A Phase II, Multicenter, Single-Arm Study of Pemigatinib in Patients With Metastatic or Unresectable Colorectal Cancer Harboring FGFR Alterations
Phase: PHASE2
Conditions: FGFR1 Gene Amplification, FGFR1 Gene Mutation, FGFR1 Gene Translocation, FGFR2 Gene Amplification, FGFR2 Gene Mutation, FGFR2 Gene Translocation, FGFR3 Gene Amplification, FGFR3 Gene Mutation, FGFR3 Gene Translocation, Metastatic Colorectal Carcinoma, Stage III Colorectal Cancer AJCC v8, Stage IIIA Colorectal Cancer AJCC v8, Stage IIIB Colorectal Cancer AJCC v8, Stage IIIC Colorectal Cancer AJCC v8, Stage IV Colorectal Cancer AJCC v8, Stage IVA Colorectal Cancer AJCC v8, Stage IVB Colorectal Cancer AJCC v8, Stage IVC Colorectal Cancer AJCC v8, Unresectable Colorectal Carcinoma
Sponsor: Academic and Community Cancer Research United

 
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Addendum 2 
 
  
 
Academic and Community Cancer Research United (ACCRU) 
 
A Phase II, Multicenter, Single-Arm Study of Pemigatinib in Patients with  
Metastatic or Unresectable Colorectal Cancer Harboring FGFR Alterations 
 
For any communications regarding this protocol, please contact the person indicated on the 
Protocol Resource page. This is a stand-alone document found on the ACCRU web site 
(
).  
 
Study Chairs 
 
 
ACCRU: 
              
              
 
              
              
              
 
 
     FDA IND  
                  Sponsor/Investigator: 
  
 
                              Correlative Science Co-Chair: 
 
 
 
                  Statistician:                 
 
 
  
      
 
 
 
 
  
Drug Availability 
Drug Company Supplied: Pemigatinib (IND144530)  
√ Study contributor(s) not responsible for patient care. 
 
 
Research Coordinating Center 
 
 
 
 
Document History 
(effective date) 
Activation ACCRU 
July 15, 2019 
Addendum 1 
Addendum 2 
April 22, 2020 
December 09, 2020 
 

 
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Index 
 
Schema 
 1.0 
Background 
 2.0 
Goals 
 3.0 
Patient Eligibility 
 4.0 
Test Schedule 
 5.0  
Grouping Factors 
 6.0 
Registration 
 7.0 
Protocol Treatment 
 8.0 
Dosage Modification Based on Adverse Events  
 9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
Appendix I – Acceptable Contraception 
Appendix II – Examples of CYP3A4 Inducers and Inhibitors 
Appendix III – Patient Medication Diary 
Appendix IV – Patient Information Sheet 
Appendix V - Linear Analogue Self Assessment (LASA) 
 
 
 
 
 
 
 
 

 
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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD=Progressive Disease 
1Cycle=21 Days 
2Refer to section 7 for dosing Information
 
Generic name:  Pemigatinib 
Availability: Incyte 
 
 
PD at any time 
Unacceptable adverse Events 
Patient refusal 
Investigator decision 
 
 
 
        Event Monitoring 
Registration 
Treatment with  
 Pemigatinib2 
  until PD or a maximum 
of 35 cycles1 
Event Monitoring 

 
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1.0 
Background  
 
1.1 
Pemigatinib 
 
Pemigatinib is an inhibitor of the fibroblast growth factor receptor (FGFR) family of 
receptor tyrosine kinases that has been investigated in the treatment of advanced 
malignancies. The FGFR pathway is critical for human development and plays a key role 
in cellular proliferation, migration, survival, and angiogenesis (Brooks, et al, 2012; 
Wesche, et al, 2011; Greulich, et al, 2011). Aberrant signaling through FGFR typically 
results from gene amplification or mutation, chromosomal translocation, and ligand-
dependent activation of the receptors. Abrogation of this pathway leads to growth 
inhibition of tumor cells, and signaling of FGFRs has been identified as a possible escape 
mechanism for tumor angiogenesis when the vascular endothelial growth factor (VEGF) 
pathway is disrupted (Casanovas, et al, 2005; Berger, et al, 2008).  
 
Activating alterations in the FGFR pathway are found in various malignancies (Marek, et 
al, 2009; Stransky, et al, 2014; Dienstmann, et al, 2014), including colorectal cancer 
(Goke, et al, 2013; Abdel-Rahman, 2015; Mathur, et al, 2014; Folprecht, et al, 2016), and 
inhibition of this pathway represents a therapeutic opportunity for patients with these 
genomically selected tumors. Refer to the Investigator's Brochure (IB) for additional 
background information on Pemigatinib , an oral inhibitor of FGFR1, FGFR2, and 
FGFR3.  
 
1.2 
Fibroblast Growth Factor Receptor Inhibitor in Oncology 
 
The mammalian FGFR family is composed of 4 highly conserved receptors (FGFR1, 
FGFR2, FGFR3, and FGFR4) that have an extracellular ligand binding domain, a single 
transmembrane domain, and an intracellular tyrosine kinase domain. Eighteen FGF 
ligands, divided into canonical and hormonal FGFs, bind to FGFRs, leading to receptor 
dimerization, activation of the kinase domain, and transphosphorylation of the receptors 
(Eswarakumar, et al, 2005). Subsequent signal transduction occurs through 
phosphorylation of substrate proteins such as fibroblast growth factor receptor substrate 
2, which leads to activation of the RAS–mitogen-activated protein kinase and PI3 kinase–
protein kinase B pathways, and phospholipase Cγ, which activates the protein kinase C 
pathway. In some cellular contexts, signal transducer and activator of transcription 
proteins are also activated by FGFRs. Signaling through the FGF-FGFR pathway is 
tightly controlled through feedback regulation. Mitogen-activated protein kinase 
phosphatases and Sprouty proteins are upregulated upon FGFR stimulation and 
antagonize FGF-dependent activation of extracellular signal-regulated kinases. In many 
cases, FGFR pathway activation promotes cell proliferation, survival, and migration; 
however, cellular context plays an important role, and in certain tissues, FGFR signaling 
results in growth arrest and cellular differentiation (Dailey, et al, 2005).  
 
There is strong genetic and functional evidence that dysregulation of FGFR can lead to 
the establishment and progression of cancer. Genetic alterations in FGFR1, FGFR2, and 
FGFR3 have been described in many tumor types (Knights and Cook 2010; Turner and 
Grose 2010). These include activating mutations, translocations, and gene amplification 
resulting in ligand-independent, constitutive activation of the receptors or aberrant 
ligand-dependent signaling through FGFRs.  
 
Dysregulation of FGF ligands has also been reported in many human cancers. Preclinical 

 
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studies have shown that high levels of FGF ligands such as FGF2 promote cancer cell 
resistance to radiation, chemotherapeutics, and targeted cancer drugs (Fuks, et al, 1994; 
Pardo, et al, 2002; Terai, et al, 2013). In triple-negative breast cancer, upregulation of 
both FGF ligands and FGFR creates an autocrine loop that supports tumor cell growth 
and survival (Sharpe, et al, 2011). Clinically, detection of high levels of FGF2 in tumors 
is associated with poorer outcome in several tumor types, including NSCLC (Donnem, et 
al, 2009; Rades, et al, 2012).  
A substantial body of evidence supports that a genetically activated FGFR pathway 
sensitizes FGFR-altered cancer cells to knockdown or inhibition of these receptors 
(Kunii, et al, 2008; Qing, et al, 2008; Weiss, et al, 2010; Lamont, et al, 2001). A large 
screen of more than 500 tumor cell lines with a selective FGFR inhibitor demonstrated 
that only a small percentage (5.9%) of all cells are sensitive to FGFR inhibition, and 
growth suppressed cell lines were highly enriched for FGFR alterations (Guagnano, et al, 
2012). These results demonstrate that FGFR inhibitors are active in a targeted manger 
against cancers with activated FGFR pathways. An implication of these data is that 
selection based on molecular, genetic, or protein-based diagnostic tests for specific FGFR 
alterations in tumors is probably most important for identifying patients most likely to 
benefit from an FGFR inhibitor.  
Results from early clinical studies of selective FGFR inhibitors other than Pemigatinib 
have also shown a tolerable safety profile for the class and have shown preliminary signs 
of clinical benefit in subjects selected for  FGFR alterations. The safety and clinical 
activity of AZD4547 was evaluated in a Phase 1 study where subjects were prospectively 
selected for FGFR1 or FGFR2 gene amplification by fluorescent in situ hybridization 
(Kilgour, et al, 2014).  
 
In the Phase 1 study of JNJ-42756493 in subjects with advanced malignancies, 65 
subjects were treated on a once-daily (QD) continuous treatment schedule at 6 different 
increasing dose levels, plus 2 doses at 1-week-on/1-week-off dosing intervals (Tabernero, 
et al, 2015). Hyperphosphatemia (HP) was the leading dose-limiting toxicity resulting in 
treatment interruptions and discontinuations. Twenty-three subjects had FGFR1-4 or 
FGF3/FGF4 alterations. There were 4 confirmed responses and 1 unconfirmed partial 
response; 16 subjects had stable disease, eight of whom had stable disease for > 3 
months.  
 
A Phase 1 study of the selective pan-FGFR inhibitor BGJ398 has also shown a tolerable 
safety profile and preliminary efficacy in multiple tumor types (Sequist, et al, 2014). The 
study enrolled subjects with any type of FGFR genetic alteration. A 125 mg QD dose of 
BGJ398 was identified as the maximum tolerated dose. In the expansion cohort, 3 
subjects achieved a confirmed PR and tumor shrinkage was observed in 2 other subjects 
that approached 30% (Nogova, et al, 2016). The disease control rate was 75%.  
 
1.3 
Metastatic Colorectal Cancer and FGFR inhibition 
 
 
Colorectal cancer (CRC) is the third  most common cancer in the United States in both 
men and women (Siegel, et al, 2018). Approximately 20% of patients present with 
metastatic disease at diagnosis, and a significant proportion of patients who are initially 
treated with potentially curative surgical resection experience disease recurrence and 
develop metastatic disease (Gill, et al, 2007). There are a number of standard intravenous 
and oral chemotherapies and biologic agents approved for the treatment of metastatic 

 
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CRC, but with time, resistance develops to these agents and patients with mCRC need 
additional therapeutic options. 
 
Better characterization of the molecular variants that drive CRC progression have led to 
development of targeted therapies that improve clinical outcomes. For example, targeting 
the epidermal growth factor receptor (EGFR) with monoclonal antibodies (cetuximab, 
panitumumab) in patients with metastatic CRC (mCRC) whose tumors are RAS wildtype 
has improved patient survival. However, there remains an unmet need for additional 
genotype-driven therapeutic targets to treat mCRC patients. 
 
Molecular alterations in FGFR has been previously described in CRC. Goke et al 
analyzed 454 primary tumors, and using a fluorescence in situ hybridization technique 
identified 24 (5.3%) samples that exhibited amplification in FGFR1 (Goke, et al, 2013). 
Mathur et al characterized a novel FGFR2 amplification in the NCI-H716 CRC cell line 
that was derived from ascites of a poorly differentiated colon adenocarcinoma. These 
authors found that FGFR2 gene amplification resulted in overexpression of the receptor 
at the cell surface and constitution activation (Mathur, et al, 2014). Most importantly, 
FGFR2 overexpression was required for NCI-H716 cell growth and survival in vitro and 
in vivo. Lastly, Folprecht et al analyzed 328 different cancer genes from 389 CRC 
patients, and observed 3.5% of samples exhibited FGFR 1/2/3 amplification (Folprecht, 
et al, 2016). 
 
It is hypothesized that Pemigatinib , an oral inhibitor of FGFR1, FGFR2, and FGFR3, 
may have more activity in selected patients with metastatic colorectal cancer (mCRC) 
whose tumors harbor activating FGFR alterations. While this population is a small subset 
of patients with mCRC, given the need for better targeted therapies and the overall large 
prevalence of patients with mCRC, we propose a phase II, multicenter study of 
Pemigatinib in patients with mCRC harboring activating FGFR alterations. 
 
1.4 
Clinical Experience with Pemigatinib 
 
 
Participants With Advanced Malignancies 
 
As of the data cutoff date (25 NOV 2018), the safety and tolerability of pemigatinib 
administered alone or in combination with another chemotherapy/immunotherapy was 
being evaluated in 5 ongoing clinical studies in participants with advanced malignancies. 
Based on preliminary unaudited data from these ongoing studies, the most frequently 
occurring TEAEs (ie, incidence > 20%) were (in descending order of frequency) 
hyperphosphatemia, diarrhea, alopecia, fatigue, dry mouth, stomatitis, constipation, 
dysgeusia, nausea, decreased appetite, and anemia. 
Additional details are presented by study in the following sections. 
 
Study INCB 54828-101 
 
Of the 150 participants with advanced malignancies who have been enrolled in 
Study INCB 54828-101 as of the data cutoff date, 43 participants have been administered 
pemigatinib in Part 1 (monotherapy dose escalation), 63 participants in Part 2 
(monotherapy dose expansion), and 44 participants in Part 3 (pemigatinib combined with 
gemcitabine and cisplatin [8 participants], docetaxel [7 participants], pembrolizumab [23 
participants], and trastuzumab [6 participants]). 
 

 
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Dose-limiting toxicities informed dose escalation procedures during Part 
1 of the study. Among participants in Part 1, 28 received pemigatinib at 
doses of 1 to 20 mg QD on a 2 weeks-on/1-week-off  therapy schedule 
(ie, interval dose regimen), and 15 participants received pemigatinib at 
doses of 9, 13.5, or 20 mg QD on a continuous schedule (ie, continuous 
dose regimen). There were no DLTs for the monotherapy dose regimens, 
and the monotherapy MTD was not reached. The recommended Part 2 
dose for pemigatinib was determined to be 13.5 mg based on PD and 
clinical effect, and the recommended Phase 2 dose regimens for 
pemigatinib based on safety and PK data and preliminary signals of 
clinical benefit (data not shown) were 13.5 mg QD following the interval 
schedule and 13.5 mg QD following the continuous schedule. 
Overall, 105 participants (99.1%) who received pemigatinib 
monotherapy (all doses and dose regimens combined) in Study INCB 
54828-101 had TEAEs. Treatment-emergent AEs occurring in ≥ 10% of 
participants who received pemigatinib monotherapy (Parts 1 and 2 
combined) are presented by dose and dose regimen and overall in Table 
13. Consistent with the expected pharmacological effect of FGFR 
inhibition on serum phosphate levels, the most frequently occurring 
TEAE was hyperphosphatemia (74 participants [69.8%]; serum 
phosphate >5.5 mg/dL). Other frequent TEAEs (> 30%) included fatigue 
in 43 participants (40.6%), dry mouth in 39 participants (36.8%), and 
alopecia in 35 participants (33.0%). Comparison of the most frequently 
occurring TEAEs for the continuous and interval dose regimens suggests 
higher incidences of hyperphosphatemia (76.7% vs 67.1%), stomatitis 
(46.7% vs 22.4%), dry mouth 
(43.3% vs 34.2%), diarrhea (43.3% vs 22.4%), constipation (40.0% vs 
25.0%), alopecia (40.0% vs 30.3%), and nausea (33.3% vs 22.4%) with 
continuous dosing. Other TEAEs that occurred more frequently with 
continuous dosing included dry eye, pain in extremity, hypercalcemia, 
onycholysis, and paronychia. 
 
Forty-five participants (42.5%) who received pemigatinib monotherapy 
had at least 1 SAE; the overall incidence of SAEs for the continuous 
dose regimen (56.7%) was higher than was seen for the interval dose 
regimen (36.8%). Pneumonia in 7 participants (6.6%) was the most 
frequently occurring SAE. Other SAEs occurring in more than 1 
participant included back pain and disease progression in 4 participants 
(3.8%) each; abdominal pain, dehydration, fatigue, hyponatremia, and 
acute renal failure in 3 participants (2.8%) each; and blood bilirubin 
increased, cerebrovascular accident, constipation, hypotension, pain in 
extremity, pleural effusion, and pyrexia in 2 participants (1.9%) each. 
Within the eye disorders SOC, a single participant had an SAE of 
ocular hyperemia (Grade 2), which was considered unrelated to 
pemigatinib by the investigator. 
A total of 11 participants (10.4%), 7 participants (9.2%) on an interval dose regimen and 
 4 participants (13.3%) on a continuous dose regimen, had SAEs with a 
fatal outcome: disease progression in 4 participants (3.8%) and 

 
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pneumonia, malignant neoplasm progression (ie, disease progression), 
cerebrovascular accident, intracranial hemorrhage, multiorgan failure, 
esophageal varices hemorrhage, pneumonia, respiratory failure, and acute 
respiratory failure secondary to acute anemia (verbatim term) in 1 
participant (0.9%) each. None of these fatal events were assessed as 
related to pemigatinib by the investigator. 
 Eleven participants (10.4%) discontinued pemigatinib monotherapy due 
to TEAEs; pneumonia in 3 participants (2.8%) and dehydration and 
small intestinal obstruction in 2 participants (1.9%) each were the only 
TEAEs leading to discontinuation of pemigatinib that occurred in more 
than 1 participant. 
 
 
 
 
Treatment-emergent AEs occurring in ≥ 10% of participants on combination therapy in 
Study INCB 54828-101 (Part 3) are presented by treatment group and overall in Table 
14. The most frequently occurring TEAEs for each treatment combination were as 
follows: 
 
• 
Pemigatinib + Gemcitabine + Cisplatin: Anemia (8/8 participants); blood 
creatinine increased, constipation, fatigue, and nausea (5/8 participants each); and 
ALT increased, AST increased, diarrhea, hyperphosphatemia, hyponatremia, 

 
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thrombocytopenia, and WBC count decreased (4/8 participants each). 
 
