Efficacy of Rapamycin (Sirolimus) in the Treatment of Peutz-Jeghers Syndrome

A prospective non-randomized open label single arm clinical trial to examine the efficacy and safety of sirolimus in patients with Peutz-Jeghers Syndrome.

Study Overview

• Status: Unknown
• Conditions: Peutz-Jeghers Syndrome
• Intervention / Treatment: Drug: Rapamycin

Detailed Description

PJS (Peutz-Jeghers Syndrome) is mostly caused by mutations in Lkb1 gene, which leads to an increased activity of mTOR pathway, thus making mTOR inhibitor (sirolimus) a promising candidate in treatment and prevention of PJS. The efficacy of sirolimus (rapamycin) on PJS has been demonstrated in mouse model, but no clinical trials have been reported. Our study was designed as a prospective non-randomized open label single arm clinical trial to examine its efficacy and safety.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jiaolin Zhou, MD; Phone Number: 13910136704; Email: conniezhjl@yahoo.com

Study Locations

• China
  • China/Beijing
    • Beijing, China/Beijing, China, 100000
      • Recruiting
      • Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences
      • Contact: Jiaolin Zhou, MD; Phone Number: 13910136704; Email: conniezhjl@yahoo.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients are diagnosed with PJS.
• 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 endoscopic treatment and surgery; or who are inappropriate or unwilling to accept the above treatment again and wish to receive pharmacotherapy.
• Conventional treatment didn't work well in patients combined with PJS-related tumors.
• Physical condition (ECGO): 0~3

• Organ function is good and biochemical indices meet the following conditions:

  • AST≤2.5×upper limit of normal value (ULN),
  • ALT≤2.5×upper limit of normal value (ULN),
  • Serum total bilirubin (TSB)≤1.5×upper limit of normal value (ULN),
  • Creatinine≤1.5×upper limit of normal value (ULN).
• No other medications have been received for intestinal polyps within 3 months prior to the clinical trial.
• Patients participate in the trial voluntarily and have signed the informed consent by the participant or his/her legal guardian.

Exclusion Criteria:

• Patients underwent a surgery within 2 weeks.
• Patients may need emergency surgery in the near future.
• Patients are allergic to any ingredient of rapamycin.
• Patients suffer from a disease requiring immediate blood transfusion.

• Patients suffer from any disease or condition that may impact implementation of the study or interpretation of the results. This type of diseases includes:

  • Known severe blood coagulation disorders
  • Known anemia that is not caused by intestinal polyps
  • Known hemoglobinopathy
  • Other gastrointestinal infectious diseases
  • Serious heart, liver, kidney and other concomitant diseases that may endanger lives
• Patients are in pregnancy and lactation.
• Alcohol or drug (such as aperient) abuse
• Patients took part in another clinical trial that may influence this study.
• The researchers believe that there are other unfavorable reasons for the patient to become a subject.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rapamycin; For children: rapamycin, 1 mg per square meter of body surface area a day, orally, for at least 6 months For adults: rapamycin, 2 mg a day, orally, for at least 6 months	Drug: Rapamycin; For children: rapamycin, 1 mg per square meter of body surface area a day, orally, for at least 6 months For adults: rapamycin, 2 mg a day, orally, for at least 6 months; Other Names: Sirolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total load of PJS-related intestinal polyps Total load of PJS-related intestinal polyps Total load of PJS-related intestinal polyps	Lesion load (cm2) = A+B. A = sum of the product of maximum diameter and maximum height of the largest 3 lesions shown by abdomen and pelvis MRI or small bowel CT reconstruction (in cm2). B = sum of the product of maximum diameter and maximum height of the largest 3 lesions shown by digestive endoscope (in cm2). Remarks: 1. If it is impossible to evaluate 3 or more lesions, results of the actual number of lesions should be taken as valid; 2. Lesions evaluated should be correspondent before and after treatment. If the lesion is difficult to assess after treatment, it should be ruled out from the assessment.	The time from start of therapy to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of hemoglobin in blood	The value indicates the amount of gastrointestinal bleeding.	The time from start of therapy to 1 year
Concentration of albumin in blood	The value indicates the status of nutrition.	The time from start of therapy to 1 year
Concentration of hsCRP in blood	The value indicates the level of inflammation.	The time from start of therapy to 1 year
Visual analogue score (VAS)	The value indicates the level of pain.	The time from start of therapy to 1 year
Dermatology life quality index (DLQI)	The value indicates the status of hyperpigmented macules on the lips and oral mucosa.	The time from start of therapy to 1 year
Adverse events	To evaluate safety	The time from start of therapy to 1 year

Collaborators and Investigators

• Sponsor: Peking Union Medical College Hospital
• Collaborators: Cancer Institute and Hospital, Chinese Academy of Medical Sciences; Air Force General Hospital of the PLA
• Investigators: Principal Investigator: Jiaolin Zhou, MD, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences

Publications and helpful links

General Publications

• Chen HY, Jin XW, Li BR, Zhu M, Li J, Mao GP, Zhang YF, Ning SB. Cancer risk in patients with Peutz-Jeghers syndrome: A retrospective cohort study of 336 cases. Tumour Biol. 2017 Jun;39(6):1010428317705131. doi: 10.1177/1010428317705131.
• Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 2004 Jul;6(1):91-9. doi: 10.1016/j.ccr.2004.06.007.
• Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, Muller O, Back W, Zimmer M. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet. 1998 Jan;18(1):38-43. doi: 10.1038/ng0198-38.
• Wei C, Amos CI, Zhang N, Zhu J, Wang X, Frazier ML. Chemopreventive efficacy of rapamycin on Peutz-Jeghers syndrome in a mouse model. Cancer Lett. 2009 May 18;277(2):149-54. doi: 10.1016/j.canlet.2008.11.036. Epub 2009 Jan 14.
• Robinson J, Lai C, Martin A, Nye E, Tomlinson I, Silver A. Oral rapamycin reduces tumour burden and vascularization in Lkb1(+/-) mice. J Pathol. 2009 Sep;219(1):35-40. doi: 10.1002/path.2562.

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2018
• Primary Completion (Anticipated): January 1, 2022
• Study Completion (Anticipated): July 1, 2022

Study Registration Dates

• First Submitted: December 6, 2018
• First Submitted That Met QC Criteria: December 17, 2018
• First Posted (Actual): December 19, 2018

Study Record Updates

• Last Update Posted (Actual): January 23, 2019
• Last Update Submitted That Met QC Criteria: January 18, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Treatment; Rapamycin (sirolimus); Mammalian target of rapamycin (mTOR) inhibitor; Peutz-Jeghers Syndrome (PJS)
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Skin Diseases; Neoplasms; Disease; Gastrointestinal Diseases; Genetic Diseases, Inborn; Intestinal Diseases; Neoplastic Syndromes, Hereditary; Intestinal Polyposis; Hyperpigmentation; Pigmentation Disorders; Melanosis; Lentigo; Syndrome; Peutz-Jeghers Syndrome; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: HS-1607

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No