Ensayos clínicos

Inclusion Criteria: 

• 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 [AJCC 2002]).
• Radiographically measurable or evaluable disease by CT or MRI per RECIST v1.1 criteria (Eisenhauer et al 2009).
• ECOG performance status 0 to 1.
• Documented FGFR2 rearrangement.

Exclusion Criteria: 

• Received prior anticancer systemic therapy for unresectable and/or metastatic disease (not including adjuvant/neo-adjuvant 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).
• Child-Pugh B and C.
• 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.
• The participant must not be a candidate for potentially curative surgery.
• 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
• 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.
• 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.
• Participants with laboratory values at screening defined below:
• Hematology
  • Platelets | ≤ 75/100 × 109/L (transfusion allowed with 2-week washout period);
  • Hemoglobin | ≤ 9.0 g/dL (transfusion allowed with 2-week washout period);
  • ANC | ≤ 1.5 × 109/L.
• Hepatic 
  • ALT | > 2.5 × ULN (> 5 × ULN if related to underlying disease or the presence of liver metastases);
  • AST | > 2.5 × ULN (> 5 × ULN if related to underlying disease or the presence of liver metastases);
  • Total bilirubin | ≥ 1.5 × ULN (≥ 2.5 × ULN if Gilbert syndrome).
  • NOTE: Participants with biliary drainage to improve liver function tests to meet above criteria are allowed.
• Renal 
  • < 60 mL/min based on Cockcroft-Gault formula.
• Chemistry 
  • Serum phosphate | > ULN;
  • Serum calcium | Outside of normal range or serum albumin-corrected calcium outside of the normal range when serum albumin is outside of the normal range.
• 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).
• Gastrointestinal conditions/disorders that may raise gastric and/or small intestinal pH that could interfere with absorption, metabolism, or excretion of pemigatinib.
• Inability of the participant to swallow and retain oral medication
• 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).
• 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/uL, undetecable viral load, receiving antiretroviral therapy that does not interact with study drug, and no HIV/AIDS-associated opportunistic infection in the last 12 months. 
• Current use of prohibited medication.
• 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.
• Known hypersensitivity or severe reaction to pemigatinib, gemcitabine, cisplatin, or their excipients (refer to the IB and commercially available product information sheets).
• Inability or unlikeliness of the participant to comply with the dose schedule and study evaluations in the opinion of the investigator.
• Inadequate recovery from toxicity and/or complications from a major surgery before starting therapy.
• 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.
• 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.
• 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.
• Inability of the participant (or parent, guardian, or legally authorized representative) to comprehend or unwilling to sign the ICF.
• Any contraindication to gemcitabine or cisplatin as per each SmPC or product insert.
• History of hypovitaminosis D requiring supraphysiologic doses (e.g., 50,000UI/weekly) to replenish the deficiency. Participants receiving vitamin D supplements are allowed.