Clinical Trials

Inclusion Criteria:

• Patients with histologically or cytologically confirmed cholangiocarcinoma at the time of diagnosis. Patients with cancers of the gallbladder or ampulla of Vater are not eligible.
• Written documentation of local or central laboratory determination of FGFR2 gene fusions/translocations.
• A representative tumor sample must be available for molecular testing at Foundation Medicine, unless agreed upon between QED Therapeutics and the Investigator. An archival tumor sample and associated pathology report may be submitted. However, if not available, a newly obtained tumor biopsy may be submitted instead.
• Evidence of measurable or evaluable disease according to RECIST Version 1.1.
• Patients must have received at least one prior regimen containing gemcitabine with or without cisplatin for advanced/metastatic disease. Patient 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 ≥ 18 years of age of either gender.
• ECOG performance status ≤ 1 (Patients with ECOG performance status of 2 may be considered on a case-by-case basis after discussion with QED Therapeutics).
• Able to read and/or understand the details of the study and provide written evidence of informed consent as approved by IRB/EC.
• Recovery from adverse events of previous systemic anti-cancer therapies to baseline or Grade 1, except for:
  • Alopecia;
  • Stable neuropathy of ≤ Grade 2 due to prior cancer therapy.
• Able to swallow and retain oral medication.
• Willing and able to comply with scheduled visits, treatment plan and laboratory tests.

Exclusion Criteria:

• Prior or current treatment with a MEK or selective FGFR inhibitor.
• 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.
• 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.
• 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.
• 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.
• 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.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral BGJ398 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
• Current evidence of endocrine alterations of calcium/phosphate homeostasis, e.g., parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis etc.
• Treatment with any of the following anti-cancer therapies prior to the first dose of BGJ398 within the stated timeframes.
  • 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);
  • 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;
  • 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;
  • 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;
  • 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.
• 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.
• Consumption of grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, pumellos, Seville oranges or products within 7 days prior to first dose.
• Use of medications that are known to prolong the QT interval and/or are associated with a risk of Torsades de Pointes (TdP) 7 days prior to first dose.
• Use of amiodarone within 90 days prior to first dose.
• Current use of therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulants. Heparin and/or low molecular weight heparins are allowed.
• Insufficient bone marrow function:
  • ANC < 1,000/mm3 [1.0 x 109/L];
  • Platelets < 75,000/mm3 [75 x 109/L];
  • Hemoglobin < 9.0 g/dL.
• Insufficient hepatic and renal function:
  • Total bilirubin > 1.5x ULN;
  • AST/SGOT and ALT/SGPT > 2.5x ULN (AST and ALT > 5x ULN in the presence of liver metastases);
  • Serum creatinine > 1.5x ULN and a calculated or measured creatinine clearance of < 45 mL/min.
• Calcium-phosphate homeostasis:
  • Inorganic phosphorus outside of normal limits;
  • Total serum calcium (can be corrected) outside of normal limits.
• Clinically significant cardiac disease including any of the following:
  • Congestive heart failure requiring treatment (NYHA Grade ≥ 2 ), L VEF < 5 0% as determined by MUGA scan or ECHO, or uncontrolled hypertension (refer to WHOISH guidelines);
  • History or presence of clinically significant ventricular arrhythmias, atrial fibrillation, resting bradycardia, or conduction abnormality;
  • Unstable angina pectoris or acute myocardial infarction ≤ 3 months prior to starting study drug;
  • QTcF > 470 msec (males and females);
  • History of congenital long QT syndrome.
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 3 months following the discontinuation of study
• treatment. Highly effective contraception methods include:
  • Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception;
  • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment;
  • Male sterilization (at least 6 months prior to screening). For female patients on the study the vasectomized male partner should be the sole partner for that patient;
  • Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine systems (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.  In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.  Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child bearing potential.
• Sexually active males unless they use a condom during intercourse while taking drug and for 3 months after the last dose of the study drug and should not father a child in this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via seminal fluid.