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

NCT ID: NCT02545907

Last Updated: 2021-04-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-14
• Study Completion Date: 2019-10-21

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.

Detailed Description

Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble fibrils that progressively disrupt tissue structure and impair function. The treatment of systemic AL amyloidosis has evolved to a risk adapted approach based on the end organ damage, particularly cardiac involvement, and the functional status of the patient. Intensive therapies like high dose melphalan followed by an autologous stem cell transplant are considered for patients with limited organ involvement, younger age and excellent functional status.

The majority of patients with AL amyloidosis, however, will not be candidates for ASCT and are generally treated with combination chemotherapy. This therapy may include bortezomib, a proteasome inhibitor which is particularly effective in AL amyloidosis but which may have a severe side-effect profile.

Carfilzomib is specific for the chymotrypsin-like active site of the 20S proteasome, is structurally and mechanistically distinct from bortezomib, and has demonstrated less reactivity against non-proteasomal proteases when compared to bortezomib. It also appears to be better tolerated. However, information regarding the use of carfilzomib in the treatment of AL amyloidosis is limited.

In the dose escalation phase of this study, a minimum of 6 (3 at dose level 0 and 3 at dose level -1)and a maximum of 18 (6 at dose level 0, 1, and 2) patients will recruited in a 3+3 design with cohorts of between 3 and 6 patients, in order to determine maximum tolerated dose and recommended dose.

At the recommended dose level identified, a further 20 (minimum) patients will be recruited to further assess safety and toxicities at the RD.

Conditions

Amyloidosis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

KTD treatment

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.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

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

Thalidomide

Intervention Type: DRUG

50mg capsule.

Dexamethasone

Intervention Type: DRUG

2mg tablet.

Interventions

Carfilzomib

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

Intervention Type: DRUG

Thalidomide

50mg capsule.

Intervention Type: DRUG

Dexamethasone

2mg tablet.

Intervention Type: DRUG

Other Intervention Names

Kyprolis; Thalidomide Celgene; Decadron

Eligibility Criteria

Inclusion Criteria

• Patients with the following characteristics are eligible for this study:

1. Aged 18 years or greater

2. Diagnosis of systemic AL amyloidosis with:

• exclusion of genetic mutations associated with hereditary amyloidosis and immunohistochemical exclusion of AA and TTR amyloidosis as appropriate.
• Amyloid related organ dysfunction or organ syndrome

3. Measurable clonal disease

4. Clonal relapse after previous chemotherapy or stem cell transplant OR refractory clonal disease to previous chemotherapy or stem cell transplant

5. Capable of providing written, informed consent and willing to follow study protocol

6. Life expectancy ≥ 6 months

7. ECOG performance status of <3

8. Platelet count ≥ 50x109/l)

9. Neutrophil count ≥ 1x109/l)

10. Haemoglobin ≥ 8g/dL

11. Bilirubin <2 times or Alkaline phosphatase <4 times upper limit of normal.

12. 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

Exclusion Criteria

• Patients with the following characteristics are ineligible for this study:

1. Overt symptomatic multiple myeloma

2. Amyloidosis of unknown or non AL type

3. 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)

4. Trivial or incidental AL amyloid deposits in the absence of a significant amyloid related organ syndrome (e.g., isolated carpal tunnel syndrome).

5. Refractory to or progressive disease with an IMid and proteasome inhibitor combination

6. Allogeneic stem cell transplantation

7. Solid organ transplantation

8. Severe peripheral or autonomic neuropathy causing significant functional impairment.

9. eGFR <20ml/min

10. Ejection fraction < 40% or NYHA class III or IV heart failure or uncontrolled hypertension

11. Pulmonary Hypertension

12. 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

13. Myocardial infarction in the preceeding 6 months or unstable angina or conduction abnormalities uncontrolled by medication or devices

14. Concurrent active malignancies, except surgically removed basal cell carcinoma of the skin or other in situ carcinomas

15. Pregnant, lactating or unwilling to use adequate contraception

16. Systemic infection unless specific anti-infective therapy is employed.

17. Known or suspected HIV infection

18. Contraindication to any of the required concomitant drugs or supportive treatments. Any other clinically significant medical disease or condition or psychiatric illness that, in the Investigator's opinion, may interfere with protocol adherence or a participant's ability to give informed consent

19. Previous experimental agents or approved anti-tumour treatment within 3 months before the date of registration

20. Known allergies to the IMPs

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University College, London

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ashutosh Wechalekar, Dr

Role: PRINCIPAL_INVESTIGATOR

University College London, National Amyloidosis Centre

Locations

Derriford Hospital

Plymouth, Devon, United Kingdom

Royal Bournemouth General Hospital

Bournemouth, Dorset, United Kingdom

Guy's Hospital

London, Greater London, United Kingdom

Manchester Royal Infirmary

Manchester, Greater Manchester, United Kingdom

Southampton General Hospital

Southampton, Hampshire, United Kingdom

Leicester Royal Infirmary

Leicester, Leicestershire, United Kingdom

Norfolk and Norwich University Hospital

Norwich, Norfolk, United Kingdom

Royal Hallamshire Hospital

Sheffield, South Yorkshire, United Kingdom

Freeman Hospital

Newcastle upon Tyne, Tyne and Wear, United Kingdom

Birmingham Queen Elizabeth Hospital

Birmingham, West Midlands, United Kingdom

Birmingham Heartlands Hospital

Birmingham, West Midlands, United Kingdom

St James' University Hospital

Leeds, West Yorkshire, United Kingdom

Bristol Haematology and Oncology Centre

Bristol, , United Kingdom

The Beatson West of Scotland Cancer Centre

Glasgow, , United Kingdom

Countries

United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

14/0786

Identifier Type: -

Identifier Source: org_study_id