The primary objective is to study whether treatment with the mTOR inhibitor Everolimus results in an objectable change in phosphorylation of the selected downstream effectors 4eBP1 and p70S6K in human prostate cancer biopsies. A secondary objective…
ID
Source
Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
In order to investigate the mTOR inhibition in the prostate by Everolimus and
the possible synergistic interaction with low dose, metronomic, oral
Cyclophosphamide treatment, phophorylation of 4eBP1 and p70S6K will be assessed
in prostate biopsies of prostate cancer patients.
Secondary outcome
PSA response
Toxicity of the combined Everolimus and Cyclophosphamide treatment
Background summary
progress has been made in the last decades in the treatment of other prevalent
solid tumors, such as breast and colorectal cancer. New treatment modalities
and new drug regimens have been developed which resulted in increased median
survival and better quality of life of patients affected by these diseases.
However, the prognosis of patients with prostate cancer, which is irresponsive
to castration, is very poor and has not changed in recent years. There is an
urgent need for new treatment modalities that will improve the quality of life
and life span of prostate cancer patients.
Study objective
The primary objective is to study whether treatment with the mTOR inhibitor
Everolimus results in an objectable change in phosphorylation of the selected
downstream effectors 4eBP1 and p70S6K in human prostate cancer biopsies.
A secondary objective is to study tolerability and PSA response of the
combination of continuous low-dose cyclophosphamide and Everolimus.
Study design
This is a phase II study.
Patients with a rising PSA under castrate serum testosterone levels and
previously treated with Docetaxel might be eligible for this study. Baseline
investigations will include prostate biopsies and blood analysis, physical
examination, recording of medical history, concomitant drug use and ECOG
performance status (Appendix 2). After 2 weeks of lead-in Everolimus treatment,
prostate biopsies and blood analysis and physical examination will be performed
and toxicity score, concomitant drug use and ECOG performance status will be
recorded. Everolimus treatment will be combined with cyclophosphamide once
daily 50 mg from week 3 on. Patients will visit their physician every 2 weeks
during the first 8 weeks of treatment followed by every 4 weeks, for history
taking, physical examination (including ECOG performance status), laboratory
tests and recording of toxicity. In order to monitor for, subclinical,
non-infectious pneumonitis, a Chest X-ray will be made every 8 weeks during
treatment. Patients will continue this treatment until PSA progression, disease
progression or > grade 3 toxicity.
Intervention
Everolimus treatment will be prescribed at two dose levels. The first ten
included patients will be treated at a dose of 5 mg once daily. In case of * 20
% Grade 3 toxicity after 6 weeks of treatment (2 weeks Everolimus single agent
and 4 weeks combined Everolimus and cyclophosphamide treatment), the Everolimus
dose will be increased to 10 mg per day for the next 10 patients.
Besides, prostate biopties will be taken prior- and after four weeks of
Everolimus alone treatment.
Study burden and risks
Patients wil visit their physician every two weeks during the fisrst eight
weeks and every four weeks thereafter. There will be more laboratort tests then
there would be outside this study. There is a significant chance that patients
will experience side effects of the treatment. In a pilot studie to combination
of Everolimus and Cyclophosphamide lymphopenia, neutropenia, thrombopenia,
anaemia and fatiue were most frequently described. Besides, prostate biopties
will be taken prior- and after four weeks of Everolimus alone treatment. Some
patients describe taking prostate biopsies as painfull. Possible risks include
bleeding or infection of the prostate.
Benefit for the patient might be a palliative effect of the treatment or
complaints might be postponed.
Plesmanlaan 121
1066 CX AMsterdam
Nederland
Plesmanlaan 121
1066 CX AMsterdam
Nederland
Listed location countries
Age
Inclusion criteria
- Prostate cancer diagnosis and a rising PSA under castrate serum testosterone levels (2 rises
in a period of at least 3 months), PSA > 10ng/ml.
- At least one prior cycle of Docetaxel treatment.
- ECOG performance status 0-2.
- Locally accessible prostate cancer for TRUS-guided biopsies.
- Written informed consent.
- Laboratory requirements:
a) Hematology:
* Hemoglobin > 5 mmol/L
* Platelet count * 100,000/*L
* No leucopenia
b) Hepatic function:
* AST and ALT * 2.5 times upper limit of normal (ULN)
* Bilirubin * 1.5 times ULN
c) Renal function:
* Calculated GFR (Cockroft) * 60 ml/min
* PT/PTT normal (no anticoagulants)
- Fertile patients must use effective contraception during and for 6 months after completion of
study therapy.
Exclusion criteria
- Small cell pathology.
- Allergy to Everolimus or cyclophosphamide or components of Afinitor ® or Endoxan ®.
- Co-medication interfering with CYP3A4 activity.
- Gastrointestinal (GI) disease, condition, or symptoms that may significantly impair GI function
and alter the absorption of Everolimus, including any of the following:
o Ulcerative disease
o Vomiting
o Diarrhea
o Malabsorption syndrome
- Other active malignancy or malignancy at * 30% risk for relapse after completion of therapy,
except nonmelanoma skin cancer .
- Recent (within 2 weeks) surgery.
- Uncontrolled concurrent illness including, but not limited to, any of the following:
o Ongoing or active infection (e.g., bacterial, viral or fungal)
o Severely impaired lung function
o Uncontrolled diabetes (fasting serum glucose > 1.5 times ULN)
o Liver disease (e.g., cirrhosis, chronic active hepatitis, or chronic persistent hepatitis)
o Symptomatic congestive heart failure
o Unstable angina pectoris
o Cardiac arrhythmia
- Lower urinary tract obstruction not treated with bladder catheterisation.
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 | EUCTR2010-018772-24-NL |
| CCMO | NL31523.031.10 |