Thalidomide, Cyclophosphamide and Prednisone in Newly Diagnosed Multicentric Castleman's Disease: a Prospective, Single-center, Single-arm, Phase-II Pilot Trial
Phase: PHASE2
Conditions: Multicentric Castleman Disease
Sponsor: Peking Union Medical College Hospital

Title ： Thalidomide, cyclophosphamide and prednisone in newly diagnosed Multicentric 
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Castleman’s disease: a prospective, single-center, single-arm, phase-II pilot trial 
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NCT number: NCT03043105 
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Document date: February 2017   
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Specific aims: 
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To explore the effectiveness and safety of thalidomide, cyclophosphamide and prednisone (TCP 
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regimen) in newly diagnosed Multicentric Castleman’s disease (MCD) patients. 
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Significance: 
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Multicentric Castleman’s disease (MCD) is a lymphoproliferative disorder associated with systemic 
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symptoms including fever, night sweats, fatigue, anorexia, and cachexia. Unlike unicentric 
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Castleman’s disease (UCD) which responds well to surgical resection, there is no ‘standard’ 
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treatment for MCD patients. A wide variety of medical therapies, including prednisone mono-
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therapy, conventional chemotherapy (eg. cyclophosphamide, hydroxydaunorubicin, vincristine and 
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prednisone, CHOP) [1] and targeted therapy (eg. Interleukin-6 antibody)[2], have been attempted in 
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MCD. However, some therapies like prednisone were not potent enough to control the disease; on 
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the other hand, some therapies like CHOP might bring safety concerns while MCD is a relatively 
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indolent disease which waxes and wanes. Moreover, although randomized controlled studies have 
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showed the efficacy and safety of Interleukin-6 (IL-6) targeted treatment (siltuximab)[2], and 
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retrospective analyses have suggested the potential role of CD-20 targeted therapy (rituximab) in 
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treating MCD[3], both drugs are very expensive, especially for patients in developing countries.  
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Thalidomide is a relatively inexpensive immunomodulatory drug which have been used to treat 
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multiple myeloma, POEMS patients [4] and occasionally, MCD [1]. Multiple myeloma is a malignancy 
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of plasma cells which might share certain pathogenesis with MCD, especially its plasma cell variant. 
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POEMS syndrome is a disorder very closely related to MCD; 11% to 30% POEMS patients have 
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documented diagnosis of Castleman’s disease. These clues suggest a potential role of thalidomide 
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in MCD patients. Moreover, thalidomide has anti-inflammatory properties and could reduce TNF-
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alpha, IL-6 and IL-10 levels [6] while elevated levels of these cytokines might contribute to the 
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pathogenesis of Castleman’s disease [7,8]. Thus, thalidomide is a promising agent in treating MCD. 
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Cyclophosphamide and prednisone are drugs which have been commonly used to treat MCD [1] 
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and bring fewer safety issues than other potent drugs like hydroxydaunorubicin or vincristine. 
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Therefore, a combination of these drugs with thalidomide (TCP regimen) is very likely to be an 
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effective and safe option in MCD patients. 
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In the present proposal, a prospective, single arm, phase-II pilot trial will be conducted to 
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determine the efficacy and safety of thalidomide, cyclophosphamide and prednisone (TCP 
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regimen). If effective, this regimen could be recommended as an economical and efficacious 
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treatment option for patients with MCD in China and other developing countries. 
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Methods： 
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Study design: This will be a single center, open-labeled , single arm, phase-II pilot study. The 
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treatment and the response evaluation phase will last from the time of enrollment up to 12 months 
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(evaluation will be carried out every 12 weeks in the first 6 months and every 3 months thereafter 
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to 12 months). The follow-up phase to assess for progression of disease will last from 12 months 
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to 4 years after enrollment (evaluation will be carried out every 12 months) 
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Flow chart illustrating the time frame of our study: 
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Enrollment     Treatment/response evaluation    Thalidomide maintenance and Follow-up 
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              0—12m                              12m-4years 
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            (treatment response)                  (progression of disease) 
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Visit# 
Time 
Plan 
Screening 
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●Pathological review of patients’ specimen. 
