A Safety Study of Carfilzomib in Patients With Previously-Treated Systemic Light Chain Amyloidosis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I Dose Escalation Study of Carfilzomib in Patients With Previously-Treated Systemic Light-Chain (AL) Amyloidosis

Conditions
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Amyloidosis, Systemic Light Chain Amyloidosis

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carfilzomib<br>All eligible subjects will receive the study intervention of Carfilzomib. Patients with suboptimal hematologic responses (<VGPR after 4 cycles) will have Dexamethasone added to their treatment. | Drug: Carfilzomib<br>* IV over 30 minutes on Days 1, 2, 8, 9, 15, and 16 every 28 days.<br>* Other names: Kyprolis;Drug: Dexamethasone<br>* Dexamethasone IV or PO on Days 1, 2, 8, 9, 15, and 16 every 28 days in patients with <VGPR after 4 cycles.<br>* Other names: Decadron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events as a Measure of Safety and Tolerability | Review of adverse events for safety and to determine the maximum tolerated dose of the combination treatment | Throughout treatment, estimated at 8 months per patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic Response | Hematologic Response Rates (PR, VGPR, and CR | Every 28 days while on treatment (estimated at 8 months per patient) | 
| Organ Response | Organ response rates by standard criteria | Every 112 days while on treatment (estimated at 8 months per patient) | 
| Progression Free Survival |  | throughout study and follow up (every 2-3 months for 2 years | 
| Time to next therapy |  | throughout follow up (every 2-3 months for 2 years) |