• 
Pemigatinib + Docetaxel: Hyperphosphatemia, diarrhea, and dysgeusia 
(6/7 participants each); fatigue and dehydration (5/7 participants each); and 
nausea (4/7 participants). 
 
• 
Pemigatinib + Pembrolizumab: Hyperphosphatemia (17/23 participants), 
anemia (11/23 participants), and diarrhea and decreased appetite (10/23 
participants each) 
 
• 
Pemigatinib + Trastuzumab: Alopecia, cough, and hyperphosphatemia 
(4/6 participants each) and decreased appetite, diarrhea, and dry mouth 
(3/6 participants each). 
 
A single participant who received pemigatinib + docetaxel had DLTs of fatigue (Grade 3) 
anddehydration (Grade 3). No other participants on combination therapy had a DLT. 
 
A total of 18 participants (40.9%) on combination therapy had at least 1 SAE: 4/8 
participants on pemigatinib + gemcitabine + cisplatin, 6/7 participants on pemigatinib + 
docetaxel, and 8/23 participants on pemigatinib + pembrolizumab. The most frequently 
occurring SAEs across all combination therapy cohorts were dehydration in 3 participants 
(6.8%) and anemia and acute renal failure in 2 participants (4.5%) each. By treatment 
combination, the only SAE occurring in more than 1 participant was dehydration in 2 
participants in the pemigatinib + docetaxel cohort. Two participants (4.5%) had SAEs 
with a fatal outcome: completed suicide (pembrolizumab +pemigatinib 9 mg) and disease 
progression (gemcitabine + cisplatin + pemigatinib 13.5 mg).Neither of these events was 
assessed as related to pemigatinib. 
Five participants (11.4%) on combination therapy had TEAEs leading to discontinuation 
of pemigatinib. No event leading to discontinuation occurred in more than 1 participant. 
 
 

 
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1.5 Justification for Dose and Regimen 
 
Pemigatinib will be administered at 13.5 mg QD, continuously, for a cycle.  Each cycle is 
3 weeks.  This dose and dosing schedule was selected based on emerging clinical and 
safety data from the INCB 54828-101 study, where the continuous dosing regimen has 
been tested in 12 and 14 participants at 9 mg and 13.5 mg QD continuous administration, 
respectively.  In Study INCB 54828-101, the emerging safety data demonstrated that 
tolerability of the continuous dosing regimen of pemigatinib was comparable to that of 
intermittent dosing. 
 
The hypothesis with a targeted therapy is that continued inhibition of the aberrant 
receptor may increase the potential for benefit from the treatment.  Therefore, 
administering pemigatinib continuously will allow that consistent inhibition of the 
aberrant FGFR receptor in this population.  Continuous dosing would still allow for dose 
holds for safety reasons with criteria and procedures for dose interruptions and 
adjustments clearly outlined in the Protocol. 
 
Hyperphosphatemia is an expected on-target pharmacological effect of FGFR inhibition.  
The incidence of hyperphosphatemia, defined as any post-baseline phosphate level 
exceeding 5.5 mg/dL, has been observed in the majority of study participants treated with 
pemigatinib (refer to the IB for complete data).  Some participants do not achieve 
hyperphosphatemia, and it is estimated that pharmacological concentration of 
pemigatinib in these participants is lower (see Figure 2).  Therefore, up titration of 
pemigatinib will be used to increase the exposure of pemigatinib in participants who do 
not achieve hyperphosphatemia when treated with 13.5 mg QD.  The goal is to increase 
the serum concentration of pemigatinib. 
 
The increase in serum phosphorus observed after treatment with pemigatinib was 
exposure-dependent and followed a sigmoid relationship.  A population Emax model of 
pemigatinib AUC and maximal serum phosphate change from baseline was developed.  
For those participants treated with pemigatinib 13.5 mg who did not develop 
hyperphosphatemia, AUC for pemigatinib 18 mg was estimated using a linear exposure 
relationship.  Maximal serum phosphate change from baseline for each individual was 
then estimated using a population model.  The maximal serum phosphate after treatment 
with pemigatinib 18 mg was calculated by adding the baseline of serum phosphate.  The 
simulation suggested that the serum phosphate would increase above 5.5 mg/dL after 
treatment with pemigatinib 18 mg for the participants treated with pemigatinib 13.5 mg 
who did not develop hyperphosphatemia. 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Figure 2:        Comparison of Steady State Exposures for Pemigatinib 13.5 mg QD 
Between Subjects With Nonhyperphosphatemia and Hyperphosphatemia 
 
 
 
 
 
  
AUCss = area under the curve at steady state; Css, min = minimum blood plasma 
concentration at steady state; HP = hyperphosphatemia. 
 
Any participant who does not reach the target serum phosphate level of > 5.5 mg/dL at 
any time during Cycle 1, and who is compliant with taking study drug and does not 
experience an ongoing Grade 2 or higher treatment-related AEs, will increase the daily 
dose to 18 mg starting at Cycle 2 Day 1. Participants who are titrated up to 18 mg QD 
will begin the next cycle at the new dose level and must agree to all Cycle 1 assessments 
(PK and safety assessments [hematology and blood chemistry]). Up-titration may occur 
no earlier than on Day 1 of Cycle 2, so that participants are observed for phosphate level 
and AEs at least for 1 cycle.  
For participants who are up-titrated from 13.5 mg to 18 mg, a maximum of 2 dose level 
reductions is also recommended: 18 mg can be decreased to 13.5 mg, and if additional 
dose reduction is required, participants can decrease to 9 mg. Dose reductions below 9 
mg are not allowed." 
 
A CYP3A4-mediated drug-drug interaction study (INCB 54828-104) indicated there is 
evidence of a clinically significant effect on pemigatinib exposure when co-administered 
with a potent CYP3A4 inhibitor, itraconazole (increased pemigatinib AUC by 88%) or 

 
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potent CYP3A4 inducer, rifampin (decrease pemigatinib AUC by 85%). A PBPK model 
was developed and validated using in vitro and clinical DDI data. PBPK model-simulated 
pemigatinib AUCs were increased by approximately 50% for moderate CYP3A4 
inhibitors and decreased by more than 50% for moderate CYP3A4 inducers. In addition, 
PBPK modeling shows no DDI effect when pemigatinib was coadministered with a weak 
CYP3A4 inhibitor or inducer. 
 
 
 
 
1.6 
Pharmacokinetic/Pharmacodynamic Summary 
 
Pemigatinib exhibited linear pharmacokinetics (PK) over the dose range evaluated, with 
rapid oral absorption and a biphasic elimination, with a terminal half-life range of 10.9 to 
31.4 hours. The projected average inhibition of FGFR2 based on PK and in vitro potency 
of Pemigatinib  ranged from 41% at 1 mg to 97% at 20mg. Consistent with this 
projection, the observed inhibition of pFGFR2 in KATOIII cells spiked to ex vivo whole 
blood samples collected from subjects at trough was 82% after the 13.5 mg QD dose and 
64% after the 9 mg QD dose. The steady-state plasma concentration of Pemigatinib after 
13.5 mg QD dose that exceeded in vivo IC50 over a 24-hour dosing period is shown in 
Figure 1.  
 
 
 
 
The magnitude and frequency of hyperphosphatemia was also dose dependent. In the 9 
mg cohorts of Part 1 and Part 2, 4 of the 6 patients experienced hyperphosphatemia. In 
the 13.5 mg cohort of Part 1, all 6 subjects developed hyperphosphatemia, which was 
managed with a low-phosphate diet and introduction of phosphate binders. Further, the 
increase in serum phosphorus observed after treatment with Pemigatinib was exposure-
dependent (see Figure 2). 
 
 
 

 
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Therefore, based on a manageable safety profile and favorable PK/PD profile, the dose 
for this Phase 2 study is 13.5 mg.  
 
1.7 
Phototoxicity 
 
 
 
There are no preclinical data available to date on the potential phototoxicity of 
Pemigatinib. Therefore, subjects enrolled in this study will be instructed by the site staff 
to take precaution to protect themselves from the sun/ultraviolet light. This includes 
wearing long sleeves, long trousers, hats, and sunglasses.  
 
 
 
1.8 
Correlative Research 
 
1.81 
Peripheral blood samples 
 
Advances in next-generation sequencing (NGS) technology have allowed for the 
opportunity to better understand the relationship between tumor biology and the 
genomic landscape. However, serial sampling of tumor tissues is challenging in 
most tumor types given the anatomic location and requirement of adequate 
quantity of tumor cells among a background of normal cells and stroma. Thus, 
the emergence of the “liquid biopsy” and advances in sequencing technology 
allow for the opportunity to serially monitor the dynamics of specific tumor 
mutations (Amodovar, et al, 2018; Montagut, et al, 2018; Strickler, et al, 2018). 
Diaz and colleagues were one of the first groups to show that KRAS mutations 
could be detected in the sera of CRC patients who, before receiving monotherapy 
with panitumumab, were KRAS wildtype (Diaz, et al, 2012). Strickler et al. 
performed large-scale genomic profiling of cell-free DNA (cfDNA) from patients 
with CRC and observed genomic alterations at frequencies comparable to 
databases with large-scale tumor sequencing data (Strickler, et al, 2018) (i.e., The 
Cancer Genome Atlas and Genomics Evidence Neoplasia Information 
Exchange). Specifically, these authors reported the ability to detect, with 
adequate sensitivity, RAS mutations and mutations in the extracellular domain of 

 
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EGFR in cfDNA. A recent clinical trial evaluating a novel EGFR mAb (Sym004) 
in RAS wildtype CRC patients that have progressed on panitumumab or 
cetuximab analyzed circulating tumor DNA throughout treatment and observed 
the emergence of extremely heterogeneous molecular landscapes where 
subclones with distinct resistance mechanisms coexist in one patient (Montagut, 
et al, 2018). Another recent clinical trial observed the emergence of KRAS and 
NRAS mutations upon disease progression in BRAF-mutant CRC patients who 
were receiving a triplet drug combination designed to inhibit BRAF, EGFR, and 
MEK (Corcoran, et al, 2018). Thus, analyzing cfDNA is becoming a viable 
clinical technique to serially monitor the emergence of resistance mechanisms 
that are driving the observed disease progression in CRC. 
 
 
Serial blood samples will be collected throughout the study according to the test 
table to analyze dynamic changes in cfDNA as a function of treatment. The 
objective is to explore the potential mutational patterns that could be associated 
with tumor response and disease progression. Samples will be collected from all 
patients. Any detected single nucleotide variants, insertions and deletions of any 
length, chimeric gene fusions that arise through chromosomal rearrangement, and 
copy number gain or copy number loss will be recorded longitudinally for each 
patient.  
 
1.82 
Archival tissue 
 
Archival tissue, if available, will be collected from each patient. Molecular profiling will 
be performed on the available tissue. Concordance results between tissue and the 
subsequent liquid biopsy results will be assessed. 
 
 
2.0 
Goals  
 
2.1 
Primary 
 
2.11 
To assess overall response rate (ORR) of Pemigatinib in patients with metastatic 
or unresectable colorectal cancer harboring activating FGFR alterations. 
 
2.2 
Secondary 
 
2.21 
To assess the clinical benefit rate (complete response + partial response + stable 
disease ) with Pemigatinib . 
 
2.22 
To assess progression free survival (PFS) and overall survival (OS) with  
Pemigatinib. 
 
2.23 
Assess changes in patient quality of life (QOL) as measured by the linear 
analogue self-assessment (LASA) questionnaire. 
 
2.24 
Assess the frequency and severity of adverse events. 
 
2.3 
Correlative Research 
 
2.31 
To assess plasma pharmacodynamic biomarkers of response and resistance to 

 
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Addendum 2 
 
therapy. 
 
 
2.32 
To explore any correlation between tissue and blood based biomarkers and 
clinical outcomes. 
 
3.0 
Patient Eligibility 
 
NOTE: Waivers to eligibility criteria are not allowed per ACCRU policy 
 
3.1 
Registration – Inclusion Criteria 
 
 
3.11 
Histologically or cytologically confirmed diagnosis of metastatic or unresectable 
colorectal cancer (mCRC), based on documentation from local or outside review 
of pathology according to each site’s established institutional procedure  
 
3.12 
Documentation of an activating genomic alteration(s) in FGF/FGFR1-3 (gain of 
function mutations, translocations, and amplifications allowed) in tumor tissue or 
blood tested at a Clinical Laboratory Improvement Amendments (CLIA) – 
certified laboratory.   
 
3.13 
Provide informed written consent. 
 
3.14 
Age ≥ 18 years. 
 
3.15 
Patient must have received and progressed on, or be intolerant to, each of the 
following treatments for mCRC (or have contraindication to these treatments): 
 
• 
Fluoropyrimidine. 
 
• 
Oxaliplatin. 
 
• 
Irinotecan. 
 
• 
Pembrolizumab 
 
• 
Nivolumab 
 
• 
Anti-VEGF (vascular endothelial growth factor) monoclonal antibody, if 
eligible for this therapy. 
 
• 
Anti-EGFR (epidermal growth factor receptor) monoclonal antibody, if 
eligible for this therapy. 
 
3.16 
Measurable disease as defined in Section 11.0 
 
3.17 
ECOG Performance Status (PS) of 0, 1, or 2. Form is available on the ACCRU 
web site. 
 
3.18 
The following laboratory values obtained ≤ 28 days prior to registration: 
 
• 
Absolute neutrophil count (ANC) ≥ 1500/mm3. 

 
17 
 ACCRU GI-1701  
Addendum 2 
 
 
• 
Platelet count ≥ 100,000/mm3. 
 
• 
Hemoglobin ≥ 9.0 g/dL. 
 
• 
Total bilirubin ≤ 1.5x upper limit of normal (ULN), or ≤ 2.5x ULN if 
patient has Gilbert syndrome or disease involving the liver. 
 
• 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)  
≤ 2.5x ULN (or ≤ 5x ULN in presence of suspected liver metastases). 
 
• 
Serum phosphate < institutional ULN. 
 
• 
Serum calcium within institutional normal range, or 
 
serum albumin-corrected calcium within institutional normal range (if 
serum albumin is outside of the institutional normal range). 
 
• 
Potassium levels > institutional lower limit of normal (supplementation  
can be used to correct potassium level during screening). 
 
• 
Serum creatinine ≤ 1.5x ULN, or 
calculated creatinine clearance > 30 mL/min using the Cockcroft-Gault 
formula (see below) or 24-hours urine collection analysis: 
 
Cockcroft-Gault Equation: 
 
Creatinine clearance for males =  (140 - age)(weight in kg)    
  
 
 
 
 
  (72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females = (140 - age)(weight in kg)(0.85) 
 
 
 
 
   (72)(serum creatinine in mg/dL) 
 
3.19 
Corrected QT interval (QTc) by Fridericia’s method (QTcF) assessed by 
electrocardiogram (ECG) completed ≤ 28 days prior to registration, and resulted 
as: 
 
• 
QTcF ≤ 450 msec in men, or 
 
• 
QTcF ≤ 470 msec in women. 
 
3.19a 
Negative serum pregnancy test completed ≤ 7 days prior to registration, for 
women of childbearing potential only. See Appendix I for definition of WOCBP. 
 
3.19b Willing to provide tissue and blood samples for correlative research purposes 
(see Sections 6.0, 14.0 and 17.0). 
 
3.19c 
Willing to allow transfer of tissue and blood samples, clinical information, and 
outcome data collected from this trial for future research (see Sections 6, 14, and 
17). 
 
 
 
3.2 
Registration – Exclusion Criteria 

 
18 
 ACCRU GI-1701  
Addendum 2 
 
 
3.21 
Prior treatment with Pemigatinib. 
 
3.22 
Prior treatment with a selective FGFR inhibitor ≤ 180 days (6 months) prior to 
registration. 
 
3.23 
Known hypersensitivity or severe reaction to an FGFR inhibitor, or to the 
excipients of Pemigatinib (i.e. microcrystalline cellulose, sodium starch 
glycolate, and magnesium stearate). 
 
3.24 
Current evidence of clinically significant corneal or retinal disorder confirmed by 
ophthalmologic examination. 
 
3.25 
Treatment with other investigational study drug for any indication for any reason, 
or receipt of anticancer medications ≤ 14 days prior to registration. 
 
3.26 
Major surgery ≤ 28 days prior to registration. 
 
3.27 
External beam radiation therapy ≤ 28 days prior to registration, or palliative 
radiation for non-CNS disease ≤ 14 days prior to registration. 
 
3.28 
Brain metastases, central nervous system (CNS) metastases, leptomeningeal 
disease, or spinal cord compression  
 
 
NOTE: Patients who are asymptomatic or previously treated and stable, without 
evidence of progression for ≥ 28 days prior to registration are eligible  
 
 
NOTE: Patients taking concomitant corticosteroids and/or anticonvulsants are 
allowed if patient is on a stable or decreasing dose of such treatment for ≥ 28 
days prior to registration. 
 
3.29 
History or presence of significant cardiovascular disease or condition including: 
 
• 
Uncontrolled angina pectoris (Canadian Cardiovascular Society Grade 
II-IV despite medical therapy).  
 
• 
Congestive heart failure (New York Heart Association Class III or IV). 
  
• 
Uncontrolled arrhythmia requiring therapy. Note: Patients with a 
pacemaker and well-controlled rhythm for  ≥ 28 days prior to registration 
are not excluded. 
 