●To find out symptomatic patients who are willing to be treated. 
●Informed consent. 
Visit 0 
0 m 
●Demographic features, past medical history. 
●Symptoms recorded according to MCD-related overall symptom 
score*.  
●Physical examination, laboratory evaluations (eg, blood tests including 
Interleukin-6 and VEGF, bone marrow aspiration, CT scan), questionnaire 
(eg, ECOG performance status score, SF-36 score).  
Visit 2-3 
3m 
6m 
 
●Symptoms recorded according to MCD-related overall symptom 
score*.  
●Physical examination, laboratory evaluations (eg, blood tests, CT scan), 
questionnaire (eg, ECOG performance status score, SF-36 score). 
●Adverse events. 
Visit 4-5 
9m 
12m 
●Symptoms recorded according to MCD-related overall symptom 
score*.  
●Physical examination, laboratory evaluations (eg, blood tests, CT scan), 
questionnaire (eg, ECOG performance status score, SF-36 score). 
●Adverse events. 
●Complete TCP treatment, initiation of Thalidomide maintenance. 
Visit 6-9 
15m 
18m 
21m 
24m 
●Symptoms recorded according to MCD-related overall symptom 
score*.  
●Physical examination, laboratory evaluations (eg, blood tests, CT scan), 
questionnaire (eg, ECOG performance status score, SF-36 score). 
●Adverse events. 
●Complete Thalidomide maintenance. 
Visit 10-11 
36m 
48m 
●Symptoms recorded according to MCD-related overall symptom 
score*.  
●Physical examination, laboratory evaluations (eg, blood tests, CT scan), 
questionnaire (eg, ECOG performance status score, SF-36 score). 
●Adverse events. 
*MCD-related overall symptom score: a published symptom score [2] calculated as the sum of the 
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toxicity grades of the NCI-CTCAE (National Cancer Institute Common Toxicity Criteria for Adverse 
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Events version 4.0 ) terms. 
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Patients:  
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Target population: Adult patients with MCD in China. 
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Accessible population: Adult patients who have been first diagnosed as MCD (proven by biopsy 
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and confirmed by pathologists’ review) in Peking Union Medical College Hospital, which is one of 
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the largest centers for hematological diseases in China and attracts patients from almost all over 
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the country.  
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Inclusion Criteria: 1. Demography: ≥18 years, all race/ethnic groups in China; 2. Newly diagnosed 
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and previously untreated (patients are allowed to have received oral prednisone for up to 1 week 
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before enrollment) symptomatic MCD patients (symptomatic disease is defined by the presence 
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of clinical symptoms with the NCI-CTCAE grading ≥1 that are attributable to the disease, and for 
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which treatment is indicated); 3. Eastern Cooperative Oncology Group (ECOG) Performance Status 
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≤2; 4. Clinical laboratory values meeting these criteria at screening: absolute neutrophil count ≥ 
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1·0 x 109/L, Platelets ≥ 50 x 109/L, Alanine aminotransferase (ALT) within 2·5 x upper limit of 
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normal (ULN); total bilirubin within 2·5 x ULN; estimated glomerular filtration rate (according to 
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MDRD formula) <15ml/min;5. Women of childbearing potential must agree to use birth control 
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measures during the study and for at least 3 months after receiving the last dose of study agent, 
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and must have a negative pregnancy test at screening period. Men must agree to use birth control 
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measures during the study and for at least 3 months after receiving the last dose of study agent; 6. 
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Informed consent must be signed. 
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Exclusion Criteria: 1.age under 18 years; 2. ECOG (eastern cooperative oncology group) status 
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above 2; 3. Immunosuppressive or anti-neoplastic drugs within the last 3 months; 4. serious 
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diseases including malignancy; 5. Plan to have babies within 1 year after enrollment (for women 
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and men), or pregnancy / breast-feeding (for women); 6. Known hypersensitivity to study agents; 
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7. Active infection requiring systemic treatment; 8. Other severe concurrent disease (eg. 
