Conditions: Advanced Cholangiocarcinoma Metastatic Cholangiocarcinoma Unresectable Cholangiocarcinoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 8
Healthy volunteers: no

Brief summary:
This phase I trial studies the side effects and best dose of gemcitabine and cisplatin when given together with ivosidenib or pemigatinib in treating patients with cholangiocarcinoma that cannot be removed with surgery (unresectable) or has spread to other places in the body (metastatic). Chemotherapy drugs, such as gemcitabine and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ivosidenib and pemigatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving gemcitabine and cisplatin with ivosidenib or pemigatinib may work better in treating patients with cholangiocarcinoma compared to gemcitabine and cisplatin alone.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate the safety, tolerability, maximum tolerated dose (MTD) and/or recommended phase 2 dose, gemcitabine and cisplatin in combination with either ivosidenib or pemigatinib.

SECONDARY OBJECTIVES:

I. To evaluate median and progression free survival (PFS) for 6 months per investigator assessment.

II. To evaluate the rate of overall survival (OS) in patients treated with gemcitabine and cisplatin in combination with either ivosidenib or pemigatinib.

III. To describe the overall toxicity and adverse events profile associated with gemcitabine and cisplatin in combination with either ivosidenib or pemigatinib.

IV. To determine the best response profile per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in patients treated with gemcitabine and cisplatin in combination with either ivosidenib or pemigatinib.

CORRELATIVE RESEARCH OBJECTIVE:

I. To measure plasma 2-hydroxglutarate (2-HG) levels =\< 21 days prior to registration and at cycle 4 day 1 (+/- 2 days).

OUTLINE: This is a dose de-escalation study. Patients are assigned to 1 of 2 arms.

ARM A (IDH1 GENE MUTATION): Patients receive ivosidenib orally (PO) on days 1-21, cisplatin intravenously (IV) on days 1 and 8, and gemcitabine IV on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM B (FGFR2 GENE ALTERATION): Patients receive pemigatinib PO on days 1-21, cisplatin IV on days 1 and 8, and gemcitabine IV on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 6 months for up to 3 years.

Arms:
arm 1: Patients receive ivosidenib PO on days 1-21, cisplatin IV on days 1 and 8, and gemcitabine IV on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive pemigatinib PO on days 1-21, cisplatin IV on days 1 and 8, and gemcitabine IV on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cisplatin intervention 2: Gemcitabine intervention 3: Ivosidenib intervention 4: Pemigatinib
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given PO intervention 4: Given PO

Protocol document:
Prot_SAP_000.pdf: 
ACCRU-ICRN-1701 
Amendment 3 
Academic and Community Cancer Research United (ACCRU) 
 
A Phase I, Multi-Center, Open Label, Dose De-escalation and Expansion Study of Gemcitabine and 
Cisplatin with AG120 or Pemigatinib for Advanced Cholangiocarcinoma  
 
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: 
 
 
 
 
Study Co-chairs: 
 
 
 
 
 
 
Statisticians: 
 
 
 
 
 Study contributor(s) not responsible for patient care. 
Drug Availability 
Commercial Agents: 
Cisplatin 
Gemcitabine 
Investigational Agents: 
Ivosidenib 
Pemigatinib 
 
IND#: 
141189 
 
Research Coordinating Center 
 
 
Document History 
Activated 
(effective date) 
06/18/2019 
Amendment  I 
05/08/2020 
Amendment II 
06/23/2020 
Amendment III 
10/06/2020 


ACCRU-ICRN-1701 
Amendment 3 
Schema 
 1.0 
Background 
 2.0 
Goals 
 3.0 
Patient Eligibility 
 4.0 
Test Schedule 
 5.0  
Stratification Factors 
 6.0 
Registration Procedures 
 7.0 
Protocol Treatment 
 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 – Patient Medication Diary 
Appendix II – Mutations Permitted for Trial Inclusion 
Appendix III – Examples of CYP3A4 Inducers and Inhibitors  
Appendix IV – NYHA Classification 
Appendix V – Corrected QT Interval Fredericia (QTcF) 
Appendix VI – Examples of Drugs that Prolong QT 


