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

Primary Purpose

Peutz-Jeghers Syndrome, Neoplastic Processes, Neoplasm Metastasis

Status

Withdrawn

Phase

Phase 2

Locations

Netherlands

Study Type

Interventional

Intervention

Everolimus

About this trial

This is an interventional treatment trial for Peutz-Jeghers Syndrome focused on measuring Peutz-Jeghers syndrome, mTOR inhibition, cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Academic Medical Center
Erasmus Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

afinitor

Arm Description

10mg afinitor daily orally

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.

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

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

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

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.

Full Information

NCT ID

NCT01178151

First Posted

July 26, 2010

Last Updated

April 21, 2015

Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Collaborators

Erasmus Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT01178151

Brief Title

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

Acronym

EVAMP

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2015

Overall Recruitment Status

Withdrawn

Why Stopped

No patients

Study Start Date

October 2010 (undefined)

Primary Completion Date

April 2015 (Actual)

Study Completion Date

April 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Collaborators

Erasmus Medical Center

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Peutz-Jeghers Syndrome, Neoplastic Processes, Neoplasm Metastasis

Keywords

Peutz-Jeghers syndrome, mTOR inhibition, cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

afinitor

Arm Type

Experimental

Arm Description

10mg afinitor daily orally

Intervention Type

Drug

Intervention Name(s)

Everolimus

Other Intervention Name(s)

Afinitor, RAD001, everolimus

Intervention Description

10mg daily orally

Primary Outcome Measure Information:

Title

To determine the response rate of Everolimus in patients with advanced cancer and PJS.

Description

Determined with regular radiological scans once every 9 weeks and measured following RECIST 1.1

Time Frame

During treatment, expected avarage of 12 months

Secondary Outcome Measure Information:

Title

To determine the overall survival of PJS patients treated with everolimus for advanced malignancies

Description

The time between date of entering the study and date of death will be collected.

Time Frame

avarage of 18 months

Title

To determine the time to progression of PJS patients treated with everolimus for advanced malignancies.

Description

Determined with regular radiological scans once every 9 weeks and measured following RECIST 1.1

Time Frame

During treatment, expected avarage of 12 months

Title

To determine the safety and toxicity of Everolimus in this patient population

Description

Number of Participants with Adverse Events determined by the CTCAE 4.0 as a Measure of Safety and Tolerability

Time Frame

During treatment, expected avarage of 12 months

Title

To determine if there is an association between measured drug blood levels and treatment outcome measured as response to treatment determined by RECIST

Description

Drug trough levels will be taken once every 3 weeks and stored frozen until measurement at the end of the study

Time Frame

During treatment, expected avarage of 12 months

Title

Description

Time Frame

During treatment, expected avarage of 12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Heinz-Josef Klumpen, MD

Organizational Affiliation

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Official's Role

Principal Investigator

Facility Information:

Facility Name

Academic Medical Center

City

Amsterdam

ZIP/Postal Code

1105AZ

Country

Netherlands

Facility Name

Erasmus Medical Center

City

Rotterdam

ZIP/Postal Code

3000 CA

Country

Netherlands

12. IPD Sharing Statement

Citations:

PubMed Identifier

29371475

Citation

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.

Results Reference

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

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