Phase I/II Trial of Pemigatinib in Combination With Atezolizumab and Bevacizumab for Treatment of Advanced Cholangiocarcinoma With FGFR2 Fusion

Inclusion Criteria:

• Ability to understand and willingness to sign informed consent.

• Age ≥18 years.

• Has histologically confirmed metastatic or advanced unresectable cholangiocarcinoma.

• Has disease that is measurable per the RECIST v1.1.

• Has at least one measurable target lesion.

• Has FGFR2 fusion or rearrangement in tumor tissue, as determined by CLIA-validatedgenomic testing of a tumor tissue specimen (DNA-based or RNA-based).

• Is refractory to, has demonstrated intolerance to, had received, or has refusedaccess to, the 1st line systemic therapy including gemcitabine-based therapy with orwithout immunotherapy including durvalumab or pembrolizumab. Participants whodiscontinued available standard therapy due to toxicity must have continued evidenceof measurable disease.

• Has available a formalin-fixed, paraffin-embedded primary tumor sample.

• Is able to take oral medication and to comply with protocol procedures and scheduledvisits..

• Has Eastern Cooperative Oncology Group performance status of 0 or 1

• Has adequate hematologic and end-organ function, defined by the following laboratorytest results, obtained within 14 days prior to initiation of study treatment:

• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (1000/µL) without granulocytecolony-stimulating factor support

• Platelet count ≥ 100 × 109/L (100,000/µL) without transfusion

• Hemoglobin ≥ 90 g/L (9 g/dL), participants may be transfused to meet this criterion.

• Aspartate amino transferate (AST), alanine aminotransferase (ALT), and alkalinephosphatase (ALP) ≤ 2.5 × upper limit of normal (ULN), with the followingexceptions:

• Participants with documented liver metastases: AST and ALT ≤ 5 × ULN

• Participants with documented liver or bone metastases: ALP ≤ 5 × ULN

• Serum bilirubin ≤ 1.5 × ULN with the following exception:

• Participants with known Gilbert disease: serum bilirubin ≤ 3 × ULN

• Serum creatinine ≤ 1.5 × ULN

• Serum albumin ≥ 25 g/L (2.5 g/dL)

• For participants not receiving therapeutic anticoagulation: international normalizedratio (INR) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN. Forpatients on anticoagulation, those on therapeutic anticoagulation over 2 weeks areeligible.

• Has a negative human immunodeficiency virus (HIV) test at screening with thefollowing exception: participants with a positive HIV test at screening are eligibleprovided they are stable on anti-retroviral therapy, have a CD4 count ≥ 200 and havean undetectable viral load.

• Has a negative hepatitis B surface antigen (HBsAg) test at screening (unlessparticipant has chronic HBV on anti-viral therapy)

• Has a negative total hepatitis B core antibody (HBcAb) test at screening, orpositive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test atscreening (unless patient has chronic HBV on anti-viral therapy)

• The HBV DNA test will be performed only for participant who have a negative HBsAgtest and a positive total HBcAb test.

• Participants with chronic HBV on antiviral therapy or HCV participants who havecompleted curative anti-viral therapy can be included.

• Contraception requirements for marketed Roche IMPs or NIMPs should be based onrecommendations in the Summary of Product Characteristics or, if there is no Summaryof Product Characteristics, national prescribing information. Length of timerequired for abstinence or use of contraceptives should take into account thereproductive toxicity profile, including genotoxicity and teratogenicity, the sizeof the molecule, and the number of doses. In the absence of specificdelayed-toxicity concerns or safety hypotheses, the following guidelines should beused: Single-dose studies Small Molecules: 5 elimination half-lives or 14 days afterthe last dose, whichever is longer Large Molecules: 2 elimination half-lives or 28days after the last dose, whichever is longer Multiple-dose studies Small Molecules: 5 elimination half-lives or 28 days after the last dose, whichever is longer LargeMolecules: 2 elimination half-lives or 28 days after the last dose, whichever islonger Options for female contraception are based on the Clinical Trial FacilitationGroup "Recommendations related to contraception and pregnancy testing in clinicaltrials." Three options for female contraception are shown below.

