EORTC ILOC study: Phase II of immunotherapy plus local tumor ablation (RFA or stereotactic radiotherapy) in patients with colorectal cancer liver metastases

Phase 1

Conditions: Metastatic colorectal cancer with Incurable liver metastases
MedDRA version: 21.0Level: LLTClassification code 10052362Term: Metastatic colorectal cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.0Level: PTClassification code 10052358Term: Colorectal cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: SOCClassification code 10029104Term: Neoplasms benign, malignant and unspecified (incl cysts and polyps)System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2017-001375-22-NL

Lead Sponsor: European Organisation for the Research and Treatment of Cancer (EORTC)

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 70

Inclusion Criteria

•Histologically confirmed CRC
•Patients with CRC liver metastases, with/without extrahepatic disease,in which curative treatment is not possible by resection and or local ablation/radiotherapy
•= 18 years of age at time of study entry
•WHO performance status 0 to 1
•Body weight >30kg
Measurable disease according to RECIST 1.1
•Stable disease or partial remission by RECIST 1.1 criteria after at least 3 months systemic therapy for CRC. Patients are eligible following first - or - second line treatment.
Note: if patient receives maintenance treatment after the first line treatment, she/he remains eligible for this study
•Complete responders or partial responders with a 80% or more decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions following last systemic therapy,taking as reference sum of diameters from baseline scan prior to initiation of systemic therapy are excluded as well as patients with almost complete cystic degeneration of liver metastases.
Note: the interval between last dose of systemic treatment to the first dose of the study drugs must be of maximum 8 weeks (in case
bevacizumab was administered as part of the systemic treatment, a min 21days wash out period is required from last administration to planned local ablative treatment initiation)
•Liver metastases amenable to ablation or stereotactic radiotherapy (SBRT) at completion of systemic therapy
•For SBRT: allowing a total ablated volume of at least 25 cm3 &a maximum of 40 cm3 with a max of 2lesions treated with SBRT
•For RFA: allowing a total ablated volume of at least 25 cm3 &a maximum advised volume of 120 cm3
•At least 2measurable liver metastases, or at least 1measurable liver metastasis and 1 measurable extrahepatic lesion should remain untreated by ablation or SBRT to allow response monitoring according to RECIST 1.1 & iRECIST
•Limited extra hepatic disease is allowed, including up to 2extra hepatic metastatic sites,either lung, abdominal, pelvis, bone, or localized lymph node metastases. Each is counted separately as 1site. 2abdominal lesions will be counted as 1extra-hepatic site; 1lung & 1abdominal lesion will be counted as 2sites. Individual extrahepatic lesions should be = 5 cm
•Availability of tumor sample for biomarkers testing (MSI, PDL-1, etc) (archival tissue from primary tumor)
•Adequate normal organ &marrow function before initial systemic treatment as well as baseline as defined below:
•Absolute neutrophil count (ANC) = 1.5 x 109/L (> 1500 per mm3)
•Platelet count = 100 x 109/L (>100,000 per mm3)
•Serum bilirubin = 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in absence of hemolysis or hepatic pathology), who will be allowed only in consultation with physician
•AST (SGOT)/ALT (SGPT) = 5 x institutional upper limit of normal
•Creatinine = 1.5 x institutional ULN or measured or calculated creatinine clearance >40 mL/min by the Cockcroft-Gault formula
•Hemoglobin = 9.0 g/dL at baseline

•PLEASE SEE THE PROTOCOL FOR FURTHER INCLUSION CRITERIA
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 42
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 28

Exclusion Criteria

•Patients with known brain metastases or history of leptomeningeal carcinomatosis
• Hilar liver lesions close to central bile ducts to be treated by RFA
• Prior treatment:
•History of radiation therapy of the liver, upper abdomen or lower thorax
•History of radioembolization of the liver
•Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of durvalumab and tremelimumab.
•Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab, a CTLA-4 including tremelimumab or other checkpoint inhibitors or other immune therapy during the last 12 months
•Any unresolved toxicity NCI CTCAE v 4.0 Grade =2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
•Patients with Grade =2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
•Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician.
•Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab and tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid, or steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
•Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab
•Active or prior documented autoimmune or inflammatory disorders (including inflammatory pulmonary disorders, interstitial lung disease, inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).
•History of allogeneic organ transplant
•History of hypersensitivity to durvalumab, tremelimumab or any excipient
•Uncontrolled intercurrent illness including, but not limited to:
•Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
•Active peptic ulcer disease or gastritis
•Liver cirrhosis CHILD B+, C
•Active bleeding diatheses
•History of primary immunodeficiency
• Cardiac disorders:
• Symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia
•Mean QT interval corrected for heart rate (QTc) =470 ms calculated from 3 electrocardiograms (ECGs) using Frediricia’s Correction
•Female patients who are pregnant or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvaluma

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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