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Low-Dose Melphalan and Dexamethasone Compared With High-Dose Melphalan Followed By Autologous Stem Cell Transplant in Treating Patients With Primary Systemic Amyloidosis

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ClinicalTrials.gov Identifier: NCT00477971
Recruitment Status : Completed
First Posted : May 24, 2007
Results First Posted : July 21, 2015
Last Update Posted : May 17, 2016
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Tracking Information
First Submitted Date  ICMJE May 23, 2007
First Posted Date  ICMJE May 24, 2007
Results First Submitted Date  ICMJE June 23, 2015
Results First Posted Date  ICMJE July 21, 2015
Last Update Posted Date May 17, 2016
Study Start Date  ICMJE October 2005
Actual Primary Completion Date July 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 23, 2015)
Hematologic Response Rate [ Time Frame: 10 years ]
Response that was confirmed on 2 consecutive evaluations during treatment. A hematologic response consisted of a Complete response, Very Good Partial Response or Partial Response.
  • Complete Response (CR): Complete disappearance of M-protein from serum and urine on immunofixation, normalization of Free Light Chain (FLC) ratio and <5% plasma cells in bone marrow.
  • Very Good Partial Response (VGPR): >=90% reduction in serum M-component; Urine M-Component <=100 mg per 24 hours.
  • Partial Response (PR): >=50% reduction in serum M-component and/or Urine M-Component >=90% reduction or <200 mg per 24 hours; or >=50% decrease in difference between involved and uninvolved FLC levels.
Original Primary Outcome Measures  ICMJE
 (submitted: May 23, 2007)
Hematologic Response Rate
Change History Complete list of historical versions of study NCT00477971 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2015)
  • 3 Year Overall Survival [ Time Frame: 3 years ]
    Percentage of patients who were alive at 3 years. The 3-year survival rate was estimated using the Kaplan Meier method.
  • Organ Response to Treatment [ Time Frame: 10 years ]
    Organ response was evaluated on the basis of improvement of one or more affected organ; only one parameter was required to satisfy the criteria. Response needed to be maintained for a minimum of 3 months to be considered valid. Renal response required a 50% reduction in 24-hour urine protein excretion (at least 0.5 g/d) with stable creatinine. Cardiac response required one of >= 2-mm reduction in the interventricular septal (IVS) thickness by echocardiogram, or improvement of ejection fraction by >= 20%, or improvement by 2 NYHA classes without an increase in diuretic use. Hepatic response required either >= 50% decrease in (or normalization of) an initially elevated alkaline phosphatase level or reduction in the size of the liver by at least 2 cm by radiographic determination. Gastrointestinal tract improvement was defined as normalization of a low serum carotene level, or reduction of diarrhea to < 50% of previous movements/day, or decrease in fecal fat excretion by 50%.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 23, 2007)
  • Toxicity
  • Overall survival
  • Organ Response to Treatment
  • Patient-reported outcomes
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Low-Dose Melphalan and Dexamethasone Compared With High-Dose Melphalan Followed By Autologous Stem Cell Transplant in Treating Patients With Primary Systemic Amyloidosis
Official Title  ICMJE Phase III Trial of Stem Cell Transplantation Compared to Parenteral Melphalan and Oral Dexamethasone in the Treatment of Primary Systemic Amyloidosis (AL)
Brief Summary

RATIONALE: Drugs used in chemotherapy, such as melphalan and dexamethasone, work in different ways to stop the growth of plasma cells, either by killing the cells or by stopping them from dividing. Having an autologous stem cell transplant to replace the blood-forming cells destroyed by chemotherapy, allows higher doses of chemotherapy to be given so that more plasma cells are killed. By reducing the number of plasma cells, the disease may progress more slowly. It is not yet known whether combination chemotherapy is more effective than chemotherapy followed by an autologous stem cell transplant in treating primary systemic amyloidosis.

PURPOSE: This randomized phase III trial is studying the side effects and how well giving low-dose melphalan together with dexamethasone works compared with high-dose melphalan followed by an autologous stem cell transplant in treating patients with primary systemic amyloidosis.

Detailed Description

OBJECTIVES:

Primary

  • Compare hematologic response rate in patients with primary systemic amyloidosis treated with conventional chemotherapy comprising low-dose melphalan and dexamethasone vs high-dose melphalan followed by autologous stem cell transplantation.
  • Compare the toxicity of these regimens in these patients.

Secondary

  • Compare the overall and progression-free survival of patients treated with these regimens.
  • Compare the regression of organ involvement in patients treated with these regimens.
  • Compare the duration of response in patients treated with these regimens.
  • Correlate clonal burden and time to in vitro amyloid formation with clinical outcomes in patients treated with these regimens.
  • Compare quality of life of patients treated with these regimens.
  • Compare the information-seeking behavior in patients treated with these regimens.

