Phase 2 Study of Rogaratinib (BAY 1163877) in the Treatment of Patients With Sarcoma Harboring Alterations in Fibroblast Growth Factor Receptor (FGFR) 1-4 and SDH-Deficient Gastrointestinal Stromal Tumor (GIST)
Phase: PHASE2
Conditions: Locally Advanced Gastrointestinal Stromal Tumor, Locally Advanced Sarcoma, Metastatic Gastrointestinal Stromal Tumor, Metastatic Sarcoma, Stage III Gastric and Omental Gastrointestinal Stromal Tumor AJCC v8, Stage III Small Intestinal, Esophageal, Colorectal, Mesenteric, and Peritoneal Gastrointestinal Stromal Tumor AJCC v8, Stage IV Gastric and Omental Gastrointestinal Stromal Tumor AJCC v8, Stage IV Small Intestinal, Esophageal, Colorectal, Mesenteric, and Peritoneal Gastrointestinal Stromal Tumor AJCC v8
Sponsor: National Cancer Institute (NCI)

i 
 
To: 
CTEP Protocol and Information Office 
From: 
Suzanne George, MD 
Date: 
April 4, 2025 
Re: 
Review of Revision 13 of Protocol #10411: “Phase 2 Study of Rogaratinib (BAY 
1163877) in the Treatment of Patients with Sarcoma Harboring Alterations in Fibroblast 
Growth Factor Receptor (FGFR) 1-4 and SDH-deficient Gastrointestinal Stromal Tumor 
(GIST).” 
 
We are submitting this amendment to clarify the information in the updated visit schedule. 
Patients will now be re-evaluated for response every 8 weeks through the end of Cycle 26, and 
then every 3 cycles thereafter (±14 days). Patients will return on Cycle 27 Day 1 for Cycle 26 
scan review, then return every 3 cycles thereafter (±14 days), so the next scan review visit will 
occur on Cycle 30 Day 1, Cycle 33 Day 1, etc. In addition, this amendment updates the 
protocol version date. 
 
SUMMARY OF CHANGES – Protocol 
 
 
I. 
CTEP-requested changes: 
 
# 
Section 
Comments 
1. 
Header 
Updated version date. 
2. 
Title/Cover 
Page 
New Protocol Amendment/Version Date 
 
 
II. 
Study team-initiated protocol changes: 
 
# 
Section 
Comments 
1. 
11.0 
The reference to “Cycle 29” is an error.  It should reference “Cycle 27” as 
the Day 1 visit when the Cycle 26 scan will be reviewed.  After Cycle 27 
Day 1, scans will occur every 3 cycles, so the next scan review visit will 
occur on Cycle 30 Day 1, Cycle 33 Day 1, etc. 
Also edited “Tumor measurements” and “Radiologic evaluation” to 
specify “through the end of Cycle 26, and then every 3 cycles thereafter 
(±14 days).” 
 
2. 
12.1 
Edited the following sentence for clarity: “For the purposes of this study, 
patients should be re-evaluated for response every 8 weeks (±3 days) 
through the end of Cycle 26, and then every 3 cycles thereafter (±14 

i 
 
days).” 

1 
 
NCI Protocol #: 
10411 
 
Local Protocol #: 
21-070 
 
ClinicalTrials.gov Identifier: NCT04595747 
 
TITLE: Phase 2 Study of Rogaratinib (BAY 1163877) in the Treatment of Patients with 
Sarcoma Harboring Alterations in Fibroblast Growth Factor Receptor (FGFR) 1-4 and SDH- 
deficient Gastrointestinal Stromal Tumor (GIST) 
 
Corresponding Organization:  LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
 
Principal Investigator: 
Suzanne George, MD 
Sarcoma Center, 
450 Brookline Avenue, 
Boston, MA 02215, USA 
617-632-5204 
617-632-3408 (fax) 
sgeorge2@partners.org 
 
Participating Organizations 
 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / UPMC Hillman Cancer Center LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
EDDOP / Early Drug Development Opportunity Program 
CATCHUP / Creating Access to Targeted Cancer Therapy for Underserved Populations 
 
Statistician: 
Emanuele Mazzola, PhD 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
CLS 11075 
Boston, MA 02215 
Telephone: 617-582-7614 
mazzola@jimmy.harvard.edu 

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Responsible Study Coordinator: 
Responsible Research Nurse: 
10411 Study Coordinator 
10411 Research Nurse 
Sarcoma Center 
Sarcoma Center 
Dana-Farber Cancer Institute 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
450 Brookline Avenue 
Boston, MA 02215 
Boston, MA 02215 
Phone: (617) 632-6910 
Phone: (617) 632-5204 
Fax: (617) 632-4041 
Fax: (617) 632-3408 
dfcisarcomatrials@partners.org 
DFCISACResearchNursing@partners.org 
 
 
 
NCI-Supplied Agent: Rogaratinib (BAY 1163877) () (NSC 804782) 
 
IND #: 
 
IND Sponsor: DCTD, NCI 
 
Protocol Type / Version # / Version Date: 
 
Original / July 22, 2020 
Revision 1 / September 9, 2020 
Revision 2a / November 18, 2020 
Revision 3 / December 22, 2020 
Revision 4 / January 14, 2021 
Revision 5 / August 2, 2021 
Revision 6 / January 18, 2022 
Revision 7 / June 30, 2022 
Revision 8 / October 25, 2022 
Revision 9 / March 7, 2023 
Revision 10 / July 26, 2023 
Revision 11 / August 14, 2024 
Revision 12 / January 7, 2025 
Revision 13 / April 4, 2025 

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TABLE OF CONTENTS 
SCHEMA ......................................................................................................................................... 3 
1. 
OBJECTIVES ..................................................................................................................... 7 
1.1 
Primary Objectives .................................................................................................. 7 
1.2 
Secondary Objectives .............................................................................................. 7 
1.3 
Exploratory Objectives ............................................................................................ 7 
2. 
BACKGROUND ................................................................................................................. 7 
2.1 
Study Disease .......................................................................................................... 7 
2.2 
CTEP IND Agent .................................................................................................. 15 
2.3 
Rationale................................................................................................................ 18 
2.4 
Correlative Studies Background ............................................................................ 22 
3. 
PATIENT SELECTION.................................................................................................... 24 
3.1 
Eligibility Criteria .................................................................................................. 24 
3.2 
Exclusion Criteria .................................................................................................. 26 
3.3 
Inclusion of Women and Minorities ...................................................................... 27 
4. 
REGISTRATION PROCEDURES ................................................................................... 27 
4.1 
Investigator and Research Associate Registration with CTEP .............................. 27 
4.2 
Site Registration .................................................................................................... 28 
4.3 
Patient Registration ............................................................................................... 31 
4.4 
General Guidelines ................................................................................................ 33 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................ 33 
5.1 
Summary Table for Specimen Collection ............................................................. 33 
5.2 
Summary Table(s) for Research Biopsies ............................................................. 34 
5.3 
Specimen Procurement Kits and Scheduling ......................................................... 35 
5.4 
Specimen Tracking System Instructions ............................................................... 35 
5.5 
Specimen Collection.............................................................................................. 39 
5.6 
Shipping Specimens from Clinical Site to the EET Biobank ................................ 41 
5.7 
Shipping Specimens from Clinical Site to the JHU SKCCC Analytical 
Pharmacology Core Lab (APC) for the ChOP-KC ............................................... 44 
5.8 
Biomarker Plan ...................................................................................................... 45 
5.9 
Integral Laboratory Studies ................................................................................... 49 
5.10 
Integrated Correlative Studies ............................................................................... 49 
5.11 
Exploratory Correlative Studies ............................................................................ 51 
6. 
TREATMENT PLAN ....................................................................................................... 52 
6.1 
Agent Administration ............................................................................................ 52 
6.2 
General Concomitant Medication and Supportive Care Guidelines ...................... 53 
6.3 
Duration of Therapy .............................................................................................. 53 
6.4 
Duration of Follow-Up .......................................................................................... 54 
7. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................... 54 

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8. 
PHARMACEUTICAL INFORMATION ......................................................................... 57 
8.1 
CTEP IND Agent .................................................................................................. 57 
9. 
STATISTICAL CONSIDERATIONS .............................................................................. 59 
9.1 
Study Design/Endpoints ........................................................................................ 60 
9.2 
Sample Size/Accrual Rate ..................................................................................... 60 
9.3 
Stratification Factors ............................................................................................. 61 
9.4 
Analysis of Secondary Endpoints .......................................................................... 61 
9.5 
Analysis of Exploratory Endpoints ....................................................................... 61 
9.6 
For phase 2 protocols only: Reporting and Exclusions ......................................... 61 
10. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ............................ 62 
10.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) ..................... 62 
10.2 
Adverse Event Characteristics ............................................................................... 64 
10.3 
Expedited Adverse Event Reporting ..................................................................... 64 
10.4 
Routine Adverse Event Reporting ......................................................................... 67 
10.5 
Pregnancy .............................................................................................................. 67 
10.6 
Secondary Malignancy .......................................................................................... 68 
10.7 
Second Malignancy ............................................................................................... 68 
11. 
STUDY CALENDAR ....................................................................................................... 68 
12. 
MEASUREMENT OF EFFECT ....................................................................................... 71 
12.1 
Antitumor Effect – Solid Tumors .......................................................................... 71 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ............................................................................................................ 77 
13.1 
Study Oversight ..................................................................................................... 77 
13.2 
Data Reporting ...................................................................................................... 77 
13.3 
Data Quality Portal ................................................................................................ 80 
13.4 
CTEP Multicenter Guidelines ............................................................................... 80 
13.5 
Collaborative Agreements Language .................................................................... 80 
13.6 
Genomic Data Sharing Plan .................................................................................. 82 
13.7 
Incidental/Secondary Findings Disclosure Procedure ........................................... 82 
14. 
REFERENCES .................................................................................................................. 83 
APPENDIX A 
PERFORMANCE STATUS CRITERIA .................................................. 85 
APPENDIX B 
FORMULA TO ESTIMATE RENAL FUNCTION USING 
SERUM CREATININE .................................................................................................... 86 
APPENDIX C 
PATIENT DRUG INTERACTIONS HANDOUT AND 
WALLET CARD .............................................................................................................. 87 
APPENDIX D 
TISSUE BIOPSY VERIFICATION ....................................................... 90 
APPENDIX E 
PATIENT’S MEDICATION DIARY .................................................... 91 

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APPENDIX F 
PATIENT’S PHARMACOKINETIC WORKSHEET ............................ 93 

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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To estimate the objective radiographic response rate to single agent rogaratinib (BAY 
1163877) in two cohorts of patients with sarcoma: Cohort A defined as patients with a 
sarcoma which harbors an alteration in fibroblast growth factor receptor (FGFR) 1,2,3 or 
4 identified by next-generation sequencing profiling, and Cohort B defined as patients 
with advanced succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor 
(GIST). 
 
1.2 
Secondary Objectives 
 
1.2.1 To estimate progression-free survival (PFS) in patients in Cohort A and Cohort B treated 
with rogaratinib (BAY 1163877). 
 
1.2.2 Further assessment for safety and tolerability. 
 
1.3 
Exploratory Objectives 
 
1.3.1 To evaluate serial measurements of FGFR and FGFR ligand in serial tumor biopsies as 
potential pharmacodynamic markers of FGFR pathway inhibition by RNA-seq (pre- 
treatment biopsy and post-progression biopsy [if available]). 
 
1.3.2 Whole exome sequencing (WES) of the pre-treatment biopsy and post-progression biopsy 
(if available) to help identify mechanisms of resistance. 
 
1.3.3 To bank tumor material, germline deoxyribonucleic acid (DNA), and peripheral blood for 
potential future research for participating subjects who provide additional consent. 
 
1.3.4 To explore rogaratinib exposure with pharmacodynamics effects (i.e., clinical response, 
toxicity, and markers of FGFR pathway inhibition). 
2. BACKGROUND 
2.1 
Study Disease 
Sarcomas represent a complex and heterogeneous group of mesenchymal malignancies arising 
from connective tissue in bone or soft tissue. There will be approximately 12-15,000 new cases 
of sarcoma each year in the United States, and 4-5,000 deaths (Siegel et al., 2014). When 
localized, many sarcomas are potentially curable with surgical resection with or without 
radiation and chemotherapy (Brennan, 2013). Unfortunately, despite adequate local control, 
metastases are common and for most patients, advanced disease, whether at diagnosis or 
recurrence, is fatal. In metastatic soft tissue sarcomas (STS), single agent or combination 
chemotherapy has led to a median survival of 12 months across histologies (Italiano et al., 2011). 
Standard single agent regimens for STS include doxorubicin (response rates <25%), ifosfamide 

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(response rates <25%), and other less active therapies including trabectedin, dacarbazine and 
platinum compounds. Combination regimens include doxorubicin plus ifosfamide (response 
rates 20- 24%), doxorubicin plus ifosfamide and dacarbazine (response rates 32- 49%), and 
additionally gemcitabine with a second agent such as docetaxel (response rate 18-53%, histology 
dependent), vinorelbine or dacarbazine (clinical benefit rate = 49%) (Brennan, 2013). In general, 
combination therapies improve response rates and PFS but have no impact on overall survival. 
Pazopanib is a multi-kinase inhibitor approved for second line or greater treatment of metastatic 
STS. In a double-blinded phase 3 trial pazopanib was compared to placebo in 369 patients with 
STS, excluding adipocytic sarcomas and gastrointestinal stromal tumor (GIST). Although the 
response rate was quite low at 6% there was a significant improvement in median PFS (4.6 
versus 1.6 months). There was no difference in OS (van der Graaf et al., 2012). 
 
Prior to the pazopanib approval in 2012, there were no therapies approved by the U.S. Food and 
Drug Administration (FDA) for sarcomas other than (GIST) since doxorubicin in the 1980's. It 
has been challenging to develop therapies in sarcoma largely due to a combination of small 
patient numbers given the rarity of each individual sub-type and the inherent biologic complexity 
of this heterogeneous group of tumors. Additionally, sarcomas tend to occur more frequently in 
a younger patient population, with tumors like synovial sarcoma, rhabdomyosarcoma and 
osteosarcoma having a disproportionate number of adolescent and young adult (AYA) patients, a 
particularly vulnerable oncology population. Novel therapies are urgently needed. 
 
There have been several published pre-clinical investigations exploring the role of FGFR in 
sarcoma. Schwartz et al evaluated platelet-derived growth factor receptor (PDGFR) / vascular 
endothelial growth factor receptor (VEGFR) and FGFR in cell lines revealing the differential 
response of the various sarcoma sub-types. The group used nintedanib (a tyrosine kinase 
inhibitor targeting FGFR, PDGFR and VEGFR) against various sarcoma cell lines. The Ewing 
sarcoma cell lines had little response, yet the synovial, dedifferentiated liposarcoma and 
malignant peripheral nerve sheath tumor (MPNST) cell lines had fairly robust responses (Figure 
1). The authors went on to examine nintedanib in a xenograft synovial model (Figure 2). There 
was tumor volume reduction after treatment when compared to imatinib and control (Patwardhan 
et al., 2018). 

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Figure 1: Effect of Nintedanib in Sarcoma Cell Lines 
 
Figure 2: Effect of Nintedanib in Xenograft Synovial Model 
Strauss, Lord, and colleagues evaluated the Astra-Zeneca FGFR inhibitor, AZD4547, focusing 
on osteosarcoma cell lines (Holme et al., 2018). In the figures below, Figure 3 is highlighting 
osteosarcoma cell lines (18 tumors) vs all other tumors (70 carcinomas) illustrating the relative 
sensitivity of osteosarcoma tumor cell lines. Figure 4 is looking specifically at FGFR1 
amplification or gain vs no FGFR1 amplification or gain. Figure 5 is showing 2 different FGFR 
inhibitors against 2 cell lines, one with FGFR1 amplified and the other FGFR1 copy number 
neutral (Holme et al., 2018). 

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Figure 3: Relative Sensitivity of Osteosarcoma Tumor Cell Lines to AZD4547 
 
Figure 4: FGFR1 amplification or gain vs no FGFR1 amplification or gain 
 
 
Figure 5: Effect of 2 different FGFR inhibitors against 2 cell lines, one with FGFR1 amplified 
and the other FGFR1 copy number neutral 
Myklebost and colleagues evaluated a slightly different aspect of FGFR signaling, fibroblast 
growth factor receptor substrate 2 (FRS2) which is downstream of FGFR (Hanes et al, 2016). 
They had 2 dedifferentiated liposarcoma tumor samples from the same patient, one from the 
ileum and the other from the diaphragm. There was high level amplification of FRS2. They 
then exposed the cell cultures to the FGFR inhibitor BGJ398. Interestingly, the drug mimicked 
what was seen with the MDM2 inhibitor (MDM2 is amplified in dedifferentiated liposarcoma). 

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On the other hand, imatinib was ineffective and palbociclib, only slightly better, which mimics 
what is typically encountered in the clinical setting. They attributed their findings of reduced 
proliferation to a reversible cell cycle arrest in the G1 and G0 phases, as the liposarcoma cells 
resume proliferation after withdrawal from treatment (Hanes et al, 2016). 
 
Figure 6: Dedifferentiated liposarcoma samples exposed to MDM2, CDK4/6, FGFR, and ckit 
inhibitors 
Schafer and colleagues evaluated alveolar rhabdomyosarcoma cell lines suggesting that FGFR4 
is responsible for the FGF-induced signaling (Crose et al., 2012). Cells treated with FGFR 
inhibitor BGJ398, inhibited FGFR4 auto-phosphorylation in rhabdomyosarcoma cells (Wachtel 
et al., 2014). Corinne Linardic’s group from Duke evaluated FGFR4 blockade specifically, 
focusing on the differential between the two distinct subtypes, embryonal and alveolar 
rhabdomyosarcoma. They found greater FGFR4 expression in alveolar tissue than in embryonal. 
However, pharmacologic inhibition is seen in both subtypes in vitro and in vivo. In the figures 
below, RD is an embryonal cell line and Rh28 is an alveolar cell line. Their group went on to 
conclude that the consequences of FGFR4 blockade were present but distinctly different in the 
different subtypes, with apoptosis in the aRMS samples, while eRMS was merely an inhibition 
of proliferation (Crose et al., 2012). 

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Figure 7: FGFR expression and blockade in alveolar and embryonal rhabdomyosarcoma 
Further elaborating on the activity of FGFR inhibitors in rhabdomyosarcoma, Javed Khan’s 
group focused on correlating high FGFR4 expression with advanced stage, aRMS histology and 
poor survival. They went on to make an inducible anti-FGFR4 shRNA cell line model and 
showed FGFR4 suppression leads to inhibition of in vivo growth and lung metastases (Taylor et 
al., 2009). 
 
Figure 8: FGFR4 suppression leads to inhibition of in vivo growth and lung metastasis. 
 
The Bernstein lab at Massachusetts General Hospital (MGH) and the Broad Institute and 
colleagues identified FGFR expression and a unique upregulation of FGF ligands in succinate 
dehydrogenase-deficient GIST (SDH-deficient GIST) (Flavahan et al., 2019). While the majority 
of GIST subtypes bear activating mutations in the receptor tyrosine kinases KIT or PDGFRA, 
approximately 10-15% of adult GIST and the majority of pediatric GIST is driven by the loss of 
an SDH complex member (Pappo et al., 2008; Boikos et al., 2016). Unlike kinase mutant GIST, 
SDH-deficient GIST does not respond to treatment with imatinib, though sunitinib has shown 
anti-tumor activity in this disease (Janeway et al., 2009; Janeway et al., 2011). The mechanism 

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of the anti-neoplastic activity of sunitinib is unclear, and no other standard treatments are 
available for this disease. 
 
More recently, in unpublished efforts to characterize PDX models of GIST, researchers at Dana 
Farber Cancer Institute (DFCI) performed RNA-seq on GIST surgical samples and PDX models 
of KIT mutant or SDH-deficient GIST tumors. Unsupervised hierarchical clustering of RNA-seq 
data demonstrate co-clustering of PDX with the tumor it was derived from, with separate 
clustering of all kinase mutant and SDH-deficient GIST (Figure 9A). In contrast to kinase 
mutant GIST, SDH-deficient GIST demonstrates reduced expression of SDH complex members 
in addition to a primary loss-of-function mutation (Figure 9B). Kinase mutant and SDH- 
deficient GIST express similar levels of KIT (Figure 9C), though PDGFRA levels are 
significantly reduced in SDH-deficient GIST (Figure 9D). 
 
Figure 9: Characterization of GIST and PDX models by RNA-seq. (A) Heat map of row mean 
normalized log2 FPKM showing hierarchical clustering of all expressed genes (n=10,000) in 
SDH-intact (n=13) and SDH-deficient (n=10) GIST tumors and PDX derived from SDH-intact 
or SDH-deficient tumors (“P”, n=2). The primary GIST gene mutation and presence of either 
localized or metastatic disease are indicated by color-coding. Samples derived from the same 
patient with SDH-deficient GIST at different tumor resection surgeries are indicated with an 
asterisk. (B) Log2 FPKM heat map of SDH complex member gene expression. The gene with 
the primary loss of function mutation in each sample is indicated with the symbol Δ. (C-D) 
FPKM of KIT and PDGFRA. Samples colored in blue bear a primary PDGFRA mutation. 
To determine genes differentially expressed between kinase mutant (SDH-intact) and SDH- 
deficient GIST, we performed differential expression analysis of RNA-seq data, which identified 
significant upregulation of FGF3 and FGF4 in SDH-deficient GIST (Figure 10A-C). Expression 
of the FGFR family was similar across all GIST subtypes (Figure 10D), with the SDH-deficient 
PDX faithfully expressing FGF receptor and ligand in a similar fashion as surgical resection 
samples. 

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Figure 10: FGF and FGFR expression in SDH-deficient GIST and susceptibility to FGFR 
inhibition. (A) Volcano plot of RNA-seq data in all expressed genes (n=~10,000) in SDH-intact 
or SDH-deficient GIST. The percent of genes unique to each subtype is indicated in the upper 
corners. FGF genes are highlighted. (B-D) FPKM or FGF3, FGF4 and FGFR1-4 in GIST 
subtypes. FPKM values for each gene in SDH-deficient GIST PDX are indicated in green 
circles. Tumors were compared by unpaired t-test; *, P<0.05; **, P<0.01; ***, P<0.001. (E) 
Effect of tyrosine kinase or FGFR inhibition in an SDH-deficient GIST PDX. Mice were treated 
for 28 days with indicated drug(s), n=8 per group. (F) Statistical comparisons of treatment 
groups by two-way ANOVA. 
As no cell line model of SDH-deficient GIST has been developed, we have tested the role of 
FGFR signaling in SDH-deficient PDX using the FGFR inhibitor BGJ-398. Compared to 
sunitinib and regorafenib, BGJ-398 significantly reduced tumor volume of the SDH-deficient 
PDX (Figure 10E-F). Combination treatment with BGJ-398 and sunitinib was more effective 
than either drug alone. Taken together, these data argue for the relevance of FGFR signaling in 
SDH-deficient GIST. Though KIT-mutant GIST also expresses high levels of FGFR proteins (Li 
et al., 2015), the clinical relevance of FGFR signaling in disease pathogenesis for the kinase- 
mutant subtype of GIST is uncertain (Kelly et al., 2019). In contrast, SDH-deficient GIST 
express similarly high levels of FGFR proteins, and their unique upregulation of FGF ligands 
suggests and auto-regulatory loop which may support the growth of these poorly understood 

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cancers. These data suggest that inhibition of FGFR, alone and in combination with sunitinib, 
may represent a novel treatment strategy for SDH-deficient GIST (Flavahan et al., 2019). 
 
2.2 
CTEP IND Agent 
 
2.2.1 Rogaratinib (BAY 1163877) (NSC 804782) 
 
Rogaratinib (BAY 1163877) is a novel small molecule kinase inhibitor which selectively inhibits 
FGFRs 1, -2, -3, and -4 (Rogaratinib Investigator’s Brochure, 2019). Rogaratinib (BAY 
1163877) exhibits strong in vivo anti-tumor efficacy with good tolerability in monotherapy in 
animal tumor models. 
 
2.2.1.1 Mechanism of Action 
 
Dysregulation of FGFR expression and activity is considered oncogenic and affects all four 
FGFR subtypes and various human cancers, including sarcoma, multiple myeloma, breast, 
bladder, prostate, gastric, or endometrium cancer (Rogaratinib Investigator’s Brochure, 2019). 
Rogaratinib (BAY 1163877) is a novel small molecule kinase inhibitor which selectively inhibits 
FGFR1, 2, 3, and 4 and showed efficacy in monotherapy in various preclinical cancer models. 
Additive to synergistic effects with broad range kinase inhibitors, targeted agents or conventional 
chemotherapeutics was also demonstrated. Rogaratinib (BAY 1163877) showed superior 
activity in models with overexpression of FGFR1, 2, or 3 mRNA or in models with pathway 
activation due to mutations in FGFR3. These results indicate that the clinical development of 
rogaratinib (BAY 1163877) could result in an improved and more effective alternative compared 
to current treatment and patient stratification options. Clinical safety and efficacy are currently 
being explored in four ongoing studies (2 monotherapy studies and 2 combination studies) in 
patients with advanced cancer. 
 
2.2.1.2 Nonclinical Summary 
 
Rogaratinib (BAY 1163877) exhibits monotherapy and combination anti-tumor efficacy in 
syngeneic and human tumor models characterized by addiction to the FGFR pathway either by 
gene alteration and/or messenger ribonucleic acid (mRNA) overexpression of FGFR1, -2, -3, -4 
and fibroblast growth factor 19 (FGF19) (Rogaratinib Investigator’s Brochure, 2019). 
Monotherapy with rogaratinib (BAY 1163877) resulted in potent anti-tumor efficacy in C51 
colon cancer syngeneic tumors. Rogaratinib (BAY 1163877) inhibits the proliferation of lung 
cancer cell lines National Cancer Institute (NCI)-H1581, DMS114 as well as bladder cancer cell 
lines RT112 and JMSU-1. Moreover, rogaratinib (BAY 1163877) specifically inhibits 
phosphorylation of downstream extracellular signal-regulated kinases (ERK). Regarding 
secondary pharmacodynamics, rogaratinib (BAY 1163877) moderately binds to imidazoline (I2), 
5-hydroxytryptamine (serotonin) receptor 2B (serotonin 5-HT2B) and 5-hydroxytryptamine 
receptor 4 (5-HT4), phosphodiesterase isozyme-5 (PDE5), adrenergic alpha2B, and adenosine 
transporter in vitro at a concentration of 10 μM. Safety pharmacology parameters of vital organ 
functions (central nervous, cardiovascular [including. electrocardiogram {ECG}], and respiratory 
system) in rats and dogs showed no effects of rogaratinib (BAY 1163877) except for a moderate 
reduction of locomotor activity and muscle tone and a slight decrease in respiratory function. 

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Rogaratinib (BAY 1163877) does not have the potential for QT/QTc (QT interval in ECG/ QT 
interval corrected for heart rate) prolongation in vivo, although in vitro human ether-a-go-go- 
related gene potassium channel (hERG K+) current was moderately blocked and repolarization 
was delayed in terms of action potential duration at 50% and 90% of repolarization 
(APD50/APD90) prolongation in rabbit Purkinje fibers. 
 
2.2.1.3 Summary of Clinical Experience 
 
As of October 10, 2019, approximately 306 patients with advanced cancer have been treated with 
rogaratinib (BAY 1163877) in four Phase I, one Phase Ib/II and one Phase II/III trials 
(Rogaratinib Investigator’s Brochure, 2019). Out of these 306 patients, approximately 264 
patients had received rogaratinib (BAY 1163877) monotherapy, 16 patients had received 
rogaratinib (BAY 1163877) in combination with copanlisib (NCT03517956) and 26 patients had 
received rogaratinib (BAY 1163877) in combination with atezolizumab (NCT03473756). 
 
2.2.1.4 Clinical Pharmacokinetics and Pharmacodynamics 
 
Pharmacokinetic results for rogaratinib (BAY 1163877) are available from the ongoing single- 
agent dose-escalation clinical trial (NCT01976741) in patients with advanced solid tumors 
(Rogaratinib Investigator’s Brochure, 2019). After oral administration, rogaratinib (BAY 
1163877) was rapidly absorbed with median time to reach maximum drug concentration in 
plasma (tmax) typically observed around 2 hours. Plasma concentrations declined with a 
geometric mean half-life of approximately 12 hours following a single dose of 800 mg. A more 
than 30% increase in area under the curve (AUC) from time 0 to time 12 hour (AUC0-12) was 
observed after multiple dosing (twice daily [BID] administration). Relative bioavailability 
assessment after 100 mg single dose indicated similar exposures were achieved using the liquid 
service formulation (LSF) and tablet formulations. After single dose, rogaratinib (BAY 
1163877) exhibited dose-proportional increase in exposure in the dose range 50 mg to 200 mg 
and less than dose-proportional increase at higher dose levels with similar observation after 
multiple dosing. Less than dose-proportional increase may be attributed to saturable absorption. 
Administration of 800 mg dose of rogaratinib (BAY 1163877) following consumption of high- 
fat high-calorie meal did not affect its pharmacokinetic (PK). Therefore, rogaratinib (BAY 
1163877) may be administered with or without food. After administration of single oral dose of 
800 mg, less than 1% of the administered drug was eliminated unchanged in cumulative urine 
collected over 24 h post-dose indicating renal elimination of rogaratinib (BAY 1163877) is a 
minor elimination pathway. PK data in Japanese patients enrolled in Study NCT02592785 and 
other Asian (South Korean and Singaporean) patients enrolled in Study NCT01976741compared 
to non-Asian patients enrolled in Study NCT01976741do not suggest clinically relevant 
differences in rogaratinib (BAY 1163877) exposure. 
NCT01976741 
 
As of October 10, 2019, 168 patients with advanced cancer were treated with rogaratinib (BAY 
1163877) in Study NCT01976741: 23 patients in the dose-escalation cohorts and 145 patients in 
the expansion cohorts (Rogaratinib Investigator’s Brochure, 2019). Out of those 168 patients, 
159 patients (21 patients in the dose-escalation cohort and 138 patients in expansion cohorts) 

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were evaluable for efficacy using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
criteria. One patient achieved complete response (CR) (urinary bladder cancer [UBC] cohort), 
18 patients had partial response (PR), 80 patients had stable disease (SD), and 51 patients had 
progressive disease (PD). 
 
NCT02592785 
 
In the completed Study 16958, 9 patients with advanced cancer were treated with 
rogaratinib (BAY 1163877) administered orally BID at 600 and 800 mg (Rogaratinib 
Investigator’s Brochure, 2019). All patients were evaluable for efficacy using RECIST 1.1 
criteria. None of the patients achieved CR (UBC cohort), one patient (11.1%) achieved PR 
(epipharynx cancer, at 800 mg BID), five patients (55.6%) had SD and three patients (33.3%) 
had PD as their best overall response. 
 
Maximum Tolerated Dose (MTD)/Recommended Dose 
 
Per the data monitoring committee (DMC) evaluation of NCT03410693 study full data analysis 
and review on August 23, 2019, the safety of rogaratinib (BAY 1163877) is consistent to the 
known safety profile of the compound (Rogaratinib Investigator’s Brochure, 2019). 800 mg BID 
could be considered as dose to use for monotherapy studies in the future. 
 
2.2.1.5 Clinical Safety Summary 
 
NCT01976741 
 
The most common treatment-emergent adverse events (TEAEs) of any grade which were 
assessed as related to the study drug occurring in ≥10% of the patients were: blood phosphorus 
increased (57.7%), diarrhea (41.7%), fatigue (20.8%), decreased appetite (19.6%), alopecia 
(19.0%), dry mouth (17.9%), nausea (15.5%), dysgeusia (14.9%), dry skin (12.5%), and 
arthralgia and stomatitis (10.1% each). The most common TEAEs which were assessed as 
related to the study drug and were classified as Grade 3 or Grade 4 or Grade 5 event occurring in 
≥3% of the patients were: lipase increased and fatigue (4.8% each). 
NCT02592785 
The most common TEAEs of any grade assessed as related to the study drug occurring in ≥20% 
of the patients were: hyperphosphataemia (88.9%), diarrhoea, dysgeusia, stomatitis and 
constipation (33.3% each), alanine aminotransferase increased, aspartate aminotransferase 
increased, gamma glutamyltransferase increased, dry skin, keratitis, blood bilirubin increased 
and blood alkaline phosphatase increased (22.2% each). The TEAEs which were assessed to be 
causally related to the study drug and classified as Grade 3 events were: hyponatraemia and 
alanine aminotransferase increased (11.1% each). There were no Grade 4 or Grade 5 TEAEs 
assessed as related to the study drug. 
 
Adverse events of special interest of rogaratinib (BAY 1163877) 

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In Study NCT01976741, 20 (11.9%) patients experienced adverse events of special interest 
(AESI) of retinal disorders assessed as causally related to rogaratinib (BAY 1163877). 
 
2.3 
Rationale 
 
FGFR has recently been explored as a potential target in multiple solid tumor sub-types. As part 
of a CTEP rogaratinib (BAY 1163877) project team presentation, Ellinghaus & Bender 
presented data that showed 40% of sarcomas from pre-screening data had FGFR mRNA 
overexpression as determined by RNAscope. In searching our own institutional molecular 
profiling data, we identified 1533 sarcomas, with 72 patients having FGFR mutations affecting 
coding regions or splice sites, and 206 patients with copy number changes. This prompted a 
more extensive systematic literature search to identify which sarcoma sub-types seem to harbor 
higher FGFR expression, and thus would be potential viable targets for FGFR inhibiting drugs 
like rogaratinib (BAY 1163877). Sarcomas that repeatedly demonstrated FGFR over-expression 
and showed pre-clinical evidence of response to various available FGFR inhibitors included: 
synovial sarcoma, dedifferentiated liposarcoma, MPNST, SDH- deficient GIST, osteosarcoma 
and rhabdomyosarcoma. For these reasons, we propose a multiple cohort, single arm, Simon two 
stage phase II study to evaluate rogaratinib (BAY 1163877) in sarcomas with FGFR alterations 
as identified on mutational testing (DNA or RNA). 
 
Of note, we have significant preclinical data on the effects of FGFR inhibition on a PDX model 
of SDH-deficient GIST. 
 
2.3.1 Effects of Rogaratinib (BAY 1163877) on Preclinical Models of SDH-deficient GIST 
 
To determine the comparative effects of various inhibitors of receptor tyrosine kinases on an 
SDH-deficient PDX, we treated mice for 28 days with sunitinib, regorafenib, BGJ398 and/or 
rogaratinib (BAY 1163877). Rogaratinib (BAY 1163877) arms included two dosing levels, and 
an additional arm of rogaratinib (BAY 1163877) in combination with sunitinib. Over the 28-day 
period, neither sunitinib nor regorafenib had significant anti-tumor activity. In contrast, treatment 
with FGFR inhibitors BGJ398 or rogaratinib (BAY 1163877) significantly limited tumor growth 
(Figure 11), with the high dose of rogaratinib (BAY 1163877) (50 mg/kg) significantly reducing 
tumor volume compared to the low dose of rogaratinib (BAY 1163877) (25 mg/kg) or BGJ398. 
Following the dosing period, mice continued to be observed and tumors were able to grow 
without ongoing FGFR inhibition. These data suggest that FGFR signaling is essential for SDH- 
deficient GIST growth, and continuous inhibitor treatment is necessary for disease control. 

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Figure 11: Effects of drug treatment on SDH-deficient GIST PDX tumor volume. Mice were 
treated for 28 days with vehicle (n=8), sunitinib 40 mg/kg QD (n=8), regorafenib 30 mg/kg QD 
(n=8), BGJ398 20 mg/kg QD (n=8), rogaratinib (BAY 1163877) 25 mg/kg BID (n=8), 
rogaratinib (BAY 1163877) 50 mg/kg BID (n=8), or combination rogaratinib (BAY 1163877) 25 
mg/kg BID and sunitinib 40 mg/kg QD (n=8). Tumor volume was measured during the 28-day 
treatment period and during the subsequent period of observation, with statistical calculations for 
these two periods indicated. Tumor volume in mm3 is indicated as mean ± SEM. The vertical 
dotted line indicates the end of the treatment period, and horizontal line the average baseline 
tumor volume. Data were analyzed by two-way ANOVA, with comparison to the vehicle 
condition unless otherwise indicated; *, P<0.05; **, P<0.01; ***, P<0.001. All single agent 
treatment groups were well tolerated. In the combination group, 4 of 8 mice required drug 
holiday between 1 and 11 days due to >15% body weight loss. 
2.3.2 Pharmacodynamic Effects of Rogaratinib (BAY 1163877) Treatment on Preclinical 
Models of SDH-deficient GIST 
To determine the mechanisms of toxicity of rogaratinib (BAY 1163877) treatment in SDH- 
deficient GIST, we treated tumor-bearing mice for five days with vehicle control, sunitinib, 
rogaratinib (BAY 1163877) or the combination of sunitinib and rogaratinib (BAY 1163877) and 
harvested tumors 4 or 24 hours after the final treatment dose. Tumor lysates were analyzed by 
Western blot for relative abundance of KIT, phospho-KIT, FGFR1, phospho-FGFR1, phospho- 
ERK and total ERK (Figure 12). Compared to control conditions, all treatment conditions 
reduced KIT and phospho-KIT levels, while phospho-FGFR1 levels were only reduced with 
rogaratinib (BAY 1163877) or combination rogaratinib (BAY 1163877) and sunitinib treatment 
(Figure 12A-C). The levels of phospho-ERK, a downstream mediator of receptor tyrosine kinase 
signaling, was significantly reduced only with rogaratinib (BAY 1163877) or combination 
treatments at the 4-hour time point, with recovery of phospho-ERK levels by 24 hours after drug 
administration. 

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Figure 12: Effects of short-term drug treatment on SDH-deficient GIST PDX protein levels. A, 
Western blot for the indicated proteins following five days of drug treatment with vehicle (n=3), 
sunitinib 40 mg/kg QD (n=3), rogaratinib (BAY 1163877) 50 mg/kg BID (n=3), or combination 
rogaratinib (BAY 1163877) 25 mg/kg BID and sunitinib 40 mg/kg QD (n=3). Tumors were 
harvested after 4h (left column) or 24h (right column) of the final treatment administration. 
Quantification of Western blot protein intensity with signal normalized to total ERK as a loading 
control and to the vehicle condition at 4h (B) or 24h (C). Data were analyzed by one-way 
ANOVA, with comparison to the vehicle condition; *, P<0.05; **, P<0.01; ***, P<0.001. 
To further explore mechanisms of rogaratinib (BAY 1163877) toxicity in SDH-deficient GIST, 
we performed RNA-seq on this five-day treatment cohort (Figure 13). Unsupervised hierarchical 
clustering of transcriptional data demonstrates co-clustering of all rogaratinib (BAY 1163877) 
and combination rogaratinib (BAY 1163877) and sunitinib samples, with separate co-clustering 
of sunitinib and vehicle treated mice (Figure 13A). Using gene set enrichment analysis (GSEA), 
rogaratinib (BAY 1163877) treated tumors showed significant decreases in transcripts related to 
cell cycle progression and MTOR signaling, both at 4 and 24 hours (Figure 13B-C). Levels of 
KIT gene expression trended towards lower transcript abundance in rogaratinib (BAY 1163877) 
treated tumors, while FGFR1 levels showed an increasing trend with rogaratinib (BAY 1163877) 
treatment (Figure 13D), as seen by Western blot (Figure 12). GPR20, another histologic marker 
of GIST, significantly decreased with rogaratinib (BAY 1163877) treatment (Figure 13D). 
Sprouty and DUSP family proteins antagonize receptor tyrosine kinase signaling, and their 

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expression is highly sensitive to changes in signal transduction. In rogaratinib (BAY 1163877) 
and combination treatment groups at 4 hours, SPRY2, SPRY4 and DUSP6 transcripts were 
significantly reduced with FGFR inhibition, and levels rebound following 24 hours of drug 
cessation (Figure 13E). Finally, while expression levels of ANO1 show a trend towards 
decreasing with rogaratinib (BAY 1163877) treatment, FGF3 and FGF4 transcripts are highly 
and significantly reduced with FGFR inhibition (Figure 13F). Taken together, these data suggest 
that signal transduction through FGFR is essential for growth of SDH-deficient GIST, and that 
FGFR inhibition with rogaratinib (BAY 1163877) reduces mitogenic signal transduction. 
Further, rogaratinib (BAY 1163877) silences expression of FGF3 and FGF4, which disrupts the 
autocrine loop driving FGFR signaling that supports this disease. 
 
Figure 13: Effects of short-term drug treatment on PG20 transcription. A, Unsupervised 
hierarchical clustering of RNA-seq data following five days of drug treatment with vehicle 
(n=3), sunitinib 40 mg/kg QD (n=3), rogaratinib (BAY 1163877) 50 mg/kg BID (n=3), or 
combination rogaratinib (BAY 1163877) 25 mg/kg BID and sunitinib 40 mg/kg QD (n=3), with 
tumors harvested after 4h or 24h of the final treatment administration. B, GSEA of Hallmark 
data sets for G2M Checkpoint and MTORC1 Signaling comparing vehicle and rogaratinib (BAY 
1163877) groups harvested 4h post-final treatment. C, GSEA of Hallmark data sets for G2M 
Checkpoint and MTORC1 Signaling comparing vehicle and rogaratinib (BAY 1163877) groups 
harvested 24h post-final treatment. D, Expression in FPKM of KIT, FGFR1 and GPR20 in 
vehicle (grayscale), sunitinib (red), rogaratinib (BAY 1163877) (blue) and combination 
rogaratinib (BAY 1163877) and sunitinib (green) tumors harvest 4h or 24h following the final 
treatment administration. E, Expression in FPKM of negative regulators of RTK signaling 
SPRY2, SPRY4 and DUSP6. F, Expression in FPKM of ANO1, FGF3 and FGF4. Data were 
analyzed by one-way ANOVA, with comparison to the vehicle condition; *, P<0.05; **, P<0.01; 
***, P<0.001. 

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2.3.3 FGFR expression across sarcoma. 
 
To evaluate levels of FGFR1-4 across sarcoma tumors, PDX and cell lines, we performed RNA- 
seq to compare transcript abundance from samples generated in our center (Figure 14). SDH- 
deficient GIST and KIT or PDGFRA mutant GIST expressed the highest levels of FGFR1 and 
FGFR2, though other histologies including leiomyosarcoma, dermatofibrosarcoma protuberans 
and others abundantly expressed FGFR1. By contrast, angiosarcoma expressed relatively higher 
levels of FGFR3, and rhabdomyosarcoma relatively higher levels of FGFR4. These preliminary 
results will support additional preclinical research on the role of FGFRs in supporting diverse 
sarcoma biology. 
 
Figure 14: Expression of FGFRs across sarcoma tumors and models. Expression in FPKM of 
FGFR1-4 in sarcoma tumors, PDX and cell lines, including SDH-deficient GIST (n=12), KIT or 
PDGFRA mutant GIST (n=36), dermatofibrosarcoma protuberans (DFSP, n=2), leiomyosarcoma 
(LMS, n=49), rhabdomyosarcoma (RMS, n=3), angiosarcoma (n=21), alveolar soft part sarcoma 
(ASPS, n=8), undifferentiated pleomorphic sarcoma (UPS, n=13), Ewing sarcoma (EWS, n=3), 
liposarcoma (n=7) and synovial sarcoma (n=2). 
 
2.4 
Correlative Studies Background 
 
2.4.1 Mutations and fusions in FGFR 1, 2, 3, and 4 
 
Alterations in FGFR 1-4 have been associated with multiple subtypes of sarcoma (See Sections 
2.1 and 2.3 for detailed discussion). We hypothesize that inhibiting these targetable, potential 
driver alterations, with rogaratinib (BAY 1163877) will disrupt tumor growth and lead to clinical 
benefit. 
 
2.4.2 SDH 
 
The Bernstein lab at Massachusetts General Hospital (MGH) and the Broad Institute and 
colleagues identified FGFR expression and a unique upregulation of FGF ligands in succinate 
dehydrogenase-deficient GIST (SDH-deficient GIST) (Flavahan et al, 2019) (See Sections 2.1 
and 2.3 for detailed discussion). We hypothesized that FGFR inhibition with rogaratinib (BAY 
1163877) will reduces mitogenic signal transduction and disrupt tumor growth in SDH-deficient 
GIST. 

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2.4.3 Whole Exome Sequencing (WES) 
 
Whole exome sequencing (WES) will be performed to identify and characterize the spectrum of 
FGFR mutations and co-occurring alterations in patients with sarcoma enrolled onto this study. 
Characterization of FGFR alterations, and any potential downstream collaborating genomic 
aberrations, may better define the spectrum of FGFR alterations predictive of therapeutic 
response. 
 
