Efficacy of Rapamycin (Sirolimus) in the Treatment of Peutz-Jeghers Syndrome
Phase: PHASE4
Conditions: Peutz-Jeghers Syndrome
Sponsor: Peking Union Medical College Hospital

 
 
 
 
 
 
 
Efficacy of Rapamycin (Sirolimus) in 
the Treatment of Peutz-Jeghers 
Syndrome 
 
 
(December 5, 2018) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
I. 
Background 
II. 
Objectives 
III. Research design 
IV. Selection of subjects 
V. 
Therapeutic schedule 
VI. Follow-up plan and content 
VII. Records and reports of adverse events 
VIII. Statistical analysis 
IX. Measures of quality control 
X. 
Expected research results 
XI. Potential risks, benefits or advantages of this study 
XII. Data preservation and confidentiality 
XIII. Measures to protect subjects and minimize risks 
 
 
 
 
 
 
 
 
 

I. 
Background 
Peutz-Jeghers syndrome (PJS) is an autosomal dominant hereditary syndrome, 
characterized by multiple hamartomatous polyps in gastrointestinal tract, pigmentation 
in skin mucosa and increased risk of cancer[1]. PJS is a rare disease, with 1 patient in 
every 8000 to 200,000 births[2]. Large intestinal polyps of PJS patients may lead to local 
necrosis, hemorrhage, intussusception and intestinal obstruction[3, 4]. The risk of 
lifelong occurrence of cancer among PJS patients is as high as 64%, with colorectal 
cancer being the most common one. Average age of cancer diagnosis in PJS patients is 
41[5]. At present, there is only invasive treatment for PJS, such as endoscopic 
polypectomy and surgery, without any drug treatment for choice. Endoscopic 
polypectomy applies to polyps over 0.5 cm in diameter. However, intestinal segmental 
resection is required when the polyps are too numerous, or progress into cancer, in 
which case endoscopic polyps control is infeasible[6]. Invasive treatment exacerbates 
patients’ suffering and increases risk of complications with high medical cost. It may 
also affect food digestion and absorption, even causing intestinal adhesions and short-
bowel syndrome. Therefore, pharmaceutical intervention of PJS’ underline pathogenesis 
is warrented,  
The disease is most frequently caused by mutations in LKB1 which is detectable 
in 50-80% of the PJS family[7, 8]. LKB1 is a tumor suppressor gene. It encodes a 
serine/threonine kinase which activates the tumor suppressor genes TSC1 and TSC2 
via stimulating adenosine 5’-monophosphate-activated protein kinase (AMPK). 
Activated TSC1-TSC2 complex inhibits the mammalian target of rapamycin (mTOR)[9]. 
Lkb1 deficiency causes PJS through activation of mTOR signaling[10]. Therefore, 
mTOR inhibitor sirolimus (rapamycin) is a potential therapy for PJS. 
 
Sirolimus is a macrolide antibiotics. It has been used to treat tuberous sclerosis 
complex, a benign tumor syndrome. The safety of rapamycin is widely recognized. The 
possible side effects are usually mild and may cause oral ulcers, hyperlipidemia, rash, 
acne and some other symptoms. While the efficacy of rapamycin on PJS has been 
demonstrated in mouse model, no clinical trial has been reported. 
Cancer susceptibility is a major life-threatening factor of PJS patients. PJS-
associated carcinogenesis is related to LKB1-AMPK-mTOR pathway, thus endowing 
rapamycin with great clinical significance in the treatment or prevention of PJS-related 
cancer. In 2011, Klümpen et al reported that everolimus, a derivative of sirolimus, was 
partially effective in the treatment of a PJS patient suffering from advanced pancreatic 
cancer. No intestinal polyps larger than 1 cm could be found after 8 months’ treatment. 
There have been no evident adverse reactions except for muscle and joint pain of grade 
1[11].  
Reference 
1. Meserve E E, Nucci M R: Peutz-Jeghers Syndrome: Pathobiology, Pathologic 
Manifestations, and Suggestions for Recommending Genetic Testing in Pathology 
Reports. Surgical Pathology Clinics 2016; 9(2):243-268. 
2.Lindor NM, Greene MH: The concise handbook of family cancer syndromes. Mayo 

Familial Cancer Program. J Natl Cancer Inst 1998; 90(14): 1039-71. 
 
