We propose to conduct a randomised phase III trial evaluating a maintenance strategy comparing hepatic arterial injection of Yttrium-90 resin microspheres plus continuing simplified chemotherapy with/without targeted therapy (bevacizumab, or…
ID
Source
Brief title
Condition
- Metastases
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary end-points:
- Time to first progression (TTP1 overall)
Secondary outcome
Secondary end-points:
- Time to global progression (TTP1 + TTP2), Time to second progression (TTP2),
TTP1 liver only
- Progression Free Survival (PFS)
- Overall Survival (OS)
- Safety
- Ro resection rate
- Quality of Life
Exploratory analysis:
- Prediction and evaluation of SIR-Spheres treatment response (only for Belgian
centres)
Background summary
Zie protocol pagina 9-10
Study objective
We propose to conduct a randomised phase III trial evaluating a maintenance
strategy comparing hepatic arterial injection of Yttrium-90 resin microspheres
plus continuing simplified chemotherapy with/without targeted therapy
(bevacizumab, or cetuximab or panitumumab) versus continuing simplified
chemotherapy with/without targeted therapy (bevacizumab, or cetuximab or
panitumumab) alone for patients with liver only or liver dominant unresectable
mCRC with controlled disease (SD or PR according RECIST1.1 criteria) after 3 to
6 months of chemotherapy induction. The aim of the study is to investigate
whether an intensified maintenance treatment consisting of SIRT + simplified
maintenance chemotherapy has a benefit in terms of time to progression (TTP)
compared to simplified chemotherapy maintenance alone, in patients with
controlled disease after 3 to 6 months of induction therapy.
We would like to demonstrate the feasibility and safety of this approach and to
investigate if this strategy has the potential to increase the outcome of the
patient.
Study design
Design of the study
Chemonaive patients with exclusive or dominant unresectable liver metastases
from CRC will be identified at diagnosis for potential inclusion in the study.
After 3 to 6 months of chemotherapy induction +/- targeted therapy, patients
will be screened and tumor response assessed. Patients presenting controlled
disease (partial response or stable disease according to RECIST1.1 (30)) and
persistent unresectable metastatic liver disease will be eligible for trial
inclusion. The timing between the last cycle of the induction chemotherapy and
trial inclusion must not exceed 6 weeks. In order to facilitate the screening
procedure and inclusion of the patient in the trial and avoid chemotherapy
interruption or inadequate timing before enrollment of the patient (see
inclusion criteria), it is highly recommended to perform a disease evaluation
every 2 to 3 months during the induction treatment period.
Liver unresectability would be determined at diagnosis and subsequently in the
disease evolution by an experienced liver surgeon in a multidisciplinary
meeting. Resectability means the potential complete surgical clearance (+/-
radiofrequency ablation) of all detectable liver lesions with tumor-free
margins and compatible with an adequate hepatic reserve. Practically, bilateral
tumor location, number and location of lesions, and inadequate hepatic reserve
remains the main decisional factors. The possibility of a two-stage hepatectomy
is left at the discretion of the investigator.
At inclusion, patient will be randomized between a hepatic arterial injection
of Yttrium-90 (HAI-90Y) resin microspheres plus continuation of 5FU/LV
with/without targeted therapy based on previous use as part of induction
therapy, or continue 5FU/LV with/without targeted therapy alone until
progression. Groups will be stratified according to previous use of targeted
therapy and oxaliplatin or/and irinotecan-based chemotherapy (induction chemo),
and the presence or absence of extra-hepatic metastases.
For response evaluation, whole body enhanced spiral CT-scan will be performed
every 2-3 months. In an exploratory analyses and for Belgian selected centres
only (optional) , FDG-PET scan will be performed at baseline, at week 6-8 and
12-14 post start of maintenance treatment to assess metabolic response. At
progression, according to RECIST 1.1 criteria, oxaliplatin or irinotecan will
be reintroduced depending on its previous use during the induction chemotherapy
treatment. In case oxaliplatin cannot be reintroduced (persistent
neurotoxicity) second line chemotherapy will be mandatory. If oxaliplatin and
irinotecan are used concomitantly (triplet regimen), choice of chemo scheme
reintroduction is left to investigator*s decision.
Study entry is defined as the date that the randomization has been done. No
patient may enter the study without signing the informed consent document. The
screening period is defined as the period before inclusion when the patient
meets the eligibility criteria to be included in the trial. Subjects are
randomized after all eligibility criteria have been confirmed. A subject is
considered to be randomised into the study once a subject identification number
has been assigned to the subject. In order to be considered eligible for the
study, patients must fulfil the inclusion and exclusion criteria specified in
3.3 below.
