A Safety Study 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.

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 (< 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

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 < 90 mm Hg, or symptomatic orthostatic hypotension, or a decrease in systolic blood pressure upon standing of > 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.