Tumor assessment for FGF/FGFR gene alteration status.
Prior receipt of a selective FGFR inhibitor.
Prior treatment with any selective inhibitor (e.g., AZD4547, BGJ398, JNJ-42756493, BAY1179470) of the fibroblast growth factor (FGF)-FGFR pathway
Previous treatment with a selective FGF19-FGFR4 targeted therapy and/or pan-FGFR inhibitor.
For expansion cohorts: Subjects will be eligible for Part 2 only if they have histological or cytological confirmed squamous non-small cell lung cancer (sqNSCLC), lung adenocarcinoma, head and neck cancer or bladder cancer (BC). All subjects in Part 2 will be stratified according to high FGFR expression levels FGFR mutation using archival or fresh tumor biopsy specimen. BC subjects with low overall FGFR expression levels can be included if activating FGFR3(FGFR tyrosine kinases3) mutations are confirmed
Previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase inhibitors or FGFR-specific antibodies)
Presence of either an FGFR3 mutation or FGFR3 over-expression within bladder tumor tissue. FGFR3 mutations in exons 7, 10, and 15 will be assessed by polymerase chain reaction (PCR)-single strand conformation polymorphism (PCR-SSCP) sequencing analysis utilizing the CertNDx® molecular grading assay performed in the Clinical Laboratory Improvement Amendments (CLIA)-certified Predictive Biosciences™ laboratories; FGFR3 over-expression will be assessed by standard immunohistochemistry (IHC) analysis performed within the Indiana University Simon Cancer Center Immunohistochemistry (IHC) Core Lab
Received prior fibroblast growth factor receptor (FGFR) inhibitor treatment
Tumors must have FGFR amplifications as determined by a Clinical Laboratory Improvement Act (CLIA) certified laboratory assay; patients with FGFR amplifications co-occurring with 11q amplification (CCND1, FGF3,4, 19 amplifications) are also eligible
Prior use of a drug targeting FGF or FGFR; patients previously treated with medications that affect FGFR signaling as a secondary target (e.g., multi-tyrosine kinase inhibitors that primarily inhibit VEGF, but to a lesser extent also affect FGFR signaling) can be considered after discussion with the principal investigator
Clinical stage IV or inoperable locoregional recurrent invasive mammary carcinoma that is:\r\n* ER+ and/or progesterone receptor (PgR)+ (>= 1% positive stained cells) by immunohistochemistry (IHC)\r\n* HER2-negative (by IHC or fluorescence in situ hybridization [FISH], per American Society of Clinical Oncology [ASCO] guidelines)\r\n* FGFR1, FGFR2, FGF3 or FGF4 amplified (may be determined by local assessment through either targeted capture next generation sequencing [NGS], plasma cell-free tumor [cf] DNA or FISH [in the case of FGFR1 amplifications]* in 50% of the patients participating in the expansion cohort of the trial [not necessary in the escalation cohort])\r\n** Cases will be considered as FGFR1-positive (‘amplified’) under one of the following conditions:\r\n*** The FGFR1/CEN8 ratio is >= 2.0\r\n*** The average number of FGFR1 signals per tumor cell nucleus is >= 6\r\n* Evaluable (may have either measurable or non-measurable disease)
Prior use of an FGFR inhibitor
