Study of Everolimus in the Treatment of Advanced Malignancies in Patients With Peutz-Jeghers Syndrome

Study Overview
=================
Brief Summary
-----------------
In this pilot study the investigators will treat all patients known with Peutz-Jeghers syndrome (PJS) who are diagnosed with advanced malignancies with everolimus 10mg daily until disease progression. Most patients with PJS have an inherited LKB1 mutation leading to aberrant m-TOR activity. Their risk to develop malignancies or intestinal polyps is probably related to this constitutive mTOR signaling. The hypothesis is that mTOR inhibition is an effective anticancer treatment in PJS patients with advanced malignancies.

Official Title
-----------------
Pilot Study of Everolimus in the Treatment of Neoplasms in Patients With Peutz-Jeghers Syndrome

Conditions
-----------------
Peutz-Jeghers Syndrome, Neoplastic Processes, Neoplasm Metastasis

Intervention / Treatment
-----------------
* Drug: Everolimus


Participation Criteria
=================
Eligibility Criteria
-----------------
Tow cohorts of PJS patients will be included. Cohort 1: Advanced malignancy Cohort 2: High risk polyps General inclusion criteria: Known Peutz-Jeghers disease (with LKB1 mutation) No concurrent systemic anti cancer treatment No prior treatment with m-TOR inhibitor Prior malignancies or concurrent second malignancies are allowed Prior systemic therapy is permitted with a washout time of at least 4 weeks ECOG/ WHO performance 0-2 Age > 18 years Adequate renal function (defined as creatinine < 150 μmol/L) Adequate liver function (bilirubin < 1.5 times upper limit of normal, ALAT or ASAT < 5.0 times upper limit of normal in case of liver metastases and < 2.5 the upper limit of normal in absence of liver metastases Adequate bone marrow function (WBC > 3.0 x 10 9/L, platelets > 100 x 10 9/L) Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. No pregnancy or lactating and ifof childbearing potential patients must agree to use a reliable contraceptive method throughout the study No serious concomitant systemic disorder that would compromise the safety of the patient,at the discretion of the investigator Signed informed consent according to ICH/GCP. No uncontrolled symptomatic hyperglycaemia Specific inclusion criteria for cohort 1: Cytological or histological confirmed carcinoma Metastatic or non-resectable disease Patients with clinically and/or radiographically documented measurable lesion according to RECIST criteria: X-ray, physical exam > 20 mm Spiral CT scan > 10 mm Non-spiral CT scan > 20 mm Specific inclusion criteria for cohort 2: Known high risk polyps (definition see page 19) Ability to undergo endoscopies Specific Exclusion criteria: Symptomatic PJ-polyps, defined as polyps likely to be responsible/causal for the abdominal symptoms the patient presents with.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: afinitor<br>10mg afinitor daily orally | Drug: Everolimus<br>* 10mg daily orally<br>* Other names: Afinitor, RAD001, everolimus;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the response rate of Everolimus in patients with advanced cancer and PJS. | Determined with regular radiological scans once every 9 weeks and measured following RECIST 1.1 | During treatment, expected avarage of 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the overall survival of PJS patients treated with everolimus for advanced malignancies | The time between date of entering the study and date of death will be collected. | avarage of 18 months | 
| To determine the time to progression of PJS patients treated with everolimus for advanced malignancies. | Determined with regular radiological scans once every 9 weeks and measured following RECIST 1.1 | During treatment, expected avarage of 12 months | 
| To determine the safety and toxicity of Everolimus in this patient population | Number of Participants with Adverse Events determined by the CTCAE 4.0 as a Measure of Safety and Tolerability | During treatment, expected avarage of 12 months | 
| To determine if there is an association between measured drug blood levels and treatment outcome measured as response to treatment determined by RECIST | Drug trough levels will be taken once every 3 weeks and stored frozen until measurement at the end of the study | During treatment, expected avarage of 12 months | 
| To assess markers for activated mTOR pathway (including phospho-S6 and phospho-4E BP1) in all pre-treatment tissue specimens and collected specimens during treatment and correlate with response to treatment. | All patients who are willing to undergo extra tissue collection will have a tumor and where possible a polyp biopsy before treatment and for tumor biopsy in week 2 and 4 and for polyps once every 6 months during treatment for biomarker investigations. The activity of mTOR and its downstream targets will be measured in the tumor as well as the arborization pattern and apoptosis activity in the polyps. | During treatment, expected avarage of 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Peutz-Jeghers syndrome, mTOR inhibition, cancer