| Eligibility |
Inclusion Criteria:
Subject must meet all of the following applicable inclusion criteria to participate in this
study:
1. Histologically/cytologically confirmed diagnosed intrahepatic cholangiocarcinoma
2. Measurable disease based on RECIST 1.1 and have 1 or more radiologic features
compatible with high risk (for resection and recurrence) but still considered
technically resectable per multidisciplinary tumor board (Surgical oncologist,
radiologist and medical oncologist minimum) meeting. High risk features would include
at least 1 of the following criteria-
• A large tumor (> 5cm) that would benefit from preoperative tumor shrinkage with
systemic therapy
- T1b-T4 tumor thought to be technically resectable
- Multifocal tumors/ a tumor with satellite lesions confined to the same lobe,
thought to be technically resectable
- Suspicious or involved lymph nodes (N1) thought to be technically resectable
- Tumor with any vascular involvement/invasion considered technically resectable
- No extrahepatic metastases
3. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this
protocol. Written informed consent and any locally required authorization (e.g.,
Health Insurance Portability and Accountability Act in the US) obtained from the
patient/legal representative prior to performing any protocol-related procedures,
including screening evaluations.
4. Adult male or female age >18 years at time of study entry
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
6. Life expectancy of > 6 months
7. Body weight >30 kg
8. Adequate normal organ and marrow function as defined below:
- Hemoglobin = 10.0 g/dL
- Absolute neutrophil count (ANC =1.5 x 109/L (> 1500 per mm3)
- Platelet count =100 x 109/L (>75,000 per mm3)
- Serum bilirubin =1.5 x institutional upper limit of normal (ULN). This will not
apply to patients with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis
or hepatic pathology), who will be allowed only in consultation with the sponsor.
- AST (SGOT)/ALT (SGPT) =2.5 x institutional upper limit of normal Measured
creatinine clearance (CL) >60 mL/min or Calculated creatinine clearance CL>60
mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour
urine collection for determination of creatinine clearance
9. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have
been amenorrhoeic for 12 months without an alternative medical cause. The following
age-specific requirements apply:
- Women <50 years of age would be considered post-menopausal if they have been
amenorrhoeic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).
- Women =50 years of age would be considered post-menopausal if they have been
amenorrhoeic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy).
10. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.
11. Provide archival tumour tissue sample or newly obtained core or excisional biopsy of a
previously unirradiated tumour lesion. Tissue blocks are preferred but unstained cut
slides acceptable. In addition, should be open to undergoing a biopsy after at least 2
cycles of therapy. Patients who do not undergo surgical resection after 4 cycles will
be advised to undergo another biopsy.
Exclusion Criteria:
1. Has had previous local (surgery, radiation, embolizing procedure) or systemic therapy
for borderline resectable intrahepatic cholangiocarcinoma.
2. Participation in another clinical study with an investigational product during the
last 3 months.
3. Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study.
4. Has ampullary cancer, extrahepatic cholangiocarcinoma or gall bladder cancer.
5. Patients with distant extrahepatic metastatic disease including distant (non-regional
lymph nodes). NOTE: Regional lymph nodes depend on tumor site; for left sided lesions,
regional lymph nodes include inferior phrenic, hilar and gastrohepatic lymph nodes.
For right sided lesions, regional lymph nodes include hilar periduodenal and
peripancreatic lymph nodes.
6. Has any other histologic subtype except adenocarcinoma or mixed histology with
adenocarcinoma/hepatocellular carcinoma.
7. Any unresolved toxicity NCI CTCAE Grade > 2 from previous anticancer therapy except
for alopecia, vitiligo and the laboratory values defined in the inclusion criteria.
8. Patients with Grade = 2 neuropathy will be evaluated on a case-by-case basis after
consultation with the sponsor-investigator.
9. Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab or tremelimumab may be included only after consultation with
the sponsor-investigator. Any medical contraindication to the use of platinum-based
doublet chemotherapy as judged by the treating physician.
10. . Major surgical procedure (as defined by the Investigator) within 28 days prior to
the first dose of study drugs.
11. History of allogenic organ transplantation.
12. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone
replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only
after consultation with the study physician
- Patients with celiac disease controlled by diet alone
13. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially increase
risk of incurring AEs or compromise the ability of the patient to give written
informed consent.
14. History of active primary immunodeficiency.
15. History of another primary malignancy except for
• Malignancy treated with curative intent and with no known active disease =3 years
before the first dose of IP and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
disease
• Adequately treated carcinoma in situ without evidence of disease
16. 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),
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. hepatitis C, Patients
positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction
is negative for HCV RNA. Testing for HIV is not required at screening but patients
with known HIV disease will be excluded from the study.
17. Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab or tremelimumab. The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
articular injection)
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication)
18. Receipt of live attenuated vaccine within 30 days prior to the first dose of study
drug. NOTE: Patients, if enrolled, should not receive live vaccine whilst receiving
study drug and up to 30 days after the last dose of study drug.
19. Female patients who are pregnant or breastfeeding 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 or180 days after
the last dose of durvalumab + tremelimumab combination therapy.
20. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.
21. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical
study regardless of treatment arm assignment.
22. Has had severe hypersensitivity (= Grade 3) to anti -PD1/PDL1 or anti-CTLA4 therapy
and/or any of their excipients in the past.
23. Patients who have received prior anti-PD-1, anti-PD-L1 or anti-CTLA-4:
• Must not have experienced a toxicity that led to permanent discontinuation of prior
immunotherapy. All AEs while receiving prior immunotherapy must have completely
resolved or resolved to baseline prior to screening for this study.
- Must not have experienced a =Grade 3 immune related AE or an immune related
neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE:
Patients with endocrine AE of =Grade 2 are permitted to enrol if they are stably
maintained on appropriate replacement therapy and are asymptomatic.
- Must not have required the use of additional immunosuppression other than
corticosteroids for the management of an AE, not have experienced recurrence of
an AE if re-challenged, and not currently require maintenance doses of > 10 mg
prednisone or equivalent per day.
24. Judgment by the investigator that the patient is unsuitable to participate in the
study and the patient is unlikely to comply with study procedures, restrictions and
requirements.
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