| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| MICROSATELLITE STABLE (MSS) COLORECTAL CANCER WITH LIVER-DOMINANT METASTASIS |
|
| E.1.1.1 | Medical condition in easily understood language |
METASTATIC COLORECTAL CANCER WITH SPECIFIC MOLECULAR PROFIL
(MSS) AND LIVER-DOMINANT METASTASIS |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Evaluate the progression-free survival at 9 months (according to RECIST 1.1) according to the investigator. |
|
| E.2.2 | Secondary objectives of the trial |
- safety (NCI-CTCAE v 4.0)
- median progression-free survival (RECIST 1.1 and immune-RECIST (iRECIST))
- liver specific progression-free survival (RECIST 1.1 and iRECIST)
- extra-hepatic progression-free survival (RECIST 1.1 and iRECIST)
- overall survival
- overall best response rate (RECIST 1.1 and iRECIST)
- response rates at weeks 9, 18 and 27 (hepatic and non-hepatic target lesions)
- early tumor shrinkage
- depth of tumor response
- secondary resection rate
- time to treatment strategy failure
- biomarker analyses (ancillary studies) |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The ancillary study on biological samples (blood and stool) and tumour samples (primary tumours) will consist at least of analysis of histological (immune score, immunohistochemistry of PD-L1 and PD-L2), phenotypal (circulating lymphocytes and gut microbiota) and molecular biomarkers
(circulating tumour DNA, mutational load, expression and/or amplification of PD-L1 and PD-L2). The primary objective of these
studies is to identify prognostic biomarkers or predictive biomarkers of response to therapy with an immune checkpoint inhibitor. We are
seeking to detect an association between the hypermutated characteristic, a high immune response and clinical response to anti-PD1
therapy (atezolizumab), as described in other tumours. |
|
| E.3 | Principal inclusion criteria |
- Age ≥18 years
- Histologically proven mismatch repair proficient metastatic colorectal cancer (pMMR and/or MSS)
- Liver-dominant disease with up to 6 extrahepatic lesions (only peritoneal lesions are not allowed) if asymptomatic and without organ dysfunction.
- Measurable disease according to RECIST 1.1
- Patient with initially unresectable disease according to the local multidisciplinary team and eligible for radioembolization according to the radiologist's opinion
- Tumor volume < 50 % of total liver volume
- No prior oncologic treatment for metastatic disease (i.e. chemotherapy, radiotherapy or investigational drug). Patients may have received adjuvant chemotherapy or (neo) adjuvant radiochemotherapy to the pelvis (tumor of the rectum), but the last dose of chemotherapy/radiotherapy must be administered at least 6 months prior to entry into this study. Analgesic radiotherapy of metastasis is permitted except on hepatic lesions and must be completed at least 14 days before inclusion.
- WHO performance status ≤ 1
- Estimated life expectancy ≥ 3 months
- Adequate hematological function: with neutrophils ≥ 1,500 /mm3, platelet count ≥ 100,000/mm3, hemoglobin > 9 g/dL (5,6 mmol/l)
- Adequate hepatic function: hepatic transaminases (ASAT and ALAT) ≤ 5 x UNL, total bilirubin ≤ 2 x UNL, alkaline phosphatase ≤ 5 x UNL
- Adequate renal function: creatinine clearance ≥ 50 ml/min according MDRD (Modification of Diet in Renal Disease)
- Patient affiliated to a social security system Information provided to patient and signature of the informed consent form by patient and the investigator
|
|
| E.4 | Principal exclusion criteria |
- Active infection still requiring intravenous antibiotics on the first scheduled day of protocol treatment
- Symptomatic or untreated central nervous system metastasis
- Medical history of other concomitant or previous malignant disease, except adequately treated in situ carcinoma of the uterine cervix, basal or squamous cell carcinoma of the skin, or cancer in complete remission for ≥ 5 years,
- Other malignancy in the 5 years prior to inclusion in the study, except for localized cancer in situ, basal or squamous cell skin cancer
- Confirmed peritoneal carcinomatosis (lesions detectable on CT-scan and/or MRI)
- Active autoimmune disease or inflammatory bowel disease
- Bone marrow allograft or solid organ transplant history
- History of idiopathic pulmonary fibrosis, drug-induced pneumonitis or evidence of active pneumonitis on screening chest CT-scan
- Positive tests for HIV or other immunodeficiency syndromes
- Active hepatitis B or hepatitis C.
1 - If patient has HBV, meets the following criteria as applicable to the infection type to be eligible: for patients with inactive/asymptomatic carrier, chronic, or active HBV: HBV DNA < 500 IU/mL (or 2500 copies/mL) at screening. Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV DNA should be managed per treatment guidelines. Patients receiving antivirals at Screening should have been treated for > 2 weeks prior to enrollment and should continue treatment on study.
2 - For patients with HCV : to be eligible, patients with detectable HCV RNA should remain on continuous, effective antiviral therapy during the study.
- Active tuberculosis
- No contraindication to angiography and selective hepatic catheterization such as bleeding diathesis or coagulopathy with serious bleeding risk that is not correctable by usual therapy of hemostatic agents. Patients on anticoagulant therapy may be included but must be on low-molecular-weight heparin (excluding VKA and NOACs) and must be stopped 24 hours before invasive procedures according to usual recommendations (SIRT)
- Significant presence of ascites, cirrhosis, portal hypertension, main portal venous tumor involvement or thrombosis on clinical or radiological evaluation Previous radiotherapy in the upper abdominal region (liver or liver vessels in the radiation field)
- If primary tumor is non-resected, it must be asymptomatic
- Long-term immunosuppressant therapy (patients requiring corticosteroid therapy are eligible if they receive a dose equivalent to no more than 10 mg of prednisone equivalent dose per day, and corticosteroid administration is permitted by a route resulting in minimal systemic exposure (cutaneous, rectal, articular, ocular or inhalation) is authorized)
- Partial or complete DPD deficiency
- Known hypersensitivity to any components of bevacizumab, Chinese Hamster Ovary cell products or other recombinant human or humanized antibodies and any other contraindications to the use of investigational medicinal products
- Allergy to contrast agents that do not allow radioembolization to be performed
- Uncontrolled hypertension (blood pressure > 150 mm Hg and/or diastolic blood pressure > 100 mm Hg)
- Clinically significant cardiovascular disease, for example cerebrovascular accidents ≤ 6 months prior to the start of study treatment, myocardial infarction ≤ 6 months prior to the start of study treatment, unstable angina, congestive heart failure of NYHA (New York Heart Association Functional Classification) grade 2 or higher, or severe cardiac arrhythmia not controlled by drug therapy or which may interfere with study treatment
- Significant vascular disease (e.g. aortic aneurysm requiring surgery or arterial thrombosis) within 6 months prior to initiation of study treatment
- Venous thromboembolic disease within 3 months prior to initiation of study treatment
- Surgical procedure (including surgical biopsy, any surgical resection, or other major surgery) or significant traumatic injury within 28 days prior to start of study treatment, or planning major surgery during the study.
- History of abdominal fistula, gastrointestinal (GI) perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to start of study treatment
- Unhealing decaying wound, active ulcer, or untreated bone fracture
- Proteinuria ≥ 2+ by urine dipstick unless a 24-hour urine protein < 1 g of protein is demonstrated
- Lack of effective contraception in patients (male and/or female) at risk of reproduction, pregnant or breastfeeding women and women at risk of reproduction who have not had a pregnancy test. (Women of childbearing potential should agree to use a method of contraception during treatment of the trial and at least 5 months following the last dose of atézolizumab).
- Persons deprived of freedom or under guardianship
- Inability to undergo medical follow-up of the study for geographical, social or psychological reasons |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival at 9 months: percentage of patients alive and without a radiological progression (whatever the type of radiological progression: hepatic or extra-hepatic) 9 months after inclusion (using RECIST v1.1 criteria) according to the investigator |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 months after last inclusion |
|
| E.5.2 | Secondary end point(s) |
- Safety: adverse events will be graded according to the NCI-CTCAE v 4.0 criteria before each cycle.
- Median progression-free survival: progression-free survival (PFS) will be defined as the time between inclusion date and the first radiological progression (whatever the type of radiological progression: hepatic or extra-hepatic, according to RECIST 1.1 and iRECIST criteria) or death (whatever occurs first). Patients alive and without progression will be censored at date of last news.
- Liver specific progression-free survival: PFS will be defined as the time between inclusion date and the first radiological hepatic progression (according to RECIST 1.1 criteria) or death (whatever occurs first). Patients alive and without hepatic progression will be censored at date of last news.
- Extra-hepatic progression-free survival: PFS will be defined as the time between inclusion date and the first radiological extra-hepatic progression (according to RECIST 1.1 criteria) or death (whatever occurs first). Patients alive and without extra-hepatic progression will be censored at date of last news.
- Overall survival: overall survival will be defined as the time between inclusion date and death (any cause). Patients alive will be censored at date of last news.
- Overall best response rate: best response according to RECIST v1.1 and iRECIST will be evaluated regarding CT-scans done during the treatment period.
- Response rates at weeks 9, 18 and 27: response (partial or complete responses) according to RECIST v1.1 and iRECIST for hepatic and non-hepatic target lesions.
- Early tumor shrinkage: early tumor shrinkage will be defined as a response >20% (according to RECIST v1.1 and iRECIST) at week 9.
- Depth of tumor response: depth of tumor response will be defined as the percentage of tumor shrinkage observed at the lowest point (nadir according to RECIST v1.1 and iRECIST).
- Time to treatment strategy failure: is defined as the time between inclusion and the date of definitive stop of the treatment strategy.
- Secondary resection rate: will be defined as secondary liver resection (R0 or R1). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy endpoint up to 3 years
Safety endpoint : From Baseline up to 10 weeks after last administration |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| last visit of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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