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uncontrolled diabetes, symptomatic coronary heart disease) that is likely to interfere with study 
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procedures or results, or that in the opinion of the investigator would constitute a hazard for 
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participating in this study; 9. Unwilling or unable to provide informed consent; 10. Unwilling to 
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return for follow-up at PUMCH. 
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Sampling: A consecutive sample of eligible and consenting patients will be enrolled into the study. 
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All adult patients with newly diagnosed and previously untreated MCD admitted or transferred to 
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our center would be seen as potential eligible subjects. Symptomatic patients (defined as above) 
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would be interviewed, those who agree to give informed consent to participate the trial would be 
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enrolled. Patients with laboratory abnormalities in the absence of clinical symptoms do not qualify 
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in this study. 
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Sample size calculation:  
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Null hypothesis: For newly-diagnosed symptomatic Chinese MCD patients, the response rates of 
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TCP regimens were lower than those of IL-6 targeted treatment. 
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Alternative hypothesis: For newly-diagnosed symptomatic Chinese MCD patients, the response 
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rates of TCP regimens were not lower than those of IL-6 targeted treatment. 
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Statistical analysis: Chi-square tests were used for the primary endpoint. 
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Effect size: as MCD is a rare disease, there is only one randomized controlled trial which evaluates 
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the response rate of IL-6 targeted therapy[2]; according to our experience using TCP regimens for 
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MCD, the response rate was about 57.1%.  With alpha=0.05; beta=0.20 & power=0.80, the 
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sample size was calculated with PASS 2008 software: the estimated sample size was 50 patients 
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(single-arm) which was closed to the sample size of prior randomized controlled trial (n=53). 
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Assuming a lost follow-up rate of 10%, the estimated number of patients enrolled was 55.  
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Our center now enrolls about 20 newly-diagnosed MCD patients each year which allows us to 
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complete the enrollment within 3-5 years. 
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Recruitment and Consent: All potential subjects will receive a thorough overview of the study 
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protocol and will review the consent form with study staff. Each potential subject will be advised 
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that a decision not to participate in the study will not affect the quality of care he/she can receive 
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at our center. Each subject will also be advised that he/she can stop participating in the study at 
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any time for any reason, and that this will not impact the services he/she receives. 
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Retention: Patients will be followed with a regular interval at clinic or during hospitalization. At the 
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time of enrollment, researchers will collect all available contact information from participants 
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including address, home phone, cell phone, email, and contact information for at least 2 relatives 
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or friends. Repeated efforts will be made to contact participants if they do not show up in their 
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regular follow-ups. 
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Measurements: 
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Primary predictors (interventions): Group 1 (single-arm study): Thalidomide, Cyclophosphamide 
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and Prednisone (TCP regimen): 
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-Thalidomide: 100mg QN for 1 year; And maintained with 100mg QN for the second year; 
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-Cyclophosphamide: 300mg/m2 on Day 1, 8, 15, 22 every month for 1 year; 
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-Prednisone: 1mg/kg on Day 1-2, 8-9, 15-16, 22-23 every month for 1 year. 
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Outcome variables: Patients will undergo a detailed examination at each visits. 
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Primary Outcome: Durable tumor and symptomatic response [2] ,which is assessed by radiologic 
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imaging and disease evaluations, is the primary outcome of this study. Durable tumor and 
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symptomatic response was defined as one of the following sustained for at least 24 weeks: 
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 Complete response (CR): complete disappearance of all measurable and evaluable disease (eg, 
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pleural effusion) and resolution of baseline symptoms attributed to MCD. 
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 Partial response (PR): a 50% decrease in sum of the product of the diameters (SPD) of index 
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lesion(s), with at least stable disease (SD) in all other evaluable disease in the absence of treatment 
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failure. 
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Note: this outcome is composed of two parts, the tumor response part and the symptom response 
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part, which are listed below: 
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Tumor response is based on the assessment of index lesions (measurable) and non-index lesions 
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(nonmeasurable). Index lesions: greatest transverse diameter (GTD) ≥ 16 mm, or short axis ≥ 11 
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mm; non-index lesion: all other lesions which do not meet the above criteria and those which 
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cannot be accurately measured. 
