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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Academic Myeloma Consortium
Sponsor:
Collaborators:
Onyx Pharmaceuticals
CORE Science Solutions
Criterium Inc.
Information provided by (Responsible Party):
Academic Myeloma Consortium
ClinicalTrials.gov Identifier:
NCT01789242
First received: February 6, 2013
Last updated: May 22, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Amyloidosis
Systemic Light Chain Amyloidosis
Drug: Carfilzomib
Drug: Dexamethasone
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Academic Myeloma Consortium:

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


Secondary Outcome Measures:
  • Hematologic Response [ Time Frame: Every 28 days while on treatment (estimated at 8 months per patient) ] [ Designated as safety issue: No ]
    Hematologic Response Rates (PR, VGPR, and CR

  • Organ Response [ Time Frame: Every 112 days while on treatment (estimated at 8 months per patient) ] [ Designated as safety issue: No ]
    Organ response rates by standard criteria

  • Progression Free Survival [ Time Frame: throughout study and follow up (every 2-3 months for 2 years ] [ Designated as safety issue: No ]
  • Time to next therapy [ Time Frame: throughout follow up (every 2-3 months for 2 years) ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • 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) ] [ Designated as safety issue: Yes ]
    Impact on hematologic response and toxicity of adding dexamethasone to carfilzomib in patients with suboptimal hematologic responses (defined as <VGPR after 4 cycles)

  • Biomarkers of carfilzomib sensitivity [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Evaluate potential biomarkers of carfilzomib sensitivity in baseline purified bone marrow plasma cells, including proteasomal capacity and in vitro sensitivity to proteasome inhibition.

  • Prognostic significance of cycle D1 expression [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    To explore the prognostic significance of cyclin D1 expression in purified bone marrow plasma cells in patients with previously treated AL amyloidosis


Estimated Enrollment: 42
Study Start Date: February 2013
Estimated Study Completion Date: February 2017
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01789242

Locations
United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Lucinda Pena    626-256-4673 ext 64816      
Principal Investigator: Michael Rosenzweig, MD         
Stanford Cancer Institute Recruiting
Stanford, California, United States, 94305
Contact: Vani Jain    650-725-5449    vani@stanford.edu   
Principal Investigator: Michaela Liedtke, MD         
United States, Georgia
Winship Cancer Institute of Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Alaina Mitchell    404-778-5747    alaina.r.mitchell@emory.edu   
Principal Investigator: Jonathan Kaufman, MD         
United States, Massachusetts
Boston University Medical Center Recruiting
Boston, Massachusetts, United States, 02118
Contact: Juliana Merhaut    617-638-8280    juliana.merhaut@bmc.org   
Principal Investigator: Vaishali Sanchorawala, MD         
United States, New Jersey
John Theurer Cancer Center at Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Kevin Barga, RN    551-996-8017    kbarga@hackensackUMC.org   
Principal Investigator: David Vesole, MD         
United States, New York
Columbia University Recruiting
New York, New York, United States, 10032
Contact: Tasha Smith    212-305-2460    ts2257@columbia.edu   
Principal Investigator: Suzanne Lentzsch, MD         
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Lauren Ciccolella    646-449-1468    ciccolel@mskcc.org   
Principal Investigator: Heather J Landau, MD         
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Kimberly Oates, RN, OCN    919-668-6524    kimberly.bartlett@duke.edu   
Principal Investigator: Cristina Gasparetto, MD         
United States, Oregon
Oregon Health and Sciences University Recruiting
Portland, Oregon, United States, 97239
Contact: Amy Bedford    503-494-6171    bedford2@ohsu.edu   
Principal Investigator: Emma Scott, MD         
United States, Pennsylvania
Abramson Cancer Center at the University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Scott Weber    215-662-8790    Scott.Weber@uphs.upenn.edu   
Principal Investigator: Adam Cohen, MD         
Sponsors and Collaborators
Academic Myeloma Consortium
Onyx Pharmaceuticals
CORE Science Solutions
Criterium Inc.
Investigators
Principal Investigator: Adam Cohen, MD AMyC; Univ of Penn Perelman Center for Advanced Medicine
Principal Investigator: Brian GM Durie, MD Academic Myeloma Consortium
Principal Investigator: Raymond Comenzo, MD AMyC, Tufts University
  More Information

No publications provided

Responsible Party: Academic Myeloma Consortium
ClinicalTrials.gov Identifier: NCT01789242     History of Changes
Other Study ID Numbers: AMyC 11MM02, IST-CAR-545
Study First Received: February 6, 2013
Last Updated: May 22, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Amyloidosis
Metabolic Diseases
Proteostasis Deficiencies
BB 1101
Dexamethasone
Dexamethasone 21-phosphate
Dexamethasone acetate
Anti-Inflammatory Agents
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Autonomic Agents
Central Nervous System Agents
Enzyme Inhibitors
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Molecular Mechanisms of Pharmacological Action
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Protease Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 28, 2014