Primary objective is to demonstrate a 25% reduction of the active irinotecan metabolite, SN38, in healthy liver tissue in patients with mCRC or other solid tumors as a result of preceding dietary restriction five days in advance. Secondary…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To demonstrate a 25% reduction of the active irinotecan metabolite, SN38, in
healthy liver tissue (without reducing the intra-tumoral SN38 concentration),
24-26 hours after irinotecan administration with preceding dietary restriction
compared to without preceding dietary restriction.
Secondary outcome
- To determine intra-tumoral irinotecan and SN-38 concentrations with and
without preceding dietary restriction.
- To determine the systemic PK parameters of irinotecan in peripheral blood
with and without preceding dietary restriction.
- To determine leukocyte number with and without preceding dietary restriction
- Toxicity of irinotecan with and without preceding dietary restriction.
- Transcriptome analysis of tumor and liver to identify mechanisms responsible
for increased intra-tumoral irinotecan concentrations and decreased side
effects.
Background summary
Currently, more than half of the metastatic colorectal cancer (mCRC) patients
do not benefit (optimally) from intravenously administered irinotecan as second
line treatment. In recent preclinical studies in mice we have shown that the
anti-tumor effects and survival of irinotecan can be enhanced by fasting before
irinotecan treatment. In addition, toxicity may be seriously reduced by
fasting. We have shown that short-term dietary restriction (DR) and fasting are
powerful means to increase acute stress resistance and also protects against
acute oxidative damage in the kidney and liver. While mice are significantly
protected from the side effects of irinotecan chemotherapy after 72 hours of
fasting, intratumoral drug concentrations of the active irinotecan metabolite
SN-38 tend to be higher.
Study objective
Primary objective is to demonstrate a 25% reduction of the active irinotecan
metabolite, SN38, in healthy liver tissue in patients with mCRC or other solid
tumors as a result of preceding dietary restriction five days in advance.
Secondary objectives are safety and systemic and intratumoral irinotecan
pharmacokinetics. Furthermore, transcriptome analysis of tumor and liver will
be performed to identify mechanisms responsible for the protective effect of
dietary restriction.
Study design
Open label randomized two-arm cross-over study. Patients will be admitted to
our hospital for 28 hours after the start of the first and second cycle in
order to perform pharmacokinetic (PK) blood withdrawal, tumor and liver
biopsies. Patients will have DR for five days during one cycle and are allowed
to eat normally during the other cycle. A synthetic diet containing an estimate
of 30% caloric restriction and 70% protein restriction based on the daily
energy requirements calculated by using indirect calorimetry is used for five
days.
Intervention
Treatment with irinotecan 600mg 3-weekly with or without dietary restriction.
Study burden and risks
Patients will be exposed to irinotecan chemotherapy, which is the standard of
care for mCRC and other solid tumors. It is hypothesized that the
study-intervention, DR before (irinotecan chemo-)therapy, results in less side
effects and a better anti-tumor activity. The burden for patients participating
in this study includes 28 hours hospital admission during two cycles,
additional blood withdrawal for PK analyses (during two cycles 12 x 4ml
additional blood withdrawals each, 96 ml in total) and two 18 gauge (G) needle
biopsies (one of healthy liver and one of liver metastasis) during two cycles
(24 hours after the first cycle and 24 hours after the second cycle). Patients
will eat a synthetic diet for 5 consecutive days during one cycle, and they
will have to fill in a diet diary before both cycles. The number of site visits
is comparable to standard treatment with irinotecan chemotherapy, extra are two
visits to dietitian and two times indirect calorimetry. The main risks
anticipated are: a small bleeding risk after the liver biopsies (see appendix
F), and weight loss and general discomfort due to DR.
Groene Hilledijk 301
Rotterdam 3075 EA
NL
Groene Hilledijk 301
Rotterdam 3075 EA
NL
Listed location countries
Age
Inclusion criteria
*Metastatic colorectal cancer or other solid tumors
*Eligible for treatment with irinotecan 600 mg 3-weekly
*Age * 18 years
*BMI 20-30kg/m2
*WHO performance status 0-1
*Written informed consent
*Adequate renal function, i.e. serum creatinin < 2 x ULN and creatinin clearance > 45 mL/min
*Patients with safely accessible liver metastases and healthy liver tissue
*Adequate coagulation status (PT-INR <1.5, APTT<1.5xULN, on the day of biopsy in patients using coumarines: PT-INR<1.5, Hb>6mmol/L, trombocyten > 100x10 9)
Exclusion criteria
*Previous treatment with irinotecan within the last 6 months
*Pregnant or lactating patients; patients with reproductive potential must use a reliable method of contraception (excluding oral contraceptives), if required.
*Serious illness or medical unstable condition prohibiting adequate treatment and follow-up.
*History of bleeding disorders (such as hemophilia) or bleeding complications from biopsies, dental procedures or surgeries.
*Patients using any anti-coagulant medication which cannot be safely stopped or counteracted at the time of biopsy
*Unable or unwilling to stop the use of (over the counter) medication of (herbal) supplements which can interact with irinotecan (e.g. by induction or inhibition of CYP3A4 (see Appendix B))
*Unable or unwilling to abstain from grapefruit or grapefruit juice during the study
*Bilirubin > 1.5 x ULN, ASAT > 5x ULN, ALAT >5x ULN
*Uncontrolled hypertension, despite medical treatment
*Cows milk and/or soy allergy and/or lactose intolerance
*Patients using insulin
*Patients with hyperventilation
*Patients unable of unwilling to fill in a food diary
*Patients using oxygen and not able to stop for 30 minutes
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| CCMO | NL55597.078.15 |
| OMON | NL-OMON29351 |