• 
Any of the following occurring ≤ 6 months prior to registration: 
Myocardial infarction, angioplasty, cardiac stenting, coronary/peripheral 
artery bypass graft, cerebrovascular accident or transient ischemic attack.  
 
3.29a 
Failure to adequately recover (i.e. to ≤ Grade 1(according to CTCAE v.5) or to 
pre-treatment baseline) from adverse events (AEs) deemed by the investigator as 
clinically significant and attributed to prior therapy.  
Exception: alopecia. 
 
3.29b Current use of prohibited medication as described in Section 9.11. 

 
19 
 ACCRU GI-1701  
Addendum 2 
 
 
3.29c 
Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers 
(see Appendix II) ≤14 days or 5 half-lives (whichever is shorter) prior to 
registration. Note: Topical ketoconazole will be allowed. 
 
3.29d History of hypovitaminosis D requiring supraphysiologic doses to replenish the 
deficiency. Note: Patients receiving vitamin D food supplements are allowed. 
 
3.29e 
History and/or current evidence of ectopic mineralization/calcification, including 
but not limited to soft tissue, kidneys, intestine, myocardia, or lung; with the 
exception of calcified lymph nodes and asymptomatic arterial or cartilage/tendon 
calcification. 
 
3.29f 
Unable or unwilling to swallow Pemigatinib and keep a medication diary, or 
significant gastrointestinal disorder(s) that could interfere with absorption, 
metabolism or excretion of Pemigatinib per the discretion of the investigator. 
 
3.29g Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
 
• 
Pregnant women. 
 
• 
Nursing women. 
 
• 
Women of childbearing potential or men able to father children who 
have a female partner of childbearing potential, who are unwilling to 
employ acceptable contraception as outlined in Appendix I. 
 
 
3.29h Known history of human immunodeficiency (HIV) infection or positivity on 
immunoassay confirmed per local standards  
 
Note: HIV test is not required for screening, but patients with a known history of 
HIV infection will be excluded. 
 
 
3.29i 
Evidence of active hepatitis B (HBV) or hepatitis C (HCV) infection 
 
 
3.29j 
Other known active malignancy ≤ 5 years prior to registration. 
 
EXCEPTIONS: Non-melanotic skin cancer or carcinoma in situ of the cervix, 
provided there is no known active disease and no additional therapy for the 
condition is ongoing or required during the trial period  
 
NOTE: Anti-estrogen/androgen therapy or bisphosphonates allowed. 
 
3.29k Co-morbid systemic illness, other severe concurrent disease, or psychiatric 
illness/social situation which, in the judgment of the investigator, would make 
the patient inappropriate for entry into this study, limit compliance with study 
requirements, or interfere significantly with the proper assessment of safety and 

 
20 
 ACCRU GI-1701  
Addendum 2 
 
toxicity of the prescribed regimen. 
 

 
21 
 
ACCRU GI-1701  
Addendum 2 
 
 
4.0 
Test Schedule 
 
4.1 
Schedule of Assessments 
 
Tests  
and  
Procedures 
Screening 
Active Monitoring 
Cycle 1 
Cycles 2+ 
End of Treatment 
Safety12 
Days 
-28 to -1 
Day 114 
 
Day 8  
±3 days10 
Day 15 ±3 
days10 
Day 1 
±3 days10 
Last day of 
treatment +14 
days11 
EOT 
+30-35 days 
COLOMATE Companion 
Trial Recommendation 
Form(optional)1 
X 
 
 
 
 
 
 
Demography and medical 
history 
X 
 
 
 
 
 
 
Hepatitis B and C screening 
X 
 
 
 
 
 
 
Vital Signs, ECOG 
performance status2 
X 
X 
X 
X 
X 
X 
X 
Physical exam, 
weight, height 
X 
X 
X 
X 
X 
X 
X 
Review AEs 
X 
X 
X 
X 
X 
X 
X 
Review prohibited meds3 
X 
X 
X 
X 
X 
X 
X 
Review patient medication 
diary 
 
 
X 
X 
X 
X 
 
Eye examinationR 
X 
 
 
 
X4 
 (every 3 
cycles 
starting with 
c3d1) 
X 
 

 
22 
 
ACCRU GI-1701  
Addendum 2 
 
Tests  
and  
Procedures 
Screening 
Active Monitoring 
Cycle 1 
Cycles 2+ 
End of Treatment 
Safety12 
Days 
-28 to -1 
Day 114 
 
Day 8  
±3 days10 
Day 15 ±3 
days10 
Day 1 
±3 days10 
Last day of 
treatment +14 
days11 
EOT 
+30-35 days 
CT or MRI5 
X 
 
 
 
X5 
(Restaging 
at end of 
cycles 3, 6, 
9 etc.) 
X5 
 
12-lead ECG6 
X 
X 
 
X 
X 
X 
X 
Hematology and Serum 
Chemistries 
X 
X 
X 
X 
X 
X 
X 
Tumor Blood Biomarkers  
(CEA)18 
X18 
X 
 
 
X 
 
 
Coagulation panel 
X 
 
 
 
X15 
 (day 1 of 
c4, 7, 10 
etc.) 
X 
 
Parathyroid hormone 
(PTH)R 
X 
X 
 
 
X 
X 
 
Lipid panelR 
 
X 
 
 
 
X 
 
Mandatory Patient 
Questionnaire Booklet 
(Appendix V)19 
 
X 
 
 
X 
X 
 
Urinalysis 
X 
 
 
 
X16 
 (day 1 of 
c4, 7, 10 
etc.) 
 
 

 
23 
 
ACCRU GI-1701  
Addendum 2 
 
Tests  
and  
Procedures 
Screening 
Active Monitoring 
Cycle 1 
Cycles 2+ 
End of Treatment 
Safety12 
Days 
-28 to -1 
Day 114 
 
Day 8  
±3 days10 
Day 15 ±3 
days10 
Day 1 
±3 days10 
Last day of 
treatment +14 
days11 
EOT 
+30-35 days 
Pregnancy test7 
X7 
X 
 
 
X 
X 
 
Blood sample-cfDNA 
Guardant360 (optional) 13,R 
 
 
 
 
 
X 
 
Mandatory archival tissue 8,R 
X 
 
 
 
 
 
 
Mandatory  blood  
sample plasma 9,R 
 
X 
 
 
X9  
(c2d1; then 
on d1 
following 
restaging 
scans (c4, 7, 
10, etc.) 
X 
 
Mandatory blood sample-
Whole bloodR 
 
X17 
 
 
 
 
 
 
Notes: 
 
R Research funded (see Section 19).  
 
    
1. If the subject is participating through the COLOMATE platform: The COLOMATE Companion Trial Recommendation Form must 
indicate that the patient has met molecular eligibility to screen. The patient must be registered to the companion study ≤30 days from date 
of COLOMATE Companion Trial Recommendation Form completion. If the COLOMATE Companion Trial Recommendation Form 
recommends a different companion study, patient may still enroll after approval by the study PI or designee. Form must be uploaded to 
supporting documentation folder in RAVE. 

 
24 
 
ACCRU GI-1701  
Addendum 2 
 
 
2. Vital Signs:   Including heart rate, blood pressure and temperature (oral or tympanic) and ideally performed with subject in a recumbent or 
semirecumbent position after 5 minutes of rest. 
    
3. Prohibited Medications : List of prohibited medications in section 9.11 should be reviewed at study entry and during treatment. 
 
4. Comprehensive Eye Examination:   To be performed by a qualified ophthalmologist at screening, once every 3 cycles starting with Cycle 
3, Day 1 (±14 days); at EOT, and as clinically indicated. The eye examination should include a visual acuity test, slit-lamp examination, 
OCT,  and funduscopy with digital imaging. Additional assessments should be performed if clinically relevant retinal findings are 
observed on ophthalmologic exams and in participants with reported visual AEs or change in visual acuity, if the events or changes are 
suspected to be of retinal origin. Every effort should be made to ensure that all subsequent examinations are performed by the same 
ophthalmologist. 
 
5. Computed Tomography (CT) / Magnetic Resonance Imaging (MRI):   Baseline evaluation of disease status by CT or MRI completed ≤ 28 
days prior to registration.    Baseline and subsequent scans to include imaging of the primary site of disease plus any additional sites of 
known or suspected disease.   Re-scanning to occur every 9 weeks  (minus 1-6 days) after initiating protocol treatment on Cycle 1, Day 1.   
(The minus 1-6 day scan window is intended for flexibility in scheduling re-scans during Week 3 of every 3rd cycle – i.e. re-scanning 
intended between Days 15-21 of Cycles 3, 6, 9, etc.) 
Same-day scanning on Day 1 of Cycles 4, 7, 10, etc. is discouraged but allowed, provided scan results receive appropriate RECIST review 
prior to initiating/continuing Pemigatinib  in the new cycle of study treatment (e.g. first re-scan is discouraged, but permitted on Cycle 4, 
Day 1, provided RECIST review occurs prior to dispensing Pemigatinib for Cycle 4). 
CT/MRI required at EOT only if it has been >28 days since the previous CT/MRI. 
 
6. Electrocardiogram (ECG):   Single trace 12-lead ECGs on site equipment ideally performed with subject in a recumbent or semirecumbent 
position after 5 minutes of rest.   ECGs will be interpreted locally by the site and used for subject management.   Management decisions 
(e.g. include or exclude a subject or withdraw a subject from the study) based on an ECG finding such as "Abnormal, Clinically 
Significant" is the responsibility of the investigator, in consultation with the sponsor-investigator, as appropriate.   Clinically notable 
abnormalities considered clinically significant by the investigator are to be reported as AEs. 
 
7. Pregnancy Test:   For all women of childbearing potential (WOCBP) – as defined in Appendix I – serum pregnancy test required during 
screening; and serum or urine pregnancy test to be conducted on Day 1 of Cycle 1 (before first dose of Pemigatinib), on Day 1 of every 
cycle, at the EOT visit, and additionally as medically indicated.   If a urine pregnancy test is positive, the results should be confirmed with 
a serum pregnancy test:   If the serum pregnancy test is negative after a urine test was positive, the investigator will assess the potential 
benefit/risk to the subject and determine whether it is in the subject's best interest to resume study drug and continue participation in the 
study. 
 

 
25 
 
ACCRU GI-1701  
Addendum 2 
 
8. Archival Tissue:    Receipt of archival tumor tissue is not required for study registration and initiation of therapy. However, it is mandatory 
to receive the required tissue within 90 days from randomization. See section 17.0. 
 
9. Mandatory Blood Sample-Plasma: Mandatory collection on Day 1, cycle 1; day 1, cycle 2; and on day 1 of each cycle which is 
immediately following radiographic assessment   for re-staging ( day 1 of cycles 4,7,10, etc.) and at EOT (see Section 14). Kits required 
for collection.  Patient must be registered prior to collection. 
 
10. Administrative Scheduling Window:   After Cycle 1, Day 1, allowance of ±3 days for subsequent study visits is permitted for scheduling 
considerations other than adverse event management (e.g. holidays, weekends, inclement weather). 
 
11. End-of -Treatment (EOT):   Reasonable effort should be made to complete End-of-Treatment (EOT) procedures on the day it is decided a 
patient will no longer receive Pemigatinib.   These procedures must be completed subsequent to and not later than 14 days after 
investigator decision to permanently discontinue Pemigatinib  and prior to any subsequent anti-cancer therapy.   CT/MRI required at EOT 
only if it has been >28 days since the previous CT/MRI. 
 
12. Safety Follow-Up:   One-month follow-up (1M F/U) visit to be performed 30 to 35 days after the EOT visit.   (In the event EOT visit not 
performed, then the safety follow-up visit is to be performed 30-35 days after the last dose of Pemigatinib.)   Any adverse event in the 
Safety Follow-up will be recorded on the adverse event assessment form in the last cycle of treatment. The Safety Follow-up is 
recommended by the study protocol, but no data collection is required other than adverse event assessment. 
 
13. Patients have the option to complete cfDNA testing at study completion and will be allowed to re-register with protocol ACCRU-GI-1611. 
Site will access results by creating an account at 
. Sites will be notified by Guardant Health via email 
when results are available in the portal. See section 13.8. See detailed instructions on the ACCRU website under Manuals and Forms. Kits 
are required for this collection. 
 
14. If screening tests occur  ≤ 3 days prior to C1 D1, they do not have to be repeated prior to dosing.  
 
15. Coagulation Panel: to be done at screening, restaging (day 1 of cycles 4, 7, 10 etc.) and end of treatment. 
 
16. Urinalysis: to be done at screening and restaging (day 1 of cycles 4, 7, 10, etc.).  
 
17. Mandatory blood sample-Whole blood: May occur prior to treatment on cycle 1 day 1. Refer to section 14.0 
 
18. Tumor Blood Biomarkers (CEA): to be done ≤7 days prior to registration, and day 1 of every cycle thereafter.  
 

 
26 
 
ACCRU GI-1701  
Addendum 2 
 
19. Patient questionnaire will be completed at baseline, day 1 of each cycle, and end of treatment (within 30 days of last dose as noted in 
appendix V). Patient questionnaire booklets must be used; copies are not acceptable for this submission. The booklet order form is located 
on the ACCRU website under Manuals and Forms. 
 
 

 
27 
 ACCRU GI-1701  
Addendum 2 
 
 
4.2 
Local Laboratory Tests: Required Analytes 
 
Serum Chemistries 
Hematology 
Urinalysis with 
Microscopic 
Examination 
Hepatitis 
Screening 
Coagulation 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphate 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
Vitamin D (25-
hydroxyvitamin D and 
1,25-dihidroxyvitamin 
D) 
 
Complete blood 
count, including: 
• Hemoglobin 
• Hematocrit 
• Platelet count 
• Red blood cell 
count 
• White Blood cell 
count 
 
Differential count, 
including: 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
 
Absolute values must 
be provided for: 
WBC differential 
laboratory results: 
Lymphocytes 
Neutrophils 
Color and 
appearance 
pH and specific 
gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Urobilinogen 
Hepatitis B surface 
antigen 
Hepatitis B surface 
antigen antibody 
Hepatitis B core 
antibody HCV 
antibody 
 
NOTE: If any of 
the above are 
positive, then  
HBV-DNA, HCV-
RNA to assess risk 
of reactivation. 
PT 
PTT 
INR 
Lipid Panel 
Other 
Pregnancy 
Testing 
Total cholesterol 
Triglycerides 
LDL 
HDL 
Endocrine: 
Parathyroid 
hormone 
 
 
Required only for 
female subjects of 
childbearing 
potential. Serum 
pregnancy test at 
screening; and 
serum or urine 
pregnancy test on 
Day 1 of Cycle 1 
(before first dose of 
Pemigatinib), on 
Day 1 of every 
cycle, and at EOT. 
 
 
 
 
 

                                                                                 28  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
5.0 
Grouping Factors  
 
Type of FGFR alteration: 
 
• 
Mutations Vs.  
• 
Translocations/Fusion Vs.  
• 
Amplifications   
 
6.0  
Registration Procedures  
 
6.1 
Registration Procedures 
 
6.11 
To register a patient, fax (
) a completed eligibility checklist to the 
Academic and Community Cancer Research United (ACCRU) Registration Office 
between 8 a.m. and 4:30 p.m. central time Monday through Friday.  
 
Only required if patient is participating in ACCRU-GI-1611.NOTE: ACCRU-GI-1611 
(COLOMATE) treating physician will provide COLOMATE Companion Trial Recommendation Form 
which will include the Patient ID that must be used for this study.  
 
6.12  
Mandatory 
 
A mandatory correlative research component is part of this study. The patient 
will be automatically registered onto this component (see Sections 3.0, 14.0 and 
17.0). 
 
Optional 
 
An optional correlative research component is part of this study. There will be an 
option to select if the patient is to be registered onto this component (see Section 
14.0). 
 
• 
Patient has/has not given permission to give his/her blood sample for 
research testing.  
 
 
6.13 
Documentation of IRB approval must be on file in the Registration Office 
before an investigator may register any patients. Approvals should be 
uploaded using the online ACCRU Regulatory Management System 
(ARMS). 
 
In addition to submitting initial IRB approval documents, ongoing IRB 
approval documentation must be on file (no less than annually) with 
ACCRU. Approvals should be uploaded using the online ACCRU 
Regulatory Management System (ARMS). If the necessary documentation 
is not submitted in advance of attempting patient registration, the 
randomization will not be accepted and the patient may not be enrolled in 
the protocol until the situation is resolved.  
 

                                                                                 29  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
Submission of annual IRB approvals is required until the study has been 
closed through your IRB. 
 
6.14 
Prior to accepting the registration/randomization, the registration/randomization 
application will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
 Existence of a signed consent form 
• 
 Existence of a signed authorization for use and disclosure of protected health 
information  
 
 
 
 
6.15 
At the time of registration, the following will be recorded: 
 
• 
Patient has/has not given permission to store and use his/her blood sample(s) 
for future research to learn about, prevent, or treat cancer. 
• 
Patient has/has not given permission to store and use his/her blood  sample(s) 
for future research to learn, prevent, or treat other health  problems (for 
example: diabetes, Alzheimer’s disease, or heart disease). 
• 
Patient has/has not given permission to store and use his/her tissue sample(s) 
for future research to learn about, prevent, or treat cancer. 
• 
Patient has/has not given permission to store and use his/her tissue sample(s) 
for future research to learn, prevent, or treat other health problems (for 
example: diabetes, Alzheimer’s disease, or heart disease). 
• 
Patient has/has not given permission for ACCRU to give his/her sample(s) to 
outside researchers. 
 
