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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01789242
Recruitment Status : Completed
First Posted : February 12, 2013
Last Update Posted : October 18, 2017
Information provided by (Responsible Party):
Criterium, Inc.

Brief 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.

Condition or disease Intervention/treatment Phase
Amyloidosis Systemic Light Chain Amyloidosis Drug: Carfilzomib Drug: Dexamethasone Phase 1

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Dose Escalation Study of Carfilzomib in Patients With Previously-Treated Systemic Light-Chain (AL) Amyloidosis
Study Start Date : February 2013
Actual Primary Completion Date : December 2016
Actual Study Completion Date : July 2017

Arm Intervention/treatment
Experimental: Carfilzomib
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
IV over 30 minutes on Days 1, 2, 8, 9, 15, and 16 every 28 days.
Other Names:
  • PR-171
  • Kyprolis

Drug: Dexamethasone
Dexamethasone IV or PO on Days 1, 2, 8, 9, 15, and 16 every 28 days in patients with <VGPR after 4 cycles.
Other Name: Decadron

Primary Outcome Measures :
  1. Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Throughout treatment, estimated at 8 months per patient ]
    Review of adverse events for safety and to determine the maximum tolerated dose of the combination treatment

Secondary Outcome Measures :
  1. Hematologic Response [ Time Frame: Every 28 days while on treatment (estimated at 8 months per patient) ]
    Hematologic Response Rates (PR, VGPR, and CR

  2. Organ Response [ Time Frame: Every 112 days while on treatment (estimated at 8 months per patient) ]
    Organ response rates by standard criteria

  3. Progression Free Survival [ Time Frame: throughout study and follow up (every 2-3 months for 2 years ]
  4. Time to next therapy [ Time Frame: throughout follow up (every 2-3 months for 2 years) ]

Other Outcome Measures:
  1. Impact on hematologic response and toxicity of adding dexamethasone [ Time Frame: Every 28 days throughout treatment after dexamethasone is added (estimated at 4 months per patient) ]
    Impact on hematologic response and toxicity of adding dexamethasone to carfilzomib in patients with suboptimal hematologic responses (defined as <VGPR after 4 cycles)

  2. Biomarkers of carfilzomib sensitivity [ Time Frame: Baseline ]
    Evaluate potential biomarkers of carfilzomib sensitivity in baseline purified bone marrow plasma cells, including proteasomal capacity and in vitro sensitivity to proteasome inhibition.

  3. Prognostic significance of cycle D1 expression [ Time Frame: Baseline ]
    To explore the prognostic significance of cyclin D1 expression in purified bone marrow plasma cells in patients with previously treated AL amyloidosis

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01789242

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United States, California
City of Hope
Duarte, California, United States, 91010
Stanford Cancer Institute
Stanford, California, United States, 94305
United States, Georgia
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States, 30322
United States, Massachusetts
Boston University Medical Center
Boston, Massachusetts, United States, 02118
United States, New Jersey
John Theurer Cancer Center at Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
United States, New York
Columbia University
New York, New York, United States, 10032
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Oregon
Oregon Health and Sciences University
Portland, Oregon, United States, 97239
United States, Pennsylvania
Abramson Cancer Center at the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Criterium, Inc.
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Principal Investigator: Adam Cohen, MD AMyC; Univ of Penn Perelman Center for Advanced Medicine
Principal Investigator: Brian GM Durie, MD AMyC
Principal Investigator: Raymond Comenzo, MD AMyC, Tufts University
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Responsible Party: Criterium, Inc. Identifier: NCT01789242    
Other Study ID Numbers: AMyC 11MM02
IST-CAR-545 ( Other Identifier: Onyx Pharmaceuticals )
First Posted: February 12, 2013    Key Record Dates
Last Update Posted: October 18, 2017
Last Verified: October 2017
Additional relevant MeSH terms:
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Proteostasis Deficiencies
Metabolic Diseases
Anti-Inflammatory Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents