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Combination Chemotherapy With or Without Thalidomide in Treating Patients With Multiple Myeloma

Primary Purpose

Multiple Myeloma and Plasma Cell Neoplasm

Status
Unknown status
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
filgrastim
recombinant interferon alfa
cyclophosphamide
dexamethasone
doxorubicin hydrochloride
melphalan
thalidomide
vincristine sulfate
bone marrow ablation with stem cell support
peripheral blood stem cell transplantation
Sponsored by
Commissie Voor Klinisch Toegepast Onderzoek
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Myeloma and Plasma Cell Neoplasm focused on measuring stage II multiple myeloma, stage III multiple myeloma

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

DISEASE CHARACTERISTICS: Histologically confirmed multiple myeloma Stage II or III No systemic amyloid light-chain amyloidosis PATIENT CHARACTERISTICS: Age: 18 to 65 Performance status: WHO 0-3 Life expectancy: Not specified Hematopoietic: Not specified Hepatic: No significant hepatic dysfunction* Bilirubin less than 1.75 mg/dL* AST/ALT less than 2.5 times normal* NOTE: *Unless related to myeloma Renal: Not specified Cardiovascular: No severe cardiac dysfunction No New York Heart Association class II, III, or IV heart disease Other: HIV negative No active uncontrolled infection No other malignancy within the past 5 years except basal cell skin cancer or carcinoma in situ of the cervix No known intolerance to thalidomide Not pregnant Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Patients 18 to 55 years of age must not have been allocated before study randomization to allogeneic stem cell transplantation with an HLA-identical sibling donor Chemotherapy: No more than 2 prior courses of melphalan and prednisone therapy for local myeloma progression No other prior chemotherapy Endocrine therapy: Not specified Radiotherapy: Prior local radiotherapy for local myeloma progression allowed No other prior radiotherapy Surgery: Not specified

Sites / Locations

  • U.Z. Gasthuisberg
  • HagaZiekenhuis - Locatie Leyenburg
  • Jeroen Bosch Ziekenhuis
  • Meander Medisch Centrum
  • Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
  • Vrije Universiteit Medisch Centrum
  • Academisch Medisch Centrum at University of Amsterdam
  • Medisch Spectrum Twente
  • University Medical Center Groningen
  • Medisch Centrum Leeuwarden - Zuid
  • Leiden University Medical Center
  • Academisch Ziekenhuis Maastricht
  • Sint Antonius Ziekenhuis
  • Universitair Medisch Centrum St. Radboud - Nijmegen
  • Daniel Den Hoed Cancer Center at Erasmus Medical Center
  • University Medical Center Utrecht
  • Isala Klinieken - locatie Sophia

Outcomes

Primary Outcome Measures

Event-free survival

Secondary Outcome Measures

Partial response and complete response
Overall survival
Progression-free survival
Toxicity

Full Information

First Posted
January 4, 2002
Last Updated
September 16, 2013
Sponsor
Commissie Voor Klinisch Toegepast Onderzoek
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1. Study Identification

Unique Protocol Identification Number
NCT00028886
Brief Title
Combination Chemotherapy With or Without Thalidomide in Treating Patients With Multiple Myeloma
Official Title
A Randomized Phase III Study On The Effect Of Thalidomide Combined With Adriamycin, Dexamethasone (AD) And High Dose Melphalan In Patients With Multiple Myeloma
Study Type
Interventional

2. Study Status

Record Verification Date
October 2012
Overall Recruitment Status
Unknown status
Study Start Date
March 2001 (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Name of the Sponsor
Commissie Voor Klinisch Toegepast Onderzoek