 
 
6.16  
Treatment cannot begin prior to registration and must begin ≤10 days after 
registration. 
 
 
6.17 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
 
6.18 
All required baseline symptoms (see Section 10.5) must be documented and 
graded. 
 
 
 
6.19a 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of a medical oncologist. 
 
 
 
6.19b Blood draw kit is available on site.  
 
 
 
Note: Guardant 360 kit does not need to be on site at the time of registration. 
 
 
 
6.19c 
Patient questionnaire booklet is available on site; copies are not acceptable for 
this submission. 
 
 
7.0 
Protocol Treatment 
 
 
7.1 
Treatment Schedule 
 

                                                                                 30  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
Agent 
Dose 
Route 
Schedule 
Pemigatinib 
13.5 mg  
(dose level 0) 
Oral 
Once daily (QD),  
on Days 1-21 of cycle 1 
Pemigatinib 
18 mg* 
Oral 
Once daily (QD),  
on Days 1-21 of cycles 2-35* 
 
During each 21-day dosing cycle, Pemigatinib is scheduled to be administered on days 1-
21 of a 21 day cycle  
 
 
Each dose of Pemigatinib should be taken by mouth with a glass of water immediately 
upon rising or after a 2-hour fast. After dosing, the patient should refrain from eating for 
1 hour. 
 
If the subject vomits after taking study drug, the subject should not take another dose that 
day. If a dose of Pemigatinib is missed by more than 4 hours, that dose should be skipped 
and the next scheduled dose should be administered at the usual time.  
 
*All of the following criteria must be met in order to increase dose level beginning at 
cycle 2 
 
• 
Participant does not reach the target serum phosphate level of > 5.5 mg/dL at any 
time during Cycle 1. 
• 
Patient is compliant with taking study drug.  
• 
Patient does not experience an ongoing Grade 2 or higher treatment-related AEs 
during cycle 1.  
• 
 If dose level escalated, please remember to report as modified treatment in Rave. 
 
 
 
 
 
7.2 
If all criteria for dose increase are not met patient will remain at dose level 0. Dose may 
be increased at a future cycle if patient meets criteria. Note: If dose escalated, please 
remember to report as modified treatment in Rave. 
 
 
7.3 
Patients can be instructed in Pemigatinib  administration techniques and granted 
treatment independence with nursing staff approval. 
 
7.4 
For this protocol, the patient must return to the consenting ACCRU institution for 
evaluation during treatment and during observation (Active Monitoring Phase) according 
to the table in Section 4.0.  
 
7.5 
Patients will be required to keep a medication diary for Pemigatinib using the diary in 
appendix III. Sites will be required to upload medication diary to RAVE at the end of 
each cycle. 
 
8.0 
Dosage Modification Based on Adverse Events  
 
For all adverse events reported in this study considered by the investigator as possibly, probably 

                                                                                 31  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
or definitely related to Pemigatinib, the following dose modification guidance should be applied. 
 
Adverse events considered by the investigator as definitely related to something other than 
Pemigatinib, or transient (≤ 72 hours) abnormal laboratory values without associated signs or 
symptoms deemed clinically significant by the investigator, may be exempt from dose-reduction 
rules unless otherwise requested or required by the sponsor-investigator.  
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
8.1  
Dose Level Reductions (if needed for management of potential adverse event)  
 
Dose Level 
Pemigatinib 
1 
18 mg PO QD 
0 
13.5 mg PO QD 
-1 
9 mg PO QD 
* All patients are scheduled to initiate Pemigatinib at Dose Level 0.  
See section 7.1 for dose escalation information. 
Note: If dose escalated, please report as modified treatment in Rave. 
 
 
 
8.2 
Dose Modifications 
 
Use the NCI Common Terminology Criteria for Adverse Events (CTCAE)  
Version 5.0 dated November 27, 2017* unless otherwise specified 
ADVERSE 
EVENT 
AGENT 
ACTION 
Chemistry 
AST and/or  
ALT > 5.0 x ULN 
and/or ALP > 5.0 x 
ULN 
 
Note: In patients 
with liver or bone 
metastasis-related 
elevations at 
baseline, contact 
sponsor-
investigator to 
discuss clinical 
management and 
possible dose 
reductions. 
Pemigatinib 
Step 1: Hold/Delay Pemigatinib up to 2 weeks (14 days) 
until the toxicity has resolved to ≤ Grade 1 except by 
written approval from the sponsor-investigator. 
 
Step 2: If assessed by the investigator as not related or 
unlikely related to Pemigatinib, then restart Pemigatinib 
at same dose; monitor as clinically indicated. 
 
Step 2: If assessed by the investigator as possibly, 
probably or definitely related to Pemigatinib, then restart 
Pemigatinib at the next lower dose level; monitor as 
clinically indicated. 

                                                                                 32  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
ANC is 0.5 x 109/L 
to < 1.0 × 10
9/L 
(grade 3)  
Platelet count is 50 
× 10
9/L to 
< 75 × 10
9/L (grade 
2) 
Pemigatinib 
Step 1: Interrupt study drug up to 2 weeks (14 days) until 
the toxicity has resolved to Grade 1 or pretherapy 
baseline. 
Step 2: Restart study drug at same dose and monitor as 
clinically indicated.  
*If neutropenia is rapidly reversible after stopping study 
drug, subjects will be allowed to stay on their dose as 
long as ANC > 1.0 × 10
9/L.  
 
 
Grade 4 ANC (< 
0.5 × 10
9/L)  
Grade 3 ANC with 
an oral temperature 
of at least 38.5°C 
OR with Grade 3 
infection  
Platelet count is < 
50 × 10
9/L (grade 3 
or 4) 
 
Pemigatinib 
Step 1: Interrupt study drug up to 2 weeks (14 days) until 
resolved to Grade 1. 
Step 2: If assessed as related to study drug, restart study 
drug at next lower dose level, except if Grade 4 
neutropenia resolves in ≤ 7 days, in which case restart at 
the same dose. 
Other Toxicities 
Any Grade 1 or 
other Grade 2 
toxicity 
Pemigatinib 
Continue Pemigatinib; treat the toxicity and monitor as 
clinically indicated. 
Any other Grade 3 
toxicity, if 
clinically 
significant and not 
manageable by 
supportive care. 
 
Pemigatinib 
Step 1: Hold/Delay Pemigatinib up to 2 weeks (14 
days), until toxicity resolves to ≤ Grade 1. 
 
Step 2: If assessed by the investigator as not related or 
unlikely related to Pemigatinib, then restart Pemigatinib 
at same dose; monitor as clinically indicated. 
 
Step 2: If assessed by the investigator as possibly, 
probably or definitely related to Pemigatinib, then restart 
Pemigatinib at the next lower dose level; monitor as 
clinically indicated. 
 
Any recurrent 
Grade 3 toxicity 
after 2 dose 
reductions. 
Pemigatinib 
Permanently discontinue Pemigatinib and initiate post-
treatment follow-up per Protocol. (Exceptions require 
written approval of sponsor-investigator.)  

                                                                                 33  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
 
Any other  
Grade 4 toxicity, if 
clinically 
significant 
 
Pemigatinib 
Permanently discontinue Pemigatinib and initiate post-
treatment follow-up per Protocol. 
* 
Located at 
  
** The following describe actions in the Action column: 
 Hold/Delay = Treatment can be made up (see Section 8.3) as part of this cycle; 
 Discontinue = Treatment is totally stopped. 
Hyperphosphatemia is an expected on-target pharmacologic effect of FGFR inhibition.  
Hyperphosphatemia should be managed with diet modifications, phosphate binders and 
diuretics, or a dose reduction per the recommendations in the below table: 
 
Recommended Approach for Hyperphosphatemia Management 
Serum 
Phosphate 
Level 
Supportive Care 
Guidance for 
Interruption/Discontinuation of 
Pemigatinib 
Guidance for 
Restarting 
Pemigatinib 
> 5.5 mg/dL  
  and  
≤ 7 mg/dL 
Initiate a  
low-phosphate diet.  
No action.  
Not applicable.  
> 7 mg/dL  
  and  
≤ 10 mg/dL  
Initiate/continue a 
low-phosphate diet 
and initiate 
phosphate-binding 
therapy once serum 
phosphate level is  
> 7 mg/dL. 
 
Monitor serum 
phosphate at least 
twice a week and 
adjust the dose of 
binders as needed; 
continue to monitor 
serum phosphate at 
least twice a week 
until return to normal 
range. 
If serum phosphate level continues 
to be > 7 mg/dL and ≤ 10 mg/dL 
with concomitant phosphate-binding 
therapy for 2 weeks, or if there is 
recurrence of serum phosphate level 
in this range, hold/delay Pemigatinib  
for up to 2 weeks  
Restart Pemigatinib 
at the same dose  
when serum 
phosphate is  
< 7 mg/dL. 
 
If serum phosphate 
level recurs at  
> 7 mg/dL, restart 
Pemigatinib with 
dose reduction. 

                                                                                 34  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
> 10 mg/dL  
Continue to maintain 
a low-phosphate diet, 
adjust phosphate-
binding therapy, and 
start/continue 
phosphaturic agent. 
 
Continue to monitor 
serum phosphate at 
least twice a week 
until return to normal 
range. 
If serum phosphate level is  
> 10 mg/dL for 1 week following 
phosphate-binding therapy and low 
phosphate diet, hold/delay 
Pemigatinib. 
 
If there is recurrence of serum 
phosphate level in this range 
following 2 dose reductions, 
permanently discontinue 
Pemigatinib. 
Restart Pemigatinib  
at reduced dose 
with phosphate 
binders when 
serum phosphate is  
< 7 mg/dL. 
** The following describe actions above: 
 Hold/Delay = Treatment can be made up (see Section 8.3) as part of this 
cycle; 
 Discontinue = Treatment is totally stopped. 
 
 
8.3 
For reasons that are consistent with the Dose Modifications outlined above in Section 8.2, 
Pemigatinib treatment that is held/delayed for purpose of adverse event management can 
be “made up” within a given cycle: 
 
• 
The scheduled duration of a cycle is 21 days (3 weeks).  
 
• 
For purpose of accommodating an established  Pemigatinib dose hold/delay, 
the number of days in any given cycle may be increased up to 14 total days, in 
order to accommodate a maximum cycle length of 35 days (5 weeks). 
 
Note: The purpose of this guidance is not to accommodate re-dosing in the 
absence of an established Pemigatinib dose hold/delay. For example, 
inadvertently missed or vomited doses of Pemigatinib are not to be “made up” 
within the cycle, but rather should be omitted from the cycle (and noted as 
such in the patient-completed medication diary).  
 
• 
Within every given cycle, an Pemigatinib dose hold/delay is permitted, with a 
maximum duration of no more than 14 total days in each cycle (regardless of 
whether such 14 total days within any given cycle are consecutive or 
cumulative days).  
 
• 
In all cases, a patient may receive no more than 21 total doses of Pemigatinib 
in a single cycle. 
 
 
• 
Dose re-escalation only allowed after discussion with study PI and sponsor, if 
clinically indicated. 
 
• 
If dosing is delayed greater than 42 days, patient should be removed from 
treatment, and proceed to event monitoring.  
 
 
 
9.0 
Ancillary Treatment/Supportive Care 
 

                                                                                 35  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
9.1 
Prohibited Medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Restricted and Cautionary Medications 
 
9.12 
The use of mild or moderate CYP3A4 inhibitors or inducers should involve 
careful monitoring. 
 
9.13 
The pH level of stomach acid impacts the absorption of Pemigatinib. As a result, 
limited use of proton pump inhibitors or antacids while on study is 
recommended. 
 
9.14 
Calcium-based phosphate binding medications while on study should be avoided 
or, if medically necessary and unavoidable, used with caution due to a concern 
for soft tissue mineralization. 
 
9.2 
Supportive Care 
 
9.21 
Hyperphosphatemia is an expected on-target pharmacologic effect of FGFR 
inhibition. Hyperphosphatemia should be managed with diet modifications, 
phosphate binders and diuretics, or a dose reduction per the recommendations in 
Section 8. 
 
9.22 
Patients should receive full supportive care while on this study. This includes 
blood product support, antibiotic treatment, and treatment of other newly 
diagnosed or concurrent medical conditions.  
 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
The site principal investigator is responsible for reporting any/all adverse events to the sponsor as 
described within the protocol. Refer to the adverse event and serious adverse event sections of the 
protocol for detailed information. 
 
 
9.11 
The following medications and measures are PROHIBITED: 
 
• 
Concomitant administration of potent CYP3A4 inhibitors and inducers and 
moderate CYP3A4 inducers. Based on the low overall bioavailability of 
topical ketoconazole, there are no restrictions on topical ketoconazole.  See 
appendix II for a list of potent CYP3A4 inhibitors and inducers. 
 
• 
Any concomitant use of a selective FGFR inhibitor (other than 
Pemigatinib). 
 
• 
Investigational study drug for any indication. 
 
•
Use of any anticancer medications (other than Pemigatinib).

                                                                                 36  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following:  
 
• 
Any suspected adverse reaction that is both serious and unexpected.  
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity.  
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug.  
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB).  
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming 
aware of the event. 
 
Routine Reporting 
Events reported to sponsor via case report forms 
 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, 
but that for a specific protocol are being reported via expedited means in order to 
facilitate the review of safety data (may be requested by the FDA or the sponsor).  
 
10.1 
Adverse Event Characteristics 
 
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 web site: 
   
 
a. Adverse event monitoring and reporting is a routine part of every clinical trial.  
 
b. Identify the grade and severity of the event using the CTCAE version 5.0.  
 

                                                                                 37  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
c. Determine whether the event is expected or unexpected (see Section 10.2).  
 
d. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
 
e. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
 
f. Determine if other reporting is required (see Section 10.5). 
 
g. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.5 and 
18.0). 
 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA Lowest 
Level Term (LLT). 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same as serious 
AE which is defined in the table in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 

                                                                                 38  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug/device and the adverse event.  
. 
  
The following hospitalizations are not considered to be SAEs because there is no 
  
“adverse event” (i.e., there is no untoward medical occurrence) associated with the 
  
hospitalization: 
 
• Hospitalizations for respite care 
 
• Planned hospitalizations required by the protocol or to administer protocol directed 
treatment 
 
• Hospitalization planned before informed consent (where the condition requiring the                       
hospitalization has not changed post study drug administration) 
 
• Hospitalization for administration of study drug 
 
• Hospitalization for routine maintenance of a device (e.g., battery replacement) that was   
in place before study entry 
 
 
*Report any clinically important increase in the rate of a serious suspected adverse reaction 
(at your study) site over that which is listed in the protocol or investigator brochure as an 
expedited event.  
*Report an expected event that is greater in severity or specificity than expected as an 
expedited event  
*An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a higher 
degree of severity or specificity, expedited reporting is required.  
A list of known/expected AEs is reported in the investigator brochure, package insert or the 
literature, including AEs resulting from a drug overdose. 
 
10.331 Death 
 
• 
Any death occurring within 30 days of the last dose, 
regardless of attribution to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 
• 
Any death occurring greater than 30 days with an attribution 
of possible, probable, or definite to an agent/intervention 
under an IND/IDE requires expedited reporting within 24-
hours. 
 
• 
Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 

                                                                                 39  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
 
• 
Death Neonatal: A disorder characterized by 
cessation of life during the first 28 days of life. 
 
• 
Death NOS: A cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
 
• 
Sudden death NOS: A sudden (defined as instant or 
within one hour of the onset of symptoms) or an 
unobserved cessation of life that cannot be attributed 
to a CTCAE term associated with Grade 5. 
 
• 
Death due to progressive disease should be reported 
as Grade 5 “Neoplasms benign, malignant and 
unspecified (including cysts and polyps) – Other 
(Progressive Disease)” under the system organ class 
(SOC) of the same name. 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. 
 
10.332 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. 
 
• 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE to be reported. Three options are available to 
describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 
o 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. 
 
10.333 Second Malignancy 

                                                                                 40  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
 
• 
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 reporting. 
 
10.334 Pregnancy 
 
An “Initial Pregnancy Report” must be completed in full and faxed to the 
ACCRU SAE coordinator at 
 within 24 hours of discovery of a 
pregnancy of a subject who has taken the Incyte product (INCB054828) or the 
pregnancy of a partner for a subject who has taken the Incyte product.  The 
“Follow-up Pregnancy Report Form” must be completed and faxed to the 
ACCRU SAE coordinator at 
 within 30 days after delivery, so 
that Incyte is provided with information regarding the outcome of the pregnancy. 
The ACCRU SAE coordinator will forward all pregnancy reports to Incyte.  If 
the pregnancy results in any events which meet the serious criteria (i.e., 
miscarriage or termination), the SAE reporting process needs to be followed and 
the timelines associated with an SAE should be followed. 
 
“Initial Pregnancy Report” and “Follow-up Pregnancy Report Form” can 
be found on the ACCRU website. 
 
Prior to obtaining private information about a pregnant woman and her 
infant, the investigator must obtain consent from the pregnant woman 
and the newborn infant’s parent or legal guardian before any data 
collection can occur. A consent form will need to be submitted to the 
IRB for these subjects if a pregnancy occurs. If informed consent is not 
obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
 
NOTE: When submitting
 
he potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation.  
 

