a safety study of carfilzomib in patients with previously-treated systemic light chain amyloidosis

Conditions: Amyloidosis; Systemic Light Chain Amyloidosis

Summary: this is a dose finding study to evaluate the safety and determine the maximum tolerated dose of carfilzomib in patients with previously treated systemic light-chain amyloidosis.

this is a dose finding study to evaluate the safety and determine the maximum tolerated dose of carfilzomib in patients with previously treated systemic light-chain amyloidosis. the study will also explore the efficacy of carfilzomib in both proteasome inhibitor-naive and proteasome inhibitor-exposed patients including hematologic response, organ response, progression free survival, and time to next therapy.

Eligibility criteria:
inclusion criteria: * 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 (\ 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 exclusion criteria: * pregnant or lactating females * major surgery within 21 days prior to first dose * acute active infection requiring systemic antibiotics, antivirals, or antifungals within 14 days prior to first dose * treatment with an experimental drug within 28 days of first dose * active human immunodeficiency virus (hiv) or hepatitis b or c infection * bone marrow plasma cells ≥ 30% or clinical manifestations of multiple myeloma, such as hypercalcemia or lytic bone lesions * cardiac exclusions: * left ventricular ejection fraction (lvef) \< 40% * amyloid cardiac biomarker stage iii disease, defined as both nt-probnp ≥ 332 pg/ml and troponin t ≥ 0.035 ng/ml. if troponin t is not available at local institution, troponin i may be used, but cut-off is ≥ 0.1 ng/ml * new york heart association (nyha) classification iii or iv heart failure (see appendix g) despite medical management * unstable angina or myocardial infarction within 6 months prior to first dose * grade 2 or 3 atrioventricular (av) block (mobitz type i is permitted) or sick sinus syndrome, unless subject has a pacemaker * known history of sustained (\> 30 second) ventricular tachycardia or cardiac syncope. known history of recurrent non-sustained ventricular tachycardia (\> 3 beats) despite anti-arrhythmic therapy * supine systolic blood pressure \ 20 mm hg despite medical management (e.g. midodrine, fludrocortisones) * significant peripheral neuropathy (grade 3, grade 4, or grade 2 with pain) within 14 days prior to first dose * severe diarrhea (≥ grade 3) not controllable with medication or that requires total parenteral nutrition * history of bleeding diathesis, known factor x deficiency (level \< 20%), or requirement for therapeutic anticoagulation with warfarin * known allergies to carfilzomib or captisol® (a cyclodextrin derivative used to solubilize carfilzomib) * presence of other active malignancy with the exception of non-melanoma skin cancer, cervical cancer, treated early-stage prostate cancer provided that prostate-specific antigen is within normal limits, or any completely resected carcinoma in situ * serious psychiatric or medical conditions that could interfere with treatment * contraindication to any of the required concomitant drugs, including antiviral (e.g. valacyclovir) * patients in whom the required program of oral and iv fluid hydration is contraindicated, e.g. due to severe pre-existing pulmonary, cardiac, or renal impairment * subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to first dose.