The SIR-Step trial

Prospective, randomized

Primary
Time to first progression (TTP1 overall)

Secondary

• Time to global progression (TTP1 + TTP2), Time to second progression (TTP2), TTP1 liver only
• Progression Free Survival (PFS)
• Overall Survival (OS)
• Safety
• R0 resection rate
• Quality of Life

Exploratory analysis:

• Prediction and evaluation of SIR-Spheres microspheres treatment response (only for Belgian centres)

1. Willing and able to provide written informed consent The regulatory criteria apply.
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 hematological, renal and hepatic function as follows:
    

    Hematological	Neutrophils	> 1.5 x 10 9 /L
    	Platelets	> 100 x 10 9 /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.

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 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 patient 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 1 st line chemotherapy.
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.
13. Angiography revealing abnormal vascularity with reflux of hepatic blood in the stomach, pancreas or intestine.

1st line treatment

Patients will be randomised to receive one of the following protocol treatments:

• 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- 90 Y radioembolization (SIR-spheres injection) + modified LV5FU2 +/- bevacizumab 5 mg/kg over 30 min or +/- cetuximab 250 mg/m² weekly or 500 g/m²
  biweekly or +/- panitumumab 6 mg/kg according its previous use as described in arm A.

Premature stop of inclusion: 06 Mar 2017

UZ Antwerpen, Prof. M. Peeters
UCL St-Luc, Dr. M; Van den Eynde
CHU Montpellier, Pr. B. Guiu

BGDO

Belgium:

1. UZ Antwerpen, Prof. M. Peeters
2. UCL St-Luc, Dr. M; Van den Eynde
3. ULB Erasme, Prof. J-L. Van Laethem
4. Institut Bordet, Dr. A. Deleporte
5. CHU Liège, Dr. M. Polus
6. Grand Hôpital de Charleroi, Dr. J. Carasco
7. ASZ Aalst, Dr. J. Van Erps
8. ZOL Genk, Dr. J. Vannoote
9. AZ Groeninge, Dr. P. Vergauwe

France:

1. CHU Montpellier, Pr. B. Guiu
2. CHU d’Amiens-Picardie, Dr. V. Hautefeuille