3.Utsunomiya J, Gocho H, Miyanaga T, et al.: Peutz-Jeghers syndrome: its natural 
course and management. Johns Hopkins Med J 1975; 136(2): 71-82. 
4.van Lier MG, Mathus-Vliegen EM, Wagner A, et al.: High cumulative risk of 
intussusception in patients with Peutz-Jeghers syndrome:  time to update surveillance 
guidelines? Am J Gastroenterol 2011; 106(5): 940-5. 
5.Chen H Y, Jin X W, Li B R, et al.: Cancer risk in patients with Peutz-Jeghers syndrome: 
A retrospective cohort study of 336 cases. TumourBiol 2017; 39(6): 101042831770513. 
6.Syngal S, Brand RE, Church JM, et al.: ACG clinical guideline: Genetic testing and 
management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015; 
110(2): 223-62; quiz 263. 
7.Olschwang S, Markie D, Seal S, et al.: Peutz-Jeghers disease: most, but not all, 
families are compatible with linkage to 19p13.3. J Med Genet 1998; 35(1): 42-4. 
8.Jenne DE, Reimann H, Nezu J, et al.: Peutz-Jeghers syndrome is caused by mutations 
in a novel serine threonine kinase. Nat Genet 1998; 18(1): 38-43. 
9. Shaw RJ, Bardeesy N, Manning BD, et al.: The LKB1 tumor suppressor negatively 
regulates mTOR signaling. Cancer Cell 2004; 6(1): 91-9. 
10. Beggs AD, Latchford AR, Vasen HF, et al. Peutz-Jeghers syndrome: a systematic 
review and recommendations for management. Gut 2010; 59(7): 975-986. 
11. Klumpen HJ, Queiroz KC, Spek CA et al. mTOR inhibitor treatment of pancreatic 
cancer in a patient With Peutz-Jeghers syndrome. J ClinOncol 2011; 29: e150-153. 
 
 
II. 
Objectives 
1. Evaluation of efficacy of sirolimus on Peutz-Jeghers Syndrome. 
2. Evaluation of safety of sirolimus in treatment of Peutz-Jeghers Syndrome. 
 
III. Research design 
1. This study is a prospective, nonrandomized, open-label, single-arm clinical trial. The 
sirolimus capsule (Rapamycin, Yixinke®), 0.5 mg/grain*20/box, is produced by North 
China Pharmaceutical Co., Ltd. 
2. All patients who meet inclusion criteria and sign informed consents receive sirolimus 
treatment for at least 6 months. Patients are followed up remotely in a regular schedule. 
3. No less than 10 patients should be enrolled. 
 
IV. Selection of subjects 
A. Inclusion criteria 
(1) Patients are diagnosed with PJS. 
(2) Patients have gastrointestinal polyps related syndromes, including abdominal pain, 
abdominal distension, gastrointestinal bleeding, etc, with imageological 

