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

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ClinicalTrials.gov Identifier: NCT02545907
Recruitment Status : Completed
First Posted : September 10, 2015
Results First Posted : April 15, 2021
Last Update Posted : April 15, 2021
Sponsor:
Information provided by (Responsible Party):
University College, London

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.

Condition or disease Intervention/treatment Phase
Amyloidosis Drug: Carfilzomib Drug: Thalidomide Drug: Dexamethasone Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 14, 2017
Actual Primary Completion Date : September 26, 2019
Actual Study Completion Date : October 21, 2019


Arm Intervention/treatment
Experimental: 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.

Drug: Carfilzomib
Lyophilized carfilzomib for injection reconstituted with water to a final concentration of 2 mg/mL.
Other Name: Kyprolis

Drug: Thalidomide
50mg capsule.
Other Name: Thalidomide Celgene

Drug: Dexamethasone
2mg tablet.
Other Name: Decadron




Primary Outcome Measures :
  1. Number of Participants With Dose-Limiting Toxicities as Assessed by Reported Data [ Time Frame: After 1 cycle of treatment; to be completed within 1 year. ]
    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.

  2. Number of Participants Experiencing Grade 3 or 4 Toxicity as Assessed by CTCAE v4.0. [ Time Frame: Between informed consent provided and 30 days post last trial treatment administration, up to 7 months ]
    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.


Secondary Outcome Measures :
  1. 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. [ Time Frame: Within 3 months, at 3 months, within 6 months and at 6 months ]

    Participant clonal response rate within 3 months, at 3 months, within 6 months and at 6 months will be assessed. The percentage of participants who achieve at least a partial response will be reported.

    Clonal response is defined as:

    CR: Negative immunofixation of serum and urine (serum alone in anuric patients) AND normal FLC concentration and kappa/lambda FLC ratio (FLC ratio alone in renal failure) AND ≤5% plasma cells in bone marrow without clonality by immunohistochemistry or immunofluorescencea

    VGPR: >90% reduction in serum paraprotein or abnormal component of FLC or dFLC over the starting value or dFLC <40mg/L

    PR: ≥50% decrease in aberrant FLC concentration or dFLC (or ≥50% decrease in dFLC if renal failure) or serum paraprotein but not fulfilling criteria for CR or VGPR

    MR: >25% but <50% decrease in aberrant FLC or dFLC or paraprotein

    NR: Not meeting FLC criteria for CR, PR or MR


  2. Amyloidotic Organ Response Rate Within 3 Months and 6 Months Based on Biochemical, Electrocardiographical, and Radiographical Assessment. [ Time Frame: Within 3 months and 6 months ]

    Amyloidotic organ response rate is assessed using the following criteria:

    Heart - Interventricular septal thickness decreased by 2 mm or 10% improvement in ejection fraction or a 30% and 35 pMol/L reduction in NT-ProBNP (only applicable if there is no change or <25% improvement in renal function) or significant improvement in lateral wall TDI S wave and E/E' ratio

    Kidney - 50% decrease (at least 0.5 g/day) in 24-hr urinary protein loss (urine protein must be>0.5 g/day pretreatment) without fall in creatinine clearance of ≥25% from baseline

    Liver - 50% decrease in abnormal alkaline phosphatase value or a decrease in liver size radiographically by at least 2 cm

    Nerve - Improvement in electromyogram nerve conduction velocity

    Soft tissue - Definite clinical and/or radiographic improvement with associated functional improvement in affected tissue.

    The percentage of patients who achieve organ response within 3 and 6 months of trial registration will be reported.


  3. Time to Amyloidotic Organ Response Based on Reported Data. [ Time Frame: Within 6 months ]
    The time to amyloidotic organ response (as outlined above) will be assessed based on reported data. The number of months this takes will be reported.

  4. Number of Deaths at 6 Months Based on Reported Data. [ Time Frame: 6 months ]
    The number of deaths at 6 months will be assessed and reported based on reported data.

  5. Number of Patients Progression-free at 6 Months Based on Reported Data. [ Time Frame: 6 months ]

    The number of patients who are progression-free at 6 months will be assessed based on reported data. Patients who are progression-free will have not had an haematological relapse or organ progression.