Inclusion Criteria:\n\n        Has histologically or cytologically confirmed, locally advanced, metastatic cancer meeting\n        the following criteria:\n\n        Phase 1 Expansion\n\n          1. Patient has failed all standard therapies or standard therapy does not exist or is not\n             tolerated.\n\n          2. Patient has specific FGF/FGFR aberrations\n\n               -  Intrahepatic or extrahepatic cholangiocarcinoma with FGFR2 gene fusions or other\n                  FGFR2 abnormalities, i.e., gene mutations (see Appendix A), rearrangements or\n                  amplifications\n\n               -  Glioblastoma or grade III glioma (i.e., anaplastic astrocytoma or anaplastic\n                  oligodendroglioma) with FGFR gene fusions or activating mutations.\n\n               -  Advanced urothelial carcinoma with FGFR3 fusions or FGFR3 activating mutations\n\n               -  All other tumor types harboring FGF9, FGF19 or FGFR2 amplifications (? 10\n                  copies), FGFR gene fusions, or FGFR activating mutations\n\n        Phase 2\n\n          1. Patient has histologically or cytologically confirmed, locally advanced, metastatic,\n             unresectable iCCA harboring FGFR2 gene fusions based on results from a NGS assay by\n             the Sponsor's designated central laboratory\n\n          2. Patient has been treated with and failed at least one prior systemic gemcitabine and\n             platinum-based chemotherapy for the advanced disease\n\n          3. Must have documentation of radiographic progression of disease on prior systemic\n             therapy\n\n          4. Patient has measurable disease as defined by Response Evaluation Criteria in Solid\n             Tumors (RECIST) guidelines (version 1.1, 2009) for advanced solid tumors or RANO\n             criteria (2010) for brain tumors.\n\n          5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1\n\n          6. Adequate organ function\n\n        Exclusion Criteria:\n\n        A patient will be excluded from this study if any of the following criteria are met:\n\n          1. History and/or current evidence of non-tumor related alteration of calcium-phosphorus\n             homeostasis.\n\n          2. History and/or current evidence of clinically significant ectopic\n             mineralization/calcification.\n\n          3. History and/or current evidence of clinically significant retinal disorder confirmed\n             by retinal examination.\n\n          4. A serious illness or medical condition(s)
FGFR genetic alterations (specifically FGFR1-3 mutation, amplification, or translocation) via deoxyribonucleic acid (DNA) or ribonucleic acid (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 University (Univ.) of Chicago for testing\r\n* The following genetic aberrations will be screened for:\r\n** FGFR1 amplification, FGFR1 somatic mutations, FGFR1 translocations\r\n** FGFR2 somatic mutations, FGFR2 translocations, FGFR2 amplification\r\n** FGFR3 somatic mutations, FGFR3 translocations, FGFR3 amplification\r\n*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. fibroblast growth factor (FGF) amplification); should one genetic aberration be overrepresented in one or both of the arms the lead investigator (Dr. Seiwert) may decide to restrict enrollment of such patients; a notification/memo will be sent out to all investigators should such a restriction on enrollment be implemented (see inclusion criteria); for example, if more than 5 pts with FGFR1 amplification are enrolled further enrollment of FGFR1 amplified patiens will be put on hold, or if FGFR translocations are under-represented enrollment may be focused on this aberration
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 (Dr. Seiwert)
Patients who received prior treatment with a selective FGFR inhibitor
Patients who have received prior FGFR targeted therapy
Documented FGF/FGFR alteration and have either 1a) failed at least 1 previous treatment for their metastatic or surgically unresectable urothelial carcinoma (ie, chemotherapy, immunotherapy) or 1b) have not received chemotherapy due to poor ECOG status or 2) have insufficient renal function.
Prior receipt of a selective FGFR inhibitor.
