| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced solid and CNS tumors with selected FGFR1-3 mutations or fusions/rearrangements, inclusive of recurrent or progressive low-grade glioma (LGG) with selected FGFR1-3 mutations or fusions/rearrangements. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced solid and central nervous system tumors (brain tumors) that is coming back after treatment (recurrent) or getting worse (progressive). |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025783 |
| E.1.2 | Term | Malignant neoplasm of brain |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- Phase 1b: To determine the pediatric recommended Phase 2 dose (RP2D) and to assess the safety of infigratinib in subjects with recurrent or progressive LGG and other advanced solid and CNS tumors with selected FGFR genetic alterations.
- To assess the antitumor activity of infigratinib in subjects with recurrent or progressive LGG with selected FGFR alterations who have received infigratinib at the RP2D. |
|
| E.2.2 | Secondary objectives of the trial |
- Phase 1b: To assess the pharmacokinetics (PK) of infigratinib and its major metabolites.
- Phase 1b: To evaluate the efficacy of infigratinib in pediatric subjects with advanced solid and non-LGG CNS tumors.
- To evaluate the efficacy of infigratinib in subjects with recurrent or progressive LGG.
- To assess the safety and tolerability of infigratinib in subjects with recurrent or progressive LGG. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase 1b:
1. must be ≥ 3 to <18 y.o. at Screening visit
2. Confirmed diagnosis of LGG (WHO Grade I/II glioma) based on histology, molecular, and clinical criteria concordant with the WHO Grading of Tumors of the Central Nervous System, including glial or mixed neuronal-glial tumor OR Histologically/cytologically confirmed CNS tumor (other than LGG) OR Histologically/cytologically confirmed advanced solid tumor
3. Disease recurrent or progressive after standard therapy (at least 1 prior standard therapy appropriate for tumor type and stage of disease unless available standard therapies are considered inadequate for subject)
4. Subjects without LGG must have either measurable/evaluable disease on imaging obtained within 4 W prior to Cycle1Day1
5. Adequate liver function includ.Bilirubin ≤ ULN for age & ALT and AST ≤ULN.
6. BSA ≥ 0.53 m2
Phase 2 at screening:
7. Diagnosis of recurrent/progressive (at least 1 prior standard therapy) LGG (WHO Grade I/II glioma), includ. glial/mixed neuronal-glial tumor
8. Age 3 years and older at screening visit
9. Adequate liver function
Phase 1b/2 (all subjects) at screening:
10. Confirmed FGFR1-3 alteration in tumor tissue
- FGFR1-3 testing performed on most recent tumor sample that meets requirements for testing and obtained before start of study treatment. Archival tumor samples collected no earlier than before start of immediate prior line of therapy
11. have availability of adequate unstained archival tissue for retrospective central confirmation of FGFR status. Subjects who enroll using local FGFR testing have sufficient pre-treatment sample for retrospective central lab confirmation of FGFR status. Central confirmatory testing of FGFR1-3 performed on most recent tumor sample that meets requirements for testing and obtained before start of study treatment. Archival tumor samples collected no earlier than before start of immediate prior line of therapy
12. Subjects with LGG must have evidence of measurable disease by RANO-LGG criteria using contrast-enhanced MRI of brain with pre- and post-contrast T1 and T2-FLAIR sequences
13. Interval of at least 3W from prior chemotherapy (6W for nitrosoureas); last dose of a biological agent given at least 7D and at least 5 half-lives before enrollment; last small molecule inhibitor given at least 4W before enrollment
14. If radiation,
Subjects with high grade CNS tumors or other solid tumors must have:
a. Had local palliative RT at least 2W prior to enrollment
b. Had substantial bone marrow radiation or radio iodized metaiodobenzylguanidine therapy at least 6W prior to enrollment
c. Had radiation to ≥50% of the pelvis, TBI, or craniospinal radiation at least 5M prior to enrollment
Subjects with LGG or other CNS tumors must have:
a. Had last fraction of local irradiation to primary tumor ≥12M prior to enrollment
b. Had last fraction of craniospinal irradiation >3M prior to enrollment
c. Had last local palliative RT at least 2W prior enrollment
d. Had radiation to ≥50% of the pelvis at least 5M prior enrollment
e. Had substantial bone marrow radiation at least 6W prior enrollment
Subjects who have received radiation therapy will require biopsy at recurrence for diagnostic confirmation
15. Stable neurologic findings for at least 1W of a dose of dexamethasone that is stable or being reduced
16. Able to swallow and retain oral medication
17. Performance score ≥50
18. Adequate renal function: eGFR of≥90 mL/minute/1.73m2
19. Adequate hematologic function
a. For subjects without known bone marrow involvement: ANC≥1.0 × 10E9/L and Platelet count ≥100 × 10E9/L and Hemoglobin ≥8.0 g/dL
b. Subjects with bone marrow involvement will not be evaluable for hematologic DLT and can enroll with ANC ≥0.75 × 10E9/L and Platelet count ≥75 × 10E9/L and Hemoglobin ≥8.0 g/dL
20. Normal calcium and phosphate levels
21. Contraceptive and barrier use as well as pregnancy testing is required as appropriate for age and sexual activity of pediatric and adult subjects and as required by local regulations.
