To determine the efficacy (as measured by objective tumor response) of single agent everolimus in the treatment of advanced malignancies or high risk polyps of patients known with PJS .
ID
Source
Brief title
Condition
- Other condition
- Chromosomal abnormalities, gene alterations and gene variants
- Miscellaneous and site unspecified neoplasms benign
Synonym
Health condition
Peutz-Jeghers syndroom
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine the efficacy(as measured by objective tumor response) of single
agent everolimus in the treatment of advanced malignancies or high risk polyps
of patients known with PJS
Secondary outcome
*To determine the overall survival of patients treated with everolimus in
patients with advanced malignancies in PJS.
*To evaluate the time to progression
*To evaluate the toxicity profile of everolimus in PJS patients
*To determine the association between drug levels of everolimus and objective
clinical response
*To determine the influence of everolimus on the proliferation signaling mTOR
pathway and its downstream targets in the tumor and blood prior and during
treatment with the use of established biomarkers.
Background summary
Peutz-Jeghers syndrome is a rare cancer predisposition syndrome characterized
by the development of gastrointestinal polyps and mucocutaneous pigmentation
abnormalities.
The syndrome was first described in 1921 by the Dutch physician Dr Johannes
Peutz working in The Hague. The syndrome was further characterized by Dr.
Harold Jeghers in 1949, who recognized that *a single pleiotropic gene was
responsible for both characteristics, the polyps and the spots.* PJS is an
autosomal dominant cancer-prone gastrointestinal polyposis disorder. The
disorder presents in 1 per 50,000 to 1 per 200,000 newborns. Due to the rarity
of the syndrome, clinical accounts of pedigrees afflicted by the syndrome are
rare, and accurate documentation of the increased cancer-risk is therefore
complex. Based on large cohort studies, patients are estimated to display an
18-fold increased cancer risk over the normal population.
Most patients with Peutz-Jehgers disease 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
most common type of malignancies are: pancreatic, gastrointestinal, colorectal,
ovarian, and breast carcinomas. Even though in this group of patients active
surveillance is performed regularly, there still is a high incidence of
advanced disease.
Everolimus is an oral selective m-TOR inhibitor. Although aberrant mTOR
activity is probably related to pre-malignant lesions in Peutz-Jeghers syndrome
(PJS), the role in established cancer in unknown, till recently. In a recent
case of a patient with PJS suffering of advanced pancreatic cancer we observed
at our institution, an impressive response to oral treatment with everolimus
monotherapy. Therefore mTOR inhibition might be a potential anti-cancer
treatment in Peutz-Jeghers related malignancies and needs confirmation in a
larger patient cohort.
Study objective
To determine the efficacy (as measured by objective tumor response) of single
agent everolimus in the treatment of advanced malignancies or high risk polyps
of patients known with PJS .
Study design
Phase II non randomized, open label, multiple centre study . In this pilot
study we will treat all patients known with PJS and diagnosed with advanced
malignancies or high risk polyps with everolimus 10mg daily.
Pharmacokinetic/dynamic studies will be performed as well.
Intervention
Treatment with everolimus 10mg daily until disease progression or occurance of
unacceptable toxicity. For cohort 2 treatment of a maximum of 12 months.
Study burden and risks
The use of low-dose everolimus hasbeen applied for many years in the treatment
of kidney and heart transplants. Since recently, everolimus has also been
approved for the treatment of renal cell carcinoma with very limited side
effects.
Therefore the burden for the patient by everolimus is very low, especially
compared with standard therapy for advanced malignancies, which is usually the
combined use of chemotherapy. The study-related examinations are similar to
standard systemic treatment of advanced malignancies and therefore provide no
increased risk to the participating patients. Patients can choose whether they
wish to participate in additional investigations like endoscopies and
tumorbiopsies. The risks of these voluntary investigations are considerably
small. Patients with high risk polyps will have endoscopic examinations or a
magnetic resonance bowel enteroclysis performed after 12 months instead of once
every two years.
Postbus 22700
1100DE Amsterdam
NL
Postbus 22700
1100DE Amsterdam
NL
Listed location countries
Age
Inclusion criteria
Two cohorts of PJS patients will be included.
Cohort 1: Advanced malignancy
Cohort 2: High risk polyps
*Known Peutz-Jeghers disease (with LKB1 mutation)
*Advanced malignancy of any tumor type, not suitable for surgery at the time of study enter
*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
*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
*ECOG/ WHO performance 0-2
*Age > 18 years
*Life expectancy > 3 months
*Adequate renal function (defined as creatinine < 150 *mol/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) E.
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:
a. X-ray, physical exam > 20 mm
b. Spiral CT scan > 10 mm
c. 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
Exclusion criteria
*Presence 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
*Patients who are pregnant or lactating
*Patients who are of childbearing potential who do not agree to use a reliable contraceptive method throughout the study
*Patients who do have serious concomitant systemic disorder that would compromise the safety of the patient, at the discretion of the investigator
*Patients who are not willing to sign the Signed informed consent according to ICH/GCP, IRB approval obtained prior to treatment
*Patients who do have uncontrolled symptomatic hyperglycaemia
* Symptomatic PJ-polyps, defined as polyps likely to be responsible/causal for the abdominal
symptoms the patient presents with.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-020451-32-NL |
| ClinicalTrials.gov | NCT01178151 |
| CCMO | NL33427.018.10 |