Efficacy of Rapamycin (Sirolimus) in the Treatment of BRBNS, Hereditary or Sporadic Venous Malformation

Venous Malformation Clinical Trial

Official title:

Efficacy of Rapamycin (Sirolimus) in the Treatment of Blue Rubber Bleb Nevus Syndrome, Hereditary or Sporadic Venous Malformation

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03767660
• Other study ID #: HS-1606
• Status: Recruiting
• Phase: Phase 4
• Start date: July 31, 2018
• Est. completion date: July 1, 2022

Study information

• Verified date: December 2018
• Source: Peking Union Medical College Hospital
• Contact: Jiaolin Zhou, MD
• Phone: 13910136704
• Email: conniezhjl[@]yahoo.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A prospective, nonrandomized, open-label, single-arm clinical trial to study efficacy of rapamycin (sirolimus) in the treatment of Blue Rubber Bleb Nevus Syndrome, hereditary or sporadic venous malformation

Description:

Blue rubber bleb nevus syndrome (BRBNS) and venous malformation are mainly caused by somatic mutation of TEK and PIK3CA, which activates the PI3K/AKT signaling pathway. As an important protein kinase downstream of the PI3K/AKT pathway, mTOR can serve as a potential therapeutic target for BRBNS. Experiments of mice have shown that rapamycin inhibited the progression of venous malformation lesions. There are a few human cases reported using rapamycin treatment. The investigator's study is designed to be a prospective, nonrandomized, open-label, single-arm clinical trial to investigate its efficacy and safety.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: July 1, 2022
• Est. primary completion date: January 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Patients diagnosed with BRBNS, VMCM, sporadic multiple VM, or large single VM;

• Age and gender are not limited;

• Physical status ECOG 0~3;

• Organ function is good, biochemical examination meets the following conditions: AST = 2.5 × upper limit of normal value (ULN), ALT = 2.5 × upper limit of normal value (ULN), serum total bilirubin = 1.5 × upper limit of normal value (ULN), creatinine = 1.5 × upper limit of normal (ULN);

• Patients volunteer to participate in the trial and sign the informed consent form by the participant or his/her legal guardian.

Exclusion Criteria:

• Patients need emergency surgery due to intestinal obstruction, intussusception, or gastrointestinal bleeding;

• History of surgery within 1 month;

• allergic to rapamycin;

• Any disease or condition that may affect the study implementation or result interpretation, including: known hemoglobinopathy, suffering from gastrointestinal infections at the same time, severe heart, liver, kidney and other serious concomitant diseases that may endanger lives

• Pregnant or lactating women;

• Alcohol or drugs (eg, laxatives) abusers;

• Participating in another clinical trial that may affect this study within one month;

• Being believed not suitable to be enrolled by the investigator for other reasons.

Exit Criteria:

• An allergic reaction to rapamycin occurs.

• The patient requests withdrawal: at his own discretion or at the request of his legal representative. Subjects may refuse to participate in further studies at any time without reasons. Subjects will not be affected because of such decision.

• Subjects are required to withdraw from the study in certain special circumstances (eg, there is significant issues of compliance, safety, or surgical intervention for the disease)

• 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.

Rejection Criteria:

• Patients who violate the requirements of the test protocol

• Patients with poor recording (with incomplete, or inaccurate data)

Related Conditions & MeSH terms

• Blue Rubber Bleb Nevus Syndrome
• Congenital Abnormalities
• Gastrointestinal Neoplasms
• Nevus, Blue
• Skin Neoplasms
• Syndrome
• Venous Malformation

Intervention

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

Locations

Country	Name	City	State
China	Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences	Beijing	Beijing

Sponsors (3)

Lead Sponsor	Collaborator
Peking Union Medical College Hospital	Air Force General Hospital of the PLA, Chinese Academy of Medical Sciences

Country where clinical trial is conducted

China, 

References & Publications (17)

Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008 Jan 10;358(2):140-51. doi: 10.1056/NEJMoa063564. — View Citation

Boscolo E, Limaye N, Huang L, Kang KT, Soblet J, Uebelhoer M, Mendola A, Natynki M, Seront E, Dupont S, Hammer J, Legrand C, Brugnara C, Eklund L, Vikkula M, Bischoff J, Boon LM. Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects. J Clin Invest. 2015 Sep;125(9):3491-504. doi: 10.1172/JCI76004. Epub 2015 Aug 10. — View Citation

Cardoso H, Dias JA, Silva M, Vilas-Boas F, Trindade E, Tavares M, Macedo G. 'Education and Imaging. Gastrointestinal: Successful treatment with sirolimus of a patient with blue rubber bleb nevus syndrome. J Gastroenterol Hepatol. 2016 Mar;31(3):519. doi: 10.1111/jgh.13178. — View Citation

Carvalho S, Barbosa V, Santos N, Machado E. Blue rubber-bleb nevus syndrome: report of a familial case with a dural arteriovenous fistula. AJNR Am J Neuroradiol. 2003 Oct;24(9):1916-8. — View Citation

Davies DM, de Vries PJ, Johnson SR, McCartney DL, Cox JA, Serra AL, Watson PC, Howe CJ, Doyle T, Pointon K, Cross JJ, Tattersfield AE, Kingswood JC, Sampson JR. Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial. Clin Cancer Res. 2011 Jun 15;17(12):4071-81. doi: 10.1158/1078-0432.CCR-11-0445. Epub 2011 Apr 27. — View Citation

Davies DM, Johnson SR, Tattersfield AE, Kingswood JC, Cox JA, McCartney DL, Doyle T, Elmslie F, Saggar A, de Vries PJ, Sampson JR. Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis. N Engl J Med. 2008 Jan 10;358(2):200-3. doi: 10.1056/NEJMc072500. — View Citation

Dobru D, Seuchea N, Dorin M, Careianu V. Blue rubber bleb nevus syndrome: case report and literature review. Rom J Gastroenterol. 2004 Sep;13(3):237-40. Review. — View Citation

Jin XL, Wang ZH, Xiao XB, Huang LS, Zhao XY. Blue rubber bleb nevus syndrome: a case report and literature review. World J Gastroenterol. 2014 Dec 7;20(45):17254-9. doi: 10.3748/wjg.v20.i45.17254. Review. — View Citation

Kisu T, Yamaoka K, Uchida Y, Mori H, Nakama T, Hisatsugu T, Miyaji H, Motooka M. A case of blue rubber bleb nevus syndrome with familial onset. Gastroenterol Jpn. 1986 Jun;21(3):262-6. — View Citation

McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011 Apr 28;364(17):1595-606. doi: 10.1056/NEJMoa1100391. Epub 2011 Mar 16. — View Citation

Moavero R, Coniglio A, Garaci F, Curatolo P. Is mTOR inhibition a systemic treatment for tuberous sclerosis? Ital J Pediatr. 2013 Sep 17;39:57. doi: 10.1186/1824-7288-39-57. Review. — View Citation

Ochiai D, Miyakoshi K, Yakubo K, Fukuiya T, Yoshimura Y. Familial blue rubber bleb nevus syndrome in pregnancy with spinal epidural involvement. Case Rep Obstet Gynecol. 2013;2013:141506. doi: 10.1155/2013/141506. Epub 2013 May 9. — View Citation

Paul E, Thiele E. Efficacy of sirolimus in treating tuberous sclerosis and lymphangioleiomyomatosis. N Engl J Med. 2008 Jan 10;358(2):190-2. doi: 10.1056/NEJMe0707153. — View Citation

Salloum R, Fox CE, Alvarez-Allende CR, Hammill AM, Dasgupta R, Dickie BH, Mobberley-Schuman P, Wentzel MS, Chute C, Kaul A, Patel M, Merrow AC, Gupta A, Whitworth JR, Adams DM. Response of Blue Rubber Bleb Nevus Syndrome to Sirolimus Treatment. Pediatr Blood Cancer. 2016 Nov;63(11):1911-4. doi: 10.1002/pbc.26049. Epub 2016 Jun 8. — View Citation

Soblet J, Kangas J, Nätynki M, Mendola A, Helaers R, Uebelhoer M, Kaakinen M, Cordisco M, Dompmartin A, Enjolras O, Holden S, Irvine AD, Kangesu L, Léauté-Labrèze C, Lanoel A, Lokmic Z, Maas S, McAleer MA, Penington A, Rieu P, Syed S, van der Vleuten C, Watson R, Fishman SJ, Mulliken JB, Eklund L, Limaye N, Boon LM, Vikkula M. Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations. J Invest Dermatol. 2017 Jan;137(1):207-216. doi: 10.1016/j.jid.2016.07.034. Epub 2016 Aug 9. — View Citation

Ünlüsoy Aksu A, Sari S, Egritas Gürkan Ö, Dalgiç B. Favorable Response to Sirolimus in a Child With Blue Rubber Bleb Nevus Syndrome in the Gastrointestinal Tract. J Pediatr Hematol Oncol. 2017 Mar;39(2):147-149. doi: 10.1097/MPH.0000000000000681. — View Citation

Yuksekkaya H, Ozbek O, Keser M, Toy H. Blue rubber bleb nevus syndrome: successful treatment with sirolimus. Pediatrics. 2012 Apr;129(4):e1080-4. doi: 10.1542/peds.2010-3611. Epub 2012 Mar 5. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total venous malformation lesion load	lesion load (cm2) = A + B + C. A = sum of the product of maximum diameter and maximum height of the largest 3 lesions shown by chest, 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) C = sum of the product of maximum diameter and maximum height of the largest 3 lesions shown by ultrasound (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	Amount of daily oral iron supplements	The value indicates the amount of gastrointestinal bleeding.	The time from start of therapy to 1 year
Secondary	Concentration of hemoglobin in blood	The value indicates the amount of gastrointestinal bleeding.	The time from start of therapy to 1 year
Secondary	Frequency of blood transfusion	The value indicates the amount of gastrointestinal bleeding	The time from start of therapy to 1 year
Secondary	Concentration of D-dimer in blood	The value indicates the extent of local coagulation caused by Venous Malformation lesions.	The time from start of therapy to 1 year