• For women of childbearing potential: agrees to remain abstinent (refrain fromheterosexual intercourse) or to use contraceptive methods, and agrees to refrainfrom donating eggs, as defined below:

• Women must remain abstinent or use contraceptive methods with a failure rate of < 1%per year during the treatment period and for 6 months after the final dose ofatezolizumab/pemigatinib/bevacizumab. Women must refrain from donating eggs duringthis same period.

• A woman is considered to be of childbearing potential if she is postmenarchal, hasnot reached a postmenopausal state (≥ 12 continuous months of amenorrhea with noidentified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/ or uterus). The definition of childbearing potential may beadapted for alignment with local guidelines or requirements.

• Examples of contraceptive methods with a failure rate of < 1% per year includebilateral tubal ligation, male sterilization, hormonal contraceptives that inhibitovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

• The reliability of sexual abstinence should be evaluated in relation to the durationof the clinical trial and the preferred and usual lifestyle of the participant.Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulationmethods) and withdrawal are not adequate methods of contraception. Options forcontraception in male patients with pregnant female partners and/ or with femalepartners of childbearing potential are based on the Clinical Trial FacilitationGroup "Recommendations related to contraception and pregnancy testing in clinicaltrials" and the Roche White Paper regarding contraception for males in clinicaltrials. Atezolizumab does not require male contraception or condom use; guidelinesbelow apply to other protocol-mandated study treatments.

• For men: agrees to remain abstinent (refrain from heterosexual intercourse) or use acondom, and agrees to refrain from donating sperm, as defined below:

• With a female partner of childbearing potential or pregnant female partner, men mustremain abstinent or use a condom during the treatment period and for 6 months afterthe final dose of atezolizumab/pemigatinib/ bevacizumab to avoid exposing theembryo. Men must refrain from donating sperm during this same period.

• The reliability of sexual abstinence should be evaluated in relation to the durationof the clinical trial and the preferred and usual lifestyle of the participant.Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulationmethods) and withdrawal are not adequate methods of preventing drug exposure.

Exclusion Criteria:

• Received prior chemotherapy, biologic therapy, immunotherapy, or investigationalagent within 3 weeks prior to initiation of study medications.

• Had previous treatment with selective FGFR inhibitors including erdafitinib,infigratinib, or futibatinib.

• Had prior therapy with any VEGFR-targeting agent targeting including bevacizumab,ramucirumab, pazopanib, lenvatinib, and other anti-angiogenesis inhibitors.

• Has a history and/or has current evidence of extensive tissue calcificationincluding, but not limited to, the soft tissue, kidneys, intestine, myocardium,vascular system, and lung. Exceptions include calcified lymph nodes, minor pulmonaryparenchymal calcifications, and asymptomatic coronary calcifications-these areallowed.

• Has corneal or retinal disorder/keratopathy with current evidence of corneal orretinal disorder/keratopathy including, but not limited to, bullous/ bandkeratopathy, inflammation, or ulceration, keratoconjunctivitis, or diabeticretinopathy, confirmed by ophthalmic physician. Participants with asymptomaticophthalmic conditions assessed by the investigator to pose minimal risk for studyparticipation may be enrolled in the study.

• Are currently receiving or are planning to receive during participation in thisstudy, treatment with any potent CYP3A4 inhibitors or inducers or moderate CYP3A4inducers within 14 days or 5 half-lives (whichever is longer) before the first doseof study drug. Moderate CYP3A4 inhibitors are not prohibited but should be avoided.Medications that increase serum phosphorus and/or calcium concentration areprohibited. Medications associated with hyperphosphatemia and/or hypercalcemiaadverse events are searchable in the Leximcomp Online Pharmacy & Formulary availableon the Inside MD Anderson Clinical Tools SharePoint site. Participants are notpermitted to receive enzyme-inducing anti-epileptic drugs, including carbamazepine,phenytoin, phenobarbital, and primidone.

• Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, starfruits, pomelos, Seville oranges or products containing juice of these fruits within 7 days prior to first dose of study drug.

• Had a Grade 3-4 gastrointestinal bleed within 3 months prior to enrollment.

