Tumor assessment for FGF/FGFR gene alteration status.
Prior receipt of a selective FGFR inhibitor.
Prior treatment with any selective inhibitor (e.g., AZD, BGJ, JNJ-, BAY) of the fibroblast growth factor (FGF)-FGFR pathway
Previous treatment with a selective FGF-FGFR targeted therapy and/or pan-FGFR inhibitor.
For expansion cohorts: Subjects will be eligible for Part  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  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 FGFR(FGFR tyrosine kinases) mutations are confirmed
Previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase inhibitors or FGFR-specific antibodies)
Presence of either an FGFR mutation or FGFR over-expression within bladder tumor tissue. FGFR mutations in exons , , and  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; FGFR 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 q amplification (CCND, FGF,,  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)+ (>= % positive stained cells) by immunohistochemistry (IHC)\r\n* HER-negative (by IHC or fluorescence in situ hybridization [FISH], per American Society of Clinical Oncology [ASCO] guidelines)\r\n* FGFR, FGFR, FGF or FGF 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 FGFR amplifications]* in % of the patients participating in the expansion cohort of the trial [not necessary in the escalation cohort])\r\n** Cases will be considered as FGFR-positive (amplified) under one of the following conditions:\r\n*** The FGFR/CEN ratio is >= .\r\n*** The average number of FGFR signals per tumor cell nucleus is >= \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  Expansion\n\n          . Patient has failed all standard therapies or standard therapy does not exist or is not\n             tolerated.\n\n          . Patient has specific FGF/FGFR aberrations\n\n               -  Intrahepatic or extrahepatic cholangiocarcinoma with FGFR gene fusions or other\n                  FGFR 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 FGFR fusions or FGFR activating mutations\n\n               -  All other tumor types harboring FGF, FGF or FGFR amplifications (? \n                  copies), FGFR gene fusions, or FGFR activating mutations\n\n        Phase \n\n          . Patient has histologically or cytologically confirmed, locally advanced, metastatic,\n             unresectable iCCA harboring FGFR gene fusions based on results from a NGS assay by\n             the Sponsor's designated central laboratory\n\n          . Patient has been treated with and failed at least one prior systemic gemcitabine and\n             platinum-based chemotherapy for the advanced disease\n\n          . Must have documentation of radiographic progression of disease on prior systemic\n             therapy\n\n          . Patient has measurable disease as defined by Response Evaluation Criteria in Solid\n             Tumors (RECIST) guidelines (version ., ) for advanced solid tumors or RANO\n             criteria () for brain tumors.\n\n          . Eastern Cooperative Oncology Group (ECOG) performance status  or \n\n          . 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          . History and/or current evidence of non-tumor related alteration of calcium-phosphorus\n             homeostasis.\n\n          . History and/or current evidence of clinically significant ectopic\n             mineralization/calcification.\n\n          . History and/or current evidence of clinically significant retinal disorder confirmed\n             by retinal examination.\n\n          . A serious illness or medical condition(s)
FGFR genetic alterations (specifically FGFR- 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** FGFR amplification, FGFR somatic mutations, FGFR translocations\r\n** FGFR somatic mutations, FGFR translocations, FGFR amplification\r\n** FGFR somatic mutations, FGFR translocations, FGFR 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  pts with FGFR amplification are enrolled further enrollment of FGFR 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 a) failed at least  previous treatment for their metastatic or surgically unresectable urothelial carcinoma (ie, chemotherapy, immunotherapy) or b) have not received chemotherapy due to poor ECOG status or ) have insufficient renal function.
Prior receipt of a selective FGFR inhibitor.
Written documentation of local or central laboratory determination of amplification or translocation to FGFR-TACC, FGFR-TACC- fusion and/or activating mutation in FGFR, FGFR,or FGFR
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., AZD, BGJ, JNJ-, BAY) of the FGF-FGFR pathway
Patients with histologically/cytologically confirmed advanced solid tumors with FGFR or FGFR amplification or FGFR mutation, for which no further effective standard anticancer treatment exists
Part : Any advanced solid tumor malignancy; Part : 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 : 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 (FGFR SISH+ ISH+, FGFR SISH+ ISH negative [-ve], FGFR SISH-ve ISH+, FGFR SISH-ve ISH-ve [FGFR 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 FGFR gene fusion.
Previous treatment with FGFR inhibitors
FGFR gene fusion status confirmed by NGS or FISH testing
Previous treatment with any FGFR inhibitor (e.g., ponatinib, dovitinib, nintedanib, AZD, NVP-BGJ, LY, BAY)
Prior receipt of a selective FGFR inhibitor.
Part B: Have alterations of FGFR.
Any of the following tumor tissue based genetic alterations: FGFR, FGFR, FGFR, VEGFA, or PDGFR? amplification; Any FGFR, FGFR, or FGFR gene fusion; FGFR, FGFR, or FGFR activating mutation
The pathologic tissue is available to determine FGFR amplification status
Prior PIKi 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, FGFR amplification or FGF or FGFR expression. If archival tissue is not available, a fresh biopsy is required. In Arms A and B, subjects will be prospectively screened for FGFR 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, FGFR gene amplification must meet one of the following criteria: a ratio of FGFR/CEN  of >=; or average number of FGFR signals per tumor nucleus of >=; or the percentage of tumor nuclei containing >= FGFR signals is >=%. In Arm C, FGF 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 : 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 FGF/FGFR alteration.
Prior receipt of a selective FGFR inhibitor within the last  months.
The patient's tumor has been evaluated and prospectively identified as having FGFR , , , or  genetic alterations.
Patients who have received adequate prior treatment with a highly selective FGFR inhibitor