Clinical Trials /

Infigratinib in Recurrent Glioblastoma Patients

NCT04424966

Description:

This trial is an open-label, multicenter, Phase 0 trial that will enroll up to 20 participants with recurrent high-grade glioma with FGFR1 K656E or FGFR3 K650E mutation or FGFR3-TACC3 translocation which are scheduled for resection. In the lead-in cohort, a total of 20 participants will be enrolled into the proposed phase 0 clinical trial. Participants will be administered infigratinib prior to surgical resection of their tumor.

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Infigratinib in Recurrent Glioblastoma Patients
  • Official Title: A Phase 0 Study of Infigratinib in Recurrent High-Grade Glioma Participants Scheduled for Resection to Evaluate Central Nervous System (CNS) Penetration With PK Triggered Expansion Cohort

Clinical Trial IDs

  • ORG STUDY ID: 2020-08
  • SECONDARY ID: 20-500-092-34-38
  • NCT ID: NCT04424966

Conditions

  • Glioma
  • Glioblastoma
  • GBM

Interventions

DrugSynonymsArms
InfigratinibArm 1

Purpose

This trial is an open-label, multicenter, Phase 0 trial that will enroll up to 20 participants with recurrent high-grade glioma with FGFR1 K656E or FGFR3 K650E mutation or FGFR3-TACC3 translocation which are scheduled for resection. In the lead-in cohort, a total of 20 participants will be enrolled into the proposed phase 0 clinical trial. Participants will be administered infigratinib prior to surgical resection of their tumor.

Trial Arms

NameTypeDescriptionInterventions
Arm 1ExperimentalPhase 0: 125 mg of infigratinib administered orally for 7 days prior to surgical resection. Expansion Cohort: 125 mg of infigratinib administered orally for 21 days of a 28-day treatment cycles.
  • Infigratinib

Eligibility Criteria

        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 (β-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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 0: Concentration of infigratinib in enhancing and non-enhancing tumor tissue
Time Frame:Day 7 at 8 hours post dose
Safety Issue:
Description:Phase 0: Tumor tissue will be collected approximately 8hrs after infigratinib administration on Day 7 to determine the concentration of infigratinib in the tumor tissue.

Secondary Outcome Measures

Measure:Phase 0: PD Analysis
Time Frame:Intraoperatively
Safety Issue:
Description:Phase 0: percentage of pERK+, MIB-1+ and Cleaved Caspase 3+ cells from the surgical tissue will be quantified and compared to baseline archival tissue.
Measure:Number of Adverse Events
Time Frame:up to 30 days after the last study dose
Safety Issue:
Description:Number of Adverse Events
Measure:Incidence of drug-related toxicity
Time Frame:up to 30 days after the last study dose
Safety Issue:
Description:Drug-related toxicity
Measure:Incidence of treatment-emergent adverse events
Time Frame:up to 30 days after the last study dose
Safety Issue:
Description:Treatment-emergent adverse events
Measure:Number of Deaths
Time Frame:up to 60 months
Safety Issue:
Description:Number and Incidence of Deaths
Measure:Number of clinical laboratory abnormalities per CTCAE
Time Frame:up to 30 days after the last study dose
Safety Issue:
Description:Clinical laboratory abnormalities per CTCAE

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Nader Sanai

Last Updated

June 5, 2020