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



Status:Completed
Conditions:Hematology
Therapuetic Areas:Hematology
Healthy:No
Age Range:18 - Any
Updated:10/20/2017
Start Date:February 2013
End Date:July 2017

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

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.
We found this trial at
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2301 Erwin Rd
Durham, North Carolina 27710
919-684-8111
Principal Investigator: Cristina Gasparetto, MD
Duke Univ Med Ctr As a world-class academic and health care system, Duke Medicine strives...
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116th St and Broadway
New York, New York 10027
(212) 854-1754
Principal Investigator: Suzanne Lentzsch, MD
Columbia University In 1897, the university moved from Forty-ninth Street and Madison Avenue, where it...
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1365 Clifton Rd NE
Atlanta, Georgia 30322
(404) 778-1900
Principal Investigator: Jonathan Kaufman, MD
Winship Cancer Institute at Emory University Winship Cancer Institute of Emory University is Georgia
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1 Boston Medical Center Place
Boston, Massachusetts 02118
617.638.8000
Principal Investigator: Vaishali Sanchorawala, MD
Boston University Medical Center Boston Medical Center is an extraordinary community of health care providers...
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Duarte, California 91010
Principal Investigator: Michael Rosenzweig, MD
Phone: 626-256-4673
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92 2nd St
Hackensack, New Jersey 07601
(201) 996-5900
Principal Investigator: David Vesole, MD
John Theurer Cancer Center at the Hackensack University Medical Center The mission of the John...
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1275 York Ave
New York, New York 10021
(212) 639-2000
Principal Investigator: Heather J Landau, MD
Memorial Sloan Kettering Cancer Center Memorial Sloan Kettering Cancer Center — the world's oldest and...
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3400 Civic Center Blvd
Philadelphia, Pennsylvania 19104
(215) 662-6065
Principal Investigator: Adam Cohen, MD
Abramson Cancer Center of the University of Pennsylvania The Abramson Cancer Center of the University...
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Portland, Oregon 97227
Principal Investigator: Emma Scott, MD
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Stanford, California 94305
Principal Investigator: Michaela Liedtke, MD
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