Melphalan and Dexamethasone With or Without Bortezomib in Treating Patients With Previously Untreated Systemic Light-Chain Amyloidosis

This study has been terminated.
(Administratively complete.)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01078454
First received: February 27, 2010
Last updated: March 18, 2013
Last verified: March 2013
  Purpose

This randomized phase III trial is studying melphalan and dexamethasone to see how well they work with or without bortezomib in treating patients with previously untreated systemic amyloidosis. 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. Bortezomib may stop the growth of plasma cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving melphalan together with dexamethasone is more effective with or without bortezomib in treating systemic amyloidosis


Condition Intervention Phase
Light Chain Deposition Disease
Primary Systemic Amyloidosis
Drug: melphalan
Drug: dexamethasone
Drug: bortezomib
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase III Trial of Melphalan and Dexamethasone (MDex) Versus Bortezomib, Melphalan and Dexamethasone (BMDex) for Untreated Patients With Systemic Light-Chain (AL) Amyloidosis Ineligible for Autologous Stem-Cell Transplantation

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Hematologic overall response (PR+VGPR+ACR+sCR) [ Time Frame: 84 days (3 courses) ] [ Designated as safety issue: No ]
    Will be performed using Mantel-Haenszel test stratified on cardiac stage with an overall one-side type I error of 2.5%. The Mantel-Haenszel estimator is used to estimate the common odds ratio (BMDex/MDex), and a two-sided 95% confidence interval is also calculated.

  • Change in the FACT-Ntx TOI mean change score [ Time Frame: Baseline and 84 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Complete hematologic response rate [ Time Frame: 84 days ] [ Designated as safety issue: No ]
    Will be compared using the Mantel-Haenszel test stratified on cardiac stage. Exact conditional inference will be performed for these analyses.

  • Partial response [ Time Frame: At completion of treatment ] [ Designated as safety issue: No ]
    Will be compared using the Mantel-Haenszel test stratified on cardiac stage. Exact conditional inference will be performed for these analyses.

  • Organ response rate [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]
    Will be compared using the Mantel-Haenszel test stratified on cardiac stage. Exact conditional inference will be performed for these analyses.

  • Time to hematologic response [ Time Frame: From confirmed hematologic response until progression or death of any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    These distributions in each of the arms will be estimated using the method of Kaplan and Meier. The comparison between the two arms will be performed by using one-sided stratified log-rank test.

  • Time to organ response [ Time Frame: From confirmed organ improvement first observed date to confirmed organ progressive disease first observed date or death of any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    These distributions in each of the arms will be estimated using the method of Kaplan and Meier. The comparison between the two arms will be performed by using one-sided stratified log-rank test.

  • Progression free survival [ Time Frame: From randomization until disease progression or death of any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    These distributions in each of the arms will be estimated using the method of Kaplan and Meier. The comparison between the two arms will be performed by using one-sided stratified log-rank test.

  • Overall survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    These distributions in each of the arms will be estimated using the method of Kaplan and Meier. The comparison between the two arms will be performed by using one-sided stratified log-rank test.

  • Treatment-related mortality [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    A two-sided 95% confidence interval on the common odds ratio (BMDex/MDex) is computed by using the exact inference, to quantify the treatment effect on the treatment-related mortality rate.

  • Rates of grade 3 or higher toxicities using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    The toxicity comparison will use the Fisher's exact test. A two-sided 95% confidence interval on the odds ratio (BMDex/MDex) will be also computed.

