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

Multiple Myeloma and Plasma Cell Neoplasm Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00028886
• Other study ID #: CDR0000069144
• Secondary ID: CKTO-2001-02HOVO
• Status: Active, not recruiting
• Phase: Phase 3
• First received: January 4, 2002
• Last updated: September 16, 2013
• Start date: March 2001

Study information

• Verified date: October 2012
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 450
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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

Study Design

Allocation: Randomized, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Myeloma
• Multiple Myeloma and Plasma Cell Neoplasm
• Neoplasms, Plasma Cell
• Plasmacytoma

Intervention

Biological:
• filgrastim

• recombinant interferon alfa

Drug:
• cyclophosphamide

• dexamethasone

• doxorubicin hydrochloride

• melphalan

• thalidomide

• vincristine sulfate

Procedure:
• bone marrow ablation with stem cell support

• peripheral blood stem cell transplantation

Locations

Country	Name	City	State
Belgium	U.Z. Gasthuisberg	Leuven
Netherlands	HagaZiekenhuis - Locatie Leyenburg	's-Gravenhage
Netherlands	Jeroen Bosch Ziekenhuis	's-Hertogenbosch
Netherlands	Meander Medisch Centrum	Amersfoort
Netherlands	Academisch Medisch Centrum at University of Amsterdam	Amsterdam
Netherlands	Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital	Amsterdam
Netherlands	Vrije Universiteit Medisch Centrum	Amsterdam
Netherlands	Medisch Spectrum Twente	Enschede
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Medisch Centrum Leeuwarden - Zuid	Leeuwarden
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Academisch Ziekenhuis Maastricht	Maastricht
Netherlands	Sint Antonius Ziekenhuis	Nieuwegein
Netherlands	Universitair Medisch Centrum St. Radboud - Nijmegen	Nijmegen
Netherlands	Daniel Den Hoed Cancer Center at Erasmus Medical Center	Rotterdam
Netherlands	University Medical Center Utrecht	Utrecht
Netherlands	Isala Klinieken - locatie Sophia	Zwolle

Sponsors (1)

Lead Sponsor	Collaborator
Commissie Voor Klinisch Toegepast Onderzoek

Countries where clinical trial is conducted

Belgium,  Netherlands, 

References & Publications (5)

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. — View Citation

Lokhorst H, van der Holt B, Zweegman S, et al.: Final analysis of HOVON-50 randomized phase III study on the effect of thalidomide combined with adriamycine,dexamethasone (AD) and high dose melphalan (HDM) in patients with multiple myeloma (MM). [Abstract

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, Bl — View 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 myelo — View 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 Ammerla — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free survival			No
Secondary	Partial response and complete response			No
Secondary	Overall survival			No
Secondary	Progression-free survival			No
Secondary	Toxicity			Yes