A Dose Escalation Study of Carfilzomib Taken With Thalidomide and Dexamethasone in Relapsed AL Amyloidosis

NCT02545907 | Completed Phase 1 Results

• 1 other identifier: 14/0786
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 14

Brief Summary

This study evaluates the safety and efficacy of carfilzomib used in combination with thalidomide and dexamethasone in patients with relapsed AL amyloidosis. The trial begins with a dose escalation phase, in which the maximum tolerated and recommended dose will be determined. The trial will then open into an expansion phase in which the combination efficacy is assessed.

Conditions

Amyloidosis

Keywords

Amyloidosis; AL Amyloidosis

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Dose-Limiting Toxicities as Assessed by Reported Data

  Dose-Limiting Toxicities (Dose escalation phase), between the time of receiving the first registered dose of carfilzomib in cycle 1 and day 1 cycle 2, in order to establish the Maximum Tolerated Dose (MTD) of carfilzomib in combination with thalidomide and dexamethasone, will be assessed based on reported data. The number of reported dose limiting toxicities will be reported.

  After 1 cycle of treatment; to be completed within 1 year.

• Number of Participants Experiencing Grade 3 or 4 Toxicity as Assessed by CTCAE v4.0.

  The percentage of patients treated who experience any grade 3 or 4 toxicity as assessed by CTCAE v4.0 throughout all treatment cycles will be assessed based on reported data.

  Between informed consent provided and 30 days post last trial treatment administration, up to 7 months

Secondary Outcomes (10)

• Clonal Response Rate Within 3 Months, at 3 Months, Within 6 Months and at 6 Months as Determined by Paraprotein and Free Light Chain Assessment.

  Within 3 months, at 3 months, within 6 months and at 6 months

• Amyloidotic Organ Response Rate Within 3 Months and 6 Months Based on Biochemical, Electrocardiographical, and Radiographical Assessment.

  Within 3 months and 6 months

• Time to Amyloidotic Organ Response Based on Reported Data.

  Within 6 months

• Number of Deaths at 6 Months Based on Reported Data.

  6 months

• Number of Patients Progression-free at 6 Months Based on Reported Data.

  6 months

Study Arms (1)

KTD treatment

EXPERIMENTAL

Participants in the escalation phase will receive carfilzomib (K), thalidomide (T), and dexamethasone (D) in combination. The dose of thalidomide will be 50mg/day. The dose of dexamethasone will be 20mg on Day 1, 8, and 15. Carfilzomib will be administered on Day 1, 8, and 15, but the level of carfilzomib delivered with depend on the cohort allocation. The dose of carfilzomib may be: * Level -1 - 27mg/m2 * Level 0 - 36mg/m2 * Level 1 - 45mg/m2 * Level 2 - 56mg/m2 Participants will receive up to six cycles of treatment. Following determination of the maximum tolerated dose and recommended dose, the trial will be opened to an expansion phase where participants will receive the RD of carfilzomib, along with thalidomide and dexamethasone, using the schedule outlined above.

Drug: Carfilzomib; Drug: Thalidomide; Drug: Dexamethasone

Interventions

Carfilzomib DRUG

Lyophilized carfilzomib for injection reconstituted with water to a final concentration of 2 mg/mL.

Also known as: Kyprolis

KTD treatment

Thalidomide DRUG

50mg capsule.

Also known as: Thalidomide Celgene

KTD treatment

Dexamethasone DRUG

2mg tablet.

Also known as: Decadron

KTD treatment

Eligibility Criteria

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

You may qualify if:

• Patients with the following characteristics are eligible for this study:
• Aged 18 years or greater
• Diagnosis of systemic AL amyloidosis with:
• Amyloid related organ dysfunction or organ syndrome
• Measurable clonal disease
• Clonal relapse after previous chemotherapy or stem cell transplant OR refractory clonal disease to previous chemotherapy or stem cell transplant
• Capable of providing written, informed consent and willing to follow study protocol
• Life expectancy ≥ 6 months
• ECOG performance status of \<3
• Platelet count ≥ 50x109/l)
• Neutrophil count ≥ 1x109/l)
• Haemoglobin ≥ 8g/dL
• Bilirubin \<2 times or Alkaline phosphatase \<4 times upper limit of normal.
• Female participants of child-bearing potential must have a negative pregnancy test prior to treatment and agree to use dual methods of contraception for the duration of the study and for 30 days following completion of study. Male participants must also agree to use a barrier method of contraception for the duration of the study and for 30 days following completion of study if sexually active with a female of child-bearing potential. Participants must comply with the Celgene pregnancy prevention programme for thalidomide

