Treatment of Atezolizumab and Derazantinib in Patients With Advanced iCCA With FGFR2 Fusions/Rearrangements

Inclusion Criteria:

Patients must meet all of the following criteria to be eligible for the study:

1. Fully informed written consent and locally required authorization (European Union [EU] Data Privacy Directive in the EU) obtained from the patient prior to performingany protocol-related procedures, including screening evaluations.

2. Patients*, age ≥ 18 years at the time of signing the Informed Consent Form.

3. Histologically documented diagnosis of non-resectable iCCA with positively confirmedFGFR2 fusion/rearrangement via NGS-Analysis. Note: Only CE-IVD marked NGS-tests are applicable which cover FGFR2 fusions andrearrangements.

4. Performance status (PS) ≤ 2 (ECOG scale).

5. At maximum one previous line of systemic anti-cancer therapy, (chemotherapy,hormonal, targeted therapy, experimental therapy) for which treatment wasdiscontinued at least 4 weeks before the first dose of study treatment, or fivehalf-lives of the respective anti-cancer therapy, whichever is the longer period. Note: For mABs in previous therapy the restriction to five half-lives does notapply.

6. No prior treatment with any FGFR or immune checkpoint inhibitor (including but notlimited to antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies) apart fromDurvalumab as PD-L1 inhibitor in first line therapy.

7. Body weight > 30 kg AND BMI ≥ 15.

8. At least one measurable site of disease as defined by RECIST 1.1 criteria.

9. Adequate bone marrow and renal function including the following:

• Hemoglobin ≥ 9.0 g/dL (previous transfusion permitted);

• Absolute neutrophil count (ANC) ≥ 1.500 per µL (1.5×109/L);

• Platelet count ≥ 75,000 per µL (75 × 109/L);

• International normalized ratio (INR) between 0.8 × ULN to 1.0 × ULN OR ≤ 3 ×ULN for subjects receving anticoagulant therapy

• Creatinine ≤ 1.5 × ULN OR CLCR ≥ 50 mL/min (as calculated by theCockcroft-Gault formula);

• serum phosphate ≤ ULN;

• corrected serum calcium ≥ 1.75 mmol/L (≥ 7.0 mg/dL) AND ≤ 3.1 mmol/L (≤ 12.5mg/dL);

• serum sodium ≥ LLN.

10. Adequate hepatic function (with stenting for any obstruction, if required) includingthe following: o Total bilirubin ≤ 2 × ULN;

• AST or ALT ≤ 3 × ULN (or ≤ 5 × ULN for subjects with liver metastases);

• Prothrombin time ≥ 60%;

• Albumin ≥ 2.8 g/dL.

11. For patients with active hepatitis B virus (HBV):

• HBV DNA ≤ 500 IU/mL obtained within 28 days prior to initiation of studytreatment, AND

• Anti-HBV treatment (per local standard of care; e.g., entecavir) prior to studyentry and willingness to continue treatment for the length of the study.

12. For patients with active hepatitis C virus (HCV):

• Patients positive for hepatitis C virus (HCV) antibody are eligible, also ifpolymerase chain reaction testing is positive for HCV ribonucleic acid (RNA).

• However, anti-viral therapy against HCV is only allowed prior to trial but notduring the trial.

13. Negative HIV test.

14. Negative pregnancy test within 72 h prior to dosing.

15. Females of childbearing potential must agree to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive methods that result in a failure rateof < 1% per year during the treatment period and for at least 5 months or for aperiod of at least 5 half-lives of the respective drug/IMP (whichever is longer)after the last study treatment. A woman is considered to be of childbearingpotential if she is postmenarcheal, has not reached a postmenopausal state (has nothad ≥ 12 continuous months of amenorrhea with no identified cause other thanmenopause), and has not undergone surgical sterilization (removal of ovaries and/oruterus). Examples of contraceptive methods with a failure rate of < 1% per yearinclude bilateral tubal ligation, male sterilization, hormonal implants,established, proper use of combined oral or injected hormonal contraceptives, andcertain intrauterine devices. The reliability of sexual abstinence should beevaluated in relation to the duration of the clinical trial and the preferred andusual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation,symptothermal, or postovulation methods) and withdrawal are not acceptable methodsof contraception.

16. With female partners of childbearing potential, men must remain abstinent or use acondom plus an additional contraceptive method that together result in a failurerate of 1% per year from screening to 5 months after the last dose of combinationtherapy or for a period of at least 5 half-lives of the respective drug/IMP afterthe last dose of combination therapy (whichever is longer). Men must refrain fromdonating sperm during this same period. Men with a pregnant partner must agree toremain abstinent or to use a condom for the duration of the pregnancy to avoidexposing the embryo.

17. The patient is willing and able to comply with the protocol for the duration of thestudy, including hospital visits for treatment and scheduled follow-up visits andexaminations.