examination suggesting intestinal obstruction or intussusception; or whose 
symptoms recur after previous digestive system endoscopic treatment and surgery; 
or who are inappropriate or unwilling to accept the above treatment again and wish 
to receive pharmacotherapy. 
(3) Conventional treatment doesn’t work well in patients with PJS-related malignant 
tumors. 
(4) Physical condition (ECGO): 0~3 
(5) Organ function is good and biochemical indices meet the following conditions: 
a) 
AST≤2.5×upper limit of normal value (ULN), 
b) 
ALT≤2.5×upper limit of normal value (ULN), 
c) 
Serum total bilirubin (TSB)≤1.5×upper limit of normal value (ULN), 
d) 
Creatinine≤1.5×upper limit of normal value (ULN). 
(6) No other medications have been received for intestinal polyps within 3 months prior 
to the clinical trial. 
(7) Patients volunteer to participate in the trial. Participant or his/her legal guardian 
signs the informed consent form. 
B. Exclusion criteria 
(1) Patients underwent a surgery within 2 weeks. 
(2) Patients may need emergency surgery in the near future. 
(3) Patients are allergic to any ingredient of rapamycin. 
(4) Patients suffer from a disease requiring immediate blood transfusion. 
(5) Patients suffer from any disease or condition that may impact implementation of the 
study or interpretation of the results. This type of diseases includes: 
a) 
Known severe blood coagulation disorders 
b) 
Known anemia that is not caused by intestinal polyps 
c) 
Known hemoglobinopathy 
d) 
Other gastrointestinal infectious diseases 
e) 
Serious heart, liver, kidney and other concomitant diseases that may endanger 
lives 
(6) Patients are in pregnancy and lactation. 
(7) Alcohol or drug (such as aperient) abuse 
(8) Patients took part in another clinical trial that may influence this study. 
(9) The researchers believe that there are other unfavorable reasons for the patient to 
become a subject. 
C. Exit criteria 
(1) An allergic reaction occurs. 
(2) The patient requests withdrawal: at his or her own discretion or at the request of his 
or her legal representative. Subjects may refuse to participate in further studies at 
any time without providing reasons. Subjects will not be affected because of such 
decision. 
(3) Subjects are required to withdraw from the study in certain special circumstances. 
(eg, there is significant issues of compliance, safety, or surgery for venous 
malformations) 
(4) Other situations in which the study must be terminated. For example, the 

investigators believe that continuing the study may be harmful to the health of 
subjects. 
D. Rejection criteria 
(1) Patients who violate the requirements of the test protocol 
(2) Patients with poor-recording, incomplete, or inaccurate data 
 
V. 
Therapeutic schedule 
A. Enrollment 
Before starting the study, the investigator clearly and colloquially explains the study and its 
potential risks and benefits to the patient or his/her authorizer. Patient or his/her authorizer and 
the investigator sign and date the informed consent form. Only after signing the informed 
consent form can patient or his/her authorizer enter the screening section and then participate 
in the study. Patients who sign a written informed consent need to be assessed to determine if 
the patient meets the study criteria: 
1) Demographic data and medical history of the patient; 
2) vital signs; 
B. Children’s dosage regimen 
Oral administration 
The initial dose of oral rapamycin intake is 1 mg/m2 of body surface area. Drug trough 
concentration in patient's blood is maintained at 5-10 ng/ml. 
C. Adults’ dosage regimen 
1) Initial dose and dosing schedule: sirolimus 2mg, once a day. Maintain drug trough 
concentration of 5-10ng / mL in blood. If adverse events are too severe to tolerate, daily 
dosage can be reduced by 0.5mg every week. The minimum dosage is 1 mg/day. If patient 
still cannot tolerate minimum dosage, withdraw from the study. If patient could tolerate the 
possible adverse events, continue to take the original dose for 3 months, and evaluate 
improvement of disease condition. 
2) Subsequent dose and dosing schedule: After taking sirolimus 2 mg once a day for 3 
months, those with improved condition continue to take the original dose. If improvement 
of disease condition is not obvious, change dosage to 2.5mg-3mg once a day. If this dosage 
cannot be tolerated, patients may withdraw from the study. If it can be tolerated, continue 
to take sirolimus for another 3 months and reassess the improvement of condition. 
3) Blood drug concentration test: Blood samples are taken at 1st month, 3rd months, and 
6th months of dosage schedules. 
4) Iron supplementation: For subjects with hemoglobin ≤ 10.9 g / dl, iron supplementation 
should be provided according to the standard dosing regimen, but iron supplementation is 
not considered as study treatment and will be recorded as concomitant medication. 
 
