A Phase I Dose Escalation Study of Carfilzomib in Patients With Previously-Treated Systemic Light-Chain (AL) Amyloidosis
The main purpose of this study is to evaluate the safety and determine the maximum tolerated dose of an investigational new drug, carfilzomib, in people with previously-treated AL amyloidosis. The study will also evaluate how well the participant's disease responds to this treatment.
- drug : Dexamethasone
- drug : Carfilzomib
Phase: Phase 1
Ages Eligible For Study:
- Males and females ? 18 years of age - Histologically-proven AL amyloidosis, confirmed by positive Congo red stain with green birefringence on polarized light microscopy with evidence of measurable clonal disease that requires active treatment as defined below: - Patients must have clonal disease measureable by serum free light chain (FreeliteTM) assay: - For the dose-escalation cohort: this is defined as having any elevation in the amyloidogenic (i.e. clonal) light chain with an abnormal free kappa:lambda ratio - For the dose expansion cohorts: in addition to the above, there must be a difference between the amyloidogenic (i.e. clonal) and non-amyloidogenic light chain (dFLC) of at least 50mg/L (5mg/dL) - Relapsed (progressed after prior response) or refractory (failed to achieve at least a partial response) to at least one prior therapy for amyloidosis. - Patients that received an autologous stem cell transplant must be at least 3 months post-transplant and recovered from acute transplant-related toxicities. - Patients that were unable to tolerate at least 1 cycle of an alkylating agent plus corticosteroid (e.g. melphalan + dexamethasone) or alternative prior regimen because of severe adverse events (e.g. hypersensitivity reaction) may be considered after discussion with the study PI/Medical Monitor. - Objective, measureable, symptomatic organ involvement, defined as one or more of the following: - Kidney: albuminuria ? 500 mg/day in a 24-hour urine specimen - Heart: presence of mean left ventricular wall thickness on echocardiogram greater than 12 mm in the absence of hypertension or valvular heart disease, or unexplained low voltage (< 0.5 mV) on ECG, or NT-proBNP > 332 ng/L in the absence of impaired renal function [estimated glomerular filtration rate (eGFR) < 45 mL/min] - Liver: hepatomegaly on physical exam with elevated alkaline phosphatase > 1.5 x ULN - GI Tract: biopsy showing amyloid deposition along with symptoms such as GI bleeding or persistent diarrhea (> 4 loose stools/day) Autonomic or Peripheral Nervous System: defined as orthostasis, symptoms of nausea or dysgeusia, recurrent diarrhea or constipation, abnormal sensory and/or motor findings on neurologic exam, or gastric atony by gastric emptying scan - Note: Skin, lymph node, or soft tissue involvement; carpal tunnel syndrome; or bone marrow amyloid as the sole clinical manifestations of amyloidosis are not sufficient for inclusion. - 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; and 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 threshold is <0.1 ng/mL.23 - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 - Clinical laboratory values as specified within 14 days of treatment: - Absolute neutrophil count (ANC) ? 1.0 x 109/L - Hemoglobin ?8 g/dL [transfusion permitted] - Platelet count ?75.0 x 109/L - Total bilirubin ? 2 x Upper Limit of Normal (ULN) - Alkaline phosphatase ? 5 x ULN - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ? 3.5 x ULN - CrCl ? 30 mL/min as measured by 24-hour urine - Screening ANC should be independent of granulocyte-and granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G-CSF for at least 2 weeks - Screening platelet count should be independent of platelet transfusions for at least 2 weeks - Written informed consent in accordance with federal, local, and institutional guidelines - Females of childbearing potential must agree to ongoing pregnancy testing and to practice contraception or abstain from heterosexual intercourse - Male patients must agree to practice contraception or to abstain from heterosexual intercourse - Male patients must agree not to donate semen or sperm - Life expectancy of ? 3 months