 
3 
ACCRU-ICRN-1701 
 
 
 
 
    Schema 
 Prior to discussing protocol entry with the patient, call the ACCRU Registration Office 
for dose level and to ensure that a place on the protocol is open to the patient.  
Registration
Arm A1,2
Gemcitabine + Cisplatin + 
ivosidenib
Arm B1,2
Gemcitabine + Cisplatin + 
INCB054828
Metastatic or nonresectable 
cholangiocarcinoma with IDH1 
mutation or FGFR alteration
Survival follow up every 
6 months for up to 3 
years
*
*
*Off-treatment for disease progression, alternative therapy, or withdrawal/refusal
1Cycle length = 21 days; refer to Section 7.0 for dosing information
2Treat until progression
IDH1 Mutation
FGFR Alteration
3 Cycles of Gemcitabine + Cisplatin 
with CR, PR, or SD at first restaging
 
 
Generic name: Ivosidenib (AG-120)  
Brand name (s): Tibsovo 
Availability: McKesson 
Generic name: Pemigatinib (INCB054828) 
 
Brand name(s): Pemazyre 
Availability: Incyte 
Generic name: Cisplatin 
Brand name(s): Platinol 
Availability: Commercial 
Generic name: Gemcitabine 
Brand name(s): Gemzar 
Availability: Commercial 


 
4  
ACCRU-ICRN-1701 
 
1.0 
Background  
 
1.1 
Cholangiocarcinoma 
 
Approximately 6000 patients are diagnosed with cholangiocarcinoma in the United States 
every year.  Patients who present with unresectable or metastatic disease face a poor 
prognosis with a median survival of approximately 12 months and 5-year survival of < 
10%.  The ABC-02 trial established combination chemotherapy with gemcitabine and 
cisplatin as the standard frontline option in this setting.  In this trial, patients were 
randomized to receive gemcitabine alone or combination chemotherapy with gemcitabine 
and cisplatin.  Patients randomized to the combination arm realized improvement in 
progression free survival (PFS, 8 months vs 5 months) and overall survival (OS, 11.7 vs 
8.1 mos.).  This trial established combination chemotherapy with gemcitabine and 
cisplatin as the standard-of-care as initial treatment in fit patients with unresectable or 
metastatic cholangiocarcinoma. 
 
The role of salvage therapy after progression on first-line therapy is poorly studied and in 
general is associated with poor outcomes.  Outside of a clinical trial, most patients treated 
with second-line agents will be treated with a fluoropyrimidine, either alone (5FU or 
capecitabine) or in combination with oxaliplatin (FOLFOX) with a median PFS in the 
range of 2-3 months.  The ongoing UK ABC-06 trial is evaluating the role of FOLFOX in 
this setting, randomizing patients to receive FOLFOX or “active symptoms control.”  
With a lack of data demonstrating a convincing benefit of salvage therapy after patients 
are treated with frontline gemcitabine and cisplatin, there is no standard treatment in this 
setting.  Unfortunately survival in this setting remains very poor. 
 
1.2 
Genomic Landscape in cholangiocarcinoma 
 
With the advent of recent genomic profiling technologies including next generation 
sequencing (NGS) and concurrent robust drug development, molecular targeting is now a 
reality in cholangiocarcinoma more so than any other gastrointestinal malignancy.  
Approximately 1/3 of patients with intrahepatic cholangiocarcinoma will have a 
potentially actionable mutation with either an activating isocitrate dehydrogenase 1 
(IDH1) mutation or FGFR alteration.  Studies suggest the frequency of IDH1 mutations 
in intrahepatic cholangiocarcinoma is approximately 20%; similarly, the frequency of 
FGF/FGFR alterations in this same patient population is approximately 10 – 15%.  Other 
potentially actionable mutations (e.g. BRCA, Her2, EGFR, PTEN, CDKN2A/B, etc.) are 
also identified in this population but occur at a much lower frequency than IDH1 
mutations and FGF/FGFR alterations. 
 
1.3 
IDH1 mutations as therapeutic target in cholangiocarcinoma 
 
The isocitrate dehydrogenase-1 (IDH1) protein is a metabolic enzyme that plays a critical 
role in the citric acid cycle, catalyzing the oxidative decarboxylation of isocitrate to 
produce carbon dioxide (CO2), alpha-ketoglutarate (alpha-KG), and adenine dinucleotide 
phosphate (NADPH).  Mutations in IDH1 most commonly affect arginine-132 (R132H or 
R132C) resulting in a neomorphic gain-of-function activity.  Namely, rather than 
synthesizing isocitrate, mutant IDH1 enzymes catalyze the reduction of alpha-KG to 2-
hydroxyglutarate (2-HG).  The abnormal accumulation of 2-HG has been shown to 
function as an oncometabolite, inhibiting alpha-KG dependent activities that impacts 
tumorigenesis through a variety of mechanisms.  These changes result in epigenetic 


 
5  
ACCRU-ICRN-1701 
 
changes, impacting chromatin structure and inducing histone and DNA 
hypermethylation. 
 
Because of these findings suggesting IDH1 as a potential therapeutic target, efforts are 
underway involving IDH1 inhibition as an anti-cancer strategy.  Ivosidenib is a novel, 
first-in-class, selective inhibitor of mutant IDH1that is currently FDA approved for 
patients with relapsed refractory AML harboring an IDH1 mutation. Ivosidenib is under 
clinical evaluation in patients with advanced IDH1 mutant solid tumors including 
cholangiocarcinoma.  In an early phase I trial utilizing ivosidenib in patients with known 
IDH1 mutations, 73 patients with intrahepatic cholangiocarcinoma were treated including 
24 in dose escalation with an additional 49 treated in an expansion cohort.  Overall 
response rate (ORR) (CR or PR) was modest at 5.5%, with 4 subjects who achieved a PR, 
but 60% demonstrated disease control (SD 56%, PR 5%) with a 6 month PFS of 40.1% 
and 12 month PFS of 21.8%. Side effects of treatment include fatigue, nausea, vomiting, 
diarrhea, decreased appetite, dysgeusia and QT prolongation. This activity has led to the 
ongoing global randomized double-blinded placebo-controlled phase III ClarIDHy (trial 
NCT02989857) evaluating the role of ivosidenib vs. placebo in patients with 
cholangiocarcinoma harboring an IDH1 mutation who have failed at least 1 and no more 
than 2 prior systemic therapies. 
 
1.4 
FGFR alterations as therapeutic target in cholangiocarcinoma 
 
The fibroblast growth factor receptor (FGFR) family is composed of 4 highly conserved 
receptors (FGFR1, FGFR2, FGFR3, FGFR4).  Each is composed of an extracellular 
ligand binding domain, a single transmembrane domain, and an intracellular tyrosine 
kinase domain.  When bound to its ligand, FGFRs will dimerize resulting in activation of 
the kinase domain with signal transduction including activation of mitogen-activated 
protein (MAP) kinase and phosphoinositide 3-kinase (PI3K) pathways as well as others.  
FGFR pathway activation promotes cell proliferation, survival and migration. 
 
FGFR alterations including mutations, translocations, and amplifications have been 
implicated in tumorigenesis in many malignancies including intrahepatic 
cholangiocarcinoma.  In general, these alterations result in constitutive receptor activation 
or aberrant ligand-dependent signaling with resultant dysregulation of FGFR activity 
which is seen as a critical component of tumorigenesis in cancers harboring these 
alterations. 
 