                                                                                 41  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
10.4 Expedited Adverse Event Reporting Requirements for IND/IDE Agents 
  
10.41  Early Phase 2 Studies: Expedited Reporting via the ACCRU Adverse Event 
Expedited Report Form for Adverse Events That Occur Within 30 Days1 of the Last Dose of the 
Investigational Agent 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event 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). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
7 Calendar Days 
24-Hour; 3 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 

                                                                                 42  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
 Special Instructions: 
 
• 
Follow site-specific reporting guidelines. 
• 
Submit the ACCRU Adverse Event Expedited Report Form to ACCRU 
Safety via email at: 
 ACCRU Safety will 
forward to Incyte via email to 
 
• 
SAE reports should be for a single subject. 
• 
ACCRU Safety will forward to ACCRU IND Coordinator 
(
) as appropriate. The ACCRU IND Coordinator will assist 
the sponsor-investigator in notifying the FDA if required.  
 
10.5 
Other Required Reporting 
 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
If the event meets the criteria for an UPIRTSO, submit to your IRB as required 
by your institutional policies.  
 
 
 

                                                                                 43  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.52 Baseline and Adverse Events Evaluations  
 
 
The following pre-treatment symptoms/conditions are to be graded at baseline 
and adverse events are to be graded at each evaluation using CTCAE v5.0 
grading. 
 
 
System Organ 
Class (SOC) 
 
Adverse event/Symptoms 
 
Baseline 
Each  
evaluation 
General disorders and  
administration site conditions  
Fatigue 
X 
X 
Gastrointestinal disorders  
 
Nausea 
X 
X 
Gastrointestinal disorders  
 
Vomiting 
X 
X 
Gastrointestinal disorders  
 
Diarrhea 
# of stools 
X 
Metabolism and nutrition  
disorders  
Anorexia 
X 
X 
Metabolism and nutrition 
disorders 
Hyperphosphatemia 
X 
X 
Investigations  
 
Alanine aminotransferase 
increased  
X 
X 
Investigations  
Aspartate aminotransferase 
increased  
X 
X 
Investigations 
Alkaline phosphatase increased  
X 
X 
Investigations 
Blood bilirubin increased  
X 
X 
Investigations 
 Platelet count decreased 
X 
X 
Investigations 
  Neutrophil count decreased 
X 
X 
Blood and lymphatic system 
disorders  
Anemia  
 
X 
X 
 
10.53  Case Report Forms - Academic and Community Cancer Research United 
(ACCRU) 

                                                                                 44  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
 
Submit the following AEs not specified in Section 10.5  
 
 
10.531 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.532 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.533 Grade 5 AEs (Deaths) 
 
10.5331 Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the 
study treatment or procedure. 
 
10.5332 Any death more than 30 days after the patient’s last 
study treatment or procedure that is felt to be at least 
possibly treatment related must also be submitted as a 
Grade 5 AE, with a CTCAE type and attribution 
assigned. 
 
 
11.0 
Treatment Evaluation Using RECIST Guideline 
 
NOTE: This study uses protocol RECIST v1.1 template dated 2/16/2011. See the footnote for the 
table regarding measureable disease in Section 11.44, as it pertains to data collection and 
analysis. 
 
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) guidelines 
(version 1.1) (Eisenhauer et al., 2009). Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the short axis measurements in the case of lymph nodes 
are used in the RECIST guideline. 
 
11.1 
Schedule of Evaluations: For the purposes of this study, patients should be reevaluated 
every 9 weeks.  
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
11.21  Measurable Disease 
 
11.211 A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with CT 
scan, or MRI.  
 
11.212 A superficial non-nodal lesion is measurable if its longest diameter is ≥ 
1.0 cm in diameter as assessed using calipers (e.g. skin nodules) or 
imaging. In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
 

                                                                                 45  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
11.213 A malignant lymph node is considered measurable if its short axis is >1.5 
cm when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm).  
 
NOTE: Tumor lesions in a previously irradiated area are not considered 
measurable disease. 
  
11.22 Non-Measurable Disease 
 
11.221 All other lesions (or sites of disease) are considered non-measurable 
disease, including pathological nodes (those with a short axis ≥1.0 to <1.5 
cm). Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-
measurable as well. 
 
Note: ‘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. In 
addition, lymph nodes that have a short axis <1.0 cm are considered non- 
pathological (i.e., normal) and should not be recorded or followed. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.31 Measurement Methods:  
 
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during follow-
up. For patients having only lesions measuring at least 1 cm to less than 2 cm 
must use CT imaging for both pre- and post-treatment tumor assessments.  
 
• 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used at the same evaluation to assess the 
antitumor effect of a treatment.  
 
11.32 Acceptable Modalities for Measurable Disease:  
 
• 
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 
or less. If CT scans have slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness.  
 
• 
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. The lesions should be measured on the same pulse 
sequence. Ideally, the same type of scanner should be used and the image 

                                                                                 46  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
acquisition protocol should be followed as closely as possible to prior scans. 
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
11.33 Measurement at Follow-up Evaluation:  
 
• 
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. 
 
• 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases  
 
11.4 
Measurement of Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 
lesions, representative of all involved organs, should be identified as “Target 
Lesions” and recorded and measured at baseline. These lesions can be non-
nodal or nodal (as defined in 11.21), where no more than 2 lesions are from 
the same organ and no more than 2 malignant nodal lesions are selected.  
 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as 
there often will be), there is no reason to perform additional studies beyond 
those specified in the protocol to discover new lesions.  
 
• 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should 
be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion (or malignant lymph node) 
does not lend itself to reproducible measurements in which circumstance the 
next largest lesion (or malignant lymph node) which can be measured 
reproducibly should be selected.  
 
• 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the baseline sum of dimensions (BSD). The 
BSD will be used as reference to further characterize any objective tumor 
response in the measurable dimension of the disease.  
 
• 
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the target lymph 
nodes will be calculated and reported as the post-baseline sum of dimensions 
(PBSD). If the radiologist is able to provide an actual measure for the target 
lesion (or target lymph node), that should be recorded, even if it is below 0.5 
cm. If the target lesion (or target lymph node) is believed to be present and is 
faintly seen but too small to measure, a default value of 0.5 cm should be 

                                                                                 47  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
assigned. If it is the opinion of the radiologist that the target lesion or target 
lymph node has likely disappeared, the measurement should be recorded as 0 
cm. 
 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and 
the PBSD. 
 
 
11.42  Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target 
lesions or non-target lymph nodes and should also be recorded at  
baseline. These lesions and lymph nodes should be followed in accord with 
11.433. 
 
11.43 Response Criteria 
 
11.431 All target lesions and target lymph nodes followed by 
 
CT/MRI must be measured on re-evaluation at evaluation times specified 
in Section 11.1. Specifically, a change in objective status to either a PR 
or CR cannot be done without re-measuring target lesions and target 
lymph nodes.  
 
Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first response or 
confirmation of response. In selected circumstances, certain non-target 
organs may be evaluated less frequently. For example, bone scans may 
need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
 
11.432 Evaluation of Target Lesions 
 
• Complete Response (CR): All of the following must be true: 
 
• 
Disappearance of all target lesions. 
 
• 
Each target lymph node must have 
reduction in short axis to <1.0 cm. 
 
 
• Partial Response (PR): 
At least a 30% decrease in PBSD (sum of 
the longest diameter for all target lesions 
plus the sum of the short axis of all the 
target lymph nodes at current evaluation) 
taking as reference the BSD (see Section 
11.41). 
 
• Progression (PD): 
At least one of the following must be true: 
 
• 
At least one new malignant lesion, which also includes any lymph node that was normal at 
baseline (< 1.0 cm short axis) and increased to ≥ 1.0 cm short axis during follow-up.  

                                                                                 48  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
 
a. At least a 20% increase in PBSD (sum 
of the longest diameter for all target 
lesions plus the sum of the short axis 
of all the target lymph nodes at current 
evaluation) taking as reference the 
MSD (Section 11.41). In addition, the 
PBSD must also demonstrate an 
absolute increase of at least 0.5 cm 
from the MSD.  
 
 
  
• Stable Disease (SD): 
Neither sufficient shrinkage to qualify for 
PR, nor sufficient increase to qualify for 
PD taking as reference the MSD. 
 
11.433 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
• Complete Response (CR): 
All of the following must be true: 
 
a. Disappearance of all non-target 
lesions.  
 
b. Each non-target lymph node must 
have a reduction in short axis to <1.0 
cm. 
 
 
• Non-CR/Non-PD: 
Persistence of one or more non-target 
lesions or non-target lymph nodes. 
 
 
• Progression (PD): 
At least one of the following must be true: 
 
a. At least one new malignant lesion, 
which also includes  
any lymph node 
that was normal at baseline (< 1.0 cm 
short axis) and increased to ≥ 1.0 cm short 
axis during follow-up.  
 
b. Unequivocal progression of existing 
non-target lesions and non-target 
lymph nodes. (NOTE: Unequivocal 
progression should not normally 
trump target lesion and target lymph 
node status. It must be representative 
of overall disease status change.)  
  
 

                                                                                 49  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
. 
 
 
11.44 Overall Objective Status 
 
 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non-target 
lymph nodes, and new disease as defined in the following tables:  
 
 
For Patients with Measurable Disease  
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
*See Section 11.431 
** NOTE: This study uses the protocol RECIST v1.1 template dated 2/16/2011. For data collection 
and analysis purposes the objective status changed from SD to PR in the ACCRU protocol RECIST 
v1.1 template as of 2/16/2011 and to match RECIST v1.1 requirements. 
 
 
 
11.45 Symptomatic Deterioration: Patients with global deterioration of health status 
requiring discontinuation of treatment without objective evidence of disease 
progression at that time, and not either related to study treatment or other medical 
conditions, should be reported as PD due to “symptomatic deterioration.” Every 
effort should be made to document the objective progression even after 
discontinuation of treatment due to symptomatic deterioration. A patient is 
classified as having PD due to “symptomatic deterioration” if any of the 
following occur that are not either related to study treatment or other medical 
conditions: 
 

                                                                                 50  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
• Significant worsening of tumor-related symptoms as per investigator discretion. 
• Decline in performance status to ≥ 3 on ECOG scale. 
 
 
12.0 
Descriptive Factors  
 
12.1 
ECOG PS: 0 vs. 1. vs. 2 
 
12.2 
Disease characteristics: Unresectable vs. Metastatic. 
 
12.3 
Prior treatment: TAS-102 vs. Regorafenib vs. neither vs both (TAS-102 and Regorafenib) 
 
12.4 
Primary tumor location: cecum vs. ascending vs. hepatic flexure vs. transverse vs. splenic 
flexure vs. descending vs. sigmoid vs. rectosigmoid vs. rectum vs other. 
 
 
12.5 
Microsatellite instability or mismatch repair deficiency tested: Yes vs. no. 
 
 
12.51 If yes, MSI-High (MSI-H) vs. microsatellite stable/MSI-Low (MSS/MSI-L); loss 
of mismatch repair protein (MMR deficient, dMMR) vs. mismatch repair proteins intact 
(MMR proficient, pMMR). 
 
12.6 
KRAS (mutated vs. wildtype vs. unknown) 
 
12.7 
NRAS (mutated vs. wildtype vs. unknown) 
 
12.8 
BRAF V600E (mutated vs. wildtype vs. unknown) 
 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
 
 
13.1 
Patients who have CR, PR, or SD will continue treatment per protocol up to 35 cycles. 
After 35 cycles, patients will go to event monitoring.  
 
13.2 
Patients who develop PD while receiving therapy will go to the event-monitoring phase. 
 
13.3 
Patients who go off protocol treatment for reasons other than PD or alternative therapy 
will go to the event-monitoring phase per Section 18.0. 
 
13.4 
Event monitoring is every 3 months for 3 years after registration. If patient is still alive 3 
years after registration, no further follow up is required.  
 
13.5 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
 
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 18.0 of 
the protocol.  

                                                                                 51  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
 
• 
If the patient never received treatment, On-study material and the Off Treatment 
Form must be submitted. No further data submission is necessary.  
  
13.6 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the event-monitoring phase of the study. The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. Event monitoring 
will be required per Section 18.0 of the protocol. 
 
13.7 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the Off Treatment Form must be 
submitted. No further data submission is necessary. 
 
13.8 
Patients have the option to complete cfDNA testing at study completion and are 
encouraged to re-register with protocol ACCRU-GI-1611 (COLOMATE). The results of 
the cfDNA test will be used for eligible patients in protocol ACCRU-GI-1611 
(COLOMATE) to identify genomic alterations and facilitate enrollment on COLOMATE 
companion clinical trials. Site will access results by creating an account at 
 Sites will be notified by Guardant Health via email 
when results are available in the portal.  See detailed instructions on the ACCRU website 
under Manuals and Forms. 
 
 
 
14.0 
Body Fluid Biospecimens  
 
14.1 
Summary Table of Research Blood/Blood Products to Be Collected for This Protocol  
 
1. May occur prior to treatment on Cycle 1 Day 1. 
2.  Day 1 of each cycle which is immediately following radiographic assessment for re-staging 
(day 1 of cycles 4,7,10 etc.) 
3. Discontinuation of study treatment. 
Indicate if 
specimen is 
mandatory or 
optional 
Collection 
tube 
description 
and/or 
additive 
(color of 
tube top) 
Volume to 
collect per 
tube 
(number of 
tubes to be 
collected) 
Blood product 
being 
processed and 
submitted by 
participating 
site 
Baseline1 
 
 
Prior to 
dosing on 
Day 1 of 
Cycle 2 
Restaging2 
End of 
Treatment3 
Additional 
processing 
required at 
site after 
blood 
draw? 
Storage 
/shipping 
conditions4 
Mandatory 
EDTA K2 
(Purple) 
10 mL (1) 
Whole Blood 
X 
 
 
 
No 
Freeze /dry 
ice 
Mandatory 
EDTA K2 
(Purple) 
10 mL (4) 
Platelet Poor 
Plasma and 
White blood 
cells 
X 
X 
X 
X 
Yes 
Freeze /dry 
ice 
Optional 
Streck 
tube5 
10 mL (2) 
Whole blood 
 
 
 
X 
No 
Room 
temperature 

                                                                                 52  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
4. After all samples have been processed according to kit instructions, ship all specimens 
according to shipping instructions (see Section 14.2 for detailed shipping instructions.) 
Patients will complete cfDNA testing at study completion and then be encouraged to re-
register with protocol ACCRU-GI-1611. See section 13.8 
14.2 
Kits are required for this study. 
 
NOTE: You will be ordering and receiving kits from two different locations.  
 
14.21 EDTA K2 
 
 
14.211 Each kit will contain supplies and instructions for collecting, processing, 
and shipping specimens. 
 
14.212 Participating institutions may obtain kits for EDTA K2 by completing 
and faxing the Supply Order Form (found in the Forms Packet) to the 
number listed on the form. Fill out the site address to where the kits will 
be shipped on the Fax Supply form. A small but sufficient supply of the 
specimen collection kits should be ordered prior to patient entry. 
Unused/expired kits should be disposed of per institution policy. Do not 
send unused kits back to BAP. Supply Order Forms must be filled in 
completely and legibly for quick processing. 
 
14.213 Kits will be sent via FedEx Ground at no cost to the participating 
institutions. Allow up to two weeks to receive the kits. Kits will arrive 
inside the shipping boxes. 
 
14.214 Kits will not be sent via rush delivery service unless the participating 
institution provides their own FedEx account number or alternate billing 
number for express service. ACCRU will not cover the cost for rush 
delivery of kits. 
 
14.22 Guardant 360 (Streck Tube)14.221 
In order to receive kits and 
access to the Guardant portal, fill out the Guardant Site Setup form for 
each treating location and email to 
 
 
14.222 If participating though ACCRU-GI-1611 (COLOMATE), sites will 
create an account at 
. Once account is 
created, Guardant Health will ship the sites their kits and their own pre-
printed TRFs (Test Requestion Form). Once that happens, kits and TRFs 
can be refreshed/replaced by contacting Guardant Health Client Services 
Team at 
 
 
14.3 
Shipping and Handling 
 
NOTE: You will be shipping kits to two different locations.  
 
14.31 EDTA K2 
 
14.311 Verify ALL sections of the Blood Specimen Submission Form (see 
Forms Packet), BAP Requisition Form (provided in kit) and specimen 
collection labels are completed and filled in correctly. 

                                                                                 53  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
 
14.312 Specimens must be shipped the same day they are drawn. 
 
14.313 Ship tubes with a properly prepared cold pack. See kit instructions for 
specific details for cold pack preparation (i.e., frozen or refrigerated) and 
proper packing of blood and cold pack to avoid freezing of specimen. 
 
14.314 Ship specimens via Priority Overnight service, Monday – Thursday, to 
BAP Freezer according to kit instructions. Do not send samples on 
weekends or just prior to federal holidays. If a patient can only be seen 
on Fridays, email the Biospecimen Manager (found on resource page) 
with the sample information and FedEx tracking number. 
 
14.315 The BAP kits will include a smart shipper label (3x5 white barcoded 
label) affixed to the shipping boxes. The smart shipper label is a pre-
addressed return label, which replaces the need for an air bill. Shipping 
costs will be covered by ACCRU if the shipping box provided with the 
BAP kit is used for shipping specimens to BAP Freezer. 
 
14.316 BAP Freezer will receive the samples and immediately forward 
specimens to the ACCRU Research Base BAP Shared Resource, Stabile 
SL-16. At study completion, specimens will be forwarded to the Duke 
Phase I Biomarker Laboratory located at Duke University for future 
processing. 
 
14.32 Guardant 360 (Streck Tube) 
 
 
14.321 Complete the Test Requisition Form and barcode labels (provided in kit). 
 
14.322 Ship tubes the same day as collecton with properly prepared gel pack. Do 
not freeze gel packs. Use as is.  
 
14.323 Place the kit into the preprinted FedEx Clinical Pak and call FedEx for a 
pickup to be shipped to Guardant Health.  
 
