| Eligibility |
Inclusion Criteria:
1. Prior resection of histologically diagnosed high-grade gliomas (III and IV) defined as
participants who have progressed on or following standard (Stupp regimen) therapy,
which included maximal surgical resection, temozolomide, and fractionated
radiotherapy.
2. Recurrence must be confirmed by diagnostic biopsy with local pathology review or
contrast-enhanced MRI.
3. Have measurable disease preoperatively, defined as at least 1 contrast-enhancing
lesion, with 2 perpendicular measurements of at least 1 cm, as per RANO criteria.
4. Sufficient archival tissue available to confirm eligibility.
5. Archival tissue must demonstrate: FGFR1 K656E or FGFR3 K650E mutation or FGFR3-TACC3
translocation from NGS sequencing or IHC and RT-PCR.
6. Ability to understand and the willingness to sign a written informed consent document
(personally or by the legally authorized representative, if applicable).
7. Has voluntarily agreed to participate by giving written informed consent (personally
or via legally authorized representative(s), and assent if applicable). Written
informed consent for the protocol must be obtained prior to any screening procedures.
If consent cannot be expressed in writing, it must be formally documented and
witnessed, ideally via an independent trusted witness.
8. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests and other procedures.
9. Age =18 at time of consent
10. Have a performance status (PS) of =2 on the Eastern Cooperative Oncology (Group (ECOG)
scale (Oken et al. 1982)
11. Ability to swallow oral medications.
12. Has adequate bone marrow and organ function as defined by the following laboratory
values (as assessed by the local laboratory for eligibility):
1. Adequate bone marrow function:
- absolute neutrophil count =1,000/mcL
- Platelets (at time of surgery) =100,000/mcL
- hemoglobin =8.0 g/dL Participants may receive erythrocyte transfusions to
achieve this hemoglobin level at the discretion of the investigator.
2. Adequate hepatic and renal function:
- total bilirubin =1.5 X ULN Participants with Gilbert's syndrome with a total
bilirubin =2.0 times ULN and direct bilirubin within normal limits are
permitted.
- AST(SGOT) =3 X institutional ULN
- ALT(SGPT) =3 X institutional ULN
- Calculated or measured creatinine clearance =45 mL/min
3. Other Lab Values:
- Amylase or lipase =2 X institutional ULN
- calcium or phosphorus, or calcium-phosphorus product <55 mg2/dL2
1. Inorganic phosphorus within normal limits
2. Total corrected serum calcium within normal limits
13. Confirmed negative serum pregnancy test (ß-hCG) before starting study treatment or
participant has had a hysterectomy.
14. For females of reproductive potential: use of highly effective contraception for at
least 1 month prior to screening and agreement to use such a method during study
participation and for an additional 3 months after the end of treatment
administration.
15. For males of reproductive potential: use of condoms or other methods to ensure
effective contraception with partner and for an additional 1 month after the end of
treatment administration. A condom is required to be used also by vasectomized men as
well as during intercourse with a male partner to prevent delivery of the drug via
seminal fluid.
16. Agreement to adhere to Lifestyle Considerations throughout study duration.
17. Participants who received chemotherapy must have recovered (Common Terminology
Criteria for Adverse Events [CTCAE] Grade =1) from the acute effects of chemotherapy
except for residual alopecia or Grade 2 peripheral neuropathy prior to Day 1. A
washout period of at least 21 days is required between last chemotherapy dose and Day
1 (provided the patient did not receive radiotherapy).
18. Participants who received radiotherapy must have completed and fully recovered from
the acute effects of radiotherapy. A washout period of at least 14 days is required
between end of radiotherapy and Day 1.
Exclusion Criteria:
1. Have a history of liver transplant.
2. Have impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of oral infigratinib (e.g., ulcerative diseases, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
3. Known active systemic bacterial infection (requiring intravenous [IV] antibiotics at
time of initiating study treatment), fungal infection, or detectable viral infection
(such as known human immunodeficiency virus positivity or with known active hepatitis
B or C [for example, hepatitis B surface antigen positive]. Screening is not required
for enrollment.
4. Have a history and/or current evidence of extensive tissue calcification including,
but not limited to, the soft tissue, kidneys, intestine, myocardium, vascular system,
and lung with the exception of calcified lymph nodes, minor pulmonary parenchymal
calcifications, and asymptomatic coronary calcification.
5. Have current evidence of corneal or retinal disorder/keratopathy including, but not
limited to, bullous/band keratopathy, inflammation or ulceration, keratoconjunctivitis
confirmed by ophthalmic examination. Subjects with asymptomatic ophthalmic conditions
assessed by the investigator to pose minimal risk for study participation may be
enrolled in the study.
6. Have current evidence of endocrine alterations of calcium/phosphate homeostasis, e.g.,
parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis
etc.
7. Have had a recent (=3 months prior to first dose of study drug) transient ischemic
attack or stroke.
8. CTCAE (v5.0) Grade =2 hearing loss.
9. CTCAE (v5.0) Grade =2 neuropathy.
10. Have clinically significant cardiac disease including any of the following:
1. Known congestive heart failure requiring treatment (New York Heart Association
Grade =2), LVEF <50% or local lower limit of normal as determined by MUGA scan or
echocardiogram (ECHO), or uncontrolled hypertension (refer to the European
Society of Cardiology and European Society of Hypertension guidelines [Williams
et al 2018]).
2. Presence of Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade =2
ventricular arrhythmias, atrial fibrillation, bradycardia, or conduction
abnormality.
3. Unstable angina pectoris or acute myocardial infarction =3 months prior to first
dose of study drug.
4. QTcF >470 msec (males and females). Note: If the QTcF is >470 msec in the first
ECG, a total of 3 ECGs separated by at least 5 minutes should be performed. If
the average of these 3 consecutive results for QTcF is =470 msec, the participant
meets eligibility in this regard.
5. Known history of congenital long QT syndrome.
11. Has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment
of the investigator, would preclude participation in this study (for example,
interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe
renal impairment [e.g. estimated creatinine clearance <30ml/min], history of major
surgical resection involving the stomach or small bowel, or preexisting Crohn's
disease or ulcerative colitis or a preexisting chronic condition resulting in baseline
Grade 2 or higher diarrhea).
12. Prior therapy with any mitogen-activated protein kinase (MEK) or FGFR inhibitor. Prior
therapy is defined as a therapeutic dosing, as determined by the Investigator.
13. Are currently receiving or are planning to receive during participation in this study,
treatment with agents that are known strong inducers or inhibitors of CYP3A4 and
medications which increase serum phosphorus and/or calcium concentration. Participants
are not permitted to receive enzyme-inducing anti-epileptic drugs, including
carbamazepine, phenytoin, phenobarbital, and primidone.
14. Current use of coumarin-derived anticoagulant for treatment, prophylaxis or otherwise.
Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed.
15. Have any known hypersensitivity to gemcitabine, cisplatin, calcium-lowering agents,
infigratinib, or their excipients.
16. Treatment with another investigational drug or other intervention within 30 days prior
to enrollment or within 5 half-lives of the investigational product, whichever is
longer.
17. Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star
fruits, pomelos, Seville oranges or products containing juice of these fruits within 7
days prior to first dose of study drug.
18. Have used medications known to prolong the QT interval and/or are associated with a
risk of Torsades de Pointes (TdP) 7 days prior to first dose of study drug.
19. Have used amiodarone within 90 days prior to first dose of study drug.
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