As of 25 NOV 2019, 3 Incyte-sponsored clinical studies of pemigatinib in healthy 
participants (Studies INCB 54828-104, -105, and -106) were completed and 9 Incyte 
sponsored clinical studies of pemigatinib were ongoing and had treated at least 1 
participant: 7 studies in participants with advanced malignancies (Studies INCB 54828 
101, -102, -201, -202, -203, -207, and -302), 1 study in participants with hepatic 
impairment and healthy-matched participants (Study INCB 54828-107), and 1 study in 
participants with renal impairment and healthy-matched participants (Study INCB 
548285-108). A total of 779 participants have been exposed to pemigatinib, and an 
additional 7 participants have been exposed to pemigatinib or gemcitabine and cisplatin 
in a randomized active controlled study (Study INCB 54828-302). 
  
Pemigatinib Monotherapy in Participants with Previously Treated 
Cholangiocarcinoma (Study INCB 54828-202) 
Efficacy of pemigatinib 13.5 mg QD on a 2-weeks-on/1-week-off schedule (i.e., 


 
6  
ACCRU-ICRN-1701 
 
intermittent schedule) in participants with advanced/metastatic or surgically unresectable 
cholangiocarcinoma who have disease progression after at least 1 previous systemic 
treatment was evaluated in Study INCB 54828-202. The ORR based on IRC-assessed, 
confirmed tumor responses among participants with tumors harboring FGFR2 
rearrangements or fusions (Cohort A) was 35.5% (95% CI: 26.50, 45.35), including 3 
complete responses (2.8%) and 35 partial responses (32.7%). The median DOR based on 
Kaplan-Meier analysis was 9.13 months (95% CI: 6.01, 14.49). All responders had at 
least 10 months of follow-up from initial response with the exception of 1 responder who 
had 6.9 months of follow-up from initial response. Observed DOR was at least 6 months 
in 24 responders (63.2%), at least 9 months in 16 responders (42.1%), and at least 12 
months in 7 responders (18.4%). 
There were no IRC-assessed, confirmed tumor responses in participants with 
cholangiocarcinoma with other FGF/FGFR alterations (Cohort B) or without FGF/FGFR 
alterations (Cohort C). 
  
As of the data cutoff date, 147 participants with advanced/metastatic or surgically 
unresectable cholangiocarcinoma had received pemigatinib 13.5 mg QD on an 
intermittent schedule in Study INCB 54828-202. Nearly all participants (99.3%) had at 
least 1 TEAE, and the most frequently occurring TEAE was hyperphosphatemia (57.8%). 
Other TEAEs occurring in > 30% of participants included alopecia, diarrhea, fatigue, 
nausea, dysgeusia, stomatitis, constipation, decreased appetite, and dry mouth. 
Sixty-seven participants (45.6%) had serious TEAEs, 7 (4.8%) of whom had serious 
events with a fatal outcome. Serious events occurring in > 2% of participants included 
abdominal pain and pyrexia in 7 participants (4.8%) each, cholangitis and pleural 
effusion in 6 participants (4.1%) each, and hyponatremia in 4 participants (2.7%). Events 
with fatal outcome included failure to thrive in 2 participants (1.4%) and bile duct 
obstruction, cholangitis, malignant neoplasm progression, pleural effusion, and sepsis in 
1 participant (0.7%) each. None of these fatal events were assessed as related to 
pemigatinib. 
  
Treatment-emergent AEs leading to pemigatinib treatment discontinuation occurred in 15 
participants (10.2%). Acute kidney injury and intestinal obstruction in 2 participants 
(1.4%) each were the only events leading to discontinuation that occurred in more than 1 
participant. 
 
1.5 
Study Rationale 
 
Given the limited benefit of standard agents in the treatment of patients with metastatic 
cholangiocarcinoma and the relatively high likelihood of harboring a potentially 
targetable genomic alteration, our hypothesis is that we can improve clinical outcomes by 
introducing targeted therapies earlier in the treatment of this disease.  With a lack of 
significant overlapping toxicity, we anticipate a favorable toxicity profile with anticipated 
improvement in disease control and survival.  This trial is modelled as a proof of 
principle, designed primarily to evaluate the safety of this approach and hopefully realize 
a signal of efficacy in this population where improved outcomes are desperately needed. 
 