OUTLINE: This is a comprehensive cohort study comprising a randomized option and a nonrandomized option. Patients consenting to randomization are stratified by risk group (high vs low) and ECOG performance status (0-1 vs 2). They are then randomized to 1 of 2 treatment arms. Patients not consenting to randomization choose their treatment arm.

  • Arm I: Patients receive low-dose melphalan IV over 15-30 minutes on day 1 or orally once daily on days 1-7 and oral dexamethasone on days 1-4 and 22-25. Treatment repeats every 6 weeks for 10 courses in the absence of disease progression or unacceptable toxicity.
  • Arm II: Patients receive filgrastim (G-CSF) on days -7 to -3 and undergo autologous hematopoietic stem cell (HSC) collection. Patients receive high-dose melphalan IV over 1 hour on days -2 and -1 and undergo autologous HSC transplantation on day 0.

Blood and bone marrow samples are collected at baseline. Samples are examined by PCR, cDNA, and nucleotide sequence analysis to determine VH and VL gene families and carrier status. Urine is collected at baseline and analyzed for light-chain protein levels by exclusion chromatography.

Quality of life is assessed at baseline, at months 3, 9, and 12, at completion of study treatment, and then every 6 months for up to 5 years.

After completion of study treatment, patients are followed every 6 months for up to 10 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Multiple Myeloma and Plasma Cell Neoplasm
Intervention  ICMJE
  • Biological: filgrastim
    No administration information given
  • Drug: dexamethasone
    Given orally
  • Drug: melphalan
    Given IV or orally
  • Procedure: autologous hematopoietic stem cell transplantation
    Given on day 0
Study Arms  ICMJE
  • Active Comparator: Arm A

    Patients receive low-dose melphalan IV over 15-30 minutes on day

    1 or orally once daily on days 1-7 and oral dexamethasone on days 1-4 and 22-25. Treatment repeats every 6 weeks for 10 courses.

    Study treatment beyond one year is not allowed.

    Interventions:
    • Drug: dexamethasone
    • Drug: melphalan
  • Experimental: Arm B
    Patients receive filgrastim (G-CSF) on days -7 to -3 and undergo autologous hematopoietic stem cell (HSC) collection. Patients receive high-dose melphalan IV over 1 hour on days -2 and -1 and undergo autologous HSC transplantation on day 0.
    Interventions:
    • Biological: filgrastim
    • Drug: melphalan
    • Procedure: autologous hematopoietic stem cell transplantation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 23, 2015)
89
Original Enrollment  ICMJE
 (submitted: May 23, 2007)
152
Actual Study Completion Date  ICMJE December 2014
Actual Primary Completion Date July 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

DISEASE CHARACTERISTICS:

  • Histologically confirmed primary systemic amyloidosis

    • Amyloid light-chain (AL) disease
  • Monoclonal protein by immunoelectrophoresis or immunofixation of the serum or urine OR abnormal free light-chain ratio
  • The following amyloid syndromes* are allowed:

    • Amyloid hepatomegaly
    • Cardiomyopathy
    • Proteinuria
    • Peripheral or autonomic neuropathy
    • Soft tissue involvement including the tongue, submandibular tissues, and vascular claudication
    • Diffuse interstitial pulmonary AL disease allowed if pulmonary function is adequate to allow safe transplantation NOTE: *Presence of amyloid deposits in a plasmacytoma or in bone marrow vessels in an asymptomatic patient does not constitute an amyloid syndrome
  • No secondary or familial amyloidosis
  • No multiple myeloma with lytic or destructive bone lesions or myeloma cast nephropathy
  • No multiple myeloma with > 30% plasma cells in the bone marrow
  • No amyloidosis manifested only by carpal tunnel syndrome or purpura

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-2
  • Platelet count ≥ 100,000/mm³
  • Bilirubin ≤ 2.0 times upper limit of normal (ULN)
  • Alkaline phosphatase ≤ 6 times ULN
  • Creatinine ≤ 3.0 mg/dL
  • No NYHA class IV heart disease
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No uncontrolled infection
  • No HIV positivity

PRIOR CONCURRENT THERAPY:

  • Prior alkylating agents, immunosuppressive drugs, or steroids allowed provided they were given for < 1 month

    • Therapeutic steroid doses of ≤ 15 mg per day (or equivalent) allowed at discretion of physician
  • No concurrent participation in another clinical trial involving a pharmacologic agent
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00477971
Other Study ID Numbers  ICMJE CDR0000546745
P30CA015083 ( U.S. NIH Grant/Contract )
MC0482 ( Other Identifier: Mayo Clinic Cancer Center )
1691-05 ( Other Identifier: Mayo Clinic IRB )
NCI-2009-01329 ( Registry Identifier: NCI-CTRP )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mayo Clinic
Study Sponsor  ICMJE Mayo Clinic
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Study Chair: Morie A. Gertz, MD Mayo Clinic
PRS Account Mayo Clinic
Verification Date June 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP