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

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.

Study Start Date

February 2013

Estimated Completion Date

December 2017

Interventions

  • Drug: Carfilzomib
  • Drug: Dexamethasone

Specialties

  • Oncology: Coagulation/Bleeding Dz

MeSH Terms

  • Carfilzomib
  • Dexamethasone
  • Systemic Light-Chain Amyloidosis

Study ID

Academic Myeloma Consortium -- AMyC 11MM02

Status

Unknown

Trial ID

NCT01789242

Study Type

Interventional

Trial Phase

Phase 1

Enrollment Quota

42

Sponsor

Academic Myeloma Consortium

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 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.

Gender

Both

Ages

18 Years and older

Accepts Healthy Volunteers

No

Study Locations and Contact Information (10)

Study Location Distance Name Phone Email
Columbia University - New York, New York 44.8 miles Susann Miao None sm3904@cumc.columbia.edu
John Theurer Cancer Center at Hackensack University Medical Center - Hackensack, New Jersey 47.6 miles Laura McBride RN None lmcbride@hackensackumc.org
Memorial SloanKettering Cancer Center - New York, New York 50.7 miles Jaime Rieff None rieffj@mskcc.org
Abramson Cancer Center at the University of Pennsylvania - Philadelphia, Pennsylvania 134.5 miles Cynthia Diaczynsky None cynthia.diaczynsky@uphs.upenn.edu
Boston University Medical Center - Boston, Massachusetts 137.1 miles Anthony Shelton None anthony.shelton@bmc.org
Duke University Medical Center - Durham, North Carolina 474.7 miles Jackie McIntyre None jackie.mcintyre@duke.edu
Winship Cancer Institute of Emory University - Atlanta, Georgia 795.6 miles Cathy Sharp None cathysharp@emory.edu
Oregon Health and Sciences University - Portland, Oregon 2,468.2 miles Jessica Kisky None kisky@ohsu.edu
City of Hope - Duarte, California 2,472.0 miles Lucinda Pena 626-256-4673 lpena@coh.org
Stanford Cancer Institute - Stanford, California 2,599.9 miles Ying Hao None yhao@stanford.edu

ClinicalTrialsLocator.com provides clinical trial listings in an easy to view format. All clinical trial information is pulled directly from ClinicalTrials.gov. This website does not guarantee acceptance into any clinical trial, and is not responsible for adverse events that may be incurred from a clinical trial.