You may not qualify if:

• Patients with the following characteristics are ineligible for this study:
• Overt symptomatic multiple myeloma
• Amyloidosis of unknown or non AL type
• Localised AL amyloidosis (in which amyloid deposits are limited to a typical single organ, for example the bladder or larynx, in association with a clonal proliferative disorder within that organ)
• Trivial or incidental AL amyloid deposits in the absence of a significant amyloid related organ syndrome (e.g., isolated carpal tunnel syndrome).
• Refractory to or progressive disease with an IMid and proteasome inhibitor combination
• Allogeneic stem cell transplantation
• Solid organ transplantation
• Severe peripheral or autonomic neuropathy causing significant functional impairment.
• eGFR \<20ml/min
• Ejection fraction \< 40% or NYHA class III or IV heart failure or uncontrolled hypertension
• Pulmonary Hypertension
• Advanced Mayo stage III disease as defined by hs-Troponin T\>0.07 and NT-proBNP \>700 pMol/L OR NT-proBNP \>1000 pMol/L OR supine SBP \<100 mm of Hg
• Myocardial infarction in the preceeding 6 months or unstable angina or conduction abnormalities uncontrolled by medication or devices
• Concurrent active malignancies, except surgically removed basal cell carcinoma of the skin or other in situ carcinomas

Sponsors & Collaborators

• University College, London: lead

Study Sites (14)

Derriford Hospital

Plymouth, Devon, PL6 8DH, United Kingdom

Location

Royal Bournemouth General Hospital

Bournemouth, Dorset, BH7 7DW, United Kingdom

Location

Guy's Hospital

London, Greater London, SE1 7EH, United Kingdom

Location

Manchester Royal Infirmary

Manchester, Greater Manchester, M13 9WL, United Kingdom

Location

Southampton General Hospital

Southampton, Hampshire, SO16 6YD, United Kingdom

Location

Leicester Royal Infirmary

Leicester, Leicestershire, LE1 5WW, United Kingdom

Location

Norfolk and Norwich University Hospital

Norwich, Norfolk, NR4 7UY, United Kingdom

Location

Royal Hallamshire Hospital

Sheffield, South Yorkshire, S10 2JF, United Kingdom

Location

Freeman Hospital

Newcastle upon Tyne, Tyne and Wear, NE7 7DN, United Kingdom

Location

Birmingham Queen Elizabeth Hospital

Birmingham, West Midlands, B15 2TH, United Kingdom

Location

Birmingham Heartlands Hospital

Birmingham, West Midlands, B9 5SS, United Kingdom

Location

St James' University Hospital

Leeds, West Yorkshire, LS9 7TF, United Kingdom

Location

Bristol Haematology and Oncology Centre

Bristol, BS2 8ED, United Kingdom

Location

The Beatson West of Scotland Cancer Centre

Glasgow, G12 0YN, United Kingdom

Location

MeSH Terms

Conditions

Amyloidosis; Immunoglobulin Light-chain Amyloidosis

Interventions

carfilzomib; Thalidomide; Dexamethasone; Calcium Dobesilate

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Paraproteinemias

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Limitations and Caveats

The trial closed to recruitment following the dose escalation stage without opening the expansion phase due to slow recruitment.

Results Point of Contact

• Title: Alexandra Pitchford
• Organization: Leeds Institute of Clinical Trials Research

medcatal@leeds.ac.uk

0113 343 9077

Study Officials

• Ashutosh Wechalekar, Dr

  University College London, National Amyloidosis Centre

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

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

Study Record Dates

• First Submitted: August 27, 2015
• First Posted: September 10, 2015
• Study Start: September 14, 2017
• Primary Completion: September 26, 2019
• Study Completion: October 21, 2019
• Last Updated: April 15, 2021
• Results First Posted: April 15, 2021

Record last verified: 2020-11

Locations

GB (14)