22. Male or female.
a. Male participants agree to Refrain from donating sperm, PLUS either:Be abstinent from heterosexual intercourse and agree to remain abstinent OR Must agree to use contraception /barrier during study treatment period and for at least 1M after last dose of study treatment
b. Female participant is not pregnant or breastfeeding, and is woman of nonchildbearing potential OR Is woman of childbearing potential and using highly effective contraceptive method during study treatment period and for at least 1M after last dose of study treatment and agrees not to donate eggs for purpose of reproduction during this period.
- woman of childbearing potential with negative serum pregnancy test within 48 hours before first dose of study treatment.
23. Written informed consent from each pediatric study subject’s legal guardian and subject’s assent or written evidence of informed consent for subjects ≥18 y.
|
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply at the screening, unless otherwise specified:
1. Prior treatment with a FGFR1–3 selective inhibitor.
2. Known serious active infection or any clinically significant systemic illness, which in the Investigator’s opinion, cannot be adequately controlled with appropriate therapy or would compromise the subject’s ability to tolerate the study drug.
3. Received anti-convulsant drugs that are strong inducers of CYP3A4 (i.e., carbamazepine, phenobarbital, phenytoin) within 4 weeks before starting study treatment.
4. Currently receiving treatment with agents that are known strong and moderate inducers of CYP3A4 within 4 weeks from start of treatment or inhibitors of CYP3A4 within 1 week from start of treatment, including herbal preparations; medications which increase serum phosphorus and/or calcium concentration; use of a proton-pump inhibitors (e.g., omeprazole) within 4 days prior to start of study therapy or H2 receptor antagonists (e.g., famotidine) within 2 days prior to the start of study therapy.
5. Uncontrollable seizures.
6. Have current evidence of corneal or retinal disorder/keratopathy including, but not limited to, bullous/band keratopathy; corneal abrasion, inflammation, or ulceration; or keratoconjunctivitis, confirmed by ophthalmic examination. Subjects with a symptomatic ophthalmic conditions assessed by the Investigator to pose minimal risk for study participation may be enrolled in the study.
7. Have current evidence of endocrine alterations of calcium/phosphate homeostasis (e .g., parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis), unless well controlled.
8. Have a history and/or current evidence of extensive tissue calcification including, but not limited to, the soft tissue, kidneys, intestine, vasculature, myocardium, and lung with the exception of calcified lymph nodes, minor pulmonary parenchymal calcifications, small renal cyst or stone calcifications, and asymptomatic coronary calcification.
9. Have impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral infigratinib (e.g., active ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
10. Prolongation of QTcF interval >480 ms.
11. History of congenital long QT syndrome.
12. Had major surgery within 2 weeks of enrollment or not fully healed from open wound.
13. Known hypersensitivity to any components of the study drug or capsules.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Phase 1b: Rate of dose limiting toxicities (DLTs) during 1st cycle.
- Efficacy: objective response rate (ORR) by blinded independent central review (BICR) assessed by Response Assessment in Neuro-Oncology (RANO) criteria for LGG. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The timepoints are defined in the Schedule of Activities (SoA Section 1.3 of the Protocol). |
|
| E.5.2 | Secondary end point(s) |
- Phase 1b: PK parameters will be determined for infigratinib and its major metabolites as data permits: Cmax, AUC, T1/2, Tmax, CL/F, and Vz/F.
- best overall response (BOR), disease control rate (DCR), ORR, duration of response (DOR), time to onset of response (TTR), progression-free survival (PFS), best change in tumor size; all per Investigator assessment.
- CNS response criteria will be used as appropriate for the tumor type and grade (RANO-HGG, RANO-LGG. Etc.). Non-CNS tumors will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
- BICR-assessed DOR.
- BICR-assessed TTR.
- BICR-assessed PFS at 6, 12, and 24 months from treatment initiation and PFS after treatment termination.
- Overall survival (OS) at 12 and 24 months.
- BICR-assessed BOR, DCR, best change in tumor size.
- Investigator-assessed BOR, DCR, ORR, DOR, TTR, PFS and best change in tumor size by RANO-LGG criteria.
- Investigator-assessed PFS after treatment termination.
- Incidence/severity of AEs, including SAEs, DLTs. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The timepoints are defined in the Schedule of Activities (SoA Section 1.3 of the Protocol). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
- maximum tolerated dose (MTD)
- recommended Phase 2 dose (RP2D) for pediatric subject |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| standard dose escalation to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United States |
| Germany |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Per protocol, the end of the study is defined as the date when all treated patients have died, been lost to follow up or have withdrawn consent to be followed for survival, or when the study is terminated by the Sponsor. A subject is considered to have completed the study if he/she has completed all phases of the study, including all survival follow-up until the study is terminated. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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