Our preclinical data in SDH-deficient GIST demonstrates expression of the ligand FGF3, FGF4 
and receptor FGFR, autocrine loop in both archival material and in a PDX model (Figure 13F). 
WES will allow for characterization of specific SDH-alterations and thereby allow further 
exploratory analyses of genomic findings to outcomes in this population. 
 
For the sarcoma cohort, baseline tumor biopsy will allow for WES prior to treatment initiation. 
This will allow for retrospective confirmation of the FGFR alteration which led to patient 
eligibility while concurrently allow for exploration of the genomic landscape of the enrolled 
population. 
 
2.4.4 RNA Sequencing (RNAseq) 
 
We have recently identified that SDH-deficient GIST is characterized by epigenetic 
dysregulation in the form of insulator dysfunction and altered chromosomal topology (Flavahan 
et al., Nature 2019). In SDH-deficient GIST tumors and our PDX model of this disease, the 
ANO1 enhancer aberrantly drives high expression of FGF3 and FGF4, leading to autocrine 
activation of FGFR1. In preclinical studies shown in Section 2.3, we have identified a gene 
expression signature in SDH-deficient GIST that is altered by FGFR inhibition by rogaratinib 
(BAY 1163877), which includes the loss of negative regulators of receptor tyrosine kinase 
signaling and reduction in FGF3 and FGF4 expression. The pre-study biopsy will establish the 
expression of FGFRs, FGF3/4 and the signal transduction system we have characterized that 
entrains tumor growth. Biopsy and RNA-seq of the flash frozen tissue at disease progression 
will help establish biological mechanisms of drug resistance and whether alterations in the 
baseline gene expression program are present. Gene expression profiling of FGFR-altered 
sarcomas would also provide the opportunity to assess the expression of FGFRs and downstream 
mediators that may be similarly predictive of disease response to FGFR inhibition. 
 
Our preclinical data in SDH-deficient GIST demonstrates expression of the ligand FGF3, FGF4 
and receptor FGFR, autocrine loop in both archival material and in a PDX model (Figure 13F). 
For patients with SDH-deficient GIST, baseline tumor biopsies will allow us to assess the 
autocrine production of FGF3 and FGF4 leading to subsequent autocrine activation of FGFR1. 
This will be assessed by RNAseq and can be correlated in an exploratory manner with response 
to therapy. 
 
For the sarcoma cohort, baseline tumor biopsy will allow for RNAseq prior to treatment 
initiation. This will allow for retrospective confirmation of the FGFR alteration which led to 
patient eligibility while concurrently allow for exploration of the genomic landscape of the 

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enrolled population. 
 
2.4.5 Pharmacokinetics (PK) 
 
These studies are necessary to characterize the variability in exposure to rogaratinib. After 
single or multiple doses, the variability in exposure ranges from ~35% in maximal 
concentrations and ~45% for total exposure (area under the curve) (Rogaratinib Investigator’s 
Brochure, 2019). Trough samples will be collected when the patients are at clinic visits to 
correlate with pharmacodynamics effects (i.e., clinical response, toxicity, and markers of FGFR 
pathway inhibition). Additional trough samples may be collected after a dose reduction to 
correlate the exposure at tolerable doses. 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
 
3.1.1 Participant must have histologically confirmed sarcoma with FGFR alteration identified 
by next-generation sequencing profiling with the exception of SDH-deficient GIST who 
can be enrolled regardless of FGFR status. Initial testing can be performed on archival 
tissue, if available. Patients must have locally advanced or metastatic disease that is not 
amenable to surgery. 
 
3.1.2 Presence of measurable disease: Patient must have measurable disease. See Section 12 
(Measurement of Effect) for the evaluation of measurable disease. 
 
3.1.3 Patients must have progressed following at least one standard prior chemotherapy 
regimen with the exception of SDH-deficient GIST for which there is no standard of care. 
 
3.1.4 Participant must be willing to undergo pre-treatment biopsy if disease site is amenable to 
biopsy and low risk for the biopsy procedure. If biopsy is not possible, eligibility may be 
approved after discussion with the Study Chair. Of note, a minimum of 15 participants in 
each arm open to stage 2 should have disease amenable to biopsy. For those arms open in 
stage 1, all patients should have biopsiable disease. 
 
3.1.5 Age ≥18 years. 
Because no dosing or adverse event data are currently available on the use of rogaratinib 
(BAY 1163877) in patients <18 years of age, children are excluded from this study. 
 
3.1.6 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.7 Patients must have adequate organ and marrow function as defined below: 
 
 
Hemoglobin 
≥ 8.0 g/dL 
 
absolute neutrophil count 
≥1,000/mcL 
 
platelets 
≥100,000/mcL 
 
total bilirubin 
≤1.5 × institutional upper limit of normal (ULN) 

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 
AST(SGOT)/ALT(SGPT) 
≤3.0 × institutional ULN (unless liver metastases 
are present in which case it must be ≤ 5 × ULN) 
 
 
glomerular filtration rate (GFR)  ≥60 mL/min/1.73 m2 (using the CDK-EPI formula 
see Appendix B) 
3.1.8 Human immunodeficiency virus (HIV)-infected patients on effective non-CYP3A4 
interacting (see Section 3.2.3) anti-retroviral therapy with undetectable viral load within 6 
months are eligible for this trial. 
3.1.9 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral 
load must be undetectable on suppressive therapy, if indicated. 
3.1.10 Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured. For patients with HCV infection who are currently on treatment, they are eligible 
if they have an undetectable HCV viral load. 
 
3.1.11 Patients with treated brain metastases are eligible if follow-up brain imaging after 
central nervous system (CNS)-directed therapy shows no evidence of progression. 
 
3.1.12 Patients must be disease-free of prior invasive malignancies for > 5 years with the 
exception of curatively-treated basal cell or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix. 
 
NOTE: 
If there is a history of prior malignancy, patients must not be receiving 
other specific treatment for that cancer. 
 
3.1.13 Patients should have completed prior treatment for their cancer: chemotherapy or 
radiotherapy must have been completed for greater than 2 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study. 
 
3.1.14 Patients should have recovered from adverse events due to prior anti-cancer therapy (i.e., 
have residual toxicities > Grade 1) with the exception of alopecia. 
 
3.1.15 Patients with known history or current symptoms of cardiac disease, or history of 
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac 
function using the New York Heart Association Functional Classification. To be eligible 
for this trial, patients should be class 2B or better. 
 
3.1.16 Patients must have a QTc interval length of below 450 msec. 
 
3.1.17 Participant is willing to comply with the protocol for the duration of the study including 
undergoing treatment and scheduled visits and examinations including follow up. 
 
3.1.18 Participant must be able to swallow and maintain pills. 

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3.1.19 Women of childbearing potential must have a negative urine or serum pregnancy test 
within 28 days of initial dose of rogaratinib (BAY 1163877), and again within 7 days 
prior to treatment on day 1. If screening occurs within 7 days of day 1, only one 
pregnancy test is required. 
 
3.1.20 The effects of rogaratinib (BAY 1163877) on the developing human fetus are unknown. 
For this reason and because kinase inhibitor agents are known to be teratogenic, women 
of child-bearing potential and men must agree to use adequate contraception (hormonal 
or barrier method of birth control; abstinence) prior to study entry, for the duration of 
study participation, and 4 months after completion of rogaratinib (BAY 1163877). 
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately. Men 
treated or enrolled on this protocol must also agree to use adequate contraception prior to 
the study, for the duration of study participation, and 4 months after completion of 
rogaratinib (BAY 1163877) administration. 
 
3.1.21 Ability to understand and the willingness to sign a written informed consent document. 
Participants with impaired decision-making capacity (IDMC) who have a legally- 
authorized representative (LAR) and/or family member available will also be eligible. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who are receiving any other investigational agents. 
 
3.2.2 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to rogaratinib (BAY 1163877). 
 
3.2.3 Concomitant administration with sensitive substrates/narrow therapeutic index drugs of 
CYP3A4, P-gp BCRP, MATE1, and MATE2K, and strong inhibitors and inducers of 
CYP3A4 should be avoided. Use caution with strong inhibitors and inducers of P-gp. 
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated medical reference. As part of the enrollment/informed 
consent procedures, the patient will be counseled on the risk of interactions with other 
agents, and what to do if new medications need to be prescribed or if the patient is 
considering a new over-the-counter medicine or herbal product. (See Appendix C Patient 
Drug Information Handout and Wallet Card). 
 
3.2.4 Concomitant administration of medications that prolong QT/QTc interval is prohibited in 
accordance with the published FDA guidance “E14 Clinical Evaluation of QT/QTc 
Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs”. 
 
3.2.5 Patients with disturbed calcium and/or phosphate metabolism are excluded from this 
study. 
 
3.2.6 Patients with uncontrolled intercurrent illness. 

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3.2.7 Patients with psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.2.8 Pregnant women are excluded from this study because rogaratinib (BAY 1163877) is 
kinase inhibitor agent with the potential for teratogenic or abortifacient effects. Because 
there is an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with rogaratinib (BAY 1163877), breastfeeding should be 
discontinued if the mother is treated with rogaratinib (BAY 1163877). 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH- 
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research. Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification. Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources. Women of 
childbearing potential should not be routinely excluded from participation in clinical research. 
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr. 
 
RCR utilizes five person registration types. 
x IVR: MD, DO, or international equivalent, 
x NPIVR: advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD), 
x AP: clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System (RUMS), OPEN, Rave, acting as a 
primary site contact, or with consenting privileges, 
x Associate (A): other clinical site staff involved in the conduct of NCI-sponsored trials, 
and 

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communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network. Site preferences can be set at the network 
or protocol level. Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
x Holds an Active CTEP status, 
x Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and 
on at least one participating roster, 
x If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
x Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and 
x Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
x An active Federalwide Assurance (FWA) number, 
x An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO), and 
x Compliance with all protocol-specific requirements (PSRs). 
4.2.1 Downloading Regulatory Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents 
is restricted based on person and site roster assignment. To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a PO on the protocol. One 
way to search for a protocol is listed below. 
x Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password, 
x Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-MA036 / 
Dana-Farber - Harvard Cancer Center LAO, and protocol number 10411, 
x Click on Documents, select Site Registration, and download and complete the forms 
provided. (Note: For sites under the CIRB, IRB data will load automatically to the 
CTSU.) 
 
4.2.2 Protocol Specific Requirements For 10411 Site Registration 
x Specimen Tracking System Training Requirement: 

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o All data entry users (Clinical Research Associate role) at each participating site will 
need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be submitted to 
the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual. If an individual has 
previously completed the training for another ETCTN study, the training does not 
need to be completed again nor does the certificate of completion need to be 
resubmitted to the CTSU. However, new versions of the Specimen Tracking System 
may require new training. 
o This training will need to be completed before the first patient enrollment at a given 
site. 
o Please contact STS Support at Theradex for the training 
(STS.Support@theradex.com, Theradex phone: 609-799-7580). 
 
4.2.3 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website. 
To access the Regulatory Submission Portal, log on to the CTSU members’ website, go to the 
Regulatory section, and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
Delegation of Tasks Log (DTL) 
 
Each site must complete a protocol-specific DTL using the DTL application in the Delegation 
Log section on the CTSU members’ website. The Clinical Investigator (CI) is required to review 
and electronically sign the DTL prior to the site receiving an Approved site registration status 
and enrolling patients to the study. To maintain an approved site registration status the CI must 
re-sign the DTL at least annually and when a new version of the DTL is released; and activate 
new task assignments requiring CI sign-off. Any individual at the enrolling site on a 
participating roster may initiate the site DTL. Once the DTL is submitted for CI approval, only 
the designated DTL Administrators or the CI may update the DTL. Instructions on completing 
the DTL are available in the Help Topics button in the DTL application and include a Master 
Task List, which describes DTL task assignments, CI signature, and CTEP registration 
requirements. 
 
4.2.4 Checking Site Registration Status 
 
Site’s registration status may be verified on the CTSU website. 
 
x Click on Regulatory at the top of the screen 
x Click on Site Registration, and 

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x Enter the site’s 5-character CTEP Institution Code and click on Go 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration requirements 
as outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with the NCI or 
their affiliated networks. 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment. OPEN or IWRS will populate the 
patient enrollment data in NCI’s clinical data management system, Medidata Rave. 
 
Requirements for OPEN access: 
x A valid CTEP-IAM account. 
x To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an Associate Plus (AP) registration type. 
x If a DTL is required for the study, the registrar must hold the OPEN Registrar task on the 
DTL for the site. 
x Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or NPIVR must be 
assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
x Patient has met all eligibility criteria within the protocol stated timeframes, and 
x All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. IWRS system also sends an email confirmation of the registration. You 
may print this confirmation for your records. 
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 

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Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN. Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System or the IWRS Slot 
Reservation System to ensure that a slot on the protocol is available to the patient. Once a slot 
reservation confirmation is obtained, site staff may then proceed to enroll the patient to this 
study. 
 
4.3.2 Special Instructions for Patient Enrollment 
The enrolling site will use the Slot Reservation System in IWRS to reserve a slot. 
Once reserved, the site will submit the following documentation to: 
Phone: (617) 632-6910 
Fax: (617) 632-4041 
Email: dfcisarcomatrials@partners.org 
 
x For COHORT A: Local NGS report documenting FGFR alteration must be submitted 
and reviewed/approved by the study team prior to registration 
x For COHORT B: Pathology reports documenting SDH-deficient GIST must be 
submitted and reviewed/approved by the study team prior to registration 
This Study will use the ETCTN Specimen Tracking System (STS). 
x All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted. 
x The system is accessed through Rave user roles: “Rave CRA” and “Rave CRA 
(Labadmin)” for data entry at the treating institutions and “Biorepository” for users 
receiving the specimens for processing and storage at reference labs and the Early-Phase 
and Experimental Clinical Trials Biospecimen Bank (EET Biobank, formerly known as 
the ETCTN Biorepository). 
x Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website in the Data Management section under the Rave Home tab and then 
under Rave Resource Materials tab. 
x Important: Failure to complete required fields in STS may result in a delay in 
sample processing. Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
Detailed instructions on use of the STS can be found in Section 5.4. 

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2 
Integrated 
RNAseq 
≥ 70% 
Flash frozen 
 
5.3 
Specimen Procurement Kits and Scheduling 
 
5.3.1 Specimen Procurement Kits 
 
Kits for the collection and shipment of frozen specimens to the EET Biobank can be ordered 
online via the Kit Management system: (https://kits.bpc-apps.nchri.org/). 
 
Users at the clinical sites will need to set up an account in the Kit Management system and select 
a specific clinical trial protocol to request a kit. Please note that protocol may include more than 
one type of kit. Each user may order two kits per kit type per day (daily max = 6 kits). Kits are 
shipped ground, so please allow 5-7 days for receipt. A complete list of kit contents for each kit 
type is located on the Kit Management system website. 
 
Note: Kits or supplies are only provided for specimens shipped to the EET Biobank. 
Institutional supplies must be used for all other specimen collection and processing. 
 