4. Oversight

5. Study Description

Brief Summary
RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Thalidomide may stop the growth of cancer cells by stopping blood flow to the cancer. Peripheral blood stem cell transplant using stem cells from the patient or a donor may be able to replace immune cells that were destroyed by chemotherapy used to kill cancer cells. The donated stem cells may also help destroy any remaining cancer cells (graft-versus-tumor effect). It is not yet known whether chemotherapy followed by peripheral blood stem cell transplant is more effective with or without thalidomide in treating multiple myeloma. PURPOSE: This randomized phase III trial is studying giving combination chemotherapy with thalidomide to see how well it works compared with giving combination chemotherapy without thalidomide in treating patients with multiple myeloma.
Detailed Description
OBJECTIVES: Compare the efficacy of doxorubicin, dexamethasone, and high-dose melphalan with versus without thalidomide, in terms of event-free survival, of patients with multiple myeloma. Determine the response rate, complete response rate, overall survival, and progression-free survival of patients treated with these regimens. Determine the safety and toxicity of thalidomide in combination with intensive chemotherapy in these patients. Assess the value of prognostic factors at diagnosis in individual patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center and treatment policy (1 course vs 2 courses of high-dose melphalan). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive induction chemotherapy (AD) comprising doxorubicin IV on days 1-4 and oral dexamethasone on days 1-4, 9-12, and 17-20. Patients receive oral thalidomide daily beginning on day 1 and continuing until 2 weeks before start of stem cell mobilization. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients receive stem cell mobilization with chemotherapy comprising cyclophosphamide IV on day 1 and doxorubicin IV and oral dexamethasone on days 1-4 (CAD). Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until last apheresis. Beginning 8-10 weeks after stem cell collection, patients receive low-dose oral thalidomide daily and high-dose melphalan IV on days -3 and -2 as intensification. Patients undergo stem cell infusion on day 0. Patients may receive a second course of high-dose melphalan 2-3 months after the first course, in which case, stem cell infusion follows the second course of melphalan. Patients receive maintenance therapy with oral thalidomide daily until disease progression or after 3 months if no response. Beginning 2 months after the last course, patients with an HLA-identical sibling donor undergo nonmyeloablative stem cell transplantation after radiotherapy. Arm II: Patients receive induction chemotherapy (VAD) comprising vincristine IV and doxorubicin IV on days 1-4 and dexamethasone on days 1-4, 9-12, and 17-20. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients receive stem cell mobilization with CAD chemotherapy as in arm I. G-CSF is given as in arm I. Patients receive high-dose melphalan and undergo stem cell infusion as in arm I. Patients receive maintenance therapy with interferon alfa SC 3 times weekly until progression or after 3 months if no partial response. Beginning 2 months after the last course, patients with an HLA-identical sibling donor undergo nonmyeloablative stem cell transplantation after radiotherapy. All patients are followed every 6 months for 3 years and then annually thereafter. PROJECTED ACCRUAL: A total of 450 patients (225 per treatment arm) will be accrued for this study within 4 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma and Plasma Cell Neoplasm
Keywords
stage II multiple myeloma, stage III multiple myeloma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Allocation
Randomized
Enrollment
450 (Anticipated)

8. Arms, Groups, and Interventions

Intervention Type
Biological
Intervention Name(s)
filgrastim
Intervention Type
Biological
Intervention Name(s)
recombinant interferon alfa
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Intervention Type
Drug
Intervention Name(s)
dexamethasone
Intervention Type
Drug
Intervention Name(s)
doxorubicin hydrochloride
Intervention Type
Drug
Intervention Name(s)
melphalan
Intervention Type
Drug
Intervention Name(s)
thalidomide
Intervention Type
Drug
Intervention Name(s)
vincristine sulfate
Intervention Type
Procedure
Intervention Name(s)
bone marrow ablation with stem cell support
Intervention Type
Procedure
Intervention Name(s)
peripheral blood stem cell transplantation
Primary Outcome Measure Information:
Title
Event-free survival
Secondary Outcome Measure Information:
Title
Partial response and complete response
Title
Overall survival
Title
Progression-free survival
Title
Toxicity