14.324 Detailed Blood Draw and Shipping Instructions are located on the 
ACCRU website under Manuals and Forms.  
 
14.4 
Study Methodology and Storage Information 
 
14.41 Blood/blood product samples will be collected for the following research: 
 
14.411 Whole blood for pharmacogenomics 
 
Whole blood will be stored for future pharmacogenetic assays (e.g., 
genetic polymorphisms such as those known to regulate angiogenesis, 
inflammation, immunity, auto-immunity, and antibody or drug action of 
clearance) that may correlate with efficacy and tolerability. The Duke 
Phase I Biomarker Laboratory located at Duke University may analyze 
the DNA for the presence of markers of interest using standard laboratory 
protocols. 

                                                                                 54  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
 
14.412 Soluble protein (blood-based) biomarkers 
 
Blood (platelet poor plasma, and white blood cells (buffy coat)) will be 
collected at baseline, every restaging, and progression for future analysis. 
The Duke Phase I Biomarker Laboratory located at Duke University may 
analyze for the following, but are not limited to soluble HGF, c-MET, 
EGF, HBEGF, HER1-3, FGFa, FGFb,  VEGFA-D, PlGF, VEGFR2, 
GAS6, AXL, SDF1, Ang2, and TIE-2. Additional biomarkers may also be 
explored using multiplex array technology. Final biomarker selection will 
reflect the best science at the time of analysis. 
 
14.413 Plasma for mutational analysis 
 
Blood (platelet poor plasma) will be stored for future analysis of cell free 
DNA (cfDNA) and will be collected at baseline, every restaging, and at 
the 30-day post-treatment visit. The Duke Phase I Biomarker Laboratory 
located at Duke University may analyze for the following, but are not 
limited to HER2 amplification, EGFR amplification, BRAF mutations, 
and extended KRAS/NRAS testing (exons 2, 3, and 4). Final biomarker 
selection will reflect the best science at the time of analysis. 
 
14.414 Future use of patient samples 
 
Any remaining biological materials (platelet poor plasma, and buffy 
coats) at the end of the study will be retained for possible use in future 
biomarker research. 
 
14.5 
Return of Genetic Testing Research Results 
 
Results of CLIA-certified assays (e.g., Guardant360) are permitted to be shared with 
patients and their treating physicians. Because the results generated by other genetic 
testing included in this section are not currently anticipated to have clinical relevance to 
the patient or their family members, the genetic results will not be disclosed to the 
patients or their physicians. 
 
If at any time, genetic results are obtained that may have clinical relevance, IRB review 
and approval will be sought regarding the most appropriate manner of disclosure and 
whether or not validation in a CLIA-certified setting will be required. Sharing of research 
data with individual patients should only occur when data have been validated by 
multiple studies and testing has been done in CLIA-approved laboratories. 
 
 
 
 
15.0 
Drug Information 
 
 
IND number (144530) 
 
• 
Investigator brochure available on ACCRU website. 
 

                                                                                 55  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
 
 
 
15.1 Pemigatinib (INCB054828):  
 
15.11  Background: Pemigatinib is an inhibitor of the FGFR family of receptor 
tyrosine kinases that is proposed for the treatment of malignant diseases or other 
diseases related to FGFR dysregulation. Aberrant signaling through FGFR 
resulting from gene amplification or mutation, chromosomal translocation, and 
ligand-dependent activation of the receptors has been demonstrated in multiple 
types of human cancers. 
 
15.12 Formulation:  Pemigatinib drug substance is a white to off-white to light brown 
to yellow solid. The pemigatinib drug product is formulated as immediate release 
tablets in strengths of 0.5, 2, 4.5, 9 and 13.5 mg. The tablets of all strengths 
contain the active drug substance along with the excipients microcrystalline 
cellulose, sodium starch glycolate, and magnesium stearate. 
 
15.13 Preparation and storage:  Pemigatinib should be stored at room temperature 
between 15°-30°C (59°-86°F) as detailed on the investigational product labeling. 
 
15.14 Administration:   The effect of food on pemigatinib exposure is modest and is 
not expected to be clinically significant; as a result, pemigatinib may be 
administered orally either with or without food.  
 
15.15 Pharmacokinetic information: 
Time to peak, serum:  0.5 - 6 hours  
Clearance:  11.2 L/hour 
Distribution:  Volume of distribution – 151 L 
Protein Binding: 90.6%   
 
Metabolism:   In vitro studies suggested that pemigatinib is predominantly 
metabolized by CYP3A4. 
Pemigatinib is not a potent inhibitor or inducer of the major CYPs 
evaluated. 
 
Half-life elimination (mean):  15 hours 
 
 
15.16 Potential Drug Interactions:   
The data from Study INCB 54828-104 demonstrated a clinically significant 
effect on pemigatinib exposure when a potent CYP3A4 inhibitor (itraconazole) 
or inducer (rifampin) is coadministered, and physiologically based 
pharmacokinetic modeling showed that coadministration of a moderate CYP3A4 
inducer decreased the pemigatinib AUC by at least 50%. In addition, the data 
from Study INCB 54828-106 demonstrated a modest effect on the overall 
exposure of pemigatinib following coadministration of the gastric pH–modifying 
agents esomeprazole and ranitidine. Therefore, pemigatinib can be dosed without 
respect to concomitant use of PPIs or H2 antagonists. 
In vitro transport studies indicated that pemigatinib is a substrate of both P-gp 
and BCRP, but it is unlikely that efflux by these 2 transporters plays an important 
role in the oral absorption of 
pemigatinib. Pemigatinib is an inhibitor of P-gp, OCT2, and MATE1. However, 
at the proposed therapeutic dose, physiologically based pharmacokinetic 

                                                                                 56  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
modeling showed that a clinical drug-drug interaction is unlikely to occur as a 
result of 
pemigatinib-mediated inhibition of these transporters. 
 
Refer to the study Protocols for details regarding restricted and prohibited 
concomitant medications. 
 
 
15.17 Known potentialAdverse Events: 
Summary of Treatment-Emergent Adverse Events Reported in ≥ 10% of 
Participants in Study INCB 54828-101: Very common adverse events (≥ 
10%):Hyperphosphatemia, hypophosphatemia, hyponatremia, dry eye, nausea, 
stomatitis, diarrhea, constipation, dry mouth, palmar-plantar erythrodysesthesia 
syndrome, alopecia, dry skin, arthralgia, fatigue, and blood creatinine increased 
  
Common adverse events (1-10%):  Serous retinal detachment, retinal 
detachment, detachment of retinal pigmented epithelium, subretinal fluid, 
punctate keratitis, vision blurred, trichiasis, nail toxicity, nail disorder, nail 
discoloration, nail dystrophy, nail ridging, nail infection, onychomycosis, 
onychalgia, onychoclasis, onycholysis, onychomadesis, and paronychia  
 
Less common adverse events (<1%):  Nail hypertrophy, retinal thickening, 
chorioretinal folds, chorioretinal scar, maculopathy, hair growth abnormal, and 
photopsia  
 
Summary of Treatment-Emergent Adverse Events Reported in ≥ 10% of 
Participants in Study INCB 54828-201:  
Diarrhea, alopecia, stomatitis, fatigue, constipation, dry mouth, 
hyperphosphatemia, dysgeusia, decreased appetite, nausea, asthenia, urinary tract 
infection, abdominal pain, vomiting, anemia, back pain, dry eye, dry skin, blood 
creatinine increased, pyrexia, arthralgia, hematuria, weight decreased, dizziness, 
acute kidney injury, cough, hyponatremia 
Summary of Treatment-Emergent Adverse Events Reported in ≥ 10% of 
Participants in Study INCB 54828-202:  
Hyperphosphatemia, alopecia, diarrhea, fatigue, dysgeusia, dry mouth, stomatitis, 
decreased appetite, nausea, constipation, arthralgia, hyperphosphatemia, 
vomiting, back pain, dry eye, dry skin, abdominal pain, oedema peripheral, 
anemia, hypercalcemia, pain in extremity, urinary tract infection, weight 
decreased, headache, asthenia, dehydration, palmar-plantar erthrodysesthesia 
syndrome, gastrointestinal reflux disease, myalgia. 
 
 
15.18 Drug procurement:   
Incyte will supply Pemigatinib through Catalent. Each participating ACCRU 
treating location will order the drug from Catalnet using the “Investigational 
supplies shipment and receipt verification form” found on the ACCRU web site. 
This form will be emailed to:  
  
  
Email: 
 
  
Each participating ACCRU treating location will be responsible for monitoring 
the supply of pemigatinib and will use the “Investigational supplies shipment and 

                                                                                 57  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
receipt verification form” to order additional supplies as needed.  
 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
 
 
 
15.19a Temperature excursions that occur at the site should be reported by the site using 
the Temperature Excursion Report Form found on the ACCRU web site for this 
study and emailed to: 
  
 
 
 
15.19b Nursing Guidelines:  
 
15.19b1 Due to the early investigational nature of this agent, not all side effects 
can be known at this time. Monitor patients closely and report any side effects to 
the treating provider/study team. 
 
15.19b2 Gastrointestinal side effects can be seen including nausea, vomiting, 
constipation, and diarrhea. Treat symptomatically and monitor for effectiveness. 
 
15.19b3 Monitor LFTs.   Report elevated LFTs to the treating provider.  
 
15.19b4 Patients may have visual changes, including blurred vision and dry eyes. 
Instruct patients to report any dry eyes, pain and/or visual changes to the study 
team immediately. 
 
15.19b5 Patients may report fatigue, monitor hemoglobin as anemia can be seen. 
Instruct patients on energy conserving lifestyle.   
 
15.19b6 Pemigatinib may be administered with or without food. 
 
15.19b7 Electrolyte abnormalities can be seen. Monitor lab values and report 
abnormal lab values to treating provider. 
 
15.19b8 Severe and serious ocular conditions, including retinal detachment have 
been seen. Instruct patient to report any visual changes to the study team. 
 
15.19b9 Nail changes can be seen, additionally patients may experience palmar-
planta erythrodysthesia has been documented. Instruct patients to report nail and 
or skin changes to the study team. 
 
 
 
 
 
16.0  
Statistical Considerations and Methodology  
 
 
16.1 
Overview and Study Design:  
 
 
 
This is a single-arm Phase II study which is designed to assess initial evidence of efficacy 

                                                                                 58  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
of Pemigatinib in patients with metastatic colorectal cancer with activating FGFR 
alterations. Overall response rate (ORR) will be used as the primary endpoint. Based on 
historical data and clinical experience, an ORR of 5% or less would not be of interest 
(null hypothesis), and an ORR of 20% or more would be considered of interest. To assess 
this endpoint, a Simon two-stage minimax design will be used. In addition to ORR, 
clinical benefit rate (complete response, partial response, or stable disease), progression-
free survival, overall survival, and adverse event rates will be of specific interest. As 
correlative research, we will assess plasma pharmacodynamics biomarkers or response 
and resistance to therapy. 
 
Given an estimated prevalence of 5% for eligible activating FGFR alterations in the 
proposed population, approximately 500 metastatic colorectal cancer patients will need to 
be screened to identify 24 genomically eligible patients for this study.  
 
Patients will be evaluated for response to therapy every 9 weeks with computed 
tomography (CT) or magnetic resonance imaging (MRI). Response and progression will 
be evaluated using RECIST 1.1 (confirmation scan will not be required). Additionally, 
blood samples will be drawn at baseline, cycle 2 day 1, day 1 following each restaging 
scan, and end of treatment for analysis of cfDNA.  
 
 
16.11 Primary Endpoint 
 
The primary endpoint for this study is overall response rate (ORR) at 36 weeks 
after registration, which is defined as the percentage of patients, among evaluable 
patients, who experience an objective response within 36 weeks. Objective 
response is defined as a complete or partial response per RECIST 1.1, without 
the confirmation scan. The evaluable patients are those who are eligible, 
consented, received any protocol treatment, and are not major violations.  
 
16.2 
Statistical Design 
 
16.21 Decision Rule 
 
 
A Simon two-stage minimax design will be used. The largest success proportion 
where the proposed treatment regimen would be considered ineffective in this 
population is 5%, and the smallest success proportion that would warrant 
subsequent studies with the proposed regimen in this patient population is 20%. 
The following two-stage design uses 12 or 21 evaluable patients to test the null 
hypothesis that the true success proportion in this given patient population is at 
most 5%.  
 
NOTE: We consider a success to be a patient with an objective response by 36 
weeks post-registration (i.e. complete response or partial response).  
 
 
 
 
16.211 STAGE 1:  
 
 
 
 
 
Enter 12 evaluable patients into the study. If 0 successes are observed in 
the first 12 evaluable patients, we will consider this treatment ineffective 
in this patient population and terminate this study. Otherwise, if at least 1 
success is observed, we will proceed to Stage 2.  
 

                                                                                 59  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
 
 
 
16.212 STAGE 2: 
 
Enter an additional 9 evaluable patients into the study. If 2 or fewer 
successes are observed in the first 21 evaluable patients, we will consider 
this treatment ineffective in this patient population. If 3 or more 
successes are observed in the first 21 evaluable patients, we may 
recommend further testing of this regimen in subsequent studies in this 
population. 
 
 
 
 
16.213 Over Accrual 
 
If more than the target number of patients are accrued, the additional 
patients will not be used to evaluate the stopping rule or used in any 
decision making process.  
 
 
 
 
16.214 NOTE: 
 
We will not suspend accrual between stages to allow the first 12 patients 
to become evaluable, unless undue toxicity is observed.  
 
 
 
 
 
16.22 Sample Size 
 
The two-stage study design to be utilized is fully described in section 16.21. A 
minimum of 12 and a maximum of 21 evaluable patients will be accrued onto 
this study unless undue toxicity is encountered. We anticipate accruing an 
additional 3 patients to account for ineligibility, cancellation, major treatment 
violations, or other reasons. Maximum projected accrual is therefore 24 patients. 
All sample size calculations were computed using PASS 15 software.  
 
 
 
16.23 Accrual Time and Study Duration 
 
The anticipated accrual rate is 1 patient per month.  Therefore, the accrual period 
for the first stage of this study is expected to be approximately 12 months.  If 
patients are accrued to the second stage, the total accrual period is expected to be 
approximately 21 months.  Should the study continue to full accrual, the final 
analysis can begin at most 30 months after the trial begins; as soon as the last 
patient has either responded to therapy, or been observed for 36 weeks. 
 
 
 
16.24 Power and Significance Level 
 
We assume that the number of successes is binomially distributed, our null 
success proportion is 0.05, and our alternative success proportion is .20. Given 
these, along with an assumed type I error rate of 0.1, a sample size of 21 
evaluable patients will provide 82% exact power (exact type II error rate = 0.18) 
to detect a true ORR of 20% or greater (vs. the null hypothesis that the true ORR 
is at most 5%).  
 
 
 
16.25 Operating Characteristics 
 
The probability of declaring that this regimen warrants further studies (i.e. 
statistical power) under various success proportions and the probability of 

                                                                                 60  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
stopping accrual after the first stage can be tabulated as a function of the true 
success proportion as shown in the following table.  
 
If the true success proportion is: 
0.05 
0.1 
0.15 
0.2 
then the probability of declaring that the regimen 
warrants further studies is: 
0.08 
0.35 
0.63 
0.82 
and the probability of stopping at stage 1 is: 
0.54 
0.28 
0.14 
0.07 
 
 
 
16.25 Other Considerations 
 
Adverse events, quality/duration of response, and patterns of treatment failure 
observed in this study, as well as scientific discoveries or changes in standard of 
care will be taken into account in any decision to terminate the study.  
 
 
16.3 
Analysis Plan 
 
The analysis for this trial will begin at planned time points (see 16.2) and at the time the 
patients have become evaluable for the primary endpoint. Such a decision will be made 
by the Statistician and Study Chair, in accord with CCS Standard Operating Procedures, 
availability of data for secondary endpoints (e.g. laboratory correlates), and the level of 
data maturity.  
 
 
 
16.31 Primary Objective 
 
 
 
 
16.311 Definition 
 
 
 
 
The primary endpoint for this study is overall response rate (ORR) at 36 
weeks after registration, which is defined as the percentage of patients, 
among evaluable patients, who experience an objective response. 
Objective response is defined as a complete or partial response per 
RECIST v1.1, without the confirmation scan. The evaluable patients are 
those who are eligible, consented, received any protocol treatment, and 
are not major violations.  
 
 
 
 
16.312 Estimation 
 
 
 
 
The proportion of successes will be estimated by the number of 
successes divided by the total number of evaluable patients. Confidence 
intervals for the true success proportion will be calculated according to 
the approach of Clopper and Pearson.  
 
 
 
 
16.313 Over Accrual 
 
If more than the target number of patients are accrued, the additional 
patients will not be used to evaluate the stopping rule or used in any 
decision making process. However, they will be included in final point 
estimates and confidence intervals as though they were accrued in the 
final stage. 
 
 
 
16.32 Secondary Objectives 
 
 
 
 

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ACCRU GI-1701 
 
 
Addendum 2 
 
 
The following objectives will be evaluated: clinical benefit rate, progression-free 
survival, overall survival, and adverse event rates. Historical controls will be 
used for comparisons when appropriate.  
 
16.321 Clinical Benefit Rate 
 
 
 
Clinical Benefit Rate is defined as the number of patients that experience 
a complete or partial response within 36 weeks post registration, or have 
stable disease for at least 36 weeks post registration, divided by the 
number of evaluable patients. Analysis of this endpoint will mirror that 
of the primary objective (section 16.31). 
 