5.3.2 Scheduling of Specimen Collections 
 
Please adhere to the following guidelines when scheduling procedures to collect tissue: 
x Tissue submitted as FFPE (blocks or slides) can be collected on any day but must be 
shipped to the EET Biobank on Monday through Thursday. 
x Tissue specimens submitted frozen can be collected on any day but must be stored frozen 
and shipped to the EET Biobank on Monday through Thursday. In the event that frozen 
specimens cannot be shipped immediately, they must be maintained in a -70°C to -80°C 
freezer. 
x Fresh blood specimens may be collected and shipped Monday through Friday. 
 
5.4 
Specimen Tracking System Instructions 
5.4.1 Specimen Tracking System Overview and Enrollment Instructions 
 
For the ETCTN STS, the following information will be requested: 
x Protocol Number 
x Investigator Identification 
o Institution and affiliate name 
o Investigator’s name 
x Eligibility Verification: Patients must meet all the eligibility requirements listed in 
Section 3. 
x Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 

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Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 
patient ID. The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this or any other protocol that uses the ETCTN Specimen Tracking 
System. The UPID contains no information or link to the treatment protocol. IWRS will 
maintain an association between the UPID for ETCTN biobanking and molecular 
characterization and any treatment protocols the patient participates in, thereby allowing analysis 
of the molecular characterization results with the clinical data. 
 
Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave. The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial. For newly acquired biopsies without a corresponding 
radiology report, the radiology and operative report(s) must also be uploaded into Rave, when 
available. Important: Remove any personally identifying information, including, but not 
limited to, the patient’s name, date of birth, initials, medical record number, and patient 
contact information from the institutional pathology report prior to submission. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software. 
 
For questions regarding the Specimen Tracking System, please contact STS Support at 
STS.Support@theradex.com. 
 
The Shipping List report must be included with all sample submissions. 
 
5.4.2 Specimen Labeling 
 
5.4.2.1 Blood Specimen Labels 
 
Include the following on blood specimens (including whole blood): 
x Patient Study ID 
x Universal Patient ID (UPID) 
x Specimen ID (automatically generated by Rave) 
x Time point 
x Specimen type (e.g., blood, serum) 
x Collection date (to be added by hand) 
x Collection time for PK samples (to be added by hand) 
5.4.2.2 Tissue Specimen Labels 
 
Include the following on all tissue specimens or containers (e.g., formalin jar): 
x Patient Study ID 
x Universal Patient ID (UPID) 
x Specimen ID (automatically generated by Rave) 

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x Time point 
x Specimen type (e.g., flash frozen, etc.) 
x Tissue type (P for primary, M for metastatic or N for normal) 
x Surgical pathology ID (SPID) number (when applicable) 
x Collection date (to be added by hand) 
x Slide section number (only if archival tissue is submitted as slides) (to be added by 
hand) 
5.4.2.3 Example of Specimen Label Generated by STS 
 
STS includes a label printing facility, accessed via the Print Label CRF in the All Specimens 
folder. A generated PDF is emailed to the user as a result of saving that form. 
 
The following image is an example of a tissue specimen label printed on a label that is 0.5” high 
and 1.28” wide. 
 
 
 
The QR code in the above example is for the Specimen ID shown on the second line. 
 
Labels may be printed on a special purpose label printer, one label at a time, or on a standard 
laser printer, multiple labels per page. Theradex recommends the use of these low temperature 
waterproof labels for standard laser printers: https://www.labtag.com/shop/product/cryo-laser- 
labels-1-28-x-0-5-cl-23-colors-available/ 
 
The last line item on the label includes the following data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. An optional alpha-numeric code that is protocol specific and is only included if the 
protocol requires an additional special code classification 
 
Space is provided at the bottom of the label for the handwritten date and optional time. 
The last line on the example label is for the handwritten date and optional time. 

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5.4.3 Overview of Process at Treating Site 
 
5.4.3.1 OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system. OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization, and any prescribed slot 
assignments. If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration with eligibility specimen analysis: 
 
1. Site enters first step data into OPEN. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal Patient 
ID, both of which are sent back to OPEN. 
3. IWRS sends first step registration data, including the IDs and a TAC of “NOT REG” 
directly to Rave. 
4. The specimen tracking system in Rave is utilized for the specimen that contributes to 
eligibility determination. 
5. Site enters second and any subsequent step data into OPEN including results of specimen 
analysis. 
6. IWRS receives all data from OPEN, then sends it onto Rave with either the treatment 
TAC or a TAC of “SCRN FAIL”. 
7. In addition to the specimen tracking forms completed to determine eligibility, data entry 
for screen failure patients should include Histology and Disease, all forms in the Baseline 
folder, any lab forms connected to eligibility determination, and Off Treatment/Off 
Study. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
5.4.3.2 Rave Specimen Tracking Process Steps 
 
Step 0: Log into Rave via your CTEP-IAM account, then navigate to the appropriate participant. 
 
Step 1: Complete the Histology and Disease form (but do not upload reports until a specimen 
label can be applied to them) and the Baseline forms regarding Prior Therapies. Enter the 
initial clinical specimen data: 
x Specimen Tracking Enrollment CRF: Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, and number of labels 
needed (include extra labels to apply to reports to be uploaded). CRF generates unique 
Specimen ID. 
Step 2: Print labels using report the Print Labels CRF located in the All Specimens folder, then 
collect specimen. 
x Label specimen containers and write collection date on each label. After collection, store 

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labeled specimens as described in Section 5.4.2. 
x Apply an extra specimen label to each report before scanning. Return to the Histology 
and Disease form to upload any initial Pathology, Radiology, Molecular Reports (up to 
4), Surgical (or Operative) reports. Return to Specimen Tracking Enrollment CRF to 
upload any molecular report (one per specimen) and/or specimen specific pathology or 
related report (one per specimen) and/or Tissue Biopsy Verification form (Appendix D). 
Uploaded reports should have protected health information (PHI) data, like name, date of 
birth, mailing address, medical record number or social security number (SSN), redacted. 
Do not redact SPID, block number, diagnosis, or relevant dates (such as collection 
date), and include the UPID and patient study ID on each document (either by 
adding a label or hand writing). 
Step 3: Complete specimen data entry. 
x Specimen Transmittal Form: Enter collection date and time and other required 
specimen details. 
Step 4: When ready to ship, enter shipment information. 
x Shipping Status CRF: Enter tracking number, your contact information, recipient, 
number of sample containers and ship date once for the first specimen in a shipment. 
x Copy Shipping CRF: In the specimen folders for additional specimens (if any) that will 
be shipped with the initial specimen, please use the Copy Shipping form to derive 
common data into additional Shipping Status forms. A few unique fields will still need 
to be entered in Shipping Status. 
Step 5: Print shipping list report and prepare to ship. 
x Shipping List report is available at the site level. 
x Print two copies of the shipping list, one to provide in the box, the other for your own 
records. 
x Print pathology or other required reports to include in the box. Be sure the printed copy 
includes the specimen label. 
Step 6: Send email notification. 
x For only one of the specimens in the shipment, click “Send Email Alert” checkbox on the 
Shipping Status CRF to email recipient. 
 
Step 7: Ship the specimen(s). 
 
Step 8: Monitor the Receiving Status form located in each specimen folder for acknowledgment 
of receipt and adequacy. 
 
5.5 
Specimen Collection 
 
5.5.1 Archival or Formalin-Fixed Paraffin-Embedded (FFPE) Tumor Specimen 
 
If previously-collected FFPE tissue will be submitted, then the following criteria must be met: 

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x FFPE tumor tissue block(s) must be submitted. The optimal block is at least 70% tumor. 
Specimen size requirement is as follows: 
o Surface area: 25 mm2 is optimal. Minimum is 5 mm2. 
o Volume: 1 mm3 optimal. Minimum volume is 0.2 mm3, however the success of 
DNA extraction decreases at suboptimal tissue volume. 
 
If an existing block cannot be submitted, the following are requested, if available: 
x One (1) H&E slide (3-5 μm) 
x Thirty to fifty (30 – 50) 10 μm unstained air-dried uncharged slides (preferred). If not 
feasible, then a minimum of twenty (20) 10 μm unstained air-dried uncharged slides 
should be submitted with a minimum tumor content of at least 30%. Submission of 
specimens with <30% tumor content may not provide sufficient material for 
analysis. 
Process and number slides sequentially (e.g., H&E stained slide should be created first and 
labeled with “1,” and additional unstained slides should be processed next and be labeled 2 – n). 
See Section 5.4.2 for labeling instructions. 
5.5.2 Collection of Snap-Frozen Biopsies 
 
1. Tissue should be frozen as soon as possible. Optimally, freeze within 30 minutes from 
resection. 
2. Prior to tissue collection: 
a. Label cryovial(s) according to instructions in Section 5.4.2. 
b. Place cryovial(s) on dry ice to freeze. The vials should appear frosty when ready. 
3. Immediately place tissue in foil and allow to completely freeze (using either direct 
contact with dry ice, or liquid nitrogen vapor). 
4. Gently remove the frozen tissue from the foil. If the tissue is sticking to the foil, then 
gently run a finger over the back of the foil to loosen the tissue. 
5. Using clean forceps place each tissue core in a separate pre-chilled cryovial. Tissue 
should move freely in the vial. 
6. Place the tissue in a -70 to -80°C freezer. Keep frozen until shipment to the EET 
Biobank. 
 
5.5.3 Blood Collection 
 
5.5.3.1 Collection of Blood in EDTA Tubes for Whole Blood Processing 
 
1. Label EDTA tubes according to the instructions in Section 5.4.2. 
2. Collect 10 mL blood in EDTA tube(s) and gently invert tube to mix. 
3. Ship on day of collection (whenever possible) according to instructions in Section 
5.6. 
4. If blood cannot be shipped on the day of collection (e.g., a late scheduled collection), 
then refrigerate until shipment. 

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5.5.3.2 Collection of Blood in EDTA Tubes for PK Processing 
 
1. Label EDTA tubes according to the instructions in Section 5.4.2. 
2. Collect 4 mL blood in EDTA tube(s) (Becton Dickinson Catalog # 367844 or 367862, 
Franklin Lakes, NJ) and gently invert tube to mix. 
3. Place samples immediately on ice after collection; samples must be processed within 
30 minutes. 
4. Invert sample 8-10 times immediately before processing. 
5. Centrifuge at ~1300 xg for 10 minutes in swinging bucket (SW) or 15 minutes in a 
fixed angel (FA) rotor at 4ºC in a refrigerated centrifuge. Make sure that the centrifuge 
reaches speed and is maintained throughout the entire spin. 
6. Carefully remove tube from centrifuge. 
7. Using a pipette, transfer equal aliquots of plasma into 2-3 labeled 1.2 mL cryovials 
(e.g., preferred are external thread, conical self-standing vials like CorningTM 430658), 
not exceeding ~1 mL per cryovial. 
8. Label samples as Rogaratinib PK, including study number (NCI10411), unique patient 
ID (assigned by the consortium), date of collection, draw time, and time point. 
9. Store plasma samples at -70oC or below until shipment or transfer to Johns Hopkins. 
 
 
5.6 
Shipping Specimens from Clinical Site to the EET Biobank 
 
5.6.1 General Shipping Information 
 
The shipping container sent with kit contents should be used to ship frozen specimens to the EET 
Biobank. Fresh blood should be shipped at ambient temperature to the EET Biobank. In winter 
months, please include extra insulation, such as bubble wrap, inside the shipping container. 
 
5.6.1.1 Required Forms for Specimen Submissions: 
 
Each document submitted with the specimen must be labeled with a label printed from the 
STS, or the Universal ID and Patient Study ID. 
 
Tissue 
Required Forms 
Archival (if available) 
1. Shipping List 
2. Corresponding Pathology Report 
New Biopsy 
1. Shipping List 
2. Tissue Biopsy Verification Form 
3. Diagnostic Pathology Report 
4. Operative and/or Radiology Report 
Blood 
1. Shipping List 

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5.6.2 Specimen Shipping Instructions 
 
Frozen specimens and archival (FFPE) tissue (if available) may be shipped on Monday through 
Thursday. 
 
Fresh blood may be shipped on Monday through Friday. Please select “Saturday Delivery” 
when shipping fresh blood on a Friday. 
 
5.6.2.1 Shipping of FFPE Blocks and Glass Slides 
 
1. Before packaging blocks or slides, verify that each specimen is labeled according to 
Section 5.4.2.2. 
2. Blocks should be placed in a hard-sided container, preferably a special block holder, to 
protect the specimen. Glass slides are to be placed in plastic slide holders. Place tissue 
paper on top of the separated slides prior to closing the slide holder to reduce slide 
movement during shipment. 
3. Place the blocks or slides in a reinforced cardboard shipping box with appropriate 
packaging filler to minimize movement of specimens within the shipping box. 
4. Include a copy of the forms listed above and a shipping manifest from the Specimen 
Tracking System with each shipment. 
5. Please include a cold pack when shipping on hot days and extra insulation on cold days. 
6. Ship specimens to the address listed below. FedEx Priority Overnight is strongly 
recommended to prevent delays in package receipt. 
 
5.6.2.2 Shipping Frozen Specimens in a Single-Chamber Kit 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions in Section 5.4.2.1. 
2. Place the specimens in zip-lock bags. Use a separate zip-lock bag for each specimen type 
and time point. 
3. Place the zip-lock bags in the biohazard envelope containing absorbent material. Expel 
as much air as possible and seal securely. 
4. Put the secondary envelope into a Tyvek envelope. Expel as much air as possible and 
seal securely. 
5. Place frozen specimens in the kit compartment with dry ice. Layer the bottom of the 
compartment with dry ice until it is approximately one-third full. Place the frozen 
specimens on top of the dry ice. Cover the specimens with the dry ice until the 
compartment is almost completely full. When packaging specimens, ensure that you 
leave enough room to include at least 5 pounds of dry ice in the shipment. 
6. Insert a copy of the required forms into a plastic bag and place in the kit chamber. 
7. Place the Styrofoam lid on top to secure specimens during shipment. Do not tape the 
inner chamber shut. 
8. Close the outer lid of the Specimen Procurement Kit and tape it shut with durable sealing 
tape. Do not completely seal the container. 
9. Complete a FedEx air bill and attach to top of shipping container. 
10. Complete a dry ice label. 

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11. Attach the dry ice label and an Exempt Human Specimen sticker to the side of the 
shipping container. 
12. Ship specimens via overnight courier to the address below. FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt. 
 
5.6.2.3 Shipping Blood Using Supplies Provided by the Institution 
 
1. Before packaging specimens, verify that the collection tube is labeled according to the 
instructions in 5.4.2. 
2. Place the blood collection tube into a zip-lock bag. 
3. Place the zip-lock bag in the biohazard envelope containing absorbent material. Expel as 
much air as possible and seal securely. 
4. Place the biohazard envelope into a Tyvek envelope. Expel as much air as possible and seal 
securely. 
5. Place specimen and a copy of the shipping manifest into a sturdy shipping container. In 
winter months, please use an insulated container and include extra insulation, such as bubble 
wrap, inside the container to prevent specimens from freezing. 
6. Close the container and tape shut. 
7. Attach a shipping label to the top of shipping container. 
8. Attach an Exempt Human Specimen sticker to the side of the shipping container. 
9. Ship specimens via overnight courier to the address below. FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt. 
5.6.3 Shipping Address 
Ship to the address below. Ship fresh blood specimens the same day of specimen collection. Do 
not ship specimens the day before a holiday. 
EET Biobank 
The Research Institute at Nationwide Children's Hospital 
700 Children's Drive, WA1340 
Columbus, Ohio 43205 
PH: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred. 
 