• Has a history of deep vein thrombosis, pulmonary embolism, or any otherthromboembolism, including portal venous thrombosis within 3 months prior toenrollment. Venous port or catheter thrombosis, incidental asymptomatic pulmonaryembolism diagnosed on imaging studies, or superficial venous thrombosis are notconsidered significant and are allowed.

• Has current or recent (within 10 days prior to study treatment start) use offull-dose oral or parenteral anticoagulants (including direct oral anticoagulants);thrombolytic agents for therapeutic (as opposed to prophylactic) purpose; use ofaspirin (> 325 mg/day); or use of clopidogrel (> 75 mg/day). Note: The use offull-dose oral or parenteral anticoagulants for therapeutic purpose is permitted aslong as the INR and/or aPTT is within therapeutic limits (according to institutionstandards) within 7 days prior to initiation of study treatment and the patient hasbeen on a stable dose of anticoagulants for ≥ 2 weeks prior to initiation of studytreatment. Prophylactic use of anticoagulants is allowed. However, the use of directoral anticoagulant therapies such as dabigatran and rivaroxaban is not recommendeddue to bleeding risk.

• Had significant cardiovascular disease (such as New York Heart Association Class IIor greater cardiac disease, myocardial infarction, transient ischemic attack orcerebrovascular accident); unstable arrhythmia; or unstable angina significantcardiovascular disease within 6 months prior to enrollment.

• Has a history of uncontrolled or poorly-controlled hypertension (>150 mmHg systolicor >100 mmHg diastolic).

• Has a history of hypertensive crisis or hypertensive encephalopathy.

• Had a serious or non-healing wound, ulcer, or bone fracture within 28 days prior toenrollment.

• Has undergone major surgery (including open biopsy, surgical resection, woundrevision; or any other major surgery involving entry into a body cavity); orsignificant traumatic injury within 28 days prior to enrollment; or subcutaneousvenous-access-device placement within 7 days prior to enrollment; or anticipatesneed for major surgical procedure, core biopsy, or other minor surgical proceduresduring the course of the study. o Note: Placement of a vascular access device shouldbe at least 2 days prior to initiation of study treatment.

• Is receiving chronic antiplatelet therapy, nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, naproxen), dipyridamole, clopidogrel, or similar agents.Once-daily aspirin use (≤325 mg/day) is allowed.

• Has had significant vascular disease (e.g., aortic aneurysm requiring surgicalrepair or recent arterial thrombosis) within 6 months prior to randomization.

• Has a history of central nervous system disease or evidence of this disease uponphysical or neurological examination.

• Has a history of Grade ≥ 2 hemoptysis (defined as ≥ 2.5 mL of bright red blood perepisode) within 1 month prior to screening.

• Has a history or evidence of inherited bleeding diathesis or significantcoagulopathy at risk of bleeding (i.e., in the absence of therapeuticanticoagulation).

• Has a history of abdominal fistula, gastrointestinal (GI) perforation,intra-abdominal abscess, or active GI bleeding within 6 months prior torandomization.

• Has a history of leptomeningeal disease.

• Has uncontrolled tumor-related pain.

• Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement)amenable to palliative radiotherapy should be treated prior to enrollment.Participants should have recovered from the effects of radiation. There is norequired minimum recovery period.

• Asymptomatic metastatic lesions that would likely cause functional deficits orintractable pain with further growth (e.g., epidural metastasis that is notcurrently associated with spinal cord compression) should be considered forloco-regional therapy, if appropriate, prior to enrollment.

• Has uncontrolled pleural effusion, pericardial effusion, or ascites requiringrecurrent drainage procedures (at a frequency of at least once monthly) oParticipants with indwelling catheters (e.g., PleurX®) are allowed. Has uncontrolledor symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, orcorrected serum calcium > ULN).

• Has current evidence of endocrine alterations of calcium/phosphate homeostasis, eg,parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoralcalcinosis, and other disorders.

• Has elevated phosphorus or abnormal serum calcium, or phosphorus, orcalcium-phosphorus product ≥ 55 mg2/dL2:

• Inorganic phosphorus > 1.02 × ULN Has active or a history of autoimmune disease orimmune deficiency, including, but not limited to, myasthenia gravis, myositis,autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,inflammatory bowel disease, antiphospholipid antibody syndrome, Wegenergranulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis (see Appendix 9 for full list), with the following exceptions:

• Participants with a history of autoimmune-related hypothyroidism who are onthyroid-replacement hormone are eligible for the study. Participants with controlledType 1 diabetes mellitus (as determined by the treating physician) who are on aninsulin regimen are eligible for the study.

• Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., participants with psoriatic arthritis areexcluded) are eligible for the study provided all of 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 conditionrequiring psoralen plus ultraviolet-A radiation, methotrexate, retinoids, biologicagents, oral calcineurin inhibitors, or high-potency or oral corticosteroids withinthe previous 12 months

• Has a history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis; orhas evidence of active pneumonitis upon screening via computed tomography (CT) scanof the chest.

• History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

• Has active tuberculosis.

• Had a major surgical procedure, other than for diagnosis, within 4 weeks prior toinitiation of study treatment, or anticipates need for a major surgical procedureduring the study.

• Had a history of malignancy other than cholangiocarcinoma within 2 years prior toscreening, with the exception of malignancies with a negligible risk of metastasisor death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situof the cervix, nonmelanoma skin carcinoma, localized prostate cancer, ductalcarcinoma in situ, or Stage I uterine cancer.

• Had a severe infection within 4 weeks prior to initiation of study treatment,including, but not limited to, hospitalization for complications of infection,bacteremia, or severe pneumonia.

• Received treatment with therapeutic oral- or IV antibiotics within 2 weeks prior toinitiation of study treatment.

• Participants receiving prophylactic antibiotics (e.g., to prevent a urinary tractinfection or chronic obstructive pulmonary disease exacerbation) are eligible forthe study.

• Had a prior allogeneic stem cell or solid organ transplantation • Has any otherdisease, metabolic dysfunction, physical examination finding, or clinical laboratoryfinding that contraindicates the use of an investigational drug, that may affect theinterpretation of the results, or that may render the patient at high risk fromtreatment complications.

• Received treatment with a live, attenuated vaccine within 4 weeks prior toinitiation of study treatment, or anticipates need for such a vaccine duringtreatment or within 5 months after the final dose of treatment. Receipt of SARS-CoVvaccine is allowed.

• Received treatment with systemic immunostimulatory agents (including, but notlimited to, interferon and interleukin 2 [IL-2]) within 2 weeks prior to initiationof study treatment, or anticipation of need for systemic immunosuppressivemedication during study treatment, with the following exceptions:

• Patients who received acute, low-dose systemic immunosuppressant medication or aone-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours ofcorticosteroids for a contrast allergy) are eligible for the study.

• Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroidsfor chronic obstructive pulmonary disease (COPD) or asthma, or low-dosecorticosteroids for orthostatic hypotension or adrenal insufficiency are eligiblefor the study.

• Received treatment with systemic immunosuppressive medication (including, but notlimited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate,thalidomide, or anti-TNF-α agents) within 2 weeks prior to initiation of studytreatment, or anticipates a need for systemic immunosuppressive medication duringstudy treatment, with the following exceptions:

• Participants who received acute, low-dose systemic immunosuppressant medication or aone-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours ofcorticosteroids for a contrast allergy) are eligible for the study after PrincipalInvestigator confirmation has been obtained.

• Participants who received mineralocorticoids (e.g., fludrocortisone),corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dosecorticosteroids for orthostatic hypotension or adrenal insufficiency are eligiblefor the study.

• Has a history of severe allergic anaphylactic reactions to chimeric or humanizedantibodies or fusion proteins.

• Has a known hypersensitivity to Chinese hamster ovary-cell products or to anycomponent of the atezolizumab formulation.

• Has a known allergy or hypersensitivity to any component of the pemigatinib,bevacizumab, or atezolizumab formulations.

• Is pregnant or breastfeeding or intends to become pregnant during study treatment orwithin 6 months after the final dose of study treatment.

• Women of childbearing potential must have a negative serum pregnancy test resultwithin 14 days prior to initiation of study treatment.

• Has a history of hypovitaminosis D requiring supraphysiologic doses (eg, 50,000UI/weekly) to replenish the deficiency. Vitamin D supplements are allowed.