A Single Arm Open Labeled Multicentre Phase 1b Dose Escalation Study of Carfilzomib Taken in Combination With Thalidomide and Dexamethasone in Relapsed AL Amyloidosis
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 10
- 试验地点
- 14
- 主要终点
- Number of Participants Experiencing Grade 3 or 4 Toxicity as Assessed by CTCAE v4.0.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with the following characteristics are eligible for this study:
- •Aged 18 years or greater
- •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
- •Measurable clonal disease
- •Clonal relapse after previous chemotherapy or stem cell transplant OR refractory clonal disease to previous chemotherapy or stem cell transplant
- •Capable of providing written, informed consent and willing to follow study protocol
- •Life expectancy ≥ 6 months
- •ECOG performance status of <3
- •Platelet count ≥ 50x109/l)
- •Neutrophil count ≥ 1x109/l)
- •Haemoglobin ≥ 8g/dL
- •Bilirubin <2 times or Alkaline phosphatase <4 times upper limit of normal.
- •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
排除标准
- •Patients with the following characteristics are ineligible for this study:
- •Overt symptomatic multiple myeloma
- •Amyloidosis of unknown or non AL type
- •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)
- •Trivial or incidental AL amyloid deposits in the absence of a significant amyloid related organ syndrome (e.g., isolated carpal tunnel syndrome).
- •Refractory to or progressive disease with an IMid and proteasome inhibitor combination
- •Allogeneic stem cell transplantation
- •Solid organ transplantation
- •Severe peripheral or autonomic neuropathy causing significant functional impairment.
- •eGFR <20ml/min
- •Ejection fraction < 40% or NYHA class III or IV heart failure or uncontrolled hypertension
- •Pulmonary Hypertension
- •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
- •Myocardial infarction in the preceeding 6 months or unstable angina or conduction abnormalities uncontrolled by medication or devices
- •Concurrent active malignancies, except surgically removed basal cell carcinoma of the skin or other in situ carcinomas
- •Pregnant, lactating or unwilling to use adequate contraception
- •Systemic infection unless specific anti-infective therapy is employed.
- •Known or suspected HIV infection
- •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
- •Previous experimental agents or approved anti-tumour treatment within 3 months before the date of registration
- •Known allergies to the IMPs
研究组 & 干预措施
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.
干预措施: Carfilzomib (Drug)
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.
干预措施: Thalidomide (Drug)
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.
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Number of Participants Experiencing Grade 3 or 4 Toxicity as Assessed by CTCAE v4.0.
时间窗: 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.
Number of Participants With Dose-Limiting Toxicities as Assessed by Reported Data
时间窗: 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.
次要结局
- Number of Deaths at 6 Months Based on Reported Data.(6 months)
- Maximum Response Determined by Paraprotein and Free Light Chain Assessment.(Within 6 months)
- 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.(Within 3 months, at 3 months, within 6 months and at 6 months)
- Time to Amyloidotic Organ Response Based on Reported Data.(Within 6 months)
- Number of Patients Experiencing Dose Delays Based on Reported Data.(Within 6 months)
- Compliance Profile of KTD Based on Reported Chemotherapy Compliance Data.(Within 6 months)
- Amyloidotic Organ Response Rate Within 3 Months and 6 Months Based on Biochemical, Electrocardiographical, and Radiographical Assessment.(Within 3 months and 6 months)
- Number of Patients Progression-free at 6 Months Based on Reported Data.(6 months)
- Time to Maximum Response Based on Reported Data.(Within 6 months)
- Number of Patients Withdrawing From Treatment Based on Reported Data.(Within 6 months)