1.6 
Correlative Research 
 
             Plasma 2-hydroxyglutarate (2-HG) levels have been shown to be elevated in patients with 
cholangiocarcinoma harboring IDH1 mutations.   In Arm A only, plasma 2-HG levels 
will be measured at baseline and on Cycle 4, D1 (+/- 2 days).  


 
7  
ACCRU-ICRN-1701 
 
2.0 
Goals  
 
2.1 
Primary 
 
2.11 
To evaluate the safety, tolerability, maximum tolerated dose (MTD) and/or 
recommended phase 2 dose, gemcitabine and cisplatin in combination with either 
ivosidenib or pemigatinib. 
 
2.2 
Secondary 
 
2.21 
To evaluate median and progression free survival (PFS) for 6 months per 
Investigator assessment. 
 
2.22 
To evaluate the rate of overall survival (OS) in patients treated with gemcitabine 
and cisplatin in combination with either ivosidenib or pemigatinib. 
 
2.23 
To describe the overall toxicity and adverse events profile associated with 
gemcitabine and cisplatin in combination with either ivosidenib or pemigatinib. 
 
2.24 
To determine the best response profile per RECIST 1.1 criteria in patients treated 
with gemcitabine and cisplatin in combination with either ivosidenib or 
pemigatinib.  
 
2.3 
Correlative Research 
 
2.31 
To measure plasma 2-hydroxglutarate (2-HG) levels GD\VSULRr to 
registration and at Cycle 4 Day 1 (+/- 2 days). 
 
3.0 
Patient Eligibility  
 
Prior to discussing protocol entry with the patient, call the ACCRU Registration Office 
(507-284-2753) for dose level and to ensure that a place on the protocol is open to the 
patient.  
 
3.1 
Registration – Inclusion Criteria  
 
3.11 
$JH\HDUV 
 
3.12 
Histopathological diagnosis (fresh) or banked tumor biopsy sample collected 
within the last 3 years from the registration date consistent with nonresectable 
or metastatic cholangiocarcinoma and are not eligible for curative resection, 
transplantation, or ablative therapies.  
 
3.13 
Documented disease without any evidence of progression following at least 3 
cycles of standard-of-care chemotherapy including gemcitabine and cisplatin as 
part of first-line systemic therapy.  
 
 


 
8  
ACCRU-ICRN-1701 
 
NOTE: Refer to Section 11.0 for response criteria. Only patients receiving 
standard-of-care chemotherapy including gemcitabine and cisplatin as first-line 
therapy for unresectable or metastatic cholangiocarcinoma will be permitted to 
enroll in this trial. Prior systemic adjuvant chemotherapy is allowed as long as 
there was no evidence of recurrence within 6 months of completing the 
adjuvant therapy 
 
3.14 
Molecular testing result from CLIA-certified laboratory (using fresh tumor 
biopsy or most recent banked tumor tissue available) confirming that the tumor 
tissue has at least one of the following: 
 
a. IDH1 gene mutation (R132C/L/G/H/S mutation) 
 
b. FGFR2 gene alteration (See Appendix II for list of mutations permitting 
trial inclusion) 
 
3.15 
ECOG Performance Status (PS) of 0 or 1 
 
NOTE: Form is available on the ACCRU website 
 
3.16 
/LIHH[SHFWDQF\PRQWKV.  
 
3.17 
At least one evaluable and measurable lesion by RECIST criteria as defined in 
Section 11.0 prior to beginning chemotherapy with gemcitabine and cisplatin. 
 
NOTE: Subjects who have received prior local therapy (including but not 
limited to embolization, chemoembolization, radiofrequency ablation, hepatic 
arterial infusion, or radiation therapy) are eligible provided measurable disease 
falls outside of the treatment. 
 
3.18 
Recovered from toxicities associated with prior anticancer therapy to baseline 
unless stabilized under medical management. 
 