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
DISEASE CHARACTERISTICS: Histologically confirmed multiple myeloma Stage II or III No systemic amyloid light-chain amyloidosis PATIENT CHARACTERISTICS: Age: 18 to 65 Performance status: WHO 0-3 Life expectancy: Not specified Hematopoietic: Not specified Hepatic: No significant hepatic dysfunction* Bilirubin less than 1.75 mg/dL* AST/ALT less than 2.5 times normal* NOTE: *Unless related to myeloma Renal: Not specified Cardiovascular: No severe cardiac dysfunction No New York Heart Association class II, III, or IV heart disease Other: HIV negative No active uncontrolled infection No other malignancy within the past 5 years except basal cell skin cancer or carcinoma in situ of the cervix No known intolerance to thalidomide Not pregnant Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Patients 18 to 55 years of age must not have been allocated before study randomization to allogeneic stem cell transplantation with an HLA-identical sibling donor Chemotherapy: No more than 2 prior courses of melphalan and prednisone therapy for local myeloma progression No other prior chemotherapy Endocrine therapy: Not specified Radiotherapy: Prior local radiotherapy for local myeloma progression allowed No other prior radiotherapy Surgery: Not specified
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
H. Lokhorst, MD, PhD
Organizational Affiliation
UMC Utrecht
Official's Role
Study Chair
Facility Information:
Facility Name
U.Z. Gasthuisberg
City
Leuven
ZIP/Postal Code
B-3000
Country
Belgium
Facility Name
HagaZiekenhuis - Locatie Leyenburg
City
's-Gravenhage
ZIP/Postal Code
2545 CH
Country
Netherlands
Facility Name
Jeroen Bosch Ziekenhuis
City
's-Hertogenbosch
ZIP/Postal Code
5211 NL
Country
Netherlands
Facility Name
Meander Medisch Centrum
City
Amersfoort
ZIP/Postal Code
3816 CP
Country
Netherlands
Facility Name
Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
City
Amsterdam
ZIP/Postal Code
1066 CX
Country
Netherlands
Facility Name
Vrije Universiteit Medisch Centrum
City
Amsterdam
ZIP/Postal Code
1081HV
Country
Netherlands
Facility Name
Academisch Medisch Centrum at University of Amsterdam
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
Facility Name
Medisch Spectrum Twente
City
Enschede
ZIP/Postal Code
7500 KA
Country
Netherlands
Facility Name
University Medical Center Groningen
City
Groningen
ZIP/Postal Code
9713 EZ
Country
Netherlands
Facility Name
Medisch Centrum Leeuwarden - Zuid
City
Leeuwarden
ZIP/Postal Code
8934 AD
Country
Netherlands
Facility Name
Leiden University Medical Center
City
Leiden
ZIP/Postal Code
2300 RC
Country
Netherlands
Facility Name
Academisch Ziekenhuis Maastricht
City
Maastricht
ZIP/Postal Code
6202 AZ
Country
Netherlands
Facility Name
Sint Antonius Ziekenhuis
City
Nieuwegein
ZIP/Postal Code
3435 CM
Country
Netherlands
Facility Name
Universitair Medisch Centrum St. Radboud - Nijmegen
City
Nijmegen
ZIP/Postal Code
NL-6500 HB
Country
Netherlands
Facility Name
Daniel Den Hoed Cancer Center at Erasmus Medical Center
City
Rotterdam
ZIP/Postal Code
3008 AE
Country
Netherlands
Facility Name
University Medical Center Utrecht
City
Utrecht
ZIP/Postal Code
3584 CX
Country
Netherlands
Facility Name
Isala Klinieken - locatie Sophia
City
Zwolle
ZIP/Postal Code
8000 GK
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
18805967
Citation
Johnson DC, Corthals S, Ramos C, Hoering A, Cocks K, Dickens NJ, Haessler J, Goldschmidt H, Child JA, Bell SE, Jackson G, Baris D, Rajkumar SV, Davies FE, Durie BG, Crowley J, Sonneveld P, Van Ness B, Morgan GJ. Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping. Blood. 2008 Dec 15;112(13):4924-34. doi: 10.1182/blood-2008-02-140434. Epub 2008 Sep 19.
Results Reference
background
PubMed Identifier
22442350
Citation
Lokhorst HM, van der Holt B, Cornelissen JJ, Kersten MJ, van Oers M, Raymakers R, Minnema MC, Zweegman S, Janssen JJ, Zijlmans M, Bos G, Schaap N, Wittebol S, de Weerdt O, Ammerlaan R, Sonneveld P. Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study. Blood. 2012 Jun 28;119(26):6219-25; quiz 6399. doi: 10.1182/blood-2011-11-393801. Epub 2012 Mar 22.
Results Reference
result
PubMed Identifier
19880501
Citation
Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. doi: 10.1182/blood-2009-05-222539. Epub 2009 Oct 30.
Results Reference
result
PubMed Identifier
18166796
Citation
Lokhorst HM, Schmidt-Wolf I, Sonneveld P, van der Holt B, Martin H, Barge R, Bertsch U, Schlenzka J, Bos GM, Croockewit S, Zweegman S, Breitkreutz I, Joosten P, Scheid C, van Marwijk-Kooy M, Salwender HJ, van Oers MH, Schaafsma R, Naumann R, Sinnige H, Blau I, Delforge M, de Weerdt O, Wijermans P, Wittebol S, Duersen U, Vellenga E, Goldschmidt H; Dutch-Belgian HOVON; German GMMG. Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma. Haematologica. 2008 Jan;93(1):124-7. doi: 10.3324/haematol.11644. Erratum In: Haematologica. 2008 Mar;93(3):480. Verhoef, Gregor [removed]; Delforge, Michel [added]; Breitkreuz, Iris [corrected to Breitkreutz, Iris].
Results Reference
result

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Combination Chemotherapy With or Without Thalidomide in Treating Patients With Multiple Myeloma

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