Chemoimmunotherapy Combined with Hyperthermia and Spatially-Fractionated Radiotherapy in Advanced Biliary Tract Cancer

Inclusion Criteria:

1. Capable of giving signed informed consent, which includes compliance with therequirements and restrictions listed in the informed consent form (ICF) and in thisprotocol

2. Provision of a signed and dated written ICF prior to any mandatory study-specificprocedures, sampling, and analyses

3. Age ≥ 21 years at the time of screening

4. Histologically-confirmed, unresectable advanced or metastatic carcinoma of thebiliary tract including intrahepatic or extrahepatic cholangiocarcinoma andgallbladder carcinoma

5. No prior systemic therapy for locally advanced, metastatic, or recurrent BTC (prioradjuvant capecitabine therapy is allowed as long as last treatment was ≥ 1 monthbefore enrollment)

6. An ECOG performance status of 0-2 at enrollment

7. At least 1 lesion that qualifies as a RECIST version 1.1 target lesion in theabdomen or pelvis that is amenable to SFRT on contrast enhanced CT or MRI

8. No prior exposure to gemcitabine or platinum-based chemotherapy

9. No prior exposure to anti-PD1 or anti-PDL1 antibodies

10. Adequate organ and marrow function as defined below:

• Hemoglobin ≥ 9.0 g/dL

• ANC ≥ 1.5 x 109/L

• Platelet count ≥ 100 x 109/L

• Serum bilirubin ≤ 2.5 x upper limit of normal (ULN)

• Alanine aminotransferase and aspartate aminotransferase ≤ 3 x ULN

• Measured creatinine clearance > 50 mL/min or calculated creatinine clearance > 50 mL/min as determined by Cockcroft-Gault (using actual body weight)

11. Life expectancy of at least 12 weeks at the time of screening

12. Body weight >30 kg

13. Participants must provide a tumor biopsy taken within 3 years prior to screening

14. Baseline vitals: heart rate of ≤ 90bpm, systolic blood pressure of 140-100mmHg anddiastolic of 90-60mmHg

Exclusion Criteria:

1. Ampullary carcinoma

2. History of allogeneic organ transplantation

3. Prior history of radiation to the proposed treatment site

4. Active or prior documented autoimmune or inflammatory disorders with the followingexceptions:

• Participants with vitiligo or alopecia

• Participants with hypothyroidism stable on hormone replacement

• Any chronic skin condition that does not requires systemic therapy

• Participants without an active disease in the last 5 years may be included butonly after consultation with the study physician

• Participants with celiac disease controlled by diet alone

5. Known history or evidence of active, non-infectious pneumonitis

6. Uncontrolled intercurrent illness including but not limited to ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease,serious chronic gastrointestinal conditions associated with diarrhea, or psychiatricillness/social situations that would limit compliance with study requirement,substantially increase the risk of incurring adverse events, or compromise theability of the participant to give written informed consent

7. Participants with documented myocardial infarction or cerebrovascular accidentwithin 6 months prior to enrollment

8. History of another primary malignancy, except for:

• Malignancy treated with curative intent and with no known active disease ≥2years before the first dose of investigational product and of low potentialrisk for recurrence

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease

• Adequately treated carcinoma in situ without evidence of disease

9. History of leptomeningeal carcinomatosis

10. Active infection including tuberculosis, hepatitis B or hepatitis C. Participantswith a past or resolved hepatitis B infection or participants positive for hepatitisC antibody with negative hepatitis C virus RNA on polymerase chain reaction areeligible to enroll. Participants with HIV with undetectable viral load and CD4 cellcount ≥200 cells/mm3 are eligible to enroll

11. Any unresolved toxicity per CTCAE version 5.0 grade ≥2 from a previous anticancertherapy, except for alopecia, vitiligo and the laboratory values defined in theinclusion criteria.

• Participants with grade ≥2 neuropathy will be evaluated on a case-by-case basisafter consultation with the study physician

• Participants with irreversible toxicity not reasonably expected to beexacerbated by treatment with durvalumab may be included only afterconsultation with the study physician

12. Untreated brain metastases or spinal cord compression. Participants with suspectedbrain metastases at screening should have an MRI (preferred) or CT scan, eachpreferably with IV contrast of the brain prior to study entry

13. Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients

14. Any concurrent chemotherapy, investigational product, biologic or hormonal therapyfor cancer treatment

• Concurrent use of hormonal therapy for non-cancer related conditions is acceptable

15. Receipt of live attenuated vaccine within 30 days prior to the enrollment

16. Major surgical procedure within 28 days prior to enrollment.

17. Prior locoregional therapy with radioembolization

18. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab with the following exceptions:

• Intranasal, inhaled, or topical steroids or local steroid injection

• Systemic corticosteroids at physiologic doses not to exceed 10mg/day ofprednisone or its equivalent

• Steroids as premedication for hypersensitivity reactions

19. Participation in another clinical study with an investigational product administeredin the last 3 months

20. Concurrent enrollment in another clinical study, unless it is an observationalclinical study or during the follow-up period of an interventional study

21. Female participants who are pregnant or breastfeeding or male or female participantsof reproductive potential who are not willing to use effective birth control fromscreening to 180 days after the last dose of gemcitabine/cisplatin or 90 days afterthe last dose of durvalumab

22. Judgement by the investigator that the participant should not participate in thestudy if they are unlikely to comply with study procedures, restrictions, andrequirements

23. Participants on anti-arrhythmic medication unless they are deemed fit for HT by aconsultant cardiologist and there is no increased risk to the patient from HTbecause of the arrhythmia in the opinion of the treating physician

24. Severe COPD with FEV1 < 50% of expected

25. Participants whose right-to-left pelvic/abdominal dimension is > 49 cm

26. Participants with incorporated metallic implants such as metallic stents, pacemakersor defibrillators, and orthopedic rods and plates of dimensions > 1000/frequency (MHz) aa. Participants who are under any therapy, which by virtue of directpharmacological action or heat interaction, could influence the intended effects ofHT or mask its side effects