Study design and defined end-point is summarized in figure 1, protocol page 11.
Intervention
ARM A: Modified LV5FU2 as described below (6.2.1) D1-2 +/- bevacizumab 5 mg/kg
over 30 min or +/- cetuximab 250 mg/m² weekly or 500 mg/m² biweekly or +/-
panitumumab 6 mg/kg (according its previous use) every 2 weeks.
ARM B: HAI-90Y radioembolization (SIR-spheres injection) + modified LV5FU2 +/-
bevacizumab 5 mg/kg over 30 min or +/- cetuximab 250 mg/m² weekly or 500 mg/m²
biweekly or +/- panitumumab 6 mg/kg according its previous use as described in
arm A.
Study burden and risks
Described in Dutch (above)
Wilrijkstraat 10
Edegem 2650
BE
Wilrijkstraat 10
Edegem 2650
BE
Listed location countries
Age
Inclusion criteria
1. Willing and able to provide written informed consent
2. Histologically confirmed adenocarcinoma of the colon or rectum, with or without primary tumour in situ. Unequivocal and measurable (RECIST 1.1) CT evidence of liver metastases which are not treatable by surgical resection or local ablation with curative intent at the time of trial entry.
3. Partial response or stable disease (RECIST 1.1 criteria, controlled metastatic disease) after chemotherapy induction with oxaliplatin and/or irinotecan- based induction chemotherapy (doublet or triplet combinations) +/- targeted therapies during 3 to 6 months.
4. Trial inclusion must be performed between 3 and 6 months since the date of the first course of chemotherapy (induction) administration.
5. Limited extra-hepatic metastases in the lung and/or lymph nodes are permitted. Metastases in the lung must either be not more than five nodules in number with no nodule more than 1 cm in diameter or 1 single lesion of up to 1.7 cm in diameter. Involvement of lymph nodes in 1 single anatomic region (pelvis, abdomen or chest) are permitted provided their longest diameter measures less than 2 cm.
6. All imaging evidence used as part of the screening process must be within 28 days prior to randomisation.
7. Suitable for either treatment regimen as determined by clinical assessment undertaken by the Investigator.
8. Patients may have received adjuvant chemotherapy or (neo-) adjuvant chemo-radiotherapy to the pelvis, provided the last dose of chemotherapy was administered at least 6 months prior to begin chemotherapy induction. Previous radiotherapy to the pelvis is not an exclusion criterion.
9. WHO performance status 0 * 1
10. Adequate haematological, renal and hepatic function as follows:
Haematological
Neutrophils > 1.5 x 109/L
Platelets > 100 x 109/L
Renal
Creatinine < 1.5 x ULN
Hepatic
Bilirubin 1.0 X ULN
Albumin * 30 g/L
ALT 5.0 x ULN
AST 5.0 x ULN
LDH 2.5 x ULN
The date of blood tests must be within 28 days prior to randomisation.
11. Aged 18 years or older.
12. Female patients must either be postmenopausal, sterile (surgically or radiation- or chemically-induced), or if sexually active using an acceptable method of contraception.
13. Male patients must be surgically sterile or if sexually active and having a pre-menopausal partner must be using an acceptable method of contraception.
14. Life expectancy of at least 3 months without any active treatment
Exclusion criteria
1. Evidence of ascites, cirrhosis, portal hypertension, main portal venous tumour involvement or thrombosis as determined by clinical or radiologic assessment.
2. More than 6 weeks since the last chemotherapy administration before trial inclusion.
3. Previous radiotherapy delivered to the upper abdomen.
4. Non-malignant disease that would render the patient unsuitable for treatment according to this protocol.
5. Prior major liver resection: remnant liver < 50% of the initial liver volume. Patient with a biliary stent can be included.
6. Liver tumor involvement > 80% before study inclusion (not at diagnosis but when trial inclusion for the patent is planned).
7. Resectable metastatic disease at trial inclusion.
8. Progressive disease during first-line metastatic chemotherapy. Adjuvant chemotherapy for colorectal cancer is not an exclusion criterion provided that it was completed more than 6 months prior to start of 1st line therapy.
9. No oxaliplatin or irinotecan use during the first 3 to 6 months induction chemotherapy.
10. Pregnant or breast feeding.
11. Concurrent or prior history of cancer other than adequately treated non melanoma skin cancer or carcinoma in situ of the cervix
12. Severe allergy to non-ionic contrast agents which would prevent contrast media use during the study.
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 |
|---|---|
| Other | 01895257 |
| CCMO | NL55801.058.15 |