3.19a 
7KHIROORZLQJODERUDWRU\YDOXHVREWDLQHG 21 days prior to registration. 
 
x 
$EVROXWHQHXWURSKLOFRXQWPP3  
x 
3ODWHOHWFRXQWPP3  
x 
+HPRJORELQJG/ 
x 
6HUXPWRWDOELOLUXELQîXSSHUOLPLWRIQRUPDO8/1XQOHVV 
considered due to Gilbert’s disease. If Gilbert’s disease or disease 
involving liver, serum total bilirubin 2.5 x ULN. 
x 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
î8/1RU[8/1LQWKHSUHVHQFHRIOLYHUPHWDVWDVHV 
x 
Have adequate renal function as evidenced by: 
 
a.  6HUXPFUHDWLQLQHî8/1 
OR 
b. Creatinine cOHDUDQFHP/PLQEDVHGRQWKH&RFNcroft-Gault   
glomerular filtration rate (GFR) estimation 
 


 
9  
ACCRU-ICRN-1701 
 
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) 
 
x 
6HUXPSKRVSKDWHLQVWLWXWLRQDO8/1DQGSRWDVVLXPZLWKLQLQVWLWXWLRQDO
normal range for Arm B only. 
 
NOTE: Supplemental potassium may be used to correct potassium prior to 
registration 
 
3.19b 
1HJDWLYHVHUXPSUHJQDQF\WHVWGRQHGD\VSULRUWRUHJLVWUDWLRQIRUZRPHQRI
childbearing potential only. 
 
NOTE: Females of reproductive potential are defined as sexually mature 
women who have not undergone a hysterectomy, bilateral oophorectomy, or 
tubal occlusion or who have not been naturally postmenopausal (i.e., who have 
QRWPHQVWUXDWHGIRUFRQVHFXWLYHPRQWKVLHKDYHQRWKDGPHQVHVDWDQ\
time in the preceding 24 consecutive months).  
 
3.19c 
Women of reproductive potential and fertile men must agree to use 2 effective 
forms of contraception (including at least 1 barrier form) from the time of 
giving informed consent throughout the study and for 90 days (both females 
and males) following the last dose of study drug.  
 
NOTE: Effective forms of contraception are defined as hormonal oral 
contraceptives, injectables, patches, intrauterine devices, intrauterine hormone-
releasing systems, bilateral tubal ligation, condoms with spermicide, or male 
partner sterilization. 
 
3.19d 
Able to understand and willing to sign the informed consent form. 
 
 
NOTE: A legally authorized representative may consent on behalf of a subject 
who is otherwise unable to provide informed consent if acceptable to and 
approved by the site’s Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC). 
 
3.19e 
Able to comply with scheduled visits, treatment plans, procedures, and 
laboratory tests, including serial peripheral blood sampling during the study. 
 
3.19f 
Willing to provide blood samples for correlative research purposes (see 
Sections 6.0and 14.0). 
 
 
 
 


 
10  
ACCRU-ICRN-1701 
 
3.2 
Registration - Exclusion Criteria 
 
3.21 
Prior therapy with either an IDH inhibitor or selective FGFR inhibitor. 
 
IDH inhibitors:  ivosidenib, FT-2012, etc.;  
FGFR inhibitors:  pemigatinib, BGJ-398, TAS-120, ARQ 087, or 
derazantinib, etc. 
 
3.22 
Progressive disease as best response on current standard-of-care chemotherapy 
including gemcitabine and cisplatin. 
 
3.23 
Known toxicity to standard-of-care chemotherapy including gemcitabine and 
cisplatin requiring cessation of this therapy. 
 
