Bortezomib and Dexamethasone Followed by High-Dose Melphalan and Stem Cell Transplantation for Primary (AL) Amyloidosis
Condition: Amyloidosis
MeSH terms: Amyloidosis
Intervention: Bortezomib; Dexamethasone; Melphalan
Intervention description: 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; Induction:
Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days; Conditioning:
Melphalan 70-100 mg/m2/day IV on days -2 and -1
Intervention MeSH terms: Dexamethasone; Bortezomib; Melphalan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 35.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Amyloid; Amyloidosis; AL Amyloidosis; Primary Amyloidosis; Stem Cell Transplant

Summary:

      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.
    

Eligibility criteria:

        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.