A Phase II Telemedicine Study of Pemigatinib in Adult Patients With Advanced or Metastatic Pancreas Cancer With FGFR Genetic Alterations

This study is designed to evaluate the efficacy of the targeted, selective panFGFR inhibitor Pemigatinib when administered as a single agent to patients with genetically selected advanced or metastatic pancreas cancer through assessment of the overall response rate. Additionally, this study will support the molecular characterization of this subset of pancreas cancer through correlative studies

PRIMARY OBJECTIVES

1. To evaluate the efficacy of single agent pemigatinib in patients with advanced or metastatic pancreas cancer of any histologic classification with FGFR2 gene fusions/translocations or other FGFR genetic alterations as measured by overall response rate assessed by investigator according to RECIST v1.1.
2. To understand response rate and potential for pemigatinib to benefit patients who have FGFR alterations such as point mutations/insertions/small deletions in pancreas cancer

SECONDARY OBJECTIVES

1. To further evaluate the efficacy of single agent pemigatinib as measured by progression free survival, best overall response, disease control rate, overall survival assessed by investigator as per RECIST v1.1
2. To characterize the safety and tolerability of single agent pemigatinib by type, frequency, and severity of Adverse Events (AEs) and Severe Adverse Events (SAEs)

Eligibility Criteria:
Inclusion Criteria:

1. Patients with histologically or cytologically confirmed advanced or metastatic pancreas cancer of any histologic classification at the time of diagnosis.
2. Written documentation of local or central CLIA-certified laboratory determination of FGFR gene fusions/translocations or activating mutations.
3. The study is open to pancreas cancer in the following cohorts:

   * Cohort 1: Pancreas cancer of any histology with FGFR2 fusion/translocation (n, up to 30) who have progressed on or are intolerant to standard of care (SOC) therapies. Prior therapy with a different FGFR inhibitor is not permitted. Patients with concurrent KRAS mutations are excluded from this cohort
   * Cohort 2: Pancreas cancer of any histology with activating point mutations, fusion/translocation \[FGFR1,3,4\] extracellular small indels, or kinase domain duplications (n, up to 10). Patients must have progressed on or are intolerant to SOC therapies. Prior therapy with a different FGFR inhibitor is not permitted. Patients with concurrent KRAS mutations are permitted in this cohort.
4. Evidence of measurable or evaluable disease according to RECIST Version 1.1.
5. Patients must have received at least one prior SOC regimen for advanced/metastatic pancreas cancer. Patients should have had evidence of progressive disease following their prior regimen, or if prior treatment was discontinued due to toxicity must have continued evidence of measurable or evaluable disease. Patients who have received prior treatment with an alternate FGFR inhibitor are not eligible for the study.
6. Patients with symptomatic CNS metastases are excluded (because it is unclear how much CNS penetration the drug has). However, asymptomatic patients with history of successfully treated CNS metastases with surgery or radiation and follow up imaging showing stability, can be eligible.
7. Patients ≥ 18 years of age of either gender.
8. ECOG performance status ≤ 1 (Patients with ECOG performance status of 2 may be considered on a case-by-case basis after discussion with Incyte).
9. Able to read and/or understand the details of the study and provide written evidence of informed consent as approved by IRB/EC.
10. Recovery from adverse events of previous systemic anti-cancer therapies to baseline or Grade 1, except for:

    1. Alopecia
    2. Stable neuropathy of ≤ Grade 2 due to prior cancer therapy
11. Able to swallow and retain oral medication.
12. Willing and able to comply with scheduled visits, treatment plan and laboratory tests

Exclusion Criteria:

1. Patients who have therapies available that are known to confer a clinical benefit will be excluded from the study.
2. Neurological symptoms related to underlying disease requiring increasing doses of corticosteroids. Note: Steroid use for management of CNS tumors is allowed but must be at a stable dose for at least 2 weeks preceding study entry.
3. History of another primary malignancy except adequately treated in situ carcinoma of the cervix or non-melanoma carcinoma of the skin or any other curatively treated malignancy that is not expected to require treatment for recurrence during the course of the study or affect survival.
4. Any other medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures.
5. Current evidence of corneal or retinal disorder/keratopathy including, but not limited to, bullous/band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjuctivitis, confirmed by ophthalmologic examination.
6. History and/or current evidence of extensive tissue calcification including, but not limited to, the soft tissue, kidneys, intestine, myocardium, and lung with the exception of calcified lymph nodes, minor pulmonary parenchymal calcifications, and asymptomatic coronary calcification.
7. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral pemigatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
8. Current evidence of endocrine alterations of calcium/phosphate homeostasis, e.g., parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis etc.
9. Treatment with any of the following anti-cancer therapies prior to the first dose of pemigatinib within the stated timeframes:

   1. Cyclical chemotherapy (intravenous) within a period of time that is shorter than the cycle length used for that treatment (e.g., 6 weeks for nitrosourea, mitomycin-C)
   2. Biological therapy (e.g., antibodies - including bevacizumab) within a period of time that is ≤ 5 t1/2 or ≤ 4 weeks, whichever is shorter, prior to starting study drug.
   3. Continuous or intermittent small molecule therapeutics within a period of time that is ≤ 5 t1/2 or ≤ 4 weeks (whichever is shorter) prior to starting study drug.
   4. Any other investigational agents within a period of time that is ≤ 5 t1/2 or less than the cycle length used for that treatment or ≤ 4 weeks (whichever is shortest) prior to starting study drug.
   5. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug.
10. Patients who are currently receiving treatment with agents that are known strong inducers or inhibitors of CYP3A4 and medications which increase serum phosphorus and/or calcium concentration are excluded. (Refer to Appendix 2 for list of prohibited medications). Patients are not permitted to receive enzyme-inducing anti-epileptic drugs.
11. Consumption of grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, pomelos, Seville oranges or products within 7 days prior to first dose.
12. Insufficient bone marrow function:

    1. Absolute Neutrophil Count (ANC) ≤ 1,000/mm3 \[1.0 x 109/L\]
    2. Platelets ≤ 75,000/mm3 \[75 x 109/L\]
    3. Hemoglobin ≤ 9.0 g/dL
13. Insufficient hepatic and renal function:

    1. Total bilirubin ≥ 1.5x Upper Limit of Normal (ULN) unless associated with patient's primary cancer and/or metastases and with Principal Investigator's approval.
    2. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≥ 3x ULN unless associated with patient's primary cancer and/or metastases and with Principal Investigator's approval.
    3. Alkaline phosphatase ≥ 2.5x ULN unless associated with patient's primary cancer and/or metastases and with Principal Investigator's approval.
    4. Calculated or measured creatinine clearance of \< 40 mL/min
14. Calcium-phosphate homeostasis:

    1. Inorganic phosphorus outside of institutional normal limits
    2. Total serum calcium (can be corrected) outside of institutional normal limits.
15. History of clinically significant or uncontrolled cardiac disease including unstable angina