 
 
 
16.322 Progression-free Survival 
 
Progression-free survival (PFS) is defined as the time from study entry to 
the first of either disease progression or death from any cause, where 
disease progression is determined based on RECIST 1.1 criteria. PFS 
will be estimated using the Kaplan-Meier method. The median PFS and 
corresponding 95% confidence interval will be reported. Patients who do 
not experience disease progression or death while on protocol will be 
censored at the last disease assessment date.  
 
 
 
 
16.323 Overall survival 
 
 
 
Overall survival (OS) is defined as the time from study entry to death 
from any cause. Analysis of this endpoint will mirror that of PFS (section 
16.322). 
 
 
 
 
16.324 Patient-reported Outcomes 
 
Patient reported quality of life (QOL) outcomes will be collected using 
the Linear Analog Self-Assessment (LASA) Questionnaire. Data will be 
collected each cycle. Mean values of the first question (regarding overall 
QOL) at each cycle will be plotted. Additional analyses using data 
collected from the LASA questionnaire may be performed but will be 
considered exploratory.   
 
 
 
 
 
16.325 Adverse Event Rates 
 
 
 
 
All patients who have initiated treatment will be considered evaluable for 
adverse event analyses. Adverse events will be summarized by frequency 
and severity using CTCAE v 5.0. They will be reviewed to determine 
overall adverse event patterns, and will be closely monitored throughout 
the study.  
 
 
 
16.33 Correlative Research 
 
 
 
 
 
 
16.331 Plasma Biomarkers 
 
In the assessment of plasma pharmacodynamic biomarkers of response 

                                                                                 62  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
and resistance to therapy, descriptive statistics (e.g. means, standard 
deviations, 95% confidence intervals for continuous variables and 
frequencies for discrete data) and graphical analyses will be used for all 
correlative laboratory procedures. The associations between laboratory 
parameters and clinical response will be evaluated using the two-sample 
t-test or Fisher’s exact test, as appropriate. Response rate with the 
corresponding 95% exact binomial confidence interval will be provided. 
 
 
16.4 
Data & Safety Monitoring 
 
 
 
16.41 Review 
 
 
 
The study chair(s) and study statisticians will review the study at least twice per 
year to identify accrual, adverse event, and any endpoint problems that might be 
developing. The Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring 
Board (DSMB) is responsible for reviewing accrual and safety data for this trial 
at least twice per year, based on reports provided by the study statistician. Any 
safety issues requiring protocol changes are communicated through protocol 
amendments.  
 
 
 
16.42 Adverse Event Stopping Rules 
 
The monitoring rule specified below is based on the knowledge available at study 
development. We note that the Adverse Event Monitoring Rule may be adjusted 
in the event of either (1) the study re-opening to accrual after any temporary 
suspension or (2) at any time during the conduct of the trial and in consideration 
of newly acquired information regarding the adverse event profile of the 
treatment(s) under investigation. The study team may also choose to suspend 
accrual because of unexpected adverse event profiles that have not crossed the 
specified rule below. 
 
Accrual may be temporarily suspended to this study if at any time we observe 
events considered at least probably related to study treatment (i.e., an adverse 
event with attribute specified as "probable" or "definite") that satisfy any of the 
following: 
 
• 
If 3 or more patients in the first 9 treated patients (or 35% or more of all 
patients after 9 are treated) experience a grade 4 or 5 adverse event at least 
probably related to treatment. 
 
We note that we will review all Grade 4 and 5 adverse events to verify their 
attribution and to monitor the emergence of a previously unrecognized treatment-
related adverse event. 
 
 
17.0  
Pathology Considerations/Tissue Biospecimens  
 
17.1 
Tissue Biospecimen Submission  
 
17.11 Summary Table of Tissue Biospecimens for This Protocol 

                                                                                 63  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
 
Type of tissue 
biospecimen to submit 
Mandatory 
or optional 
When to submit 
Reason for 
submission 
(background/me
thodology 
section) 
Where to find 
specific 
details for 
biospecimen 
submission 
FFPE tissue block with 
corresponding H&E 
slide or up to twenty-
five (25) 4-micron, 
unstained slides and up 
to three (3) 
corresponding H&E 
slides from primary 
tumors present prior 
to study entry (if 
primary tissue not 
available, please use 
tissue from metastatic 
lesions) 
Mandatory 
 Within 90 days from 
randomization 
Correlative 
studies (Section 
17.3) 
Section 17.2 
 
 
17.2 
Paraffin Embedded Tissue Blocks/Slides 
 
17.21 Submit one formalin fixed paraffin-embedded (FFPE) tumor tissue block with 
largest amount of invasive tumor (at least 1 cm of tumor for cases of surgical 
resection) from original surgery at the time of diagnosis. Biopsy material 
obtained at the time of metastatic diagnosis may be submitted, if blocks from the 
surgical resection are inadequate or unavailable a corresponding H&E slide for 
each submitted block must be provided. The H&E slide for each block should 
be reviewed by the institution’s pathologist to assess tissue quality prior to 
submission. 
 
17.22 The FFPE tissue block is preferred; however, if an institution is unable to 
provide a tissue block, cut up to 25 (twenty-five) 4-micron sections and mount 
on charged glass slides. Label the slides with ACCRU patient ID number, 
accession number, and order of sections, and thickness of sections. NOTE: 
do not place “sticky” labels directly on slides, the institution label needs to be 
visible.. H&E stain every tenth slide (i.e., slides labeled 1, 11, 21, etc.). The H&E 
slides should be reviewed by the institution’s pathologist to assess tissue quality 
prior to submission. For samples containing less than 7 square millimeters of 
tumor tissue, multiple sections should be mounted onto each slide to ensure that 
the appropriate amount of tumor tissue is available. Ideally, each slide should 
have a minimum of 75% tumor tissue on the slide to be deemed adequate for 
study. Do not bake or place covers slips on the slides. 
 
17.23 The following materials below are mandatory (unless indicated otherwise) and 
required for shipment: 
 

                                                                                 64  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
• 
Paraffin embedded tissue blocks with corresponding H&E slide(s) (OR 
up to 25 (twenty-five) unstained slides with corresponding H&E 
slide(s)).  
• 
Specimen Submission: Tissue form 
• 
Surgical Pathology Report 
• 
Operative Report (optional) 
 
NOTE: Please include the ACCRU patient ID number on all materials listed 
above. 
 
17.24 The block/slides must be appropriately packed to prevent damage (e.g., slides 
should be placed in appropriate slide container) and placed in an individual 
plastic bag. Label the bag with the protocol number, ACCRU patient ID number, 
and patient initials. 
 
17.25 Tissue specimens must be shipped ≤90 days from date of registration.  
 
17.26 Verify that the appropriate sections of the Specimen Submission: Tissue form are 
completed and filled in correctly. Enter information from the Specimen 
Submission: Tissue form into the remote data entry system on the same day the 
specimen is submitted (see Forms Packet). 
 
17.27 Ship all block/slide tissue specimens and accompanying materials to the ACCRU 
Research Base: 
 
 
 
 
 
17.28 When an appropriate request is submitted, the ACCRU Operations Office will 
forward the block(s) to the 
 
 At study completion 
specimens will be sent to the Duke Phase I Biomarker Laboratory located at 
Duke University for processing as outlined in Section 17.3. 
 
 
17. 3 
Study Methodology and Storage Information 
 
Submitted tissue samples will be analyzed as follows: 
 
17.31 At the completion of the study, any unused/remaining material will be stored in 
Duke Phase I Biomarker Laboratory located at Duke University for future 
research according to the patient consent permission (see Section 6. 5). Potential 
future research may include immunohistochemistry (IHC) analyses to analyze 
predictive biomarkers, changes in expression pattern with therapy, and 
correlation with response and/or adverse events. When a protocol is developed, it 
will be presented for IRB review and approval. 
 

                                                                                 65  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
17.32 Banking of tumor tissue, according to the patient consent permission (see Section 
6. 5), is for future research. As protocols are developed, they will be presented 
for ACCRU and IRB review and approval. (This collection is part of a general 
strategy of investigation for ACCRU studies). 
 
17.33 The institutional pathologist will be notified by the Pathology Coordinator if the 
block may be depleted. 
 
17.34 Blocks requested to accommodate individual patient management will be 
returned promptly upon request. 
 
17.35 Return of Genetic Testing Research Results: No genetic specimens will be 
collected from tissue biospecimens for this study. If future genetic testing is 
being requested for stored tissue, patient reconsent is required. 
 
18.0 
Records and Data Collection Procedures 
 
All data must be entered by Remote Date Entry (RDE) and completed by qualified and authorized 
personnel. Access the RAVE RDE system through the iMedidata portal at 
. All data on the CRF must reflect the corresponding source 
document. Please refer to the ACCRU website for instructions (
).  
 
 
18.1 
Submission Timetable 
 
 
Initial Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
Institutional Contacts 
≤2 weeks after registration 
On-Study  
On-Study: Prior Surgery1 
On-Study: Prior Systemic Therapy 
On-Study: Prior Radiation1 
Adverse Event: Baseline  
RECIST Measurements: Baseline 
Laboratory Tests & Results: Baseline 
Supporting Documentation: Baseline2 
Specimen Submission: Blood (Baseline) (see 
Section 14.0) 
Specimen Submission: Tissue (Baseline) (see 
Section 17.0) 
Patient Status: Baseline  
Notice of New Primary1 
OP and Path Reports (see Section 17.0)2 
Imaging Report2 
 
Patient Questionnaire Booklet-PRO/QOL: 
Linear Analogue Self Assessment (LASA) 
≤ 2 weeks after registration - Patient questionnaire booklet 
must be used; copies are not acceptable for this submission. 
PRO/QOL : Booklet Compliance 
≤ 2 weeks after registration - This form must be completed 

                                                                                 66  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
only if the (LASA) contains absolutely NO patient provided 
assessment information. 
Off Treatment 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
ACCRU Deviation Form1 
Submit only if applicable during all phases of the study  
(initial, active and observation) 
1. Submit only if applicable. 
2.   Upload via the Supporting Documentation: Baseline form. This is in addition to the pathology 
material requirements for tissue submission (Section 17.0). Required items to be uploaded include: 
COLOMATE Companion Trial Recommendation Form (Only required if participating on ACCRU-GI-
1611), Imaging Report, and Pathology report. 
 
 
 
 
 
 
 
 
 
          
 
 
 Test Schedule Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule 
Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
 
Treatment (Intervention) 
X 
X 
Treatment (Intervention): Dose Modifications, Omissions and 
Delays1 
X 
 
Adverse Events: Solicited 
X 
X 
Adverse Events: Other1 
X 
X 
RECIST Measurements1,2 
X 
X 
Supporting Documentation1,2 
X 
X 
Laboratory Tests and Results 
X 
X 
Specimen Submission: Blood (see Section 14.0)1 
X  
 
Patient Status: Treatment (Intervention) 
X 
X 
PRO/QOL: Booklet Compliance 
X 
X 
Patient Questionnaire Booklet-PRO/QOL: Linear Analogue 
Self Assessment (LASA) (if applicable)3 
X 
X 
Patient Medication Diary5 
X 
 
PRO/QOL : Booklet Compliance (if applicable)4 
X 
X 

                                                                                 67  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule 
Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
 
Notice of New Primary1 
X 
X 
Consent Withdrawal (choose appropriate form)1 
• 
Consent Withdrawal: Specimen Only 
• 
 
• 
Consent Withdrawal: All Follow-Up 
X 
X 
Off Treatment 
 
X 
ACCRU Deviation Form1 
X 
X 
1. Submit only if applicable. 
2. Upload imaging for all scans to support RECIST measurements and clinic note in the Supporting 
Documentation Form. 
3. Patient questionnaire booklet must be used; copies are not acceptable for this submission. 
4. This form must be completed only if the Linear Analogue Self Assessment (LASA) contains 
absolutely NO patient provided assessment information. 
5. This form is to be completed by the patient and uploaded to RAVE in the Treatment (Intervention) 
folder for each cycle. 
 
 
 
 
 
 
 
 
 
 
 
           Follow-up Material(s)  
CRF 
Event Monitoring Phase1 
 
 
q. 3 
months 
until PD 
 
 
 
At PD 
After 
PD q. 3 
mos. 
 
 
 
Death 
 
 
 
New Primary 
Patient Status: Survival and Disease 
Status Follow-Up/Event Monitoring  
X2 
X2 
X 
X 
At each occurrence 
Adverse Events: Late3 
 
 
 
 
X 
Supporting Documentation3 
 
 
 
 
 
Notice of New Primary3 
 
 
 
 
X 
Consent Withdrawal (choose 
appropriate form)3 
• Consent Withdrawal: Specimen 
Only 
 
 
 
 
X 

                                                                                 68  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
CRF 
Event Monitoring Phase1 
 
 
q. 3 
months 
until PD 
 
 
 
At PD 
After 
PD q. 3 
mos. 
 
 
 
Death 
 
 
 
New Primary 
• Consent Withdrawal: All Follow-
Up 
Lost to Follow-Up4 
 
 
 
 
 
1. If a patient is still alive 3 years after registration, no further follow-up is required. 
2. Upload a copy of documentation of response or progression in RAVE on the Supporting 
Documentation Form. 
3. Submit only if applicable. 
4. Patients are eligible to be confirmed lost to follow-up after 2 years of unsuccessful contact with the 
patient. 
 
 
 
 
19.0 
Budget 
 
19.1 
Each site should review the test schedule (Section 4.0), taking into account local and 
regional coverage policies, to determine which items are standard of care and which are 
research at their site. Refer to the payment synopsis for funding provided per accrual for 
covering study costs, as well as any additional invoiceables that may be allowed.  
 
19.2 
Other budget concerns: 
 
 
19.21 Pemigatinib will be supplied by Incyte. 
 
 
20.0 
References 
 
Abdel-Rahman O. Targeting FGF receptors in colorectal cancer: from bench side to bed side. Future 
Oncol 2015; 11(9): 1373-1379. 
 
Almodovar K, Iams WT, Meador CB, et al: Longitudinal Cell-Free DNA Analysis in Patients with Small 
Cell Lung Cancer Reveals Dynamic Insights into Treatment Efficacy and Disease Relapse. J Thorac 
Oncol 13:112-123, 2018. 
 
Berger G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008; 8:592-603. 
 
Brooks AN, Kilgour E, Smith PD. Molecular pathways: fibroblast growth factor signaling: a new 
therapeutic opportunity in cancer. Clin Cancer Res 2012; 18(7):1855-62. 
 
Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting 
of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005; 8(4):299-309. 
 
Corcoran RB, Andre T, Atreya CE, et al: Combined BRAF, EGFR, and MEK Inhibition in Patients with 
BRAFV600E-Mutant Colorectal Cancer. Cancer Discov, 2018. 

                                                                                 69  
ACCRU GI-1701 
 
 
Addendum 2 
 
 
 
Clinical Trial Facilitation Group (CTFG). Recommendations related to contraception and pregnancy 
testing in clinical trials. September 15, 2014. http://www.hma.eu/ctfg.html. Accessed April 04, 2018. 
 
Dailey L, Ambrosetti D, Mansukhani A, Basilico C. Mechanisms underlying differential responses to 
FGF signaling. Cytokine Growth Factor Rev 2005;16:233-247.  
 
Diaz LA, Jr., Williams RT, Wu J, et al: The molecular evolution of acquired resistance to targeted EGFR 
blockade in colorectal cancers. Nature 486:537-40, 2012. 
 
Dienstmann R, Rodon J, Prat A, et al. Genomic aberrations in the FGFR pathway: opportunities for 
targeted therapies in solid tumors. Ann Oncol 2014; 25(3):552-63.  
 
Donnem T, Al-Shibli K, Al-Saad S, Busund LT, Bremnes RM. Prognostic impact of fibroblast growth 
factor 2 in non-small cell lung cancer: coexpression with VEGFR-3 and PDGF-B predicts poor survival. J 
Thorac Oncol 2009;4:578-585.  
 
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, 
Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 45(2): 228-247, 
2009. 
 
Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. 
Cytokine Growth Factor Rev 2005;16:139-149.  
 
Folprecht G, Beer P, Salazar R, et al. Frequency of potentially actionable genetic alterations in EORTC 
SPECTAcolor. Ann Oncol 2016; 27(suppl 6): 458O. 
 
Fuks Z, Persaud RS, Alfieri A, et al. Basic fibroblast growth factor protects endothelial cells against 
radiation-induced programmed cell death in vitro and in vivo. Cancer Res 1994;54:2582-2590.  
 
Graham RP, Barr Fritcher EG, Pestova E, et al: Fibroblast growth factor receptor 2 translocations in 
intrahepatic cholangiocarcinoma. Hum Pathol 45:1630-8, 2014. 
 
Gill S, Blackstock AW, Goldberg RM: Colorectal cancer. Mayo Clin Proc 82:114-29, 2007. 
 
Goke F, Goke A, von Massenhausen A, et al. Fibroblast growth factor receptor 1 as a putative therapy 
target in colorectal cancer. Digestion 2013; 88(3):172-81. 
 
Greulich H, Pollock PM. Targeting mutant fibroblast growth factor receptors in cancer. Trends Mol Med 
2011; 17:283-292. 
 
Guagnano V, Kauffmann A, Wöhrle S, et al. FGFR genetic alterations predict for sensitivity to NVP-
BGJ398, a selective pan-FGFR inhibitor. Cancer Discov 2012;2:1118-1133.  
 
Investigator’s Brochure: INCB 54828-101. Version 2, September 2016. 
 
Kilgour E, Ferry D, Saggese M, et al. Exploratory biomarker analysis of a phase I study of AZD4547, an 
inhibitor of fibroblast growth factor receptor (FGFR), in patients with advanced solid tumors. J Clin 
Oncol 2014;32(suppl): Abstract 11010.  
 

