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

NCT01789242 | Completed Phase 1

• 2 other identifiers: AMyC 11MM02IST-CAR-545
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 10

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.

Conditions

Amyloidosis; Systemic Light Chain Amyloidosis

Outcome Measures

Primary Outcomes (1)

• Adverse Events as a Measure of Safety and Tolerability

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

  Throughout treatment, estimated at 8 months per patient

Secondary Outcomes (4)

• Hematologic Response

  Every 28 days while on treatment (estimated at 8 months per patient)

• Organ Response

  Every 112 days while on treatment (estimated at 8 months per patient)

• Progression Free Survival

  throughout study and follow up (every 2-3 months for 2 years

• Time to next therapy

  throughout follow up (every 2-3 months for 2 years)

Other Outcomes (3)

• Impact on hematologic response and toxicity of adding dexamethasone

  Every 28 days throughout treatment after dexamethasone is added (estimated at 4 months per patient)

• Biomarkers of carfilzomib sensitivity

  Baseline

• Prognostic significance of cycle D1 expression

  Baseline

Study Arms (1)

Carfilzomib

EXPERIMENTAL

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; Drug: Dexamethasone

Interventions

Carfilzomib DRUG

IV over 30 minutes on Days 1, 2, 8, 9, 15, and 16 every 28 days.

Also known as: PR-171, Kyprolis

Carfilzomib

Dexamethasone DRUG

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

Also known as: Decadron

Carfilzomib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Criterium, Inc.: lead
• Amgen: collaborator

Study Sites (10)

City of Hope

Duarte, California, 91010, United States

Location

Stanford Cancer Institute

Stanford, California, 94305, United States

Location

Winship Cancer Institute of Emory University

Atlanta, Georgia, 30322, United States

Location

Boston University Medical Center

Boston, Massachusetts, 02118, United States

Location

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Columbia University

New York, New York, 10032, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Oregon Health and Sciences University

Portland, Oregon, 97239, United States

Location

Abramson Cancer Center at the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

Amyloidosis

Interventions

carfilzomib; Dexamethasone; Calcium Dobesilate

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 6, 2013
• First Posted: February 12, 2013
• Study Start: February 1, 2013
• Primary Completion: December 1, 2016
• Study Completion: July 1, 2017
• Last Updated: October 18, 2017

Record last verified: 2017-10

Locations

US (10)