Existence of archival or fresh biopsy for FGFR testing
Written documentation of local or central laboratory determination of amplification or translocation to FGFR1-TACC1, FGFR3-TACC-3 fusion and/or activating mutation in FGFR1, FGFR2,or FGFR3
Prior or current treatment with a FGFR inhibitor
Patients must not have had any prior exposure to any agent with FGFR inhibition as its primary pharmacology
Prior treatment with any selective inhibitor (e.g., AZD4547, BGJ398, JNJ-42756493, BAY1179470) of the FGF-FGFR pathway
Patients with histologically/cytologically confirmed advanced solid tumors with FGFR1 or FGFR2 amplification or FGFR3 mutation, for which no further effective standard anticancer treatment exists
Availability of tumor tissue sufficient for confirmatory testing of FGFR1 and 11q amplification status
Part 1: Any advanced solid tumor malignancy; Part 2: Subjects with squamous non-small cell lung cancer, cholangiocarcinoma/gastric cancer, urothelial cancer, breast/endometrial cancer, multiple myeloma, or MPNs that have a tumor or malignancy that has been evaluated and confirmed to harbor genetic alterations in FGF or FGFR genes. A subject's fibroblast growth factor (FGF) or fibroblast growth factor receptor (FGFR) alteration may be based on local or central laboratory results. Part 3: Dose finding: subjects with solid tumor malignancies who qualify for combo therapy; dose-expansion: FGF/FGFR+ subjects qualified to receive combo therapy
Prior receipt of a selective FGFR inhibitor
PART B: Patients must be proven to meet marker criteria (FGFR1 SISH+ ISH+, FGFR1 SISH+ ISH negative [-ve], FGFR1 SISH-ve ISH+, FGFR1 SISH-ve ISH-ve [FGFR1 double negative cohort] or ret proto-oncogene [RET] FISH+) prior to enrollment into Part B (treatment); adenocarcinoma patients must be known to not possess either an EGFR mutation or an ALK rearrangement in their tumor (if positive for one, testing for both is not required)
PART B: No previous or current exposure to other FGFR inhibitors in the FGFR-pathway selected cohorts, or RET inhibitors in the RET selected cohorts
Histologically or cytologically confirmed, locally advanced, inoperable, or metastatic solid tumors. Subjects eligible for enrollment in the Expanded Cohort must have documented and/or confirmed FGFR genetic alterations, including iCCA with FGFR2 gene fusion.
Previous treatment with FGFR inhibitors
FGFR2 gene fusion status confirmed by NGS or FISH testing
Previous treatment with any FGFR inhibitor (e.g., ponatinib, dovitinib, nintedanib, AZD4547, NVP-BGJ398, LY2784455, BAY1163877)
Prior receipt of a selective FGFR inhibitor.
Part B: Have alterations of FGFR3.
Any of the following tumor tissue based genetic alterations: FGFR1, FGFR2, FGFR3, VEGFA, or PDGFR? amplification; Any FGFR1, FGFR2, or FGFR3 gene fusion; FGFR1, FGFR2, or FGFR3 activating mutation
The pathologic tissue is available to determine FGFR1 amplification status
Prior PI3Ki or selective FGFR inhibitor treatment (for patients enrolled to expansion part)
Availability of archival tumor tissue required for assessment of deregulated FGF pathway signalling, but not limited to, FGFR1 amplification or FGF2 or FGFR1 expression. If archival tissue is not available, a fresh biopsy is required. In Arms A and B, subjects will be prospectively screened for FGFR1 gene amplification using a Fluorescence in situ hybridization (FISH) assay for the dose expansion and the MTD/MFD cohorts only. For inclusion in this study, based on the central laboratory testing, FGFR1 gene amplification must meet one of the following criteria: a ratio of FGFR1/CEN 8 of >=2; or average number of FGFR1 signals per tumor nucleus of >=6; or the percentage of tumor nuclei containing >=5 FGFR1 signals is >=50%. In Arm C, FGF2 expression by IHC will be evaluated retrospectively in tissue samples by a central laboratory and is not a requirement for study entry.
Prior FGFR inhibitor therapy
Part 1: HCC; cholangiocarcinoma; or esophageal, nasopharyngeal, or serous ovarian cancer, regardless of FGF/FGFR status.
Cohort C: cholangiocarcinoma, esophageal, nasopharyngeal or serous ovarian cancers (regardless of FGF/FGFR status), or other solid tumor malignancies with documented FGF19/FGFR4 alteration.
Prior receipt of a selective FGFR4 inhibitor within the last 6 months.
The patient's tumor has been evaluated and prospectively identified as having FGFR 1, 2, 3, or 4 genetic alterations.
Patients who have received adequate prior treatment with a highly selective FGFR inhibitor