Bortezomib and Dexamethasone Followed by High-Dose Melphalan and Stem Cell Transplantation for Primary (AL) Amyloidosis

Phase II Trial of Induction Therapy With Bortezomib and Dexamethasone Followed by High-Dose Melphalan and Stem Cell Transplantation in Patients With AL Amyloidosis

The drugs dexamethasone and bortezomib are both FDA-approved for the treatment of multiple myeloma, a disease very similar to amyloidosis. However, they are currently investigational for the treatment of amyloidosis.

We want to find out if the addition of dexamethasone and bortezomib to standard high dose chemotherapy and stem cell transplant can help improve response.

Standard treatment includes four steps: 1) Stem Cell Mobilization (standard) 2) Stem Cell Collection (standard) 3) Conditioning Regimen (Melphalan chemotherapy). The conditioning regimen helps to kill the abnormal cells in the body and makes room in the bone marrow for new blood stem cells to grow. 4) Stem Cell Infusion

Participants in this study will have an additional treatment step called "induction therapy", designed as the first step towards reducing the number of abnormal cells in the body. Two cycles of the investigational drugs bortezomib and dexamethasone will be given during induction therapy. In addition, bortezomib will given as part of the conditioning regimen, in addition to the standard melphalan chemotherapy.

Study Overview

• Status: Completed
• Conditions: Amyloidosis
• Intervention / Treatment: Drug: Bortezomib; Drug: Dexamethasone; Drug: Melphalan

Detailed Description

The drugs dexamethasone and bortezomib are both FDA-approved drugs for the treatment of multiple myeloma, a disease very similar to amyloidosis. However, they are currently investigational for the treatment of amyloidosis.

The investigators want to find out if the addition of dexamethasone and bortezomib to standard treatment of high dose chemotherapy and stem cell transplant can help improve response to treatment.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histological diagnosis of primary systemic (AL) amyloidosis based on:

  1. Deposition of amyloid material by congo red stain showing characteristic green birefringence, and
  2. monoclonal light chain protein in the serum or urine or immunohistochemical studies or serum free light chain assay and

  3. evidence of tissue involvement other than carpal tunnel syndrome, i.e. positive immunohistochemical staining of bone marrow demonstrating clonal plasma cells; or tissue amyloid deposits with anti-kappa or anti-lambda anti-serum; evidence for a plasma cell dyscrasia (PCD) by serum/urine or bone marrow; or overwhelmingly convincing clinical features e.g. macroglossia, associated with other systemic manifestations.

     Note: Patients with senile, secondary, localized, dialysis-related or familial amyloidosis are not eligible. Confirmation of tissue diagnosis at all sites of organ dysfunction is encouraged, but not required.

• Must be at least 18 years of age.
• Must have a performance status of 0-2 by Southwest Oncology Group criteria
• Must have left ventricular ejection fraction (LVEF) at least 45% by echocardiogram within 60 days of enrollment
• Prior chemotherapy with alkylating agent allowed only if no evidence of Myelodysplastic Dysplastic Syndrome (MDS) morphologically or cytogenetically. Total cumulative dose of oral melphalan must be less than 300 mg. Patients should not have received any cytotoxic therapy less than 4 weeks prior to registration and should have fully recovered from the effects of such therapy.
• Pulmonary Function Tests must show Diffusing capacity of the lungs for carbon monoxide (DLCO) at least 50%.
• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
• Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.
• Male subject agrees to use an acceptable method for contraception for the duration of the study.

Exclusion Criteria:

• No overt multiple myeloma (over 30% bone marrow plasmacytosis, extensive (great than 2) lytic lesions, hypercalcemia).
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 3 years.
• No known to be HIV positive.
• No platelet count of less than or equal to 70,000 within 14 days before enrollment.
• No absolute neutrophil count of less than or equal to 1000 within 14 days before enrollment.
• No greater than or equal to Grade 2 peripheral neuropathy within 14 days before enrollment.
• No myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
• No hypersensitivity to bortezomib, boron or mannitol.
• No pregnant or breast-feeding females. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
• Must not have received other investigational drugs with 14 days before enrollment
• No serious medical or psychiatric illness likely to interfere with participation in this clinical study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Single Arm - Investigational; Induction: Bortezomib (Velcade) 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1

Drug: Bortezomib; Induction: Velcade 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4; Other Names: Velcade; Drug: Dexamethasone; Induction: Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days; Other Names: Decadron; Drug: Melphalan; Conditioning: Melphalan 70-100 mg/m2/day IV on days -2 and -1; Other Names: Alkeran

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Disease Response	Complete response: Normal serum free light chain ratio and Negative serum and urine immunofixation electrophoresis Very good partial response: Difference in serum free light chains less than 40 mg/L Partial Response: >50% Reduction in the difference in serum free light chains	One year
Number of Participants Surviving at 100 Days Post Transplant		100 days
Number of Participants Proceeding to Transplant Following Induction		2 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of Participants Surviving at 5 Years	5 years

Collaborators and Investigators

• Sponsor: Boston Medical Center
• Collaborators: Millennium Pharmaceuticals, Inc.

Publications and helpful links

Helpful Links

• Boston Medical Center Active Clinical Trials

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2009
• Primary Completion (ACTUAL): August 1, 2013
• Study Completion (ACTUAL): September 4, 2020

Study Registration Dates

• First Submitted: November 2, 2009
• First Submitted That Met QC Criteria: March 8, 2010
• First Posted (ESTIMATE): March 9, 2010

Study Record Updates

• Last Update Posted (ACTUAL): September 25, 2020
• Last Update Submitted That Met QC Criteria: September 4, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Amyloidosis; Stem Cell Transplant; Amyloid; AL Amyloidosis; Primary Amyloidosis
• Additional Relevant MeSH Terms: Metabolic Diseases; Proteostasis Deficiencies; Amyloidosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dexamethasone; Melphalan; Bortezomib
• Other Study ID Numbers: H-28441; X05292 (OTHER: Millennium)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes