Efficacy and Safety Study of 3 Thalidomide Doses for the Treatment of Relapsed Refractory Multiple Myeloma

Multiple Myeloma Clinical Trial

— OPTIMUM  

Official title:

Randomised, Controlled, Open-labelled, Multi-centre Comparison of Thalidomide Versus High-dose Dexamethasone for the Treatment of Relapsed Refractory Multiple Myeloma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00452569
• Other study ID #: THA PH INT 2005 CL001
• Status: Completed
• Phase: Phase 3
• Start date: February 1, 2006
• Est. completion date: January 1, 2009

Study information

• Verified date: November 2019
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 499
• Est. completion date: January 1, 2009
• Est. primary completion date: December 1, 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 ß-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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Thalidomide
Oral thalidomide (100mg or 200mg or 400 mg/day) administered to the patient once daily until progression of the disease and for a maximum of 336 + 36 days (12 cycles of 28 +/- 3 days).
• Dexamethasone
High dose oral dexamethasone will be administered at a dose of 40mg/day on days 1-4, 9-12 and 17-20 of each 28-day cycle for cycles 1-4. Beginning with cycle 5, the oral dexamethasone dosing schedule will be reduced to 40mg/day on days 1-4 of each 28-day cycle. Dexamethasone will be administered until progression of the disease and for a maximum of 336 +/- 36 days (12 cycles of 28 +/- 3 days).

Locations

Country	Name	City	State
Bulgaria	Clinic of Haematology, University Multiprofiled Hospital for Active Treatment "G. Stranski"	Pleven
Bulgaria	Clinic of Haematology, University Multiprofiled Hospital for Active Treatment	Plovdiv
Bulgaria	Military Medical Academy/Dept Haematology and Oncology	Sofia
Bulgaria	National Center of Haematology & Transfusiology	Sofia
Bulgaria	University of Multiprofiled Hospital for Active Treatment "Alexandrovska" - Sofia	Sofia
Bulgaria	Clinic of Haematology, Multiprofiled Hospital for Active Treatment "Sveta Marina"	Varna
Croatia	Klinicki Bolnicki Centar Rijeka Interna Klinika	Rijeka
Croatia	Klinika Bolnica SPLIT - Klinika za Unutarnje Bolesti	Split
Croatia	KBC Zagreb - Klinika za Unutarnje Bolesti	Zagreb
Croatia	Klinicka Bolnica "Dubrava" Klinika za Unutarnje Bolesti	Zagreb
Croatia	Klinicka Bolnica "Sestre milosrdnice" Klinika za Unutarnje Bolesti	Zagreb
Croatia	Klinicka Bolnica MERKUR - Klinika za Unutarnje Bolesti	Zagreb
Czechia	Interni Hemato-Onkologicka Klinika	Brno
Czechia	Hematologicka Klinika, Fakultni Nemocnice Hradec Kralove	Hradec Kralove
Czechia	Onkologicke Centrum J.G. Mendela	Novi Jicin
Czechia	Interni Klinika, Oddeleni Hematoonkologie	Olomouc
Czechia	Hematologicka Klinika, Fakultni Nemocnice Kralovske Vinohrady Srobarova	Prague 10
Czechia	Interni Klinika, Oddeleni Hematoonkologie	Prague 2
France	CHRU de Lille - Hopital Claude Huriez	Lille
France	CHU de Nancy - Hopital Brabois	Nancy Cedex
France	Hematologie - CHU Purpan Place du Dr. Baylac	Toulouse
Germany	Charite, Universitatsmedizin Berlin, Campus Robert-Rossle Klinik	Berlin
Germany	Med. Klinik I/University Bonn	Bonn
Germany	Medizinische Klinik und Poliklinik I/Carl-Gustav-Carus University	Dresden
Germany	Hematology, Oncology & Clinical Immunology/Heinrich-Heine-University	Duesseldorf
Germany	Abt. Haematologie - Onkologie/ Allg. Krankenhaus	Hamburg
Germany	Allgemeinse Krankenhaus St. Georg Hamatologische Abteilung	Hamburg
Germany	Medizinische Klinik Abteilung Innere V/Universitatsklinikum	Heidelberg
Germany	Universitat Schleswig Holstein II Med. Klinik	Kiel
Germany	Universitaetsklinik - Klinik fur innere Medizin	Koeln
Germany	Medizinische Klinik und Poliklinik III/Klinikum der Universitaet Muenchen	Muenchen
Germany	Innere Medizin University Hospital	Muenster
Germany	Abteilung Haematologie - Univeresitaetsklinikum	Saale
Germany	Robert-Bosch-Krankenhaus GmbH, Stuttgart	Stuttgart
Germany	Universitaetsklinik - Abteilung Innere Medizin III	Ulm
Germany	Med. Klinik II/Klinikum of the Julius-Maximilians-University	Wuerzburg
Hungary	National Medical Centre Dpt Haematology	Budapest
Hungary	Petz Aladar Megyei Oktato Korhaz, II. Belgyogyaszat	Gyor
Hungary	Pandy Kalman Megyei Korhaz, Megyei Onkologiai Centrum	Gyula
Hungary	Szent-Gyorgyi Albert University II Clinic of Internal Medicine	Szeged
India	Nizam's Institute of Medical Sciences, Department of Medical Oncology	Hyderabaad
India	Department of Medical Oncology, Amrita Institute of Medical Sciences	Kerala
India	Orchid Nursing Home	Kolkata
India	Department of Medical Oncology, Dayanand Medical College DMCH	Ludhiana
India	Department of Medical Oncology, Jaslok Hospital and Research Centre	Mumbai
India	Department of Medical Oncology, S.L. Raheja Hospital	Mumbai
India	Department of Medical Oncology/Tata Memorial Hospital	Mumbai
India	Department of Medical Oncology, Deenanath Mangeshkar Hospital	Pune
India	Department of Medical Oncology/Regional Cancer Centre	Trivandrum
Italy	Instituto di Ematologia e Oncologia Medica	Bologna
Italy	Dipartimento Medicina ed Oncologia Sperimentale - Divisione Universitaria di Ematologia Azienda Ospedaliera S. Giovanni Battista	Torino
Philippines	Department of Internal Medicine - Baguio General Hospital & Medical Center	Baguio City
Philippines	Chong Hua Hospital	Cebu City
Philippines	Doctors Clinic Makati Medical Center	Makati City
Philippines	University of Sto Tomas Hospital	Manila City
Philippines	Doctors Clinic - National Kidney & Transplant Institute	Quezon City
Philippines	St. Luke's Medical Center	Quezon City
Poland	SPSK, Klinika Hematologii Akademii Medycznej	Bialystok
Poland	Klinika Hematologii Akademii Medycznej w Gdanskuul	Gdansk
Poland	Katedra i Klinika Hematologii i Transplantacji Szpiku - Slaska Akademia Medyczna	Katowice
Poland	Swietokrzyskie Centrum Onkologii SPZOZ Poradnia Hematologii	Kielce
Poland	Klinika Hematologii Uniwersytetu Medycznego	Lodz
Poland	Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie	Warszawa
Poland	Instytut Hematologii i Transfuzjologii - Klinika Hematologiczna	Warszawa
Poland	Katedra i Klinika Hematologii, Onkologii I Chorob Wewnetrznych	Warszawa
Poland	Klinika Chorob Wewnetrznych i Hemagologii	Warszawa
Poland	Klinika Hematologii Nowotworow Krwi i Transplantacji - Szpiku Akademii Medycznej	Wroclaw
Portugal	Hospital da Universidade de Coimbra - Servico de Hematologia Clinica	Coimbra
Portugal	Instituto Portugues de Oncologia	Lisboa
Portugal	Hospital Geral de Santo Antonio - Servico de Hematologia Clinica	Porto
Serbia	Institute of Hematology, Clinical Centre of Serbia	Belgrade
Serbia	Clinic for Hematology, Clinical Centre Nis	Nis
Serbia	Clinic for Hematology, Clinical Centre Novi Sad	Novisad
Slovakia	Department of Internal Medicine, National Cancer Institute	Bratilslava
Slovakia	Hematology Department University Hospital	Bratilslava
Slovakia	Hematology Department, University Hospital PJS	Kosice
South Africa	University of Free State, Faculty of Health Science, Dept of Hematology & Cell Biology	Bloemfontein
South Africa	Department of Haematology, UCT Medical School	Cape Town
South Africa	Tygerberg Hospital, University of Stellenbosch, Department of Haematology	Cape Town
South Africa	Chris Hani Baragwanath Hospital, Clinical Haematology Unit	Johannesburg
South Africa	Medical Oncology Centre of Rosebank	Johannesburg
South Africa	Johannesburg Hospital, Department of Medical Oncology	Parktown
United Kingdom	Oncology Research Unit Heartlands Hospital	Birmingham
United Kingdom	Clinical Haematology, Guy's Hospital	London
United Kingdom	Haematology Department - King's College Hospital	London
United Kingdom	Department of Haematology-Oncology, The Royal Marsden NHS Foundation Trust	Surrey