VI. Follow-up plan and content 
A. Evaluation before the trial 
Each subject should complete the following items in four weeks before the treatment: 
1) Complete medical history 

2) Detailed personal profile 
3) A physical examination 
4) VAS pain score 
5) (Patients suspected with secondary malignant lesions) tumor markers examination, 
including CEA, CA199 and CA125 
6) (Female aged 25 or elder) ultrasonic examination of uterus and its appendages 
7) Blood and urine routine examination 
8) Liver and kidney function, blood lipid test 
9) (Patients with secondary malignant tumor) chest CT and other related examinations 
10) Abdominal and pelvic cavity contrast-enhanced CT + small intestine reconstruction CT 
examination  
11) Digestive system endoscopy 
12) (Female of childbearing age) blood/urine pregnancy test 
B. Evaluation during sirolimus treatment 
Adverse reactions are evaluated weekly during the first month of drug treatment. The efficacy 
and safety are then evaluated at the 3rd and 6th months, and the contents of the examination is 
the same as the pre-trial evaluation. 
1) Efficacy assessment: 
a. Clinical symptom assessment (including ileus, VAS pain score, gastrointestinal 
bleeding and some other related symptoms); 
b. Changes in hemoglobin; 
c. Nutritional status (including albumin, etc.); 
d. Abdominal and pelvic cavity contrast-enhanced CT + small intestine reconstruction 
CT examination, digestive system endoscopy to measure the size, quantity and total load 
of intestinal polyps; 
e. (For patients with secondary malignant tumor) Tumor response to the drug, such 
as changes of tumor marker, tumor regression shown by imaging, metastasis and etc.   
2) Safety assessment: Safety parameters (such as asking adverse events, measuring 
laboratory values, vital signs, gastrointestinal bleeding, etc.) will be closely monitored on 
a regular basis throughout the study. 
3) Treatment compliance: In order to monitor compliance, subjects are required to complete 
an electronic diary during the entire study period. Dates of drug intake will be tracked by 
this diary. At every visit, the investigator and the subject will review the integrity of the 
electronic diary data together. 
C. Evaluation after treatment 
Evaluation of curative effects and safety is conducted at the end of the drug therapy, six and 
twelve months after the treatment. Its content is the same as pre-trial evaluation. 
 
VII. Records and reports of adverse events 
A. Adverse events 
The term of adverse events encompass any signs, symptoms, syndromes or diseases affecting 
health condition of subjects during the trial. The term also includes clinically relevant 
conditions found by laboratory test or other diagnostic procedures. It may call for unplanned 

treatment, or lead to withdrawal from the trial. Adverse events may be: new disease; 
deterioration of symptoms accompanying disease progression during treatment; certain events 
not related to the trial; combination of one or more events above.  
Serious adverse events 
At any dose of the test drug or at any time during the observation period, the following 
adverse events occurs: death; immediate life-threatening events; requirement of 
hospitalization or prolonged hospital stay; disability; congenital malformations; other events 
with important medical implications (those do not immediately endanger life or cause death 
or require hospitalization, but may harm the patient or require interventions to prevent one of 
the consequences defined above) and requiring medical treatment to prevent permanent 
injury. 
B. Adverse reactions 
Harmful and unexpected reactions caused by pharmaceutical applications under normal use of 
drugs and prescribed doses. 
C. Degree of adverse reactions: 
1) Mild: causing mild discomfort which can be tolerated and does not affect daily life; 
under this circumstance, the subject does not need to discontinue medication. 
2) Moderate: causing discomfort which affects patients’ daily life. 
3) Severe: affecting daily life; cannot be endured by the subject or cause organ damage 
and need to withdraw medication. 
4) Very serious: risk of disability or death; require emergent rescue and drug 
withdrawal. 
D. Evaluation of the relationship between adverse reactions and experimental drug 
According to the 5-level judgment system, the relationships can be divided into 5 types: 
definitely related, very likely related, may be related, may be irrelevant, and definitely 
irrelevant. The first three are counted as adverse reactions, in which case the incidence of 
adverse reactions and adverse events should be reported. 
E. Record and report 
The investigator should explain to the patient or his/her legal guardian that it is required to 
truthfully reflect the changes in the condition after administration. Doctors should avoid 
suggestive questions. While observing the efficacy, pay close attention to the observation of 
adverse events or unanticipated side effects (including symptoms, signs, laboratory tests), 
analyze the causes, make judgments, and report the incidence of adverse reactions and 
adverse events. 
For adverse events occurring during the trial, time, symptoms, extent, duration, treatment 
measures, outcomes, and some other items should be recorded in the case report form to 
evaluate the correlation with the test drug. Investigator should record it in detail, and then 
signs and dates. 
F. Treatment of adverse events 
1) reporting system 
Any adverse events, such as subjective discomfort and abnormal laboratory tests, should be 
taken seriously and carefully analyzed. Immediate measures should be taken to protect 
safety of the subject. 
2) treatment procedure 

