Patient case: 11-year-old male with Peutz-Jeghers syndrome; genetic feature: STK11

Clinical trial: suPERficial Slow-flow Vascular malFORMations Treated With sirolimUS

Summary: The most recent classification, adopted by International Society for the Study of Vascular Anomalies (ISSVA) in 1996, and updated in Melbourne in 2014, divides these lesions into two broad categories: vascular tumors and vascular malformations. Vascular malformations (VMs) are subdivided into high-flow VM and slow-flow VM.
  Slow-flow VMs consist of congenital anomalies which may involve abnormal capillaries vessels, venous vessels, lymphatic vessels or combination of several of them. They can be superficial (involving cutaneous and subcutaneous tissues) and/or may have visceral involvement. They can be limited or diffuse, and are sometimes components of genetic hypertrophic syndromes.
  The diagnosis of slow-flow VMs is performed on physical examination (biopsy may be required for confirmation), and is completed with imaging (ultrasonography and magnetic resonance imaging (MRI)). Slow-flow VMs may be particularly voluminous; associated with underlying hypertrophy responsible for functional impairment; painful; associated with seepage or continuous cutaneous bleeding; complicated with visceral signs or hematologic disturbances (anemia, thrombopenia). Management requires dedicated multispecialty care. There are no guidelines for treatment, and management may include no intervention - but natural history of these VMs is progressive worsening -, compression by physical bandage, sclerotherapy, resection (when feasible),anti-inflammatory or anti-coagulation drugs.
  Case reports and series have provided evidence for supporting the need for a clinical trial of sirolimus by reporting successful treatment on several children with complicated vascular anomalies. The choice of sirolimus is rational. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase regulated by phosphoinositide-3-kinase involved in cell mobility, cell growth and angiogenesis. Sirolimus inhibits mTOR, which induces inhibition of angiogenesis, in particular lymphangiogenesis, which has been demonstrated in several models.

Detailed description: Vascular anomalies include a heterogeneous group of disorders of newborns and children. While infantile hemangioma are common (10% of infants), generally not complicated and easily managed, the majority of other vascular anomalies are rare (<2% altogether) and have no guidelines for management. The most recent classification, adopted by International Society for the Study of Vascular Anomalies (ISSVA) in 1996, divides these lesions into two broad categories: vascular tumors and vascular malformations. Vascular malformations (VMs) are subdivided into high-flow VM and slow-flow VM.
  Slow-flow VMs consist of congenital anomalies which may involve abnormal capillaries vessels, venous vessels, lymphatic vessels or combination of several of them. They can be superficial (involving cutaneous and subcutaneous tissues) and/or may have visceral involvement. They can be limited or diffuse, and are sometimes components of genetic hypertrophic syndromes. They always result from defective embryologic vasculogenesis.
  The diagnosis of slow-flow VMs is performed on physical examination - a biopsy may be required for confirmation -, and is completed with imaging, which includes ultrasonography and magnetic resonance imaging (MRI). Slow-flow VMs may be simple to manage or can be complicated for several reasons: they may be particularly voluminous; associated with underlying hypertrophy responsible for functional impairment; painful; associated with seepage or continuous cutaneous bleeding; complicated with visceral signs or hematologic disturbances (anemia, thrombopenia). Management requires dedicated multispecialty care. There are no guidelines for treatment, and management may include no intervention - but natural history of these VMs is progressive worsening -, compression by physical bandage, sclerotherapy, resection (when feasible), anti-inflammatory or anti-coagulation drugs.
  The vast majority of literature reporting medical therapies consists of paediatric case reports, and is complicated by publication bias, inconsistent use of nomenclature and absence of clinical trials. Case reports and series have provided evidence for supporting the need for a clinical trial of sirolimus by reporting successful treatment on several children with complicated vascular anomalies. The choice of sirolimus is rational. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase regulated by phosphoinositide-3-kinase involved in cell mobility, cell growth and angiogenesis. Sirolimus inhibits mTOR, which induces inhibition of angiogenesis, in particular lymphangiogenesis, which has been demonstrated in several models.
  Randomized observational-phase design (Feldman et al. J Clin Epidemiol 2001;54:550-557):
  -  each patient will be followed during a 12-month-period
  -  each patient will start by an observational period and will end being treated by sirolimus
  -  at a random date (between month 4 and month 8), each patient will switch from the observational period to the sirolimus period Therefore, each patient will be his/her own control, as in a cross-over trial (but the difference is that the cross-over is all in one direction, from observational period to treatment period). This explains why variation in volume will be standardized by period durations.
  As specified by Feldman et al, the randomized placebo-phase design is well adapted in situations where "a placebo controlled study would be perceived as being unacceptable by enrolling physicians and by patient" and "may be especially useful when highly potent therapies for rare diseases"

Eligibility: -  Patients aged from 6 years to 18 years
  -  With a slow-flow vascular malformation confirmed by MRI, included or not into a genetic disorder, among the following:
  -  microcystic lymphatic malformation
  -  mixed micro- and macrocystic malformation
  -  venous malformation
  -  combined lymphatic and venous malformation
  -  Malformation voluminous and complicated (pain, functional impairment, bleeding, seepage)
  -  Extended to the underlying subcutaneous tissue, to the fascias, the muscles and/or the underlying bone
  -  MRI of the VM performed within 8 months
  -  Vaccination schedule updated
  -  Informed, written consent of the subject's parents or the 18 years old subject
  -  Cooperative parent or subject, aware of the necessity and duration of controls so that perfect adhesion to the protocol could be expected
  -  Subjects or subject's parents covered by or having the rights to social security.
  Exclusion criteria:
  -  Slow-flow VMs which are only macrocystic lymphatic malformations
  -  Visceral life-threatening involvement
  -  Patients who received prior per os treatment with an mTOR inhibitor
  -  Immunosuppression (immunosuppressive disease or immunosuppressive treatment)
  -  Known chronic infectious disease
  -  History of cancer in the 2 previous years
  -  Brest feeding or pregnant women, or women on childbearing age without effective contraception, up to 12 weeks after treatment discontinuation
  -  Known allergy to mTOR inhibitor
  -  Concomitant treatment that inhibits or activates CYP3A4, and P-gp glycoprotein, cytotoxic drugs, antilymphocyte immunoglobulines and metoclopramide
  -  Intolerance to fructose, intolerance or malabsorption to glucose, galactose, metabolic insufficiency in sucraseisomaltase, metabolic defect in lactase
  -  Known allergy to peanuts or soyabean
  -  Liver insufficiency (elevated transaminases > 2.5 N)
  -  Anemia with Hb < 9 g/dl
  -  Leukopenia < 1000/mm3
  -  Thrombocytopenia < 80 000/mm3
  -  Hypercholesterolemia (LDL-cholesterol ≥ 2g/l)
  -  Patients with risk of opportunistic infections
  -  Contraindication of MRI
  -  Known allergy to lidocaïne
  -  Live attenuated vaccine up to 3 months after sirolimus discontinuation
  -  Subject already participating to a therapeutic study

Relevance to patient case: not relevant