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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Neoplasm Metastasis; Neoplastic Processes; Peutz-Jeghers Syndrome
• Intervention / Treatment: Drug: Everolimus

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1105AZ
    • Academic Medical Center
  • Rotterdam, Netherlands, 3000 CA
    • Erasmus Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Tow cohorts of PJS patients will be included. Cohort 1: Advanced malignancy Cohort 2: High risk polyps

General inclusion criteria:

1. Known Peutz-Jeghers disease (with LKB1 mutation)
2. No concurrent systemic anti cancer treatment
3. No prior treatment with m-TOR inhibitor
4. Prior malignancies or concurrent second malignancies are allowed
5. Prior systemic therapy is permitted with a washout time of at least 4 weeks
6. ECOG/ WHO performance 0-2
7. Age > 18 years
8. Adequate renal function (defined as creatinine < 150 μmol/L)
9. 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
10. Adequate bone marrow function (WBC > 3.0 x 10 9/L, platelets > 100 x 10 9/L)
11. 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.
12. No pregnancy or lactating and ifof childbearing potential patients must agree to use a reliable contraceptive method throughout the study
13. No serious concomitant systemic disorder that would compromise the safety of the patient,at the discretion of the investigator
14. Signed informed consent according to ICH/GCP.
15. No uncontrolled symptomatic hyperglycaemia

Specific inclusion criteria for cohort 1:

1. Cytological or histological confirmed carcinoma
2. Metastatic or non-resectable disease
3. Patients with clinically and/or radiographically documented measurable lesion according to

RECIST criteria:

1. X-ray, physical exam > 20 mm
2. Spiral CT scan > 10 mm
3. Non-spiral CT scan > 20 mm

Specific inclusion criteria for cohort 2:

1. Known high risk polyps (definition see page 19)
2. 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.

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: afinitor; 10mg afinitor daily orally	Drug: Everolimus; 10mg daily orally; 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

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Erasmus Medical Center
• Investigators: Principal Investigator: Heinz-Josef Klumpen, MD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Publications and helpful links

General Publications

• de Brabander J, Eskens FALM, Korsse SE, Dekker E, Dewint P, van Leerdam ME, van Eeden S, Klumpen HJ. Chemoprevention in Patients with Peutz-Jeghers Syndrome: Lessons Learned. Oncologist. 2018 Apr;23(4):399-e33. doi: 10.1634/theoncologist.2017-0682. Epub 2018 Jan 25.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: July 26, 2010
• First Submitted That Met QC Criteria: August 9, 2010
• First Posted (Estimate): August 10, 2010

Study Record Updates

• Last Update Posted (Estimate): April 22, 2015
• Last Update Submitted That Met QC Criteria: April 21, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: cancer; Peutz-Jeghers syndrome; mTOR inhibition
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Skin Diseases; Disease; Gastrointestinal Diseases; Genetic Diseases, Inborn; Intestinal Diseases; Neoplastic Syndromes, Hereditary; Intestinal Polyposis; Hyperpigmentation; Pigmentation Disorders; Melanosis; Lentigo; Neoplasms; Syndrome; Neoplasm Metastasis; Peutz-Jeghers Syndrome; Neoplastic Processes; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: AMCmedonc010; 2010-020451-32 (EudraCT Number)