Patient case: 38-year-old male with Liposarcoma. Genetic variant: CDK4 Amplification. Other conditions: GERD.

Clinical trial: Study of the Efficacy of Single Agent BGJ398 in FGFR1-3 Translocated, Mutated, or Amplified Squamous Cell Carcinoma of the Head and Neck

Summary: This phase IIa proof-of-concept open-label trial will consist of two cohorts namely, HPV(+) and HPV(-) and will be run across multiple centers through the University of Chicago PCC Consortium. All eligible patients with histologically-confirmed recurrent/metastatic HNSCC and FGFR alteration will receive BGJ398 at 125 mg PO daily. Patients with FGFR1-3 high level amplification, mutation, or translocation will be included.

Detailed description: Primary Objectives
  To assess efficacy of BGJ398 in FGFR altered HPV (-) and HPV (+) HNSCC.
  Secondary Objectives
  1. To assess efficacy of BGJ398 in relation to specific genetic aberrations in HPV (+) and HPV (-) FGFR altered HNSCC (i.e. FGFR3-TACC3 translocation, FGFR1 high copy number/amplification, FGFR2 mutation, FGFR3 mutation).
  2. To assess safety and tolerability of BGJ398 in patients with Head and Neck Cancer.
  3. To assess progression free and overall survival.
  Exploratory Objectives To determine mechanisms of resistance to FGFR inhibition at disease progression.

Eligibility: Inclusion Criteria
  Must meet all of the following:
  1. Histologically documented diagnosis of squamous cell carcinoma of the head/neck including nasopharyngeal carcinomas (lymphephithelioma histology is ok if criteria 2 is met).
  a) Patients must have progressed on prior platinum based therapy (or have become intolerant) prior to enrollment on this study.
  2. FGFR genetic alterations (specifically FGFR1-3 mutation, amplification, or translocation) via DNA or RNA based assay. Prescreening has to be completed prior to enrollment on this study. Commercial or local testing is typically expected, but samples can also be sent to the Univ. of Chicago for testing.
  The following genetic aberrations will be screened for:
  -  FGFR1 amplification, FGFR1 somatic mutations, FGFR1 translocations.
  -  FGFR2 somatic mutations, FGFR2 translocations, FGFR2 amplification.
  -  FGFR3 somatic mutations, FGFR3 translocations, FGFR3 amplification.
  Other genetic FGF/FGFR pathway aberrations may be acceptable should such genetic changes be observed to emerge and require approval per the Lead Investigator for enrollment (e.g. FGF amplification).
  3. Consent to undergo a fresh biopsy in case of benefit from therapy and subsequent progression
  4. ECOG performance status ≤1
  5. Patients must provide written informed consent prior to any screening procedures.
  6. Age 18 years or older.
  7. Willing and able to comply with scheduled visits, treatment plan and laboratory tests
  8. Patient is able to swallow and retain oral medication, unless approval per the manufacturer of other administration routes/methods is provided.
  9. 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
  10. HPV status in Oropharyngeal Carcinomas. While HPV status (e.g. via p16) does not have to be known prior to consenting, the HPV status (e.g. using p16 IHC) needs to be established prior to start of therapy.
  11. Presence of measurable disease by RECIST 1.1
  12. Availability of tumor tissue (e.g. FFPE) for genomic profile (typically 12 unstained FFPE 5-10 micron slides, minimum of 10).
  Exclusion Criteria:
  1. 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 has not been treated in the prior 3 months or expected to require treatment for recurrence during the course of the study.
  2. Patients with metastatic CNS tumors are allowed provided that they are clinically stable for a period of 30 days prior to study entry and there is not a requirement for steroid (other than close to physiologic doses) or anti-convulsant therapy. Patients with leptomeningeal involvement are excluded.
  3. Patients who received a prior selective FGFR inhibitor in the recurrent/metastatic disease setting. Prior use of a multikinase inhibitor that includes anti-FGFR activity is acceptable after review by the Lead Investigator
  4. History and/or current evidence of tissue calcification including, but not limited to, the soft tissue, kidneys, intestine, myocardium and lung with the exception of calcified lymph nodes and asymptomatic coronary calcification
  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. 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)
  7. History and/or current evidence of endocrine alterations of calcium/phosphate homeostasis, e.g., parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis, etc unless the lead investigator obtains approval from Novartis.
  8. 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 2 weeks unless there are ongoing side effects > Grade 2.
  -  Biological therapy (including small molecules, and/or) within a period of time that is ≤2 weeks prior to starting study drug unless there are ongoing side effects > Grade 2.
  -  Any other investigational agents within a period ≤ 2 weeks prior to starting study drug unless there are ongoing side effects > Grade 2.
  -  Wide field radiotherapy (including radioisotopes) ≤ 2 weeks prior to starting study drug unless there are ongoing side effects > Grade 2.
  9. Patients who are currently receiving treatment with agents that are known strong inducers or inhibitors of CYP3A4 are prohibited.
  10. Enzyme inducing anti-epileptic drugs.
  11. Consumption of grapefruit, grapefruit juice, pomegranates, star fruits, Seville oranges or products within 7 days prior to first dose.
  12. Use of medications that are known to prolong the QT interval and/or are associated with a risk of Torsades de Pointes 7 days prior to first dose.
  13. Use of amiodarone within 90 days prior to first dose.
  14. Use of medications that increase serum levels of phosphorus and/or calcium.
  15. Current use of therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulants. Heparin and/or low molecular weight heparins or other anticoagulants are allowed.
  16. Insufficient bone marrow function
  -  ANC <1,000/mm3 [1.0 x 109/L]
  -  Platelets < 75,000/mm3 [75 x 109/L]
  -  Hemoglobin < 10.0 g/dL
  17. Insufficient hepatic and renal function
  -  Total bilirubin > 1.5x ULN (unless evidence of Gilbert's disease)
  -  AST/SGOT and ALT/SGPT > 2.5x ULN
  -  Serum creatinine ≥ ULN and/or calculated or measured creatinine clearance < 75% LLN
  18. Calcium-phosphate homeostasis
  -  Inorganic phosphorus outside of normal limits
  -  Total and ionized serum calcium outside of normal limits
  19. Clinically significant cardiac disease including any of the following:
  -  Congestive heart failure requiring treatment (NYHA grade ≥ 2), LVEF < 50% as determined by MUGA scan or ECHO, or uncontrolled hypertension (refer to WHO-ISH 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 > 450 msec (both genders)
  -  History of congenital long QT syndrome
  20. 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
  21. Known positive serology for HIV, active Hepatitis B, and/or active Hepatitis C infection.
  22. Study medication cannot be administered through G-tube, unless additional information from the manufacturer becomes available in the future.
  23. Women of child-bearing potential, 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 must be used by both sexes (=female patients and their male partners). Highly effective contraception methods include:
  -  Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. 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 subjects on the study the vasectomized male partner should be the sole partner for that subject.
  -  Combination of the following (a+b or a+c, or b+c):
  1. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception
  2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
  3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
  Note: Oral contraceptives (OC), injected or implanted hormonal methods are not allowed as the sole method of contraception because BGJ398 has not been characterized with respect to the potential to interfere with PK and/or the effectiveness of OCs.
  Post-menopausal women are allowed to participate in this study. 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 six 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.
  24. 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 in order to prevent delivery of the drug via seminal fluid.

Relevance to patient case: not relevant