3.24 
Received radiotherapy to metastatic sites of disease 2 weeks prior to 
registration. 
 
3.25 
Underwent hepatic radiation, chemoembolization, or radiofrequency ablation  
4 weeks prior to registration 
 
3.26 
Known symptomatic brain metastases requiring steroids.  
 
NOTE: Subjects with previously diagnosed brain metastases are eligible if they 
have completed their treatment and have recovered from the acute effects of 
radiation therapy or surgery prior to study entry, have discontinued 
corticosteroid treatment for these metastases for at least 4 weeks and have 
radiographically stable disease for at least 3 months prior to registration.  
 
NOTE: up to 10 mg per day of prednisone equivalent will be allowed. 
 
3.27 
2WKHUDFWLYHPDOLJQDQF\ 5 years prior to registration.  
 
EXCEPTIONS:  
 
a. Non- melanoma skin cancer unless stage 1a or carcinoma-in-situ of the 
cervix. 
b.  Breast cancer with ongoing hormone therapy being administered as 
     
adjuvant therapy. 
 
NOTE: If there is a history or prior malignancy, they must not be receiving 
other specific treatment  
 
3.28 
Major surgery 4 weeks prior to registration or have not recovered from post-
surgery toxicities.  
 
3.29a 
Any of the following because this study involves investigational agents whose 
genotoxic, mutagenic, and teratogenic effects on the developing fetus and 
newborn are unknown: 
x 
Pregnant women 
x 
Nursing women 


 
11  
ACCRU-ICRN-1701 
 
x 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
 
3.29b 
Arm A: Use of strong CYP3A4 inducers or strong or moderate CYP3A4 
inhibitors. In addition, sensitive CYP3A4 substrate medications with a narrow 
therapeutic window (Appendix III), unless they can be transferred to other 
medications 4 days or 5 half-lives (whichever is shorter) prior to registration  
 
 
 
Arm B: Use of strong CYP3A4 inducers or inhibitors or moderate CYP3A4 
inducers. 
 
 
NOTE: Study PI approval is needed if continued use of CYP3A4 inducers or 
inhibitors. Approval can be obtained via email (documentation of 
approval/eligibility needed) 
 
3.29c 
For Arm B only: Current evidence of clinically significant corneal (including 
but not limited to bullous/band keratopathy, corneal abrasion, 
inflammation/ulceration, and keratoconjuctivitis) or retinal disorder (including 
but not limited to central serous retinopathy, macular/retinal degeneration, 
diabetic retinopathy, retinal detachment) as confirmed by ophthalmologic 
examination. 
 
3.29d 
Known history and/or current evidence of ectopic mineralization/ calcification, 
including but not limited to soft tissue, kidneys, intestine, myocardia, or lung, 
excepting calcified lymph nodes and asymptomatic arterial or cartilage/tendon 
calcification for Arm B only. 
 
3.29e 
Known history of hypovitaminosis D requiring supraphysiologic doses to 
replenish the deficiency for Arm B only. 
 
NOTE: Subjects receiving vitamin D food supplements are allowed. 
 
3.29f7 
Active infection requiring systemic anti-infective therapy or with an 
unexplained fever >38.5°C 7 days of registration. 
 
NOTE: at the discretion of the Investigator, subjects with tumor fever may be 
enrolled. 
 
3.29g 
Any known hypersensitivity to any of the components of ivosidenib or 
pemigatinib. 
 
3.29h 
Significant, active cardiac disease 6 months prior to registration, including  
 
x 
New York Heart Association (NYHA) Class III or IV congestive heart 
failure (Appendix IV) 
x 
myocardial infarction 
x 
unstable angina 
x 
stroke 
 


 
12  
ACCRU-ICRN-1701 
 
3.29i 
Have a heart-rate corrected QT interval (using Fridericia’s formula) (QTcF) 
(Appendix V) PVHFRURWKHUIDFWRUVWKDWLQFUHDVHthe risk of QT 
prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family 
history of long QT interval syndrome).   
 
NOTE: Bundle branch block and prolonged QTcF interval are permitted with 
approval of the Medical Monitor. 
 
3.29j 
Taking medications that are known to prolong the QT interval, unless they can 
be transferred to other medications 5 half-lives prