A Phase 2, Open-Label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of Pemigatinib in Participants With Previously Treated Locally Advanced/Metastatic or Surgically Unresectable Solid Tumor Malignancies Harboring Activating FGFR Mutations or Translocations (FIGHT-207)

Inclusion Criteria

Participants are eligible to be included in the study only if all of the following criteria apply:

• Age 18 years or older, inclusive at the time of signing the informed consent.

• Histologically or cytologically confirmed solid tumor malignancy that is advanced or metastatic (Stage IIIB or IV per the AJCC Cancer Staging Manual, 6th ed; AJCC 2002) or is surgically unresectable.

• Radiographically measurable disease (per RECIST v1.1 or RANO for primary brain tumors). Tumor lesions located in a previously irradiated area, or in an area subjected to other loco-regional therapy, are considered measureable if progression has been clearly demonstrated in the lesion.

• Documentation of an FGFR1-3 gene mutation or translocation (Section 8.5.1 and Appendix C). Participants will be assigned to 1 of 3 cohorts:

• Cohort A: FGFR1-3 in-frame fusions or FGFR2 intron 17 rearrangements.

• Cohort B: Known/predicted activating point mutations in FGFR1-3 (excluding kinase domain, see Appendix C).

• Cohort C: Any FGFR1-3 point mutations in the kinase domain or FGFR1/FGFR3 rearrangements with unknown partners and variants of unknown significance not included in Appendix C.

• Must have objective progression after at least 1 prior therapy, and must have no therapy available that is likely to provide clinical benefit. Participants who are intolerant to or decline the approved therapy are eligible only if they have no therapy available that is likely to provide clinical benefit.

• ECOG performance status 0 to 2.

• Baseline archival tumor specimen (if less than 12 months from date of screening) or willingness to undergo a pretreatment tumor biopsy to obtain the specimen. Must be a tumor block or approximately 15 unstained slides from biopsy or resection of primary tumor or metastasis.

• Willingness to avoid pregnancy or fathering children based on the criteria below:

• Men 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 study drug(s)/treatment 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.

• 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. Permitted methods that are at least 99% effective in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed.

• Women of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea) are eligible.

Exclusion Criteria**

Participants are excluded from the study if any of the following criteria apply:

• Prior receipt of a selective FGFR inhibitor.
• Receipt of anticancer medications or investigational drugs for any indication or reason within 28 days before first dose of pemigatinib. Participants must have recovered (≤ Grade 1, as per CTCAE v5.0, or at pretreatment baseline) from AEs from previously administered therapies (excluding alopecia).
• Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, investigational therapy, or tumor embolization).
• Cannot 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, keratoconjunctivitis) or retinal disorder (including, but not limited to, macular/retinal degeneration, diabetic retinopathy, retinal detachment) as confirmed by ophthalmologic examination.
• Radiation therapy administered within 2 weeks of enrollment/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 1-week washout is permitted for palliative radiation to non-CNS disease.
• Untreated brain or CNS metastases or brain or CNS metastases that have progressed (eg, evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain or CNS metastases). Participants who have previously treated and clinically stable brain or CNS 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 if they are on a stable or decreasing dose of corticosteroids for at least 1 week.

Note: Participants with progressing primary brain tumors are allowed if they have no new neurological symptoms and are on a 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 in Table 9.

Table 9: Exclusionary Laboratory Values

• Laboratory Parameter Exclusion Criterion

• Hematology

• a Platelets ≤ 75 × 109/L (transfusion allowed with 2-week washout period)

• b Hemoglobin ≤ 9.0 g/L (transfusion allowed within 2-week washout period)

• c ANC ≤ 1.5 × 109/L

• Hepatic

• e ALT ≥ 3 × ULN (> 5 × ULN for liver metastasis)

• f AST ≥ 3 × ULN (> 5 × ULN for liver metastasis)

• g Total bilirubin ≥ 1.5 × ULN (≥ 2.5 × ULN if Gilbert's syndrome or liver metastasis)

• h Alkaline phosphatase ≥ 3 × ULN

• Renal

• i Serum creatinine clearance ≤ 30 mL/minute based on Cockcroft-Gault formula.

• Chemistry

• j Serum phosphate > ULN

• k 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 tendon, or vessels due to injury, disease, or aging in the absence of systemic mineral imbalance).

• Gastrointestinal condition/disorders that may raise gastric and/or small intestinal pH that could interfere with absorption, metabolism, or excretion of pemigatinib.

• Inability 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 drug/treatment administration, New York Heart Association Class III or 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 that, in the investigator's opinion, is clinically meaningful. A screening QTcF interval > 480 ms is excluded. For participants with an intraventricular conduction delay (QRS interval > 120 ms), the JTc interval may be used in place of the QTc with medical monitor approval. The JTc must be ≤ 340 ms if JTc is used in place of the QTc.

• Active chronic or current infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment within 2 weeks before enrollment (participants with asymptomatic chronic infections on prophylactic treatment are allowed).

• Evidence of active HBV or HCV infection (defined as participants with elevated transaminases or cirrhosis. Participants with chronic HBV/HCV infection with no cirrhosis and no elevated transaminases are allowed).

• Known HIV infection.

• Current use of prohibited medication as described in Section 6.6.2.

• Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14 days or five half lives (whichever is longer) before the first dose of study drug/treatment. Note that moderate CYP3A4 inhibitors are not prohibited.

• Known hypersensitivity or severe reaction to pemigatinib or excipients of pemigatinib (refer to the IB).

• 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.

• Women who are pregnant or breastfeeding.

• Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug/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 the ICF or unwillingness to sign the ICF.

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