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

Bulgaria,  Croatia,  Czechia,  France,  Germany,  Hungary,  India,  Italy,  Philippines,  Poland,  Portugal,  Serbia,  Slovakia,  South Africa,  United Kingdom, 

References & Publications (2)

Kropff M, Baylon HG, Hillengass J, Robak T, Hajek R, Liebisch P, Goranov S, Hulin C, Bladé 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. — View 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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The evaluation of Independent Review Committee-documented time to progression (TTP).		>160 "IRC confirmed" disease progression in the Dexamethasone or Thalidomide 400 mg/day arms
Secondary	Response rate (CR + PR), according to the EBMT criteria		Every 4 weeks
Secondary	Response duration		Every 4 weeks
Secondary	Clinical benefit as measured by ECOG performance status, transfusion requirement and Grade =3 infections (assessed by the National Cancer Institute Common Toxicity Criteria)		Every 4 weeks
Secondary	Progression-free survival (PFS)		Disease progression evaluated every 4 weeks
Secondary	Overall survival (OS)		Evaluated after 150 deaths occurring in Dexamethasone and Thalidomide 400 mg arms
Secondary	Composite of disease progression and death (recurrent time(s) from randomisation to disease progression and/or death)		Evaluated after 160 "IRC confirmed" disease progression in the Dexamethasone or Thalidomide 400 mg/day arms
Secondary	Quality of life as determined by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30)		Baseline/Week 8/ Week 16/Week 24/Week 32/Week 40/Week 48
Secondary	Adverse events (AEs)		Every 4 weeks
Secondary	Assessment of peripheral neuropathy		Screening, Week 24, Week 48
Secondary	Vital signs and physical examination		Every 4 weeks
Secondary	Clinical laboratory tests		Every 4 weeks