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Addendum 2 
 
 
Knights V, Cook SJ. De-regulated FGF receptors as therapeutic targets in cancer. Pharmacol Ther 
2010;125:105-117.  
 
Kunii K, Davis L, Gorenstein J, et al. FGFR2-amplified gastric cancer cell lines require FGFR2 and 
Erbb3 signaling for growth and survival. Cancer Res 2008;68:2340-2348.  
 
Le DT, Uram JN, Wang H, et al: PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J 
Med 372:2509-20, 2015. 
 
Marek L, Ware KE, Fritzsche A, Hercule P, et al. Fibroblast growth factor and FGF receptor-mediated 
autocrine signaling in non-small-cell lung cancer. Mol Pharmacol 2009; 75(1): 196-207. 
 
Mathur A, Ware C, Davis L, et al. FGFR2 is amplified in the NCI-H716 colorectal cancer cell line and is 
required for growth and survival. PLoS One 2014; 9(6):e98515. 
 
Montagut C, Argiles G, Ciardiello F, et al: Efficacy of Sym004 in Patients With Metastatic Colorectal 
Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor 
DNA Analyses: A Phase 2 Randomized Clinical Trial. JAMA Oncol:e175245, 2018. 
 
Nogova L, Sequist LV, Garcia JMP, et al. Evaluation of BGJ398, a fibroblast growth factor receptor1-3 
kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth 
factor receptors: results of a global phase I, dose-escalation and dose- expansion study. J Clin Oncol 
2016;35:157-165.  
 
Pardo OE, Arcaro A, Salerno G, Raguz S, Downward J, Seckl MJ. Fibroblast growth factor-2 induces 
translational regulation of Bcl-XL and Bcl-2 via a MEK-dependent pathway: correlation with resistance 
to etoposide-induced apoptosis. J Biol Chem 2002;277:12040-12046.  
 
Qing J, Du X, Chen Y, et al. Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-
positive multiple myeloma in mice. J Clin Invest 2009;119:1216-1229. Lamont FR, Tomlinson DC, 
Cooper PA, Shnyder SD, Chester JD, Knowles MA. Small molecule FGF receptor inhibitors block 
FGFR-dependent urothelial carcinoma growth in vitro and in vivo. Br J Cancer 2011;104:75-82.  
 
Rades D, Setter C, Dahl O, Schild SE, Noack F. Fibroblast growth factor 2 – a predictor of outcome for 
patients irradiated for stage II-III non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2012;82:442-
447. 
 
Sequist LV, Cassier P, Varga A, et al. Phase I study of BGJ398, a selective pan-FGFR inhibitor in 
genetically preselected advanced solid tumors. In: Proceedings of the 105th Annual Meeting of the 
American Association for Cancer Research, April 5-9, 2014, San Diego, CA. Cancer Res 2014;74(19 
suppl): Abstract CT326.  
 
Siegel RL, Miller KD, Jemal A: Cancer statistics, 2018. CA Cancer J Clin 68:7-30, 2018 
 
Sharpe R, Pearson A, Herrera-Abreu MT, et al. FGFR signaling promotes the growth of triple-negative 
and basal-like breast cancer cell lines both in vitro and in vivo. Clin Cancer Res 2011;17:5275-86.  
 
Stransky N, Cerami E, Schalm S, et al. The landscape of kinase fusions in cancer. Nat Commun 2014; 
5:4846. 
 

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ACCRU GI-1701 
 
 
Addendum 2 
 
 
Strickler JH, Loree JM, Ahronian LG, et al: Genomic Landscape of Cell-Free DNA in Patients with 
Colorectal Cancer. Cancer Discov 8:164-173, 2018. 
 
Tabernero J, Bahleda R, Dienstmann R, et al. Phase I dose-escalation study of JNJ-42756493, an oral 
pan-fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors. J Clin Oncol 
2015;33:3401-3408.  
 
Terai H, Soejima K, Yasuda H, et al. Activation of the FGF2-FGFR1 autocrine pathway: a novel 
mechanism of acquired resistance to gefitinib in NSCLC. Mol Cancer Res 2013;11:759-767.  
 
Turner N, Pearson A, Sharpe R, et al. FGFR1 amplification drives endocrine therapy resistance and is a 
therapeutic target in breast cancer. Cancer Res 2010;70:2085-2094.  
 
Weiss J, Sos ML, Seidel D, et al. Frequent and focal FGFR1 amplification associates with therapeutically 
tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 2010;2:62ra93.  
 
Wesche J, Haglund K, Haugsten EM. Fibroblast growth factors and their receptors in cancer. Biochem J 
2011; 
437:199-21

 
 

                                                                                 1  
ACCRU GI-1701 
Addendum 2 
 
                                                                                
 
 
 
 
 
Appendix I: Acceptable Contraception 
A woman of childbearing potential (WOCBP) must agree to use at least one method of acceptable 
contraception (that is included in the table in this Appendix), from the time she signs consent, and until at 
For purpose of this study, acceptable birth control methods that can achieve a failure 
rate of less than 1% per year when used consistently and correctly are considered as 
highly effective and include: 
• 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation1: 
− 
oral 
− 
intravaginal 
− 
transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation1: 
− 
oral 
− 
injectable 
− 
implantable2 
• 
Intrauterine device (IUD)2 
• 
Intrauterine hormone-releasing system (IUS)2 
• 
Bilateral tubal occlusion2 
• 
Vasectomised partner2,3 
• 
Sexual abstinence4 
 
For purpose of this study, acceptable birth control methods which may not be 
considered as highly effective that result in a failure rate of more than 1% per year 
include: 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action 
• 
Male or female condom with or without spermicide5 
• 
Cap, diaphragm or sponge with spermicide5 
 
 
 
1  Hormonal contraception may be susceptible to interaction with the investigational medicinal 
product (IMP), which may reduce the efficacy of the contraception method. 
2  Contraception methods that in the context of this guidance are considered to have low user 
dependency. 
3  Vasectomised partner is a highly effective birth control method provided that partner is the sole 
sexual partner of the WOCBP trial participant and that the vasectomised partner has received 
medical assessment of the surgical success. 
4  In the context of this guidance sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of risk associated with 
the study treatments.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 
5  A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) are also considered acceptable, but not highly effective, birth control methods. 
Source:  Clinical Trial Facilitation Group (CTFG), 2014. 

                                                                                 2  
ACCRU GI-1701 
Addendum 2 
 
                                                                                
 
 
 
 
 
least 30 days after her final dose of Pemigatinib. 
 
A man able to father children who has a female partner of childbearing potential must agree to use at least 
one method of acceptable contraception (that is included in the table in this Appendix), from the time he 
signs consent, and until at least 90 days after his final dose of Pemigatinib .  
 
A woman of childbearing potential participating in the study must have a negative serum pregnancy test 
during screening and a negative serum or urine pregnancy test on Cycle 1, Day 1 prior to her first dose of 
Pemigatinib. 
 
• 
Women will be considered of childbearing potential (WOCBP), i.e. fertile, following menarche 
and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
 
• 
A post-menopausal state will be defined as no menses for 12 months without an alternative 
medical cause.  
 
A high follicle stimulating hormone (FSH) level in the post-menopausal range may be used to 
confirm a post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient and the medical judgment of the investigator will determine the 
number of FSH measurements greater than one (>1) which constitute a consistently elevated FSH 
level in the post-menopausal range.  
 
• 
Male patients able to father children are defined as those who are not surgically sterile (i.e. patient 
has not had a vasectomy).  
 
A trial physician or clinical designee shall counsel female patients of childbearing potential, and male 
patients able to father children who have a female partner of childbearing potential, regarding the 
importance of pregnancy prevention, the implications of an unexpected pregnancy, and the use of 
acceptable contraception. At a minimum, applicable patients must agree to the consistent and correct use 
of at least one method of acceptable contraception, as listed in the above table in this appendix. 
 
 
 

                                                                                 1  
ACCRU GI-1701 
Addendum 2 
 
                                                                                
 
 
 
 
 
Appendix II: Examples of CYP3A4 Inducers and Inhibitors 
 
Please see 
 for examples of CYP3A4 therapies. This 
list is not comprehensive. Contact your investigational/central pharmacy for any questions. 
 
 
 (Strong and moderate classifications may be referenced on Lexi-Comp Online, drug information 
reference 
 
 
CYP3A4 INHIBITORS 
GENERIC NAME 
TRADE NAME 
Indinavir 
Crixivan 
Nelfinavir 
Viracept 
Ritonavir 
Norvir 
clarithromycin 
Biaxin 
itraconazole 
Sporanox 
ketoconazole 
Nizoral 
Nefazodone 
Serzone 
Saquinavir 
Invirase 
telithromycin 
Ketek 
Aprepitant 
Emend 
erythromycin 
Ery-Tab 
Fluconazole 
Diflucan 
grapefruit juice 
 
Verapamil 
Calan 
Diltiazem 
Cardizem 
Cimetidine 
Tagamet 
Amiodarone 
Cordarone 
chloramphenicol 
Chloroptic 
Delavirdine 
Rescriptor 
diethyldithiocarbamate 
Imuthiol 
fluvoxamine 
Luvox 
gestodene 
Minesse 
mibefradil* 
Posicor 
mifepristone 
Mifeprex 
norfloxacin 
Noroxin 
norfluoxetine 
N/A 
star fruit 
 
voriconazole 
VFEND 
amprenavir1 
Agenerase 
atazanavir1 
Reyataz 
fosamprenavir1 
Lexiva 
seville oranges 
 
 
 
 
 

                                                                                 2  
ACCRU GI-1701 
Addendum 2 
 
                                                                                
 
 
 
 
 
 
 
 
CYP3A4 INDUCERS 
GENERIC NAME 
TRADE NAME 
efavirenz 
Sustiva 
nevirapine 
Viramune 
barbiturates 
Luminal 
carbamazepine 
Tegretol 
glucocorticoids 
 
modafinil 
Provigil 
nevirapine 
Viramune 
oxcarbazepine 
Trileptal 
phenobarbital 
Luminal 
phenytoin 
Dilantin 
pioglitazone 
Actos 
rifabutin 
Mycobutin 
rifampin 
Rifadin 
St. John's wort 
 
troglitazone* 
Rezulin 
 
 
 
 

                                                                                 3  
ACCRU GI-1701 
Addendum 2 
 
                                                                                
 
 
 
 
 
 
CYP3A Inducers 
 
 
Inducers 
Therapeutic class 
Potent CYP3A Inducers 
Rifampin 
Antibiotics 
Mitotane 
Other Antineoplastics 
Avasimibe 
Other Antilipemics 
Rifapentine 
Antibiotics 
Apalutamide 
Antiandrogens 
Phenytoin 
Anticonvulsants 
Carbamazepine 
Anticonvulsants 
Enzalutamide 
Antiandrogens 
St John’s Wort extract 
Herbal medications 
Lumacaftor 
Cystic fibrosis treatments 
Rifabutin 
Antibiotics 
Phenobarbital 
Anticonvulsants 
Moderate CYP3A Inducers 
Ritonavir and St. John’s wort 
None 
Semagacestat 
Alzheimer’s treatments 
Efavirenz 
NNRTIs 
Tipranavir and ritonavir 
Protease inhibitors 
Dabrafenib 
Kinase inhibitors 
Lesinurad 
Antigout and uricosuric agents 
Bosentan 
Endothelin receptor antagonists 
Genistein 
Food products 
Thioridazine 
Antipsychotics 
Nafcillin 
Antibiotics 
Talviraline 
NNRTIs 
Lopinavir 
Protease inhibitors 
Modafinil 
Psychostimulants 
Pf-06282999 
Myeloperoxidase inactivators 
Etravirine 
NNRTIs 
Lersivirine 
NNRTIs 
Telotristat ethyl 
Antidiarrheals 

                                                                                 1  
ACCRU GI-1701 
Addendum 2 
 
                                                                                
 
 
 
 
 
 
 
Appendix III: ACCRU-GI-1701 SUBJECT MEDICATION DIARY 
 
Name: 
Subject ID Number: 
Cycle:  
 
ORAL MEDICATION DIARY 
Subject Instructions 
• 
Please bring your Medication Diary and any empty or unused medication container(s) with you to 
every appointment 
• 
Please use an ink pen when completing the Medication Diary as these will be retained in our 
research record. 
• 
Please contact your physician and study coordinator any time you go into the hospital. Your 
physician can advise if you should stop taking your medication or continue it.  
• 
To correct an error or mistake, please make a single line through that entry and write your initials 
and date next to the error or mistake. 
• 
Please record each dose as soon as you take it and fill in the date as directed. 
• 
Please indicate on the calendar below every day that you take your study medication by placing 
the dose taken on the line under the date. 
• 
If you miss a dose, place a “0” under the date, but remember to take your prescribed dose at the 
next regularly scheduled time. 
• 
If you accidentally take more than you are instructed to, contact your doctor or the emergency 
room immediately. 
• 
If you miss a dose, do not make up the dose or double up the next dose. 
• 
Your dose may be held due to side effects, be sure to record a 0 on those days your medication is 
held.  Once you restart the medication, record the dose again. 
• 
There will only be a maximum of 21 days of medication for each cycle recorded on this form 
 
 
Example: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date 
1/1/2018 
1/2/2018 
1/3/2018 
1/4/2018 
1/5/2018 
1/6/2018 
1/7/2018 
Time 
7:00 AM 
 
 
 
 
 
 
 Pemigatinib 
Daily 
dose in 
mg 
 
 
 
 
 
 

                                                                                 2  
ACCRU GI-1701 
Addendum 2 
 
                                                                                
 
 
 
 
 
 
 
 
 
ACCRU-GI-1701 SUBJECT MEDICATION DIARY –  Pemigatinib 
 
 
 
 
 
 
 
 
Date:__________________ 
Subject’s Signature___________________________________ 
 
Area Below Only To Be Completed only by Coordinator 
  
Week 
1 
2 
3 
4 
5 
Discrepancy (Yes or 
No) 
Date of Pill Count 
 
 
 
 
 
 
Number of Pills 
Returned 
 
 
 
 
 
 
Study Coordinator 
Initials 
 
 
 
 
 
 
 
 
 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
 Pemigatinib Dose 
 
 
 
 
 
 
 
 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
 Pemigatinib  Dose 
 
 
 
 
 
 
 
 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Date 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
 Pemigatinib Dose 
 
 
 
 
 
 
 
 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Date 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
 Pemigatinib  Dose 
 
 
 
 
 
 
 
 
Day 29 
Day 30 
Day 31 
Day 32 
Day 33 
Day 34 
Day 35 
Date 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
 Pemigatinib  Dose 
 
 
 
 
 
 
 

                                                                                 1  
ACCRU GI-1701 
Addendum 2 
 
                                                                                
 
 
 
 
 
Appendix IV: ACCRU-GI-1701 SUBJECT INFORMATION SHEET 
Subject Completed Quality of Life Booklet 
(Baseline, Each Cycle, and end of treatment) 
________________________________________________________________________ 
 
You will be given booklets to complete for this study. This booklet contains some questions 
about your ‘quality-of-life’ as a subject receiving treatment for cancer. Your answers will 
help us to better understand how the treatment you are receiving is affecting the way you 
feel. 
 
1. You are being asked to complete a questionnaire booklet for this study. This booklet must 
be completed prior to dosing at each cycle and at the end of treatment (within 30 days 
after your last dose).   
 
2. This booklet contains the following questionnaire: 
a. Linear Analogue Self Assessment (LASA) 
 
3. Directions on how to complete each set of questions are written on the top of the page. 
 
4. You will be given the nurse’s or study coordinator’s name and telephone number. You 
can call anytime with any concerns or questions. 
 
5. Please complete the booklet and return it to your study staff. It is very important that you 
return the booklet to us. 
 
Thank you for taking the time to help us. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

                                                                                 1  
ACCRU GI-1701 
Addendum2 
 
                                                                                
 
 
 
 
 
Appendix V: ACCRU-GI-1701 LINEAR ANALOGUE SELF ASSESSMENT 
 
Patient Name: ________________________________ 
Date: _____________________ 
Patient Number:  ______________________________ 
 
 
Directions: Please circle the number (0-10) best reflecting your response to the following 
 
 
that describes your feelings during the past week, including today. 
How would you describe: 
 
1. your overall Quality of Life? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
2. your overall mental (intellectual) well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
3. your overall physical well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
4. your overall emotional well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
5. your level of social activity? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
6. your overall spiritual well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
7. the frequency of your pain? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No pain  
 
 
 
 
 
 
 
 
Constant pain 
 
8. the severity of your pain, on the average? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No pain  
 
 
 
 
 
 
 
 
Pain as bad as  
 
 
 
 
 
 
 
 
 
 
 
you can imagine 
9. your level of fatigue, on the average? 

                                                                                 2  
ACCRU GI-1701 
Addendum2 
 
                                                                                
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No fatigue 
 
 
 
 
 
 
 
 
 
Constant  
 
 
 
 
 
 
 
 
 
 
 
 
Tiredness 
 
 
 
10. your level of support from friends and family? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No support  
 
 
 
 
 
 
 
 
Highest level of  
 
 
 
 
 
 
 
 
 
 
 
 
support 
 
11. your financial concerns? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Constant concerns 
 
 
 
 
 
 
 
 
No concerns 
 
12. your legal concerns (will, advanced directives, etc.)? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Constant concerns 
 
 
 
 
 
 
 
 
No concerns 
 
© 1996  Mayo Foundation for Medical Research