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

• ClinicalTrials.gov Identifier: NCT03781050
• Recruitment Status: Unknown
• First Posted: December 19, 2018
• Last Update Posted: January 23, 2019
• Sponsor: Peking Union Medical College Hospital
• Collaborators: Air Force General Hospital of the PLA; Cancer Institute and Hospital, Chinese Academy of Medical Sciences
• Information provided by (Responsible Party): Peking Union Medical College Hospital

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Peutz-Jeghers Syndrome	Drug: Rapamycin	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy of Rapamycin (Sirolimus) in the Treatment of Peutz-Jeghers Syndrome
• Actual Study Start Date: September 16, 2018
• Estimated Primary Completion Date: January 1, 2022
• Estimated Study Completion Date: July 1, 2022

Arms and Interventions

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 Name: Sirolimus

Outcome Measures

Primary Outcome Measures :

1. Total load of PJS-related intestinal polyps Total load of PJS-related intestinal polyps Total load of PJS-related intestinal polyps [ Time Frame: The time from start of therapy to 1 year ]
   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.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Jiaolin Zhou, MD; 13910136704; conniezhjl@yahoo.com

Locations

China, China/Beijing

Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences; Recruiting

Beijing, China/Beijing, China, 100000

Contact: Jiaolin Zhou, MD 13910136704 conniezhjl@yahoo.com

Sponsors and Collaborators

Peking Union Medical College Hospital

Air Force General Hospital of the PLA

Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Investigators

• Principal Investigator: Jiaolin Zhou, MD; Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences

  Study Documents (Full-Text)

Documents provided by Peking Union Medical College Hospital:

Study Protocol and Statistical Analysis Plan  [PDF] December 5, 2018

More Information

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.

• Responsible Party: Peking Union Medical College Hospital
• ClinicalTrials.gov Identifier: NCT03781050
• Other Study ID Numbers: HS-1607
• First Posted: December 19, 2018
• Last Update Posted: January 23, 2019
• Last Verified: January 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Peking Union Medical College Hospital:

Peutz-Jeghers Syndrome (PJS); Rapamycin (sirolimus); Mammalian target of rapamycin (mTOR) inhibitor; Treatment

Additional relevant MeSH terms:

Peutz-Jeghers Syndrome; Syndrome; Disease; Pathologic Processes; Neoplastic Syndromes, Hereditary; Neoplasms; Intestinal Polyposis; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Genetic Diseases, Inborn; Lentigo; Melanosis; Hyperpigmentation; Pigmentation Disorders; Skin Diseases; Sirolimus; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs