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