Physicians are pre-trained to prevent certain types of adverse events or reactions that may 
occur in the study, so as to protect safety of patients. Treatment procedure of adverse event 
should be recorded in detail. Persistence and disappearance of adverse events should also 
be recorded. 
3) treatment of serious adverse events 
On the occurrence of any serious adverse event, research physician should report to 
primary PI within 24 hours, in addition to emergency treatment. 
4) follow-up of unresolved adverse events 
All adverse events should be tracked until they are properly resolved. Adverse events with 
abnormal laboratory values should be tracked until the value returns to baseline. 
 
VIII. Statistical analysis  
Statistical analysis will be conducted by SPSS.  
A. Methods of statistical analysis  
The categorical variables will be described by frequency distribution (number of cases and 
percentage). Continuous variables will be described with mean, median, minimum, 
maximum, first and third quartile. The confidence interval of all parameters is set to be 95%. 
All analyses will be conducted with SPSS.  
B. Contents of statistical analysis  
1) General data analysis: Demographic variables and baseline characteristics will be 
summarized comprehensively by mean of descriptive statistics and/or appropriate 
frequency tables.  
2) Evaluation of efficacy: According to follow-up and reexamination results, the patients’ 
quality of life, size and volume of the polyps, total polyp load control and improvement of 
symptoms will be analyzed.  
3) Analysis of adverse events: Side effects and adverse events during medication will be 
assessed.  
4) Evaluation of the relationship between adverse events and the tested drug  
 
IX. Measures of quality control  
1. Supervision by the project leader  
2. Establish a standardized evaluation method, unify various diagnostic criteria and 
efficacy criteria 
3. Formulate plans for monitoring and treatment of adverse reactions  
4. All researchers are trained before the study begun 
5. Designate quality controllers and develop a plan for quality control, with regular 
inspections  
6. Devise a follow-up plan and system  
 
X. Expected research results  
The results will be published in a paper and fed back to the subjects.  

 
XI. Potential risks, benefits or advantages of this study  
As a drug that has been on the market for years, it is applied to this study beyond its 
indication. It is recommended by doctors considering that its benefits outweigh its risks and 
the subjects have no better choice. For subjects, it may relieve their symptoms and improve 
quality of life, and complications associated with surgery and damage to intestinal function 
can be avoided. The testing drug is free during the study and subjects should bear the risks of 
treatment.  
 
XII. Data preservation and confidentiality  
It will be stated in the informed consent that personal information of subjects will be strictly 
confidential in this study. Results of this study may be published in scientific paper, but 
personal information of subjects, including their names, will not appear in the paper. All data 
relevant to this study will be preserved by Peking Union Medical College Hospital and 
Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, and strict 
confidentiality measures will be established.  
 
XIII. Measures to protect subjects and minimize risks  
In the whole course of this study, safety supervision will be carried out by experts from the 
digestive surgery department of our hospital to strictly control diagnostic criteria and 
treatment indicators of Peutz-Jeghers’s syndrome, making the collected clinical data meet 
international diagnostic criteria and providing favorable treatment for these patients.