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

*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 treatment, 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 &amaximum 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

*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 durvalumab + tremelimumab combination therapy.
*Any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up
schedule; those conditions should be discussed with the patient before
registration in the trial
Important note: All eligibility criteria must be adhered to, in case of
deviation discussion with Headquarters and study coordinator is mandatory.