HYPERION CCA: a Phase 2 Trial of Systemic Therapy With or Without Liver-directed Radiation Therapy for Patients With Advanced Intrahepatic Cholangiocarcinoma

1. Patients older than the age of 18 years old at the time of study entry.

2. Patients with a body mass greater than 30 kg.

3. Patients with a pathological diagnosis of intrahepatic cholangiocarcinoma and at least one intrahepatic tumor measuring 3 cm in greatest dimension

4. Patients must have pathological or radiographic evidence of either:

c. locally advanced unresectable iCCA - a multidisciplinary discussion should be documented for patients who have liver confined disease, confirming that the patient is not resectable.

d. extrahepatic metastasis at the time of enrollment - allowable extrahepatic metastases may include disease in non-regional lymph nodes (note that metastatic involvement of regional lymph nodes in the hilum of the liver alone do not qualify as M1 disease), lung, and/or bone.

5. Patients should receive at least 4 cycles of systemic therapy with gemcitabine/cisplatin with durvalumab. If one of the drugs (gemcitabine/cisplatin/durvalumab) was held at any point for medical reasons during the initial 4 cycles, the patient is still eligible as long as the treating team agrees about the ability of the patient to continue systemic therapy.

6. Patients must be appropriate candidates for radiation therapy with adequate liver function, at the discretion of the treating physician.

1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.

2. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.

5. Major surgical procedure (as defined by the treating physician) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.

6. History of allogenic organ transplantation.

7. 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:

1. Patients with vitiligo or alopecia

2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement

3. Any chronic skin condition that does not require systemic therapy

4. Patients without active disease in the last 5 years may be included but only after consultation with the study physician

5. Patients with celiac disease controlled by diet alone

8. 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 diarrhea, 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

9. History of another primary malignancy except for

1. 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

2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease

3. Adequately treated carcinoma in situ without evidence of disease

10. History of leptomeningeal carcinomatosis

11. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry. Patients with brain metastasis or metastases confirmed on imaging will be excluded.

12. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart)

13. History of active primary immunodeficiency

14. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening. Participants with a past or resolved HBV infection (defined as the presence of antiHBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Adjust wording as necessary and consider evaluating at screening for studies with known hepatotoxicity or other relevant requirements.

1. Participants co-infected with HBV and HCV, or co-infected with HBV and HDV, namely: HBV positive (presence of HBsAg and/or anti HBcAb with detectable HBV DNA); AND

2. HCV positive (presence of anti-HCV antibodies); OR

3. HDV positive (presence of anti-HDV antibodies). Subjects with HBV infection, characterised by positive HBsAg and/or anti-HBcAb with detectable HBV DNA (≥ 10 IU/ml or above the limit of detection per local laboratory standard), must be treated with antiviral therapy, per institutional practice. Following antiviral therapy initiation, subjects must show adequate viral suppression (ie, HBV DNA ≤ 2000 IU/mL) as prior to randomisation. Participants will remain on antiviral therapy for the study duration and for 6 months after the last dose of IP.

4. Subjects with HBV infection, characterised by positive HBsAg and/or anti-HBcAb with undetectable HBV DNA (\< 10 IU/ml or under the limit of detection per local lab standard) do not require antiviral therapy prior to randomisation. These subjects will be tested at every cycle to monitor HBV DNA levels; if HBV DNA is detected (≥ 10 IU/ml or above the limit of detection per local lab standard), antiviral therapy must be initiated, continued for the study duration and for 6 months after the last dose of IP.

15. Known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA load for 6 months, CD4+ count of \>200, no history of AIDS-defining opportunistic infection within the past 12 months, and stable for at least 6 months on the same anti HIV medications.

16. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:

1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)

2. Systemic corticosteroids at physiologic doses not to exceed \<\<10 mg/day\>\> of prednisone or its equivalent

3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

17. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 90days after the last dose of IP.

18. 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.

19. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

20. Prior randomisation or treatment in a previous durvalumab clinical study regardless of treatment arm assignment.

21. Patients who have received prior anti-PD-1 or anti PD-L1:

1. Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.

2. All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.

3. 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 enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.

4. 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.

22. Judgment by the treating physician that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.

What this study is about