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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02545907
Recruitment Status : Unknown
Verified September 2015 by University College, London.
Recruitment status was:  Not yet recruiting
First Posted : September 10, 2015
Last Update Posted : September 10, 2015
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)
Estimated Enrollment : 36 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
Study Start Date : October 2015
Estimated Primary Completion Date : October 2016
Estimated Study Completion Date : April 2018

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. 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: End of study; 30 months from opening. ]
    The proportion 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. The percentage of participants experiencing these toxicities will be reported.

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: End of study; 30 months from opening. ]
    Participant clonal response rate within 3 months, at 3 months, within 6 months and at 6 months will be assessed using measurement of the participant's paraprotein levels and free light chain levels. The proportion of participants who achieve at least a partial response will be reported.

  2. Amyloidotic organ response rate within 3 months and 6 months based on biochemical, electrocardiographical, and radiographical assessment. [ Time Frame: End of study; 30 months from opening. ]

    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 proportion 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: End of study; 30 months from opening. ]
    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: End of study; 30 months from opening. ]
    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: End of study; 30 months from opening. ]
    The number of patients who are progression-free at 6 months will be assessed based on reported data.

  6. Maximum response determined by paraprotein and free light chain assessment. [ Time Frame: End of study; 30 months from opening. ]
    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: End of study; 30 months from opening. ]
    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.

  8. Number of patients withdrawing from treatment based on reported data. [ Time Frame: End of study; 30 months from opening. ]
    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: End of study; 30 months from opening. ]
    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: End of study; 30 months from opening. ]
    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 compliant and non-compliant.

  11. Relative dose intensity based on pharmacokinetic assessments. [ Time Frame: End of study; 30 months from opening. ]
    The Relative Dose intensity of KTD treatment will be assessed and calculated as the percentage ratio between the received and planned intensities, where dose intensity is the cumulative dose divided by the duration of treatment. This information will be expressed as a dose (e.g., 150mg/m^2).

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

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 identifier (NCT number): NCT02545907

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Contact: Sarah Flynn 0044113 3439141
Contact: James D Williamson 0044113 3431658

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United Kingdom
Derriford Hospital
Plymouth, Devon, United Kingdom, PL6 8DH
Contact: Hannah Hunter, Dr    01752517505   
Contact: Claire Brown   
Principal Investigator: Hannah Hunter, Dr         
Sub-Investigator: Tim Nokes, Dr         
Royal Bournemouth General Hospital
Bournemouth, Dorset, United Kingdom, BH7 7DW
Contact: Rachel Hall, Dr    01202726246   
Contact: Nicola Naraine    01202726127   
Principal Investigator: Rachel Hall, Dr         
Principal Investigator: Helen McCarthy, Dr         
Guy's Hospital
London, Greater London, United Kingdom, SE1 7EH
Contact: Matthew Streetly, Dr    02071882900   
Contact: Abhijit Jadhav    02071882022   
Principal Investigator: Matthew Streetly, Dr         
Manchester Royal Infirmary
Manchester, Greater Manchester, United Kingdom, M13 9WL
Contact: Eleni Tholouli, Dr    01612768676   
Contact: Ian Venables    01619014575   
Principal Investigator: Eleni Tholouli, Dr         
Sub-Investigator: Alberto Rocco, Dr         
Sub-Investigator: Rajesh Krishna, Dr         
Southampton General Hospital
Southampton, Hampshire, United Kingdom, SO16 6YD
Contact: Matthew Jenner, Dr    02381205764   
Contact: Julie Gwilt    02381204202   
Principal Investigator: Matthew Jenner, Dr         
Sub-Investigator: Srinivasan Narayanan, Dr         
Leicester Royal Infirmary
Leicester, Leicestershire, United Kingdom, LE1 5WW
Contact: Mamta Garg, Dr    01162586037   
Contact: Amy King    01162585998   
Principal Investigator: Mamta Garg, Dr         
Sub-Investigator: Ashish Masurekar, Dr         
Sub-Investigator: Linda Barton, Dr         
Norfolk and Norwich University Hospital
Norwich, Norfolk, United Kingdom, NR4 7UY
Contact: Martin Auger, Dr    01603268895   
Contact: Helen Darby    01603288897   
Principal Investigator: Martin Auger, Dr         
Sub-Investigator: Kris Bowles, Dr         
Sub-Investigator: Matthew Lawes, Dr         
Royal Hallamshire Hospital
Sheffield, South Yorkshire, United Kingdom, S10 2JF
Contact: John Snowden, Dr    01142713357   
Contact: Rachael Selby    01142261023   
Principal Investigator: John Snowden, Dr         
Sub-Investigator: Yousef Ezaydi, Dr         
Sub-Investigator: Andrew Chantry, Dr         
Freeman Hospital
Newcastle-upon-Tyne, Tyne and Wear, United Kingdom, NE7 7DN
Contact: Jonathan Wallis, Dr    01912138479   
Contact: Tobias Menne, Dr    01912138480   
Principal Investigator: Jonathan Wallis, Dr         
Sub-Investigator: Tobias Menne, Dr         
Sub-Investigator: Graham Jackson, Professor         
Birmingham Queen Elizabeth Hospital
Birmingham, West Midlands, United Kingdom, B15 2TH
Contact: Mark Cook, Dr    01214721311 ext 8597   
Contact: Peter Hazlewood    01213714396   
Principal Investigator: Mark Cook, Dr         
Sub-Investigator: Timothy Wong, Dr         
Birmingham Heartlands Hospital
Birmingham, West Midlands, United Kingdom, B9 5SS
Contact: Guy Pratt, Dr    01214243698   
Contact: James Whitehouse    01214244075   
Principal Investigator: Guy Pratt, Dr         
Sub-Investigator: Shankara Paneesha         
St James' University Hospital
Leeds, West Yorkshire, United Kingdom, LS9 7TF
Bristol Haematology and Oncology Centre
Bristol, United Kingdom, BS2 8ED
Contact: Jenny Bird, Dr    01173424394   
Contact: Anja Schmidtmann    01173426743   
Principal Investigator: Jenny Bird, Dr         
Sub-Investigator: James Griffin, Dr         
The Beatson West of Scotland Cancer Centre
Glasgow, United Kingdom, G12 0YN
Contact: Grant McQuaker, Dr    01413017140   
Contact: Donna Kelly    01413017090   
Principal Investigator: Grant McQuaker, Dr         
Sub-Investigator: Richard Soutar, Dr         
Sub-Investigator: Jennifer Travers, Dr         
Sponsors and Collaborators
University College, London
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Principal Investigator: Ashutosh Wechalekar, Dr University College London, National Amyloidosis Centre
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Responsible Party: University College, London Identifier: NCT02545907    
Other Study ID Numbers: 14/0786
First Posted: September 10, 2015    Key Record Dates
Last Update Posted: September 10, 2015
Last Verified: September 2015
Keywords provided by University College, London:
AL Amyloidosis
Additional relevant MeSH terms:
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Immunoglobulin Light-chain Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Anti-Inflammatory Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
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