    Haematological relapse is defined as:

    From CR: Increase in the aberrant serum free light chain concentration to outside the normal range and by a factor of ≥2 from that at the time of CR or re-appearance of the original paraprotein

    From PR or VGPR: Increase in the aberrant free light chain concentration by a factor of ≥2 from that at the time of PR (≥50% change in ratio away from normal in patients with renal failure) or doubling of the serum paraprotein level (if starting >5g/L) or doubling and increase of serum paraprotein to >5g/L (if starting <5g/L)

    Organ progression is defined, by organ, as:

    Heart: Interventricular septal thickness increased by >2 mm compared with baseline or 20% decline in ejection fraction

    Kidney: 50% increase (at least 1 g/day) in 24-hr urinary


  6. Maximum Response Determined by Paraprotein and Free Light Chain Assessment. [ Time Frame: Within 6 months ]
    The maximum response to therapy will be determined by assessing the best reported response for each participant. Maximum response will be determined based on free light chain and paraprotein assessments by the National Amyloidosis Centre. The data will be reported using the response rates observed (complete, very good partial, partial, no response).

  7. Time to Maximum Response Based on Reported Data. [ Time Frame: Within 6 months ]
    The time to maximum response to treatment will be assessed by determining the time required for each participant to achieve maximum response (defined above), and will be presented on Kaplan-Meier curves. The number of months taken to achieve this maximum response will be reported. Time to maximum response was analysed overall only, and not by arm due the small sample size.

  8. Number of Patients Withdrawing From Treatment Based on Reported Data. [ Time Frame: Within 6 months ]
    The number of patients withdrawing from treatment will be assessed based on reported data.

  9. Number of Patients Experiencing Dose Delays Based on Reported Data. [ Time Frame: Within 6 months ]
    The number of patients experiencing dose delays will be assessed based on reported data.

  10. Compliance Profile of KTD Based on Reported Chemotherapy Compliance Data. [ Time Frame: Within 6 months ]
    The compliant profile of participants to KTD will be assessed by determining the number of missed doses from recorded data. Participants will be regarded as compliant if participants have missed no more than 14 days of thalidomide, 2 days of dexamethasone, and 1 dose of carfilzomib per cycle. Compliance will be reported in terms of the number of participants who were compliant.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02545907


Locations
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United Kingdom
Derriford Hospital
Plymouth, Devon, United Kingdom, PL6 8DH
Royal Bournemouth General Hospital
Bournemouth, Dorset, United Kingdom, BH7 7DW
Guy's Hospital
London, Greater London, United Kingdom, SE1 7EH
Manchester Royal Infirmary
Manchester, Greater Manchester, United Kingdom, M13 9WL
Southampton General Hospital
Southampton, Hampshire, United Kingdom, SO16 6YD
Leicester Royal Infirmary
Leicester, Leicestershire, United Kingdom, LE1 5WW
Norfolk and Norwich University Hospital
Norwich, Norfolk, United Kingdom, NR4 7UY
Royal Hallamshire Hospital
Sheffield, South Yorkshire, United Kingdom, S10 2JF
Freeman Hospital
Newcastle-upon-Tyne, Tyne And Wear, United Kingdom, NE7 7DN
Birmingham Queen Elizabeth Hospital
Birmingham, West Midlands, United Kingdom, B15 2TH
Birmingham Heartlands Hospital
Birmingham, West Midlands, United Kingdom, B9 5SS
St James' University Hospital
Leeds, West Yorkshire, United Kingdom, LS9 7TF
Bristol Haematology and Oncology Centre
Bristol, United Kingdom, BS2 8ED
The Beatson West of Scotland Cancer Centre
Glasgow, United Kingdom, G12 0YN
Sponsors and Collaborators
University College, London
Investigators
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Principal Investigator: Ashutosh Wechalekar, Dr University College London, National Amyloidosis Centre
  Study Documents (Full-Text)

Documents provided by University College, London:
Study Protocol  [PDF] January 24, 2018
Statistical Analysis Plan  [PDF] May 1, 2019

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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT02545907    
Other Study ID Numbers: 14/0786
First Posted: September 10, 2015    Key Record Dates
Results First Posted: April 15, 2021
Last Update Posted: April 15, 2021
Last Verified: November 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University College, London:
Amyloidosis
AL Amyloidosis
Additional relevant MeSH terms:
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Immunoglobulin Light-chain Amyloidosis
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Paraproteinemias
Thalidomide
Dexamethasone
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Leprostatic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Angiogenesis Inhibitors