  • FACT-Ntx TOI score [ Time Frame: Up to 9 months ] [ Designated as safety issue: No ]
  • Total score of the FACT/GOG-Ntx subscale [ Time Frame: Up to 9 months ] [ Designated as safety issue: No ]

Enrollment: 98
Study Start Date: November 2010
Estimated Primary Completion Date: November 2022 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (melphalan and dexamethasone)
Patients receive melphalan PO and dexamethasone PO on days 1-4. Treatment repeats every 28 days for up to 9 courses in the absence of disease progression or unacceptable toxicity.
Drug: melphalan
Given PO
Other Names:
  • Alkeran
  • CB-3025
  • L-PAM
  • L-phenylalanine mustard
  • L-Sarcolysin
Drug: dexamethasone
Given PO
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM
Experimental: Arm II (melphalan, dexamethasone, and bortezomib)
Patients receive melphalan PO and dexamethasone PO on days 1-4 and bortezomib intravenously (IV) on days 1, 4, 8, and 11. Treatment repeats every 28 days for 2 courses. Patients then receive melphalan PO and dexamethasone PO on days 1-4 and bortezomib IV on days 1, 8, 15, and 22. Treatment repeats every 35 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: melphalan
Given PO
Other Names:
  • Alkeran
  • CB-3025
  • L-PAM
  • L-phenylalanine mustard
  • L-Sarcolysin
Drug: dexamethasone
Given PO
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM
Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE

Detailed Description:

PRIMARY OBJECTIVES:

I. To compare hematologic overall response (partial response [PR], very good PR, amyloid complete hematologic response [ACR], and stringent complete response [sCR]) after 3 courses of therapy in patients with previously untreated systemic light-chain amyloidosis treated with melphalan and dexamethasone with vs without bortezomib.

SECONDARY OBJECTIVES:

I. To evaluate the ACR rate after 3 courses of therapy and at completion of therapy.

II. To evaluate organ response rates after 3 courses of therapy and at 6, 9, and 12 months.

III. To evaluate treatment-related mortality. IV. To evaluate toxicity. V. To evaluate progression-free and overall survival. VI. To evaluate PR or better at completion of therapy. VII. To evaluate time to hematologic and organ response. VIII. To evaluate the duration of hematologic and organ response. IX. To assess quality of life (QOL) at baseline, at 3, 6, and 9 months during the therapy, at completion of therapy, and 3 and 6 months after therapy.

TERTIARY OBJECTIVES:

I. To determine the prognostic impact of t(11;14) translocation and cyclin D1 overexpression on response and overall survival.

II. (Correlative) To compare sCR rates and to determine the impact of sCR on the outcomes.

III. (Correlative) To perform a descriptive analysis of amyloid typing and proteomic composition of amyloid tissues.

OUTLINE: This is a multicenter study. Patients are stratified according to cardiac stage (I vs II) and are randomized to 1 of 2 treatment arms.

ARM I: Patients receive melphalan orally (PO) and dexamethasone PO on days 1-4. Treatment repeats every 28 days for up to 9 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive melphalan PO and dexamethasone PO on days 1-4 and bortezomib intravenously (IV) on days 1, 4, 8, and 11. Treatment repeats every 28 days for 2 courses. Patients then receive melphalan PO and dexamethasone PO on days 1-4 and bortezomib IV on days 1, 8, 15, and 22. Treatment repeats every 35 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Blood, urine, bone marrow, and fat samples may be collected periodically for laboratory analysis. Health-related quality of life is assessed periodically before, during, and after therapy. After completion of study treatment, patients are followed up periodically for 5 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed diagnosis of systemic light-chain amyloidosis

    • Histologic diagnosis of disease must be confirmed by pathology (positive Congo red stain with green birefringence on polarized light microscopy)
  • Genetic testing must be negative for transthyretin mutations associated with hereditary amyloidosis (required in patients who are African-American or who present with peripheral neuropathy as the dominant organ involvement)
  • Measurable disease, defined by >= 1 of the following:

    • Serum M-protein >= 1 g/dL by serum protein electrophoresis (SPEP)
    • Serum kappa or lambda free light chain of >= 7.5 mg/dL allowed provided the kappa to lambda free light chain ratio is abnormal
  • Symptomatic organ involvement* (heart, kidney, liver/gastrointestinal tract, peripheral nervous system, or soft tissue), defined as any of the following:

    • NOTE: *Carpal tunnel syndrome skin purpura or the presence of vascular amyloid on a bone marrow biopsy alone are not sufficient to meet criteria for "symptomatic organ involvement"
    • Renal involvement is defined as proteinuria (predominantly albumin) > 0.5 g/day by 24-hour urine collection
    • Cardiac involvement is defined as the presence of a mean left ventricular wall thickness of > 12 mm by ECHO in the absence of a history of hypertension or valvular heart disease or in the presence of unexplained low voltage (< 0.5 mV) by ECG
    • Hepatic involvement is defined as hepatomegaly or an alkaline phosphatase > 1.5 times upper limit of normal (ULN)
    • Peripheral nerve involvement is defined by clinical history or abnormal sensory and/or motor findings on neurologic exam
    • Gastrointestinal (GI) involvement is defined as gross GI bleeding or diarrhea (at least 4 stools per day over baseline); a positive GI biopsy is not sufficient to document clinical involvement
    • Autonomic nerve involvement is defined as orthostasis, symptoms of nausea or dysgeusia, gastric atony by gastric emptying scan, diarrhea, or constipation
    • Soft tissue and lymphatic involvement may be ascertained based on classic physical exam findings (macroglossia, shoulder pad sign, raccoon eyes, carpal tunnel syndrome, synovial enlargement, firm enlarged lymph nodes) or biopsy
  • Amyloid cardiac biomarker stage I or II disease

    • Staging defined by NT-proBNP and troponin T cut-offs of < 332 pg/mL and < 0.035 ng/mL, respectively, as thresholds: stage I, both under threshold; stage II, either troponin or NT-proBNP (but not both) over threshold (if troponin T is not available at local institution, troponin I may be used, but the threshold must be < 0.1 ng/mL)
  • No clinically overt myeloma (hypercalcemia or lytic bone lesions)
  • Ineligible for autologous stem cell transplantation with melphalan 200 mg/m^2 or refuses to undergo transplantation
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Absolute neutrophil count (ANC) > 1,500/mm^3
  • Platelet count > 140,000/mm^3
  • Hemoglobin > 11 g/dL
  • Total bilirubin < 2.5 mg/dL
  • Alkaline phosphatase < 5 times upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) < 3 times ULN
  • Creatinine clearance > 30 mL/min
  • Bone marrow plasma cells < 30%
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No repetitive ventricular arrhythmias on 24-hour Holter electrocardiogram (ECG) (in spite of antiarrhythmic treatment)
  • The absence of supine systolic blood pressure < 100 mmHg and difficult to managesymptomatic orthostatic hypotension
  • No symptomatic orthostatic hypotension that is difficult to manage
  • No cardiac syncope
  • No uncompensated NYHA class III or IV congestive heart failure
  • No uncontrolled infection
  • No active malignancy within the past 5 years except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or adequately treated stage I cancer currently in complete remission
  • No serious medical or psychiatric illness likely to interfere with study participation, including recent myocardial infarction (within the past 6 months) or poorly controlled diabetes mellitus
  • No peripheral neuropathy >= grade 2
  • Human immunodeficiency virus (HIV)-positivity allowed provided the following criteria are met:

    • No history of acquired immunodeficiency syndrome (AIDS)-defining events including history of CD4 cell count < 200/mm^3
    • Current CD4 cell count >= 350/mm^3
    • Not receiving zidovudine or stavudine
    • No secondary amyloidosis
  • No known hypersensitivity to bortezomib, boron, or mannitol
  • No prior chemotherapy or radiotherapy for the treatment of myeloma or systemic light-chain amyloidosis
  • More than 3 weeks since radiotherapy

    • Enrollment of subjects who require radiotherapy (which must be localized in field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy
  • More than 14 days since prior and no concurrent participation in clinical trials with other investigational agents not included in this trial
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01078454

  Show 204 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Angela Dispenzieri Eastern Cooperative Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01078454     History of Changes
Other Study ID Numbers: NCI-2011-02010, E4A08, U10CA021115
Study First Received: February 27, 2010
Last Updated: March 18, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Bortezomib
Melphalan
BB 1101
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Immunosuppressive Agents

ClinicalTrials.gov processed this record on August 27, 2014