well controlled \& under strict supervision during dexamethasone treatment
* Patient enrolled in another clinical trial or who have participated in another trial with the last 4weeks before randomization

Primary outcomes:
measure: The evaluation of Independent Review Committee-documented time to progression (TTP).
timeFrame: >160 "IRC confirmed" disease progression in the Dexamethasone or Thalidomide 400 mg/day arms
Secondary outcomes:
measure: Response rate (CR + PR), according to the EBMT criteria
timeFrame: Every 4 weeks
measure: Response duration
timeFrame: Every 4 weeks
measure: Clinical benefit as measured by ECOG performance status, transfusion requirement and Grade ≥3 infections (assessed by the National Cancer Institute Common Toxicity Criteria)
timeFrame: Every 4 weeks
measure: Progression-free survival (PFS)
timeFrame: Disease progression evaluated every 4 weeks
measure: Overall survival (OS)
timeFrame: Evaluated after 150 deaths occurring in Dexamethasone and Thalidomide 400 mg arms
measure: Composite of disease progression and death (recurrent time(s) from randomisation to disease progression and/or death)
timeFrame: Evaluated after 160 "IRC confirmed" disease progression in the Dexamethasone or Thalidomide 400 mg/day arms
measure: Quality of life as determined by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30)
timeFrame: Baseline/Week 8/ Week 16/Week 24/Week 32/Week 40/Week 48
measure: Adverse events (AEs)
timeFrame: Every 4 weeks
measure: Assessment of peripheral neuropathy
timeFrame: Screening, Week 24, Week 48
measure: Vital signs and physical examination
timeFrame: Every 4 weeks
measure: Clinical laboratory tests
timeFrame: Every 4 weeks
Other outcomes:
Locations:
city: Pleven
country: Bulgaria
facility: Clinic of Haematology, University Multiprofiled Hospital for Active Treatment "G. Stranski"
city: Plovdiv
country: Bulgaria
facility: Clinic of Haematology, University Multiprofiled Hospital for Active Treatment
city: Sofia
country: Bulgaria
facility: University of Multiprofiled Hospital for Active Treatment "Alexandrovska" - Sofia
city: Sofia
country: Bulgaria
facility: Military Medical Academy/Dept Haematology and Oncology
city: Sofia
country: Bulgaria
facility: National Center of Haematology & Transfusiology
city: Varna
country: Bulgaria
facility: Clinic of Haematology, Multiprofiled Hospital for Active Treatment "Sveta Marina"
city: Rijeka
country: Croatia
facility: Klinicki Bolnicki Centar Rijeka Interna Klinika
city: Split
country: Croatia
facility: Klinika Bolnica SPLIT - Klinika za Unutarnje Bolesti
city: Zagreb
country: Croatia
facility: KBC Zagreb - Klinika za Unutarnje Bolesti
city: Zagreb
country: Croatia
facility: Klinicka Bolnica "Dubrava" Klinika za Unutarnje Bolesti
city: Zagreb
country: Croatia
facility: Klinicka Bolnica "Sestre milosrdnice" Klinika za Unutarnje Bolesti
city: Zagreb
country: Croatia
facility: Klinicka Bolnica MERKUR - Klinika za Unutarnje Bolesti
city: Brno
country: Czechia
facility: Interni Hemato-Onkologicka Klinika
city: Hradec Kralove
country: Czechia
facility: Hematologicka Klinika, Fakultni Nemocnice Hradec Kralove
city: Novi Jicin
country: Czechia
facility: Onkologicke Centrum J.G. Mendela
city: Olomouc
country: Czechia
facility: Interni Klinika, Oddeleni Hematoonkologie
city: Prague 10
country: Czechia
facility: Hematologicka Klinika, Fakultni Nemocnice Kralovske Vinohrady Srobarova
city: Prague 2
country: Czechia
facility: Interni Klinika, Oddeleni Hematoonkologie
city: Lille
country: France
facility: CHRU de Lille - Hopital Claude Huriez
city: Nancy Cedex
country: France
facility: CHU de Nancy - Hopital Brabois
city: Toulouse
country: France
facility: Hematologie - CHU Purpan Place du Dr. Baylac
city: Berlin
country: Germany
facility: Charite, Universitatsmedizin Berlin, Campus Robert-Rossle Klinik
city: Bonn
country: Germany
facility: Med. Klinik I/University Bonn
city: Dresden
country: Germany
facility: Medizinische Klinik und Poliklinik I/Carl-Gustav-Carus University
city: Duesseldorf
country: Germany
facility: Hematology, Oncology & Clinical Immunology/Heinrich-Heine-University
city: Hamburg
country: Germany
facility: Abt. Haematologie - Onkologie/ Allg. Krankenhaus
city: Hamburg
country: Germany
facility: Allgemeinse Krankenhaus St. Georg Hamatologische Abteilung
city: Heidelberg
country: Germany
facility: Medizinische Klinik Abteilung Innere V/Universitatsklinikum
city: Kiel
country: Germany
facility: Universitat Schleswig Holstein II Med. Klinik
city: Koeln
country: Germany
facility: Universitaetsklinik - Klinik fur innere Medizin
city: Muenchen
country: Germany
facility: Medizinische Klinik und Poliklinik III/Klinikum der Universitaet Muenchen
city: Muenster
country: Germany
facility: Innere Medizin University Hospital
city: Saale
country: Germany
facility: Abteilung Haematologie - Univeresitaetsklinikum
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus GmbH, Stuttgart
city: Ulm
country: Germany
facility: Universitaetsklinik - Abteilung Innere Medizin III
city: Wuerzburg
country: Germany
facility: Med. Klinik II/Klinikum of the Julius-Maximilians-University
city: Budapest
country: Hungary
facility: National Medical Centre Dpt Haematology
city: Gyor
country: Hungary
facility: Petz Aladar Megyei Oktato Korhaz, II. Belgyogyaszat
city: Gyula
country: Hungary
facility: Pandy Kalman Megyei Korhaz, Megyei Onkologiai Centrum
city: Szeged
country: Hungary
facility: Szent-Gyorgyi Albert University II Clinic of Internal Medicine
city: Hyderabaad
country: India
facility: Nizam's Institute of Medical Sciences, Department of Medical Oncology
city: Kerala
country: India
facility: Department of Medical Oncology, Amrita Institute of Medical Sciences
city: Kolkata
country: India
facility: Orchid Nursing Home
city: Ludhiana
country: India
facility: Department of Medical Oncology, Dayanand Medical College DMCH
city: Mumbai
country: India
facility: Department of Medical Oncology/Tata Memorial Hospital
city: Mumbai
country: India
facility: Department of Medical Oncology, S.L. Raheja Hospital
city: Mumbai
country: India
facility: Department of Medical Oncology, Jaslok Hospital and Research Centre
city: Pune
country: India
facility: Department of Medical Oncology, Deenanath Mangeshkar Hospital
city: Trivandrum
country: India
facility: Department of Medical Oncology/Regional Cancer Centre
city: Bologna
country: Italy
facility: Instituto di Ematologia e Oncologia Medica
city: Torino
country: Italy
facility: Dipartimento Medicina ed Oncologia Sperimentale - Divisione Universitaria di Ematologia Azienda Ospedaliera S. Giovanni Battista
city: Baguio City
country: Philippines
facility: Department of Internal Medicine - Baguio General Hospital & Medical Center
city: Cebu City
country: Philippines
facility: Chong Hua Hospital
city: Makati City
country: Philippines
facility: Doctors Clinic Makati Medical Center
city: Manila City
country: Philippines
facility: University of Sto Tomas Hospital
city: Quezon City
country: Philippines
facility: Doctors Clinic - National Kidney & Transplant Institute
city: Quezon City
country: Philippines
facility: St. Luke's Medical Center
city: Bialystok
