A Phase 3, Open-Label, Randomized, Active-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Pemigatinib Versus Gemcitabine Plus Cisplatin Chemotherapy in First-Line Treatment of Participants With Unresectable or Metastatic Cholangiocarcinoma With FGFR2 Rearrangement (FIGHT-302)

Prior treatment

• Received prior anticancer systemic therapy for unresectable and/or metastatic disease (not including adjuvant/neoadjuvant treatment completed at least 6 months prior to enrollment, and participants that have received treatment for locally advanced disease with trans-arterial chemoembolization or selective internal radiation therapy, if clear evidence of radiological progression is observed before enrollment, or enrolled as of Amendment 6 and the participant received 1 cycle of gemcitabine plus cisplatin [the start of study drug {Cycle 1 Day 1} must be at least 14 days and ≤ 4 weeks {28 days} from the last dose of gemcitabine plus cisplatin]).
• Inability of the participant to swallow and retain oral medication
• Current use of prohibited medication as described in Section 6.6.2.of the Protocol
• Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14 days or 5 half-lives (whichever is longer) before the first dose of study treatment. Note: Moderate CYP3A4 inhibitors are not prohibited.
• Inadequate recovery from toxicity and/or complications from a major surgery before starting therapy.
• For Japanese participants, pregnant or breastfeeding women or participants expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 90 days after last dose of pemigatinib (men; based on the spermatogenetic cycle) and 30 days after last dose of pemigatinib (women; based on menstrual cycle) and 6 months after the last dose of gemcitabine and/or cisplatin (men and women). Female participants who are breastfeeding and wish to enroll must discontinue breastfeeding before receiving study drug and must not resume breastfeeding until at least 30 days after last dose of study treatment, which exceeds 5 times the half-life of pemigatinib.
• History of hypovitaminosis D requiring supraphysiologic doses (eg, 50,000UI/weekly) to replenish the deficiency. Participants receiving vitamin D supplements are allowed.
• Toxicities related to prior therapy(ies) must be CTCAE v5.0 ≤ Grade 1 at the time of screening.
• Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, investigational therapy, or tumor embolization), other than the therapies being tested in this study.
• Participant is a candidate for potentially curative surgery.
• Radiation therapy administered within 4 weeks of enrollment/randomization/first dose of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. Evidence of fibrosis within a radiation field from prior radiotherapy is permitted with medical monitor approval. A 2-week washout is permitted for palliative radiation to non-CNS disease.

Other illness

• Significant gastrointestinal disorder(s) that could interfere with absorption, metabolism, or excretion of pemigatinib.
• Clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study treatment administration, New York Heart Association Class III and IV congestive heart failure, and uncontrolled arrhythmia (participants with pacemaker or with atrial fibrillation and well controlled heart rate are allowed).
• Known hypersensitivity or severe reaction to pemigatinib, gemcitabine, cisplatin, or their excipients (refer to the IB and commercially available product information sheets).
• Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study treatment and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
• Current evidence of clinically significant corneal (including but not limited to bullous/band keratopathy, corneal abrasion, inflammation/ulceration, and keratoconjunctivitis) or retinal disorder (including but not limited to central serous retinopathy, macular/retinal degeneration, diabetic retinopathy, retinal detachment) as confirmed by ophthalmologic examination
• Known CNS metastases or history of uncontrolled seizures. Participants with treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT scan) during the screening period, and they are on stable or decreasing dose of corticosteroids for at least 1 week.
• Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.

Lab values

• Participants with laboratory values at screening defined in Table 11 of the protocol
• History of calcium and phosphate hemostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues (exception: commonly observed calcifications in soft tissues, such as the skin, kidney, tendons or vessels due to injury, disease, and aging, in the absence of systemic mineral imbalance).
• History or presence of an abnormal ECG, which, in the investigator's opinion, is clinically meaningful. A screening QTcF interval > 480 milliseconds is excluded. For participants with an interventricular conduction delay (QRS interval >120 ms), the JTc interval may be used in place of the QTc with sponsor approval (the JTc must be ≤ 340 milliseconds if JTc is used in place of the QTc).
• Chronic or current active infectious disease requiring systemic antibiotics or antifungal or antiviral treatment within 2 weeks prior to enrollment (participants with asymptomatic chronic infections on prophylactic treatment are allowed). Note: HIV-positive participants are allowed if all of the following criteria are met: CD4+ count ≥ 300/μL, undetectable viral load, receiving antiretroviral therapy that does not interact with study drug, and no HIV/AIDS-associated opportunistic infection in the last 12 months.

Other

• In participants with liver cirrhosis, Child-Pugh B and C (Note: Ascites attributed to cholangiocarcinoma rather than liver dysfunction (eg, in the presence of peritoneal metastases) should not be taken into consideration when scoring).
• Inability or unlikeliness of the participant to comply with the dose schedule and study evaluations in the opinion of the investigator.
• For NA, EU, and ROW participants, women who are pregnant or breastfeeding or participants expecting to conceive or father children within the projected duration of the study, starting with the screening visit through completion of safety follow-up or through 90 days from the date of last dose of pemigatinib and 6 months after the last dose of gemcitabine and/or cisplatin for male participants.
• Inability of the participant (or parent, guardian, or legally authorized representative) to comprehend or unwilling to sign the ICF. GERMANY ONLY: Only participants who can provide their own consent are able to participate in this clinical study.
• Any contraindication to gemcitabine or cisplatin as per each SmPC or product insert.

• Ability to comprehend and willingness to sign a written ICF for the study.
• Male and female participants at least 18 years of age at the time of signing the ICF; a legally minor participant from Japan needs written parental consent.
• Histologically or cytologically confirmed cholangiocarcinoma that is previously untreated and considered unresectable and/or metastatic (Stage IV per the AJCC Cancer Staging Manual.
• Radiographically measurable or evaluable disease by CT or MRI per RECIST v1.1criteria (Eisenhauer et al 2009).
• ECOG performance status 0 to 1
• Documented FGFR2 rearrangement
• For NA, EU, or ROW participants, willingness to avoid pregnancy or fathering children based on the criteria below: a. Male participants must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through 90 days after the last dose of pemigatinib and 6 months after the last dose of gemcitabine and/or cisplatin and must refrain from donating sperm during this period. Permitted methods that are at least 99% effective in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed. NOTE: Men being treated with gemcitabine must be advised to seek further advice regarding cryoconservation of sperm before treatment because of the possibility of infertility due to therapy with gemcitabine. b. Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea). c. Women of childbearing potential must have a negative serum pregnancy test at screening and before the first dose on Day 1 and must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through safety follow-up (30-35 days after last dose of pemigatinib) and through 6 months after the last dose of gemcitabine and/or cisplatin. Permitted methods that are at least 99% effective in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed.
• For Japanese participants, willingness to avoid pregnancy or fathering children based on the criteria below: a. Female participants should agree to use medically acceptable contraceptive measures, should not be breastfeeding, and must have a negative pregnancy test before the start of study treatment administration if of childbearing potential or must have evidence of nonchildbearing potential by fulfilling 1 of the following criteria at screening: − Postmenopausal, defined as aged >50 years and amenorrheic for at least 12 months after cessation of all exogenous hormonal treatments. Note: Female participants who have been amenorrheic for at least 12 months resulting from chemotherapy/radiotherapy are considered of childbearing potential and should agree to use adequate contraceptive measures. − Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation. − All women of childbearing potential must understand and accept that pregnancy must be avoided during participation in the study, from screening through 30 days after last dose of pemigatinib (based on menstrual cycle) and 6 months after last dose of gemcitabine and/or cisplatin. b. Male participants should avoid unprotected sex with women of childbearing potential during the study and for a washout period of 3 months after the last dose of pemigatinib or 6 months after the last dose of gemcitabine and/or cisplatin. Participants should refrain from donating sperm from the start of the study treatment administration until 6 months after discontinuing study treatment.