18. Must have a life expectancy of at least 12 weeks. *There are no data that indicatespecial gender distribution. Therefore, patients will be enrolled in the studygender-independently.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry:

1. Mixed cholangiocarcinoma and HCC.

2. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) study or a study without a medical intervention (specificallythe PLATON registry [ClinicalTrials.gov identifier: NCT04484636] is allowed). Note: After the Safety Follow-up (28 days post treatment discontinuation)participation in another clinical study is allowed.

3. Major surgery (as defined by the Investigator) within 4 weeks prior to enrollmentinto the study; patients must have recovered from effects of any major surgery. Note: Local non-major surgery for palliative intent (e.g. surgery of isolatedlesions, per-cutaneous biliary drainage or biliary stenting) is acceptable.

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

5. History of another primary malignancy except for:

• Malignancy treated with curative intent and with no known active disease ≥ 3years before the first dose of IMP and of low potential risk for recurrence;

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

• Adequately treated carcinoma in situ without evidence of disease.

6. Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ effective birth control fromscreening to 5 months after the last dose of combination therapy or for a period ofat least 5 half-lives of the respective drug/IMP after the last dose of combinationtherapy (whichever is longer).

7. Known allergy or hypersensitivity to any of the IMPs or any of the constituents ofthe product.

8. Any co-existing medical condition that in the investigator's judgement willsubstantially increase the risk associated with the patient's participation in thestudy.

9. Active or History of autoimmune disease including, but not limited to, myastheniagravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoidarthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener'sgranulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis,vasculitis, or glomerulonephritis.

Note: History of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone, or controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible based on consultation with the sponsor. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all following conditions are met:

• Rash must cover < 10% of body surface area;

• Disease is well controlled at baseline and requires only low- potency topicalcorticosteroids;

• No occurrence of acute exacerbations of the underlying condition requiring psoralenplus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oralcalcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months.

10. History of non-infectious pneumonitis requiring steroids, or patients withGrade ≥ 2 pneumonitis.

11. History of active primary immunodeficiency. 12. History of allogeneic bonemarrow transplantation or prior solid organ transplantation.

12. Treatment with systemic immunosuppressive medication (including, but notlimited 14. 15. to, corticosteroids, cyclophosphamide, azathioprine,methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior toinitiation of study treatment, or anticipation of need for systemicimmunosuppressive medication during study treatment, with the followingexceptions:

• Patients who received acute, low-dose systemic immunosuppressant medication ora one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hoursof corticosteroids for a contrast allergy) are eligible for the study.

• Patients who received mineralocorticoids (e.g., fludrocortisone),corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, orlow-dose corticosteroids for orthostatic hypotension or adrenal insufficiencyare eligible for the study.

16. Administration of a live, attenuated vaccine within four weeks or for aperiod of at least 5 half-lives of the respective drug/IMP (whichever islonger) prior to start of enrollment, or anticipation that such a liveattenuated vaccine will be required during the study or within 5 monthsafter the last dose of atezolizumab.
17. Significant cardiovascular disease, such as cardiac disease (New YorkHeart Association Class II or greater), myocardial infarction orcerebrovascular accident within 3 months prior to initiation of studytreatment, unstable arrhythmias, unstable angina, and/or concurrent andclinically significant abnormalities on electrocardiogram (ECG) atScreening, including QTcF > 450 ms for males or > 460 ms for females.
18. Clinically significant valvular defect. 19. Unable or unwilling to swallowthe complete daily dose of derazantinib capsules.
19. Clinically unstable central nervous system (CNS) metastases (to beeligible, subjects must have stable disease > 3 months, confirmed bymagnetic resonance imaging (MRI) or computed tomography (CT) scan, and/orhave CNS metastases well controlled by low-dose steroids, anti-epileptics,or other symptom-relieving medications).
20. Current evidence of clinically significant corneal or retinal disorder,including but not limited to bullous/band keratopathy,keratoconjunctivitis (except for keratoconjunctivits sicca), cornealabrasion (except if related to trauma), inflammation/ulceration, confirmedby ophthalmologic examination.
21. Significant gastrointestinal disorder(s) that could, in the opinion of theInvestigator, interfere with the absorption, metabolism, or excretion ofderazantinib and/or atezolizumab (e.g., Crohn's disease, ulcerativecolitis, extensive gastric resection).
22. Active tuberculosis. 24. Co-infection with hepatitis B and hepatitis C.Patients who are negative for HCV RNA will be considered non-infected forHCV.
23. Severe bacterial, fungal, viral and/or parasitic infections on therapeuticoral or IV medication at the time of first dose of study drugadministration.
24. Treatment with strong CYP3A4 inducers within 14 days prior to initiationof study treatment, including rifampin (and its analogues) or St. John'swort.
25. Patient who has been incarcerated or involuntarily institutionalized bycourt order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
26. Patients who are unable to consent because they do not understand thenature, significance and implications of the clinical trial and thereforecannot make a rational/informed decision after receiving the studyinformation [§ 40 Abs. 1 S. 3 Nr. 3a AMG].