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 Tumor CR: complete disappearance of all index lesions and evaluable disease (eg, pleural effusion) 
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 Tumor PR: a  50% decrease in SPD of index lesion(s), with at least SD in all other evaluable 
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disease 
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 Tumor SD: failure to attain CR or PR, without evidence of progressive disease (PD) 
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 Tumor PD: a ≥50% increase in SPD of index lesion(s) compared to nadir, or at least 1 new lesion 
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that has been confirmed and measures > 15 mm in longest dimension. Malignant transformation 
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in a previously defined mass will also be considered tumor PD. 
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Symptomatic response: MCD-related Overall Symptom Score [2] will be used to evaluate 
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symptomatic response. 
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 Durable symptomatic response (partial and complete): Defined as a ≥50% reduction in overall 
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MCD-related Overall Symptom Score sustained for at least 24 weeks prior to treatment failure. 
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 Durable complete symptomatic response: Defined as a 100% reduction in the baseline MCD-
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related Overall Symptom Score sustained for at least 24 weeks prior to treatment failure. 
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Treatment failure: defined as sustained increase in grade ≥2 disease-related symptoms persisting 
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≥12 weeks; new disease-related grade ≥3 symptoms; sustained >1 point increase in ECOG-PS 
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persisting for ≥12 weeks; radiological progression; or initiation of another treatment for MCD. 
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Secondary Outcomes:  
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Progression-free survival (PFS): defined as the time to tumor PD; 
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Overall survival (OS): defined as the time to patients’ death; 
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Change in SF-36 score [9]: SF-36 score is a self-administered scoring system which contains several 
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aspects and reflects a patient’s general health status. 
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Safety issues: Adverse events during and after the treatment period would be recorded according 
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to NCI-CTCAE (National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0 ). 
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Statistical analysis plan 
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Analyses will be performed with SPSS 22 (SPSS, Inc, Chicago, IL). The independent samples Student 
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t test (for parameters with normal distribution) and Mann-Whitney test (for parameters that are 
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not normally distributed) will be used for comparison of baseline characteristics between 
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responders and nonresponders. The Wilcoxon signed-rank test will be used to compare parameters 
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before and after the TCP regimen. For patients who are evaluated as treatment failure, the time of 
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treatment failure is considered as the end of treatment. OS and PFS are calculated from the date 
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of treatment. For PFS analyses, death or treatment failure are considered as events. Survival curves 
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will be plotted with the Kaplan-Meier method. P<0.05 is considered statistically signiﬁcant. 
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Reference: 
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patients with multicentric Castleman disease.Br J Haematol. 2015 Jan;168(1):82-93. 
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[2] van Rhee F, Wong RS, Munshi N,et al. Siltuximab for multicentric Castleman's disease: a 
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randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2014 Aug;15(9):966-74. 
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[3] Reid E, Nooka A, Blackmon J, Lechowicz MJ. Clinical use of rituximab in patients with HIV 
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related lymphoma and Multicentric Castleman's disease. Curr Drug Deliv. 2012 Jan;9(1):41-51. 
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[4] Kuwabara S, Misawa S, Kanai K, Sawai S, Hattori T, Nishimura M, Nakaseko C. Thalidomide 
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reduces serum VEGF levels and improves peripheral neuropathy in POEMS syndrome. J Neurol 
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Neurosurg Psychiatry. 2008 Nov;79(11):1255-7. 
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[5] Andhavarapu S, Jiang L. POEMS syndrome and Castleman disease. Blood. 2013 Jul 
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11;122(2):159. 
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[6] Puzik A, Thiel A, Faust K, Härtel C. Thalidomide has anti-inflammatory properties in neonatal 
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immune cells. Innate Immun. 2013 Feb;19(1):42-52. 
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[7] Newsom-Davis T1, Bower M, Wildfire A,et al. Resolution of AIDS-related Castleman's disease 
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[8] Oksenhendler E, Carcelain G, Aoki Y, et al. High levels of human herpesvirus 8 viral load, human 
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interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric 
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castleman disease in HIV-infected patients. Blood 2000; 96:2069. 
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[9] Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual 
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