country: Poland
facility: SPSK, Klinika Hematologii Akademii Medycznej
city: Gdansk
country: Poland
facility: Klinika Hematologii Akademii Medycznej w Gdanskuul
city: Katowice
country: Poland
facility: Katedra i Klinika Hematologii i Transplantacji Szpiku - Slaska Akademia Medyczna
city: Kielce
country: Poland
facility: Swietokrzyskie Centrum Onkologii SPZOZ Poradnia Hematologii
city: Lodz
country: Poland
facility: Klinika Hematologii Uniwersytetu Medycznego
city: Warszawa
country: Poland
facility: Klinika Chorob Wewnetrznych i Hemagologii
city: Warszawa
country: Poland
facility: Katedra i Klinika Hematologii, Onkologii I Chorob Wewnetrznych
city: Warszawa
country: Poland
facility: Instytut Hematologii i Transfuzjologii - Klinika Hematologiczna
city: Warszawa
country: Poland
facility: Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie
city: Wroclaw
country: Poland
facility: Klinika Hematologii Nowotworow Krwi i Transplantacji - Szpiku Akademii Medycznej
city: Coimbra
country: Portugal
facility: Hospital da Universidade de Coimbra - Servico de Hematologia Clinica
city: Lisboa
country: Portugal
facility: Instituto Portugues de Oncologia
city: Porto
country: Portugal
facility: Hospital Geral de Santo Antonio - Servico de Hematologia Clinica
city: Belgrade
country: Serbia
facility: Institute of Hematology, Clinical Centre of Serbia
city: Nis
country: Serbia
facility: Clinic for Hematology, Clinical Centre Nis
city: Novisad
country: Serbia
facility: Clinic for Hematology, Clinical Centre Novi Sad
city: Bratilslava
country: Slovakia
facility: Department of Internal Medicine, National Cancer Institute
city: Bratilslava
country: Slovakia
facility: Hematology Department University Hospital
city: Kosice
country: Slovakia
facility: Hematology Department, University Hospital PJS
city: Bloemfontein
country: South Africa
facility: University of Free State, Faculty of Health Science, Dept of Hematology & Cell Biology
city: Cape Town
country: South Africa
facility: Tygerberg Hospital, University of Stellenbosch, Department of Haematology
city: Cape Town
country: South Africa
facility: Department of Haematology, UCT Medical School
city: Johannesburg
country: South Africa
facility: Chris Hani Baragwanath Hospital, Clinical Haematology Unit
city: Johannesburg
country: South Africa
facility: Medical Oncology Centre of Rosebank
city: Parktown
country: South Africa
facility: Johannesburg Hospital, Department of Medical Oncology
city: Birmingham
country: United Kingdom
facility: Oncology Research Unit Heartlands Hospital
city: London
country: United Kingdom
facility: Clinical Haematology, Guy's Hospital
city: London
country: United Kingdom
facility: Haematology Department - King's College Hospital
city: Surrey
country: United Kingdom
facility: Department of Haematology-Oncology, The Royal Marsden NHS Foundation Trust
Study officials:
affiliation: Universitatsklinikum Munster
name: Martin Kropff, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kropff M, Baylon HG, Hillengass J, Robak T, Hajek R, Liebisch P, Goranov S, Hulin C, Blade J, Caravita T, Avet-Loiseau H, Moehler TM, Pattou C, Lucy L, Kueenburg E, Glasmacher A, Zerbib R, Facon T. Thalidomide versus dexamethasone for the treatment of relapsed and/or refractory multiple myeloma: results from OPTIMUM, a randomized trial. Haematologica. 2012 May;97(5):784-91. doi: 10.3324/haematol.2011.044271. Epub 2011 Dec 1.
citation: Kropff M, et al. OPTIMUM Dose of Thalidomide for Relapsed Multiple Myeloma. Presented at American Society of Hematology 2009, New Orleans, LA. Abstract No. 959