Clinical trial NCT02545907: A Dose Escalation Study of Carfilzomib Taken With Thalidomide and Dexamethasone in Relapsed AL Amyloidosis
Official title: A Single Arm Open Labeled Multicentre Phase 1b Dose Escalation Study of Carfilzomib Taken in Combination With Thalidomide and Dexamethasone in Relapsed AL Amyloidosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Amyloidosis
Keywords: Amyloidosis
AL Amyloidosis
Lead sponsor: University College, London
Sponsor class: OTHER
First posted: 2015-09-10
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicities as Assessed by Reported Data
timeFrame: After 1 cycle of treatment; to be completed within 1 year.
measure: Number of Participants Experiencing Grade 3 or 4 Toxicity as Assessed by CTCAE v4.0.
timeFrame: Between informed consent provided and 30 days post last trial treatment administration, up to 7 months
Secondary outcomes:
measure: 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.
timeFrame: Within 3 months, at 3 months, within 6 months and at 6 months
measure: Amyloidotic Organ Response Rate Within 3 Months and 6 Months Based on Biochemical, Electrocardiographical, and Radiographical Assessment.
timeFrame: Within 3 months and 6 months
measure: Time to Amyloidotic Organ Response Based on Reported Data.
timeFrame: Within 6 months
measure: Number of Deaths at 6 Months Based on Reported Data.
timeFrame: 6 months
measure: Number of Patients Progression-free at 6 Months Based on Reported Data.
timeFrame: 6 months
measure: Maximum Response Determined by Paraprotein and Free Light Chain Assessment.
timeFrame: Within 6 months
measure: Time to Maximum Response Based on Reported Data.
timeFrame: Within 6 months
measure: Number of Patients Withdrawing From Treatment Based on Reported Data.
timeFrame: Within 6 months
measure: Number of Patients Experiencing Dose Delays Based on Reported Data.
timeFrame: Within 6 months
measure: Compliance Profile of KTD Based on Reported Chemotherapy Compliance Data.
timeFrame: Within 6 months
Other outcomes:
Locations:
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
state: Devon
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth General Hospital
state: Dorset
city: London
country: United Kingdom
facility: Guy's Hospital
state: Greater London
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
state: Greater Manchester
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: Hampshire
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: Leicestershire
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
state: Norfolk
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
state: South Yorkshire
city: Newcastle-upon-Tyne
country: United Kingdom
facility: Freeman Hospital
state: Tyne And Wear
city: Birmingham
country: United Kingdom
facility: Birmingham Queen Elizabeth Hospital
state: West Midlands
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
state: West Midlands
city: Leeds
country: United Kingdom
facility: St James' University Hospital
state: West Yorkshire
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
city: Glasgow
country: United Kingdom
facility: The Beatson West of Scotland Cancer Centre
Study officials:
affiliation: University College London, National Amyloidosis Centre
name: Ashutosh Wechalekar, Dr
role: PRINCIPAL_INVESTIGATOR
References: