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

Phase 1
18 Years
Open (Enrolling)
Amyloidosis, Systemic Light-Chain Amyloidosis

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Trial Information

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

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, defined as a dFLC of at least 50 mg/L (5 mg/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

- 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

- 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

- 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

- 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.

- 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

- Subjects with pleural effusions requiring thoracentesis or ascites requiring
paracentesis within 14 days prior to first dose.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Adverse Events as a Measure of Safety and Tolerability

Outcome Description:

Review of adverse events for safety and to determine the maximum tolerated dose of the combination treatment

Outcome Time Frame:

Throughout treatment, estimated at 8 months per patient

Safety Issue:


Principal Investigator

Adam Cohen, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

AMyC; Fox Chase Cancer Center


United States: Food and Drug Administration

Study ID:

AMyC 11MM02



Start Date:

February 2013

Completion Date:

February 2017

Related Keywords:

  • Amyloidosis
  • Systemic Light-Chain Amyloidosis
  • Amyloidosis



Winship Cancer Institute of Emory University Atlanta, Georgia  30322
Columbia University New York, New York  10032-3784
Duke University Medical Center Durham, North Carolina  27710
Oregon Health and Sciences University Portland, Oregon  
John Theurer Cancer Center at Hackensack University Medical Center Hackensack, New Jersey  07601
Stanford Cancer Institute Stanford, California  94305