NOTE: The EET Biobank FedEx Account will not be provided to submitting institutions. 
There is no central Courier account for this study. Sites are responsible for the cost of shipments 
to the EET Biobank. 
 
5.6.4 Contact Information for Assistance 
 
For all queries, please use the contact information below: 

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EET Biobank 
Toll-free Phone: (800) 347-2486 
E-mail: BPCBank@nationwidechildrens.org 
 
 
5.7 
Shipping Specimens from Clinical Site to the JHU SKCCC Analytical Pharmacology 
Core Lab (APC) for the ChOP-KC 
 
5.7.1 General Shipping Information 
 
Specimens should be stored through the end of Cycle 3 Day 1 and shipped as a batch by 
participant (more than one participant/shipment is acceptable if the site has >1 participant on- 
study). A participant's samples should be shipped to the APC lab within 2 weeks of the last 
sample's collection date. (i.e., if C1D28 sample is collected on 9/1/2020, all of that participant's 
samples should be at the APC lab by 9/15/2020). The APC lab may contact the study team to 
request shipment off-schedule. 
 
Please ship 1-2 aliquots to the APC laboratory. Once receipt is confirmed, the back-up 
aliquot may be shipped. The back-up can be shipped at a later date with subsequent 
batches. 
 
5.7.2 Preparing the Specimen Shipment Instructions 
 
1. Samples should be stored in cardboard boxes (5 1/8” x 5 1/8” x 2”, LxWxH) with dividers. 
(e.g., VWR Box item number is 82021-114; divider item number is 82007-154.) 
2. Please organize the samples by Patient and Time point in the box. 
3. Do not store in plastic bags (they break on dry-ice and labels will detach). 
4. A copy of each of the pharmacokinetic sample collection forms for the respective patients 
or a sample list should be included with each shipment. To prevent problems with illegible 
writing on tubes, consider numbering them (in addition to sample label) and numbering 
samples on the sample sheet. 
5. Note the study number, PI, and the drugs used/to be measured. 
6. A name, phone number and email address should be included with samples so that receipt 
can be acknowledged. 
7. Please notify the lab by email (onc-pharmacology@lists.johnshopkins.edu) or telephone 
(410-502-7192 or 410-955-1129) at least 24 hours prior to shipment. 
 
5.7.3 Specimen Shipping Instructions 
1. Samples collected at Johns Hopkins University can be transferred utilizing the current 
SOPs. 
2. All samples should be shipped via overnight express courier in insulated containers with 
enough dry ice to maintain the samples in a frozen state. 
3. Overnight shipments should occur on Monday through Wednesday (Tuesday is the 
preferred day) except when the following day is a holiday. 

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5.7.4 Shipping Address 
 
Ship to the address below. 
 
Analytical Pharmacology Core Laboratory 
Attn: Rogaratinib (NCI10411) Study Samples 
1650 Orleans St. CRB1 Rm 184 
Baltimore, MD 21231-1000** 
Phone: 410-502-7192 or 410-955-1129 
Email: onc-pharmacology@lists.johnshopkins.edu 
**This zip code is for FedEx shipments. Please change to 21287 if utilizing UPS to 
ship. 
 
5.8 
Biomarker Plan 

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5.9 
Integral Laboratory Studies 
 
5.9.1 Mutations and fusions in FGFR 1, 2, 3, and 4 
 
5.9.1.1 Specimen(s) Receipt and Processing at Local Laboratory 
For Cohort A, local NGS report documenting FGFR alteration must be submitted and 
reviewed/approved by the study team prior to registration. 
 
5.9.1.2 Site(s) Performing Correlative Study 
This assay will be performed at a local laboratory (e.g., Foundation One) as part of SOC prior to 
enrollment. 
 
5.9.1.3 Contact information for notification of specimen shipment 
Not applicable. 
5.9.2 SDH 
5.9.2.1 Specimen(s) Receipt and Processing at Local Laboratory 
For Cohort B, pathology reports documenting SDH-def GIST must be submitted and 
reviewed/approved by the study team prior to registration. 
5.9.2.2 Site(s) Performing Correlative Study 
This assay will be performed at a local laboratory as part of SOC prior to enrollment. 
5.9.2.3 Contact information for notification of specimen shipment 
Not applicable. 
5.10 
Integrated Correlative Studies 
 
5.10.1 Whole Exome Sequencing (WES) 
 
5.10.1.1 Specimen(s) Receipt and Processing at the EET Biobank 
 
Available archival FFPE tissue will be received as an FFPE tissue block or as H&E-stained and 
unstained slides. FFPE tissue blocks and stained slides will be stored at room temperature, and 
unstained slides will be vacuum sealed and banked in refrigerated storage until processing. 
 
H&E stained slides will undergo a pathology QA review to assess tumor content and annotate for 
macrodissection, when needed. Following macrodissection, tumor tissue from unstained slides 
will be scraped for co-extraction of DNA and RNA. The nucleic acids will be analyzed to 
determine concentration and quality prior to storage in a -80°C freezer. The remaining FFPE 
block and H&E stained slides will be stored at room temperature. Aliquots of DNA will be 
shipped to the central sequencing laboratory for analysis. 

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Frozen tissue received for pre-treatment and progression time points will be barcoded and stored 
in a liquid nitrogen vapor phase freezer until nucleic acids are extracted. 
 
Prior to extraction, an H&E stained slide will be created from frozen tissue. All H&E stained 
slides will undergo a pathology QA review to assess tumor content. DNA and RNA will be co- 
extracted from frozen tissue, and nucleic acids will be analyzed to determine concentration and 
quality prior to storage in a -80°C freezer. All remaining frozen tissue will be stored in a liquid 
nitrogen vapor phase freezer. Aliquots of DNA will be shipped to the central sequencing 
laboratory for analysis. 
 
 
DNA will be extracted from blood collected in EDTA tubes at pre-treatment. DNA will be 
quantitated, and then stored in a -80°C freezer until shipping for analysis. 
 
5.10.1.2 Site(s) Performing Correlative Study 
 
This assay will be performed at the NCLN Genomics Laboratory or MoCha, Frederick National 
Laboratory for Cancer Research (FNLCR) under the supervision of Mickey Williams, Ph.D. 
5.10.1.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
Specimens will be shipped from the EET Biobank to one of the laboratories designated in 
Section 5.10.1.2. 
5.10.1.4 Contact Information for Notification of Specimen Shipment 
Thomas Forbes (NCLNGenomicsReceiving@nih.gov) 
5.10.2 RNA Sequencing 
 
5.10.2.1 Specimen(s) Receipt and Processing at the EET Biobank 
 
Available archival FFPE tissue will be received as an FFPE tissue block or as H&E-stained and 
unstained slides. FFPE tissue blocks and stained slides will be stored at room temperature, and 
unstained slides will be vacuum sealed and banked in refrigerated storage until processing. 
 
H&E stained slides will undergo a pathology QA review to assess tumor content and annotate for 
macrodissection, when needed. Following macrodissection, tumor tissue from unstained slides 
will be scraped for co-extraction of DNA and RNA. The nucleic acids will be analyzed to 
determine concentration and quality prior to storage in a -80°C freezer. The remaining FFPE 
block and H&E stained slides will be stored at room temperature. Aliquots of RNA will be 
shipped to the central sequencing laboratory for analysis. 
 
Frozen tissue received for pre-treatment and progression time points will be barcoded and stored 

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in a liquid nitrogen vapor phase freezer until nucleic acids are extracted. 
 
Prior to extraction, an H&E stained slide will be created from frozen tissue. All H&E stained 
slides will undergo a pathology QA review to assess tumor content. DNA and RNA will be co- 
extracted from frozen tissue, and nucleic acids will be analyzed to determine concentration and 
quality prior to storage in a -80°C freezer. All remaining frozen tissue will be stored in a liquid 
nitrogen vapor phase freezer. Aliquots of RNA will be shipped to the central sequencing 
laboratory for analysis. 
 
5.10.2.2 Site(s) Performing Correlative Study 
 
This assay will be performed at the NCLN Genomics Laboratory or MoCha, Frederick National 
Laboratory for Cancer Research (FNLCR) under the supervision of Mickey Williams, Ph.D. 
 
5.10.2.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to one of the laboratories designated in 
Section 5.10.2.2. 
5.10.2.4 Contact Information for Notification of Specimen Shipment 
Thomas Forbes (NCLNGenomicsReceiving@nih.gov) 
5.11 
Exploratory Correlative Studies 
5.11.1 Pharmacokinetics (PK) 
 
5.11.1.1 Specimen(s) Receipt and Processing at the JHU SKCCC Analytical Pharmacology Core 
Lab for the ChOP-KC 
 
Rogaratinib will be extracted from plasma isolated from blood collected in EDTA tubes at pre- 
treatment (prior to C1D1, C1D15, C2D1, C2D15, and C3D1) and at the time of Progression at 
the sites. Additional trough samples may be collected after a dose reduction to correlate the 
exposure at tolerable doses. Plasma will be stored in a -80°C freezer until shipping for analysis. 
 
NOTES regarding the PK collection: 
x The dates of the PK samples are when the physical exams are scheduled. If a physical 
exam is shifted due to a holiday or inclement weather, the PK should be collected on that 
day (and not the exact day listed above). 
x If rogaratinib has been held for non-toxicity reasons (Section 7) for longer than 6 doses (3 
days), the PK sample should not be collected. 
x If rogaratinib has been held for toxicity reasons (Section 7), the PK sample should not be 
collected with documentation of the last dose administered (date and time). 

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5.11.1.2 Site(s) Performing Correlative Study 
 
This assay will be performed at the JHU SKCCC Analytical Pharmacology Core Lab for the 
ChOP-KC under the supervision of Michelle Rudek, PharmD, PhD. 
5.11.1.3 
Contact information for notification of specimen shipment 
Michelle Rudek, PharmD, PhD. 
Email: onc-pharmacology@lists.johnshopkins.edu 
 
6. TREATMENT PLAN 
 
6.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in Section 10. Appropriate dose modifications are described in Section 7. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Rogaratinib 
(BAY 1163877) 
N/A 
800 mg 
PO 
BID Day 1 
– Day 28 
28 days 
(4 weeks) 
PO = Orally, BID =Twice a Day 
 
The patient will be requested to maintain a medication diary of each dose of medication (see 
Appendix E). The medication diary will be returned to clinic staff at the end of each course. 
 
6.1.1 CTEP IND Agent 
6.1.1.1 Rogaratinib (BAY 1163877) (NSC 804782) 
Patients will receive rogaratinib (BAY 1163877) orally 800mg po BID for a 28-day cycle. 
Rogaratinib (BAY 1163877) may be administered with or without food. If a dose is missed, it 
can be taken within 3 hours of the usual dosing time. If it is after 3 hours of the usual dosing 
time, the dose should be skipped and the next dose should be taken at the usual time. Vomited 
doses should not be replaced. Rogaratinib (BAY 1163877) should be swallowed whole. Do not 
chew. Patients should be instructed to bring their morning dose of rogaratinib (BAY 1163877) 
with them to the clinic on Day 1 of Cycles 1-3 and Day 15 of Cycles 1-2. 

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6.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of rogaratinib (BAY 1163877) with other 
concomitantly administered drugs, the case report form must capture the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies. The Principal Investigator 
should be alerted if the patient is taking any agent known to affect or with the potential for drug 
interactions. The study team should check a frequently-updated medical reference for a list of 
drugs to avoid or minimize use of. Appendix C (Patient Drug Interaction Handout and Wallet 
Card) should be provided to patients if available. 
 
Rogaratinib (BAY 1163877) exhibited characteristics of a P-gp substrate (Rogaratinib 
Investigator’s Brochure, 2019). Additionally, it was shown that rogaratinib (BAY 1163877) 
exhibited inhibitory potential on P-gp and BCRP. Oxidative metabolism of rogaratinib (BAY 
1163877) is mainly catalyzed by CYP3A4 and to a lower extent by CYP2C9. Hence, 
concomitant use of strong inhibitors as well as of strong inducers of CYP3A4 may result in 
altered plasma exposure levels of rogaratinib (BAY 1163877). Based on in vitro study results 
indicating inhibition of CYP3A4, P-gp and BCRP, narrow therapeutic index drugs that are 
CYP3A4, P-gp, BCRP, MATE1, and MATE2K substrates and strong inhibitors and inducers of 
CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, and tacrolimus) should be avoided. Use caution with strong inhibitors and 
inducers of P-gp. 
 
Concomitant administration of medications that prolong QT/QTc interval is prohibited in 
accordance with the published FDA guidance “E14 Clinical Evaluation of QT/QTc Interval 
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs”. 
 
6.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
x 
Disease progression 
 
x 
Intercurrent illness that prevents further administration of treatment 
 
x 
Unacceptable adverse event(s) 
 
x 
Patient decides to withdraw from the study 
 
x 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
x 
Clinical progression 

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x 
Patient non-compliance 
 
x 
Pregnancy 
 
o All women of child bearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period) at any time during study participation. 
 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
x 
Termination of the study by sponsor 
 
x 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
6.4 
Duration of Follow-Up 
 
Patients will be followed for 30 days after removal from study or until death, whichever occurs 
first. Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
 
7. DOSING DELAYS/DOSE MODIFICATIONS 
 
x Toxicity modifications are for adverse events (AEs) thought to be at least possibly related 
to agent. 
x A delay of up to 3 weeks (21 days) is permitted from the scheduled cycle start date to 
allow for toxicity thought to be at least possibly related to agent to resolve such that 
criteria for allowing continuation of therapy as detailed below are met. If toxicity has not 
resolved by that time, study treatment should be discontinued. 
x Only two dose reductions will be allowed. If AE recurs requiring dose reduction then the 
patient will be removed from protocol. 
 
Dose Level 
Rogaratinib (BAY 1163877) Dose 
-2 
400 mg, PO, BID 
-1 
600 mg, PO, BID 
0 
800 mg, PO, BID 
 
ALT or AST 
elevations 
Management/Next Dose for Rogaratinib (BAY 1163877) 
Grade 0-2 
No change in dose 

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ALT or AST 
elevations 
Management/Next Dose for Rogaratinib (BAY 1163877) 
Grade 3 
Hold* until ≤ Grade 2. Resume at one dose level lower.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >3 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Patients with ALT or AST > 3x ULN with bilirubin > 2x ULN without findings of cholestasis 
(i.e. alk phos < 2x ULN) or other etiology for LFT changes should go off protocol. 
 
Hyperphosphatemia: 
Dose modifications of rogaratinib for elevated serum phosphate levels (≥ 7 mg/dL) and 
management guidance for hyperphosphatemia are presented in the Table below. Dose 
interruptions for hyperphosphatemia for >21 consecutive days, requires treatment 
discontinuation. 
 
Serum phosphate 
Countermeasures 
 
 
Initial phosphate value is 
abnormally high, but less than 7 
mg/dL 
≥ 7 mg/dL for two weeks despite 
phosphate lowering treatment 
 
 
≥ 7 mg/dL despite optimal phosphate 
lowering treatments and two 
rogaratinib treatment interruptions on 
the same dose within four weeks 
≥ 7 mg/dL despite optimal phosphate 
lowering treatments and two 
rogaratinib treatment interruptions 
within four weeks at 400 mg b.i.d. 
b.i.d. = Twice daily, bis in die. 
Continue rogaratinib at the same dose. 
Consider low phosphate diet a and / or initiate 
phosphate chelators. 
Hold rogaratinib and increase dose of phosphate 
chelators until recovery below 7 mg/dL. 
Re-start rogaratinib at the same dose level and 
continue phosphate chelators. 
Hold rogaratinib and continue phosphate chelators 
until recovery below 7 mg/dL. 
Re-start rogaratinib, but at one dose level lower and 
continue phosphate chelators. 
Hold rogaratinib and continue phosphate chelators 
until recovery below 7 mg/dL. 
Re-start rogaratinib at 400 mg b.i.d. and continue 
phosphate chelators. 
a: Low phosphate diet can be considered if the patient’s nutritional status is not affected. 
 
 
In case phosphate chelators are not tolerated, low-phosphorus diet should be considered. 
For patients with elevated serum phosphate levels ≥ 7 mg/dL, serum phosphate level and 

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standard single 12-lead ECG has to be checked weekly until resolution (serum phosphate < 7 
mg/dL). 
 
For patients with hypocalcemia of CTCAE Grade ≥ 2, an additional standard single 12-lead ECG 
has to be obtained on the day of detection of hypocalcemia and should be repeated as clinically 
indicated. 
 
Hyperphosphatemia may be associated with soft tissue mineralization (e.g., cutaneous 
calcification). Any patient with newly diagnosed soft-tissue mineralization suspected to be 
caused by rogaratinib should permanently discontinue the study treatment. 
 
Retinal disorders: 
 
Patients who experience any decrease in visual acuity, or symptomatic or asymptomatic retinal 
disorders including retinal detachment / retinal pigment epithelial detachment (RPED) / serous 
retinopathy / retinal vein occlusion (Grade 1 classified analog to CTCAE) have to undergo 
ophthalmologic examinations on Day 1 of every cycle for as long as determined clinically 
indicated per treating team. 
 
Patients that experience any decrease in visual acuity, or symptomatic or asymptomatic retinal 
disorders including retinal detachment / retinal pigment epithelial detachment / serous 
retinopathy / retinal vein occlusion classified analog to CTCAE as Grade 2 or higher have to be 
permanently discontinued from study treatment. 
 
Neutropenia or 
thrombocytopenia 
Management/Next Dose for Rogaratinib (BAY 1163877) 
Grade 0-2 
No change in dose 
Grade 3 
Hold* until ≤Grade 2. Resume at one dose level lower.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >3 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
 
 
Other non- 
hematologic AEsº 
Management/Next Dose for Rogaratinib (BAY 1163877) 
Grade 0-2 
No change in dose 
Grade 3 
Hold* until ≤ Grade 2. Resume at one dose level lower**. 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >3 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. Allow 48 hours for 
optimal management of grade 3 events such as other electrolyte abnormalities, diarrhea, nausea 
or emesis. 
º Excluding alopecia. Nausea and vomiting only if refractory to anti-emetics, diarrhea refractory 
to anti-diarrheal agents. 
It is recommended that investigators optimize treatment for nausea, vomiting and diarrhea. 

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8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 10.1. 
 
8.1 
CTEP IND Agent 
 
 
8.1.1 Rogaratinib (BAY 1163877) (NSC 804782) 
 
Chemical Name or Amino Acid Sequence: 4-{[4-amino-6-(methoxymethyl)-5-(7-methoxy-5- 
methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazin-2-one 
 
Other Names: BAY 1163877 (rogaratinib), BAY 1213802 (rogaratinib hydrochloride hydrate) 
 
Classification: Fibroblast growth factor receptors (FGFR) inhibitor 
CAS Registry Number: 1443530-05-09 
Molecular Formula (BAY1163877): C23H26N6O3S 
M.W.: 
466.56 
g/mol 
Molecular Formula (BAY1213802): C23H26N6O3S·HCl·H2O 
M.W.: 
521.04 
g/mol 
 
Approximate Solubility: BAY 1213802 is slightly soluble in water, very slightly soluble in ethanol, 
sparingly soluble in polyethylene glycol (PEG) 400. 
Mode of Action: Rogaratinib (BAY 1163877) is a small molecule kinase inhibitor of fibroblast 
growth factor receptor (FGFR) 1, 2, 3, and 4. FGFRs drive crucial developmental signaling pathways, 
which are responsible for many functions of the tumor cell, including cell proliferation, survival, and 
migration. 
Description: BAY 1213802 is a white to yellow solid that is isolated as a hydrate. BAY 1231802 is 
the active pharmaceutical ingredient and the hydrochloride hydrate of rogaratinib. 
 
How Supplied: Rogaratinib (BAY 1163877) is supplied by Bayer HealthCare AG and distributed by 
the Pharmaceutical Management Branch, CTEP/DCTD/NCI as 200 mg coated immediate release 
tablets in bottles containing 56 tablets. The 200 mg tablets are oblong, red coated tablets with a size 
of 16 x 8 mm. Excipients include cellulose microcrystalline, lactose monohydrate, crospovidone, 
copovidone, magnesium stearate, silica colloidal anhydrous, and lacquer red (hypromellose, 
macrogol, titanium dioxide, and ferric oxide red). 
 
Storage: Do not store above 25°C. Do not freeze. 

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If a storage temperature excursion is identified, promptly return rogaratinib to below 25°C and 
quarantine the supplies. Provide a detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for 
determination of suitability. 
 
Stability: Stability studies are ongoing. Dispense in the original container. 
 
Route and Method of Administration: Take by mouth with or without food with a glass of water. 
Swallow whole. Do not chew. If a dose is missed, take within 3 hours of the usual dosing time. If it 
is after 3 hours of the usual dosing time, skip the dose and take the next dose at the usual time. 
 
Potential Drug Interactions: 
In vitro, rogaratinib (BAY 1163877) is mainly metabolized by CYP3A4 and to a lesser extent by 
CYP2C9 and CYP1A1. It is a weak inhibitor of CYP2C8, 2C9, UGT1A1, UGT1A4, and UGT1A9. 
It did not inhibit CYP1A2, 2A6, 2B6, 2C19, 2D6, 2E1, 2J2, 3A4, UGT1A6, UGT2B4, and UGT2B7. 
However, irreversible inhibition of CYP3A4 was observed after pre-incubation of rogaratinib (BAY 
1163877) with human liver microsomes. In vitro, rogaratinib (BAY 1163877) did not induce 
CYP1A2, 3A4, 2B6, or 2C19. Avoid concomitant administration with sensitive substrates/narrow 
therapeutic index drugs of CYP3A4, and strong inhibitors and inducers of CYP3A4. 
 
In vitro, rogaratinib (BAY 1163877) is a moderate P-gp substrate but not BCRP, OATP1B1, 1B3, or 
OCT1. Rogaratinib (BAY 1163877) showed weak to moderate inhibition of MATE2K, MATE1, 
BCRP, BSEP, P-gp, OATP1B1, OATP1B3, and OCT1 in vitro. It does not inhibit OAT1, OAT3, 
and OCT2. Avoid concomitant administration with sensitive substrates/narrow therapeutic index 
drugs of P-gp BCRP, MATE1, and MATE2K. Use caution with strong inhibitors and inducers of P- 
gp. 
 
Availability 
 
Rogaratinib (BAY 1163877) (NSC 804782 is an investigational agent supplied to investigators 
by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Rogaratinib (BAY 1163877) (NSC 804782) is provided to the NCI under a Collaborative 
Agreement between the Pharmaceutical Collaborator and the DCTD, NCI (see Section 13.5). 
 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents. The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF). If there are several participating investigators at one institution, CTEP-supplied 

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investigational agents for the study should be ordered under the name of one lead 
participating investigator at that institution. 
 
Sites can place orders for PMB-supplied agents only after enrollment onto the study. 
Please provide the patient ID# when placing an order. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status. For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time. 
Refer to the PMB’s website for specific policies and guidelines related to agent 
management. 
 
8.1.2.2 Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page. Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
 
8.1.3 Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application. Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, a “current” password and 
active person registration status. Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
 
8.1.4 Useful Links and Contacts 
x CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/
x NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov
x PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent management.htm
x 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP
x CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/
x CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov
x IB Coordinator: IBCoordinator@mail.nih.gov
x PMB email: PMBAfterHours@mail.nih.gov
x PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET)
9. STATISTICAL CONSIDERATIONS 

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9.3 
Stratification Factors 
 
Not applicable. 
 
9.4 
Analysis of Secondary Endpoints 
 
Time-to-event endpoints, including PFS, will be estimated using Kaplan-Meier method. 
Correlative and biomarker objectives will be considered exploratory. Assuming the study moves 
to the second stage, the maximal width of a 90% confidence interval for any binomial parameter 
will be no wider than 35.3%, hence estimation of binomial quantities will be fairly accurate. 
Estimation of continuous biomarker measures will be via mean or median as appropriate and 
standard deviation. There will be limited power to correlate clinical measures with biomarker 
endpoints with this limited phase 2 sample size, hence those analyses will be considered 
exploratory. 
 
9.5 
Analysis of Exploratory Endpoints 
 
Trough samples for rogaratinib will be used to assess exposure-response relationships with 
various PD endpoints (i.e., clinical response, toxicity, and markers of FGFR pathway inhibition). 
Rogaratinib concentrations in these samples will be quantitatively measured using liquid 
chromatography/tandem mass spectrometric (LC/MS/MS) method developed by the Analytical 
Pharmacology Core Laboratory at the Sidney Kimmel Comprehensive Cancer Center (SKCCC) 
at Johns Hopkins for the ChOP-KC. For rogaratinib, the average trough concentration (Cmin) 
will be calculated as an average of all samples at the same dose. If multiple dose reductions 
occur for a single patient, the Cmin at each dose level will be calculated. Exploratory correlative 
studies with pharmacodynamic (biological endpoints, toxicity and efficacy) will be analyzed 
using nonparametric statistics. Significance for comparisons will be at the p<0.05 level. 
9.6 
For phase 2 protocols only: Reporting and Exclusions 
 
9.6.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with rogaratinib 
(BAY 1163877). 
 
9.6.2 Evaluation of Response 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations. Each patient will be assigned one of the following 
categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) 
early death from malignant disease, 6) early death from toxicity, 7) early death because of other 
cause, or 9) unknown (not assessable, insufficient data). [Note: By arbitrary convention, 
category 9 usually designates the “unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 

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received no study medication) should be included in the main analysis of the response rate. 
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression). Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate. Precise definitions for categories 4-9 will be 
protocol specific. 
 
All conclusions should be based on all eligible patients. Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.). However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported. 
 
 
10. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of AEs (Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 
10.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
10.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
10.1.1 CAEPRs for CTEP IND Agent 
10.1.1.1 CAEPR for Rogaratinib (BAY 1163877, NSC 804782) 
 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Rogaratinib (BAY 1163877, NSC 804782) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 279 patients. Below is the CAEPR for Rogaratinib 
(BAY 1163877). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
Version 2.2, February 14, 20231 

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64 
 
 
Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Fever; General disorders and 
administration site conditions - Other (general physical health deterioration) 
INFECTIONS AND INFESTATIONS - Mucosal infection; Paronychia; Rhinitis infective 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; Aspartate 
aminotransferase increased; Blood bilirubin increased; Creatinine increased; GGT increased; 
Investigations - Other (calcium phosphate 
product increased); Neutrophil count decreased 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hypoglycemia; Hyponatremia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (pharyngeal cancer) 
NERVOUS SYSTEM DISORDERS - Neuralgia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other 
(nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Pneumonitis; Respiratory, thoracic 
and mediastinal disorders - Other (interstitial lung disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Pruritus; Purpura; Rash acneiform; Rash maculo- 
papular; Skin and subcutaneous tissue disorders - Other (cutaneous calcification/soft tissue 
mineralization) 
 
Note: Rogaratinib (BAY 1163877) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
10.2 
Adverse Event Characteristics 
x CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
x For expedited reporting purposes only: 
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 10.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
 
x Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 
Expedited Adverse Event Reporting 

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10.3.1 Rave-CTEP-AERS Integration 
 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP- 
AERS) integration enables evaluation of post-baseline AEs entered in Rave to determine 
whether they require expedited reporting, and facilitates entry in CTEP-AERS for those 
AEs requiring expedited reporting. 
 
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period, and used to 
collect AEs that start during the period or persist from the previous reporting period. 
CRA will enter AEs that occur prior to the start of treatment on a baseline form that is not 
included in the Rave-CTEP-AERS integration. AEs that occur prior to enrollment must 
begin and end on the baseline Adverse Event form and should not be included on the 
standard Adverse Events form that is available at treatment unless there has been an 
increase in grade. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
x The reporting period (course/cycle) is correct, and 
x AEs are recorded and complete (no missing fields) and the form is query-free 
(fields added to the form during study build do not need to be query-free for the 
integration call with CTEP-AERS to be a success). 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form. Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting. A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements. The CRA completes the report by accessing CTEP- 
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
 
In the rare occurrence that internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the direct link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU 
website: 
 
x Study specific documents: Protocols > Documents > Education and Promotion, 
and 

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x Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU 
Operations Information > User Guides & Help Topics. 
NCI requirements for SAE reporting are available on the CTEP website: 
x NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid 
elines.pdf. 
10.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals: Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter. CTEP-AERS provides a copy feature for other e-mail recipients. 
 
10.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note: A death on study requires both routine and expedited reporting, regardless of 
causality as long as the death occurred within 30 days after the last administration of the 
investigational agent. Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted. 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY SAEs, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64). 
An AE is considered serious if it results in ANY of the following outcomes: 
1) 
Death 
2) 
A life-threatening AE 
3) 
An AE that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours. 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
 

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submitted to CTEP. Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome. Newborn infants should be followed until 30 days old. Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP. 
 
10.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS. Three options are available to 
describe the event: 
 
x Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML]) 
x Myelodysplastic syndrome (MDS) 
x Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
 
10.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
11. STUDY CALENDAR 

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Pre-treatment evaluations are to be conducted within 1 week prior to start of protocol therapy. Scans and x-rays must be done <4 
weeks prior to the start of therapy. Informed consent may be obtained within ≤ 4 weeks prior to start of protocol therapy. Screening 
ophthalmologic exam and biopsy may be done ≤ 14 days prior to start of protocol therapy. In the event that the patient’s condition is 
deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. All cycle visits 
and radiologic evaluations are tied to C1D1. 
 
Procedures 
Pre- 
treatment 
Cycles 1 - 4 
Cycles 5 -26 
Cycle 27 and Every 3 Cycles Thereafter 
Off Studya 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 1 
Window 
±2 days 
±2 days 
±2 days 
±2 days 
±2 days 
±14 days 
Rogaratinib (BAY 1163877)e 
X 
X 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
X 
Physical exam 
X 
X 
 
X 
 
X 
X 
X 
Vital signs 
X 
X 
 
X 
 
X 
X 
X 
Weight 
X 
 
 
 
 
 
Performance status 
X 
 
 
 
 
 
CBC w/diff, plts 
X 
X 
 
X 
 
X 
X 
X 
Comprehensive Chemistry Panelb 
X 
X 
 
X 
 
X 
X 
X 
ECG (as indicated) 
X 
 
 
 
 
 
Adverse event evaluation 
X 
X 
X 
Tumor measurements 
X 
Tumor measurements are repeated every 8 weeks (±3 days) through the end of Cycle 26, and then every 3 
cycles thereafter (±14 days). Documentation (radiologic) must be provided for patients removed from study 
for progressive disease. 
X 

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Procedures 
Pre- 
treatment 
Cycles 1 - 4 
Cycles 5 -26 
Cycle 27 and Every 3 Cycles Thereafter 
Off Studya 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 1 
Radiologic evaluation 
Xf 
Radiologic measurements should be performed every 8 weeks (±3 days) through the end of Cycle 26, and 
then every 3 cycles thereafter (±14 days). 
X 
Pregnancy testc 
X 
 
 
 
 
 
Ophthalmologic examination 
Xg 
 
 
 
 
 
Archival Tissue (if available) 
Xh 
 
 
 
 
 
Biopsy 
Xi 
 
 
 
 
 
Xd 
Biomarker Blood Test 
X 
 
 
 
 
 
PK Blood TestJ 
X 
X 
 
X 
 
 
 
X 
a: 
Off-study evaluation should be performed within 30-days of last dose of study drug. 
b: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
Conjugated and unconjugated bilirubin will be evaluated if the bilirubin is found to be elevated and if there is a clinical need.  
c: 
Pregnancy test for women of childbearing potential. 
d: 
Optional biopsy at progression. 
e: 
800 mg PO BID each day of a 28 day cycle (see Appendix E). Rogaratinib (BAY 1163877) must be taken twice a day with 8 oz. water, with or without food. Swallow whole. Do not 
chew. 
f: 
pre-treatment radiologic evaluations (scans and x-rays) should be done ≤4 weeks prior to the start of protocol therapy. 
g: 
Ophthalmologic examination is recommended for screening. Additional monitoring as described in Section 7.0. May be done ≤ 14 days prior to start of protocol therapy.  
h: 
Archival tissue (if available) should be submitted for all participants on study. 
i: May be done ≤ 14 days prior to start of protocol therapy. Pre-treatment biopsy is mandatory if disease site is amenable to biopsy and low risk for the biopsy procedure. If biopsy not 
possible, eligibility may be approved after discussion with medical monitor. 
j: 
Pre-dose (at pre-treatment [prior to C1D1], C1D15, C2D1, C2D15, and C3D1) is mandatory and can be shifted to coincide with the physical exam (due to a holiday or inclement 
weather) and at the time of Progression (optional). Additional trough samples may be collected at the next physical exam after a dose reduction. 

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12. MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks (±3 
days) through the end of Cycle 26, and then every 3 cycles thereafter (±14 days). In addition to 
a baseline scan, confirmatory scans should also be obtained 8 weeks (not less than 4) weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
12.1.1 Definitions 
 
Evaluable for Toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with rogaratinib (BAY 1163877). 
 
Evaluable for Objective Response. Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. 
 
12.1.2 Disease Parameters 
 
Measurable Disease. Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. 
 
Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm [0.5 cm]). At baseline and in follow-up, 

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only the short axis will be measured and followed. 
 
Non-Measurable Disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] 
short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target Lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-Target Lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 
 
12.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 

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Clinical Lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 
calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
 
Chest X-Ray. Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT scans have slice 
thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of 
MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed. 
 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 

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complete response (CR) or surgical resection is an endpoint. 
 
Tumor Markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 
2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008]. In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
 
Cytology, Histology. These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG- 
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG- 
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 

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12.1.4 Response Criteria 
 
12.1.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm (0.5 cm). (Note: the appearance of one or more new lesions is 
also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
12.1.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
12.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 

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For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non- 
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** Only for non-randomized trials with response as primary endpoint. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
12.1.5 Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 

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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
 
12.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
12.1.7 Response Review 
 
The PI or designee will review all objective responses. 
 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section. The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s). The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study. This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
13.2 
Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments. 

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Requirements to access Rave via iMedidata: 
 
x 
A valid account, and 
x 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. 
x 
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role, must have a minimum of an 
Associate Plus (AP) registration type, 
o Rave Investigator role, must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR), and 
o Rave Read Only role, site staff must have at a minimum an Associates (A) 
registration type. 
x 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page. Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen. If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name. 
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
13.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS). Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP). Information on CTMS reporting is available at: 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. On-site 

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audits will be conducted on an 18-36 month basis as part of routine cancer center site visits. 
More frequent audits may be conducted if warranted by accrual or due to concerns regarding 
data quality or timely submission. For CTMS monitored studies, after users have activated their 
accounts, please contact the Theradex Help Desk at (609) 619-7862 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
13.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave. 
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks. The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS. Metrics for timeliness will be followed and assessed on a quarterly basis. 
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received. Queries will be issued by CTMS directly within Rave. The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve. Monthly web- 
based reports are posted for review by the Drug Monitors in the IDB, CTEP. Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm) and 
CTSU websites. 
 
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics- 
resources/interoperability-and-semantics/metadata-and-models). Customized eCRFs will be 
included when appropriate to meet unique study requirements. The PI is encouraged to review 
the eCRFs, working closely with CTMS to ensure prospectively that all required items are 
appropriately captured in the eCRFs prior to study activation. CTMS will prepare the eCRFs 
with built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex. CDUS submissions are performed by Theradex on a monthly 
basis. The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 

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(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
13.3 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics. 
 
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries. DQP Queries, DQP Delinquent Forms, and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports. Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality. 
 
13.4 
CTEP Multicenter Guidelines 
 
Not applicable. 
 
13.5 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 

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be maintained as such by the investigators. The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI. If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement. A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non- 
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 

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comment prior to submission for publication. Collaborator(s) will have 30 days from the 
date of receipt for review. Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected. 
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings. Press 
releases and other media presentations must also be forwarded to CTEP prior to release. 
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
13.6 
Genomic Data Sharing Plan 
 
Not applicable. 
 
13.7 
Incidental/Secondary Findings Disclosure Procedure 
 
Not applicable. 

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14. REFERENCES 
 
Rogaratinib Investigator’s Brochure, 2019, BAY 1163877 (Rogaratinib), Version 11.0, 10 
December 2019, Bayer AG. 
 
Boikos, S.A., A.S. Pappo, J.K. Killian, et al. (2016). Molecular Subtypes of KIT/PDGFRA 
Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health 
Gastrointestinal Stromal Tumor Clinic. JAMA Oncol. 2(7):922-928. 
 
Brennan, M.F. (2013). Lessons learned from the study of soft tissue sarcoma. Int J Surg. 11 
Suppl 1:S8-10. 
 
Crose, L.E., K.T. Etheridge, C. Chen, et al. (2012). FGFR4 blockade exerts distinct 
antitumorigenic effects in human embryonal versus alveolar rhabdomyosarcoma. Clin Cancer 
Res. 18(14):3780-3790. 
 
Flavahan, W.A., Y. Drier, S.E. Johnstone, et al. (2019). Altered chromosomal topology drives 
oncogenic programs in SDH-deficient GIST. Nature. Epub 2019/10/17. 
 
Hanes, R., I. Grad, S. Lorenz, et al. (2016). Preclinical evaluation of potential therapeutic 
targets in dedifferentiated liposarcoma. Oncotarget. 7(34):54583-54595. 
 
Holme, H., A. Gulati, R. Brough, et al. (2018). Chemosensitivity profiling of osteosarcoma 
tumour cell lines identifies a model of BRCAness. Sci Rep. 8(1):10614. 
 
Italiano, A., S. Mathoulin-Pelissier, A.L. Cesne, et al. (2011). Trends in survival for patients 
with metastatic soft-tissue sarcoma. Cancer. 117(5):1049-1054. 
 
Janeway, K.A., K.H. Albritton, A.D. Van Den Abbeele, et al. (2009). Sunitinib treatment in 
pediatric patients with advanced GIST following failure of imatinib. Pediatr Blood Cancer. 
52(7):767-71. 
 
Janeway, K.A., S.Y. Kim, M. Lodish, et al. (2011). Defects in succinate dehydrogenase in 
gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A. 
108(1):314-318. 
 
Kelly, C.M., A.N. Shoushtari, L.X. Qin, et al. (2019). A phase Ib study of BGJ398, a pan- 
FGFR kinase inhibitor in combination with imatinib in patients with advanced gastrointestinal 
stromal tumor. Invest New Drugs. 37(2):282-290. 
Li, F., H. Huynh, X. Li, et al. (2015). FGFR-Mediated Reactivation of MAPK Signaling 
Attenuates Antitumor Effects of Imatinib in Gastrointestinal Stromal Tumors. Cancer Discov. 
5(4):438-451. 
 
Pappo, A.S., K.A. Janeway. (2009). Pediatric gastrointestinal stromal tumors. Hematol Oncol 

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Clin North Am. 23(1):15-34. 
 
Patwardhan, P.P., E. Musi, G.K. Schwartz. (2018). Preclinical Evaluation of Nintedanib, a 
Triple Angiokinase Inhibitor, in Soft-tissue Sarcoma: Potential Therapeutic Implication for 
Synovial Sarcoma. Mol Cancer Ther. 17(11):2329-2340. 
 
Siegel, R., J. Ma, Z. Zou, et al. (2014). Cancer Statistics, 2014. CA Cancer J Clin. 64(1):9-29. 
 
Taylor, J.G., A.T. Cheuk, P.S. Tsang, et al. (2009). Identification of FGFR4-activating 
mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models. J 
Clin Invest. 119(11):3395-3407. 
 
van der Graaf, W.T., J.Y. Blay, S.P. Chawla, et al. (2012). Pazopanib for metastatic soft-tissue 
sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 
2;379(9829):1879-1886. 
 
Wachtel, M., J. Rakic, M. Okoniewski, et al. (2014). FGFR4 signaling couples to Bim and not 
Bmf to discriminate subsets of alveolar rhabdomyosarcoma cells. Int J Cancer. 135(7):1543- 
1552. 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
 
 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
 
 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 

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APPENDIX C 
PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible Interactions with 
Other Drugs and Herbal Supplements 
 
Patient 
Name: 
Diagnosis: 
Trial #: 
10411 
Study 
Study Doctor 
Study 
Rogaratinib (BAY 
Doctor: 
Phone #: 
Drug(s): 
1163877) 
 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse practitioners, 
pharmacists), and tell them you are taking part in a clinical trial sponsored by the National Cancer Institute. 
 
These are the things that your healthcare providers need to know: 
Rogaratinib (BAY 1163877) interacts with certain specific enzyme in your liver or other tissues like the gut and 
certain transport proteins that help move drugs in and out of the cell. 
 
Explanation 
 
CYP 
isoenzymes 
The enzyme in question is CYP3A4. Rogaratinib (BAY 1163877) is broken down by 
this enzyme and may be affected by other drugs that inhibit or induce this enzyme. 
Rogaratinib (BAY 1163877) can also inhibit this enzyme and may affect sensitive 
drugs or drugs with a narrow therapeutic window that are broken down by this 
enzyme. 
 
Transport 
proteins 
The proteins in question are P-gp, BCRP, MATE1, and MATE2K. Rogaratinib (BAY 
1163877) is moved in and out of cells/organs by P-gp and may be affected by other 
drugs that inhibit or induce this transport protein. Rogaratinib (BAY 1163877) inhibits 
P-gp, BCRP, MATE1, and MATE2K and may be affect sensitive drugs or drugs with 
narrow therapeutic window that are moved in and out of cells/organs by this transport 
protein. 
These are the things that you need to know: 
The study drug rogaratinib (BAY 1163877), may interact with other drugs which can cause side effects. For this 
reason, it is very important to tell your doctors about all your medicines, including: (a) medicines you are taking 
before this clinical trial, (b) medicines you start or stop taking during this study, (c) medicines you buy without a 
prescription (over-the-counter remedy), (d) herbals or supplements (e.g. St. John’s Wort). It is helpful to bring your 
medication bottles or an updated medication list with you. 
Before you enroll onto the clinical trial, your study doctor will work with your regular health care providers to 
review any medicines and herbal supplements that are considered strong inhibitors and inducers of CYP3A4 and P- 
gp, and sensitive substrates/narrow therapeutic index drugs of CYP3A4, P-gp, BCRP, MATE1, and MATE2K. 
 
x Please be very careful! Over-the-counter drugs (including herbal supplements) may contain ingredients that 
could interact with your study drug. Speak to your doctors or pharmacist to determine if there could be any 
side effects. 
x No grapefruit juice, Seville oranges, or grapefruit can be consumed while on rogaratinib (BAY 1163877) 

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x Make sure your doctor knows to avoid certain prescription medications. 
x Your regular health care provider should check a frequently updated medical reference or call your study 
doctor before prescribing any new medicine or discontinuing any medicine. 
 
 
 
 
 
Version JUN/2020 
 
(Next page: Patient Drug Interaction Wallet Card) 

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APPENDIX D 
TISSUE BIOPSY VERIFICATION 
A copy of the diagnostic pathology report must be shipped with all tissue specimens sent to the 
EET Biobank. 
 
If the corresponding pathology report is not available for the biopsy, then a copy of the radiology report 
or operative report from the biopsy procedure and the diagnostic pathology report must be sent to the 
EET Biobank. A completed copy of this appendix (i.e., Tissue Biopsy Verification) must also be 
submitted to the EET Biobank. 
 
Note: If this information is not provided with the biopsy specimen, then it will not be accepted by the EET 
Biobank. 
 
 
Please have the Clinician* responsible for signing out this patient’s case complete the following: 
 
ETCTN Universal Patient ID:  
 
 
ETCTN Patient Study ID:  
 
 
Date of Procedure (mm/dd/yyyy):  
 
 
Tissue Type (circle one): 
Primary 
 
Metastatic 
Time point (circle one): Pre-Treatment 
Progression 
Site Tissue Taken From:  
 
 
Diagnosis:  
 
I agree that this tissue may be released for research purposes only and that the release of this tissue will not 
have any impact on the patient’s care. 
 
 
 
Clinician Signature 
Date 
 
 
 
Clinician Printed Name 
*Note: For the purposes of this form, Clinician could include the Nurse Practitioner, Registered Nurse, Pathologist, Radiologist, 
Interventional Radiologist, Surgeon, Oncologist, Internist, or other medical professional responsible for the patient’s care. 
Version: 1 
Effective Date: 9/2019 

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APPENDIX F
PATIENT’S PHARMACOKINETIC WORKSHEET
CTEP-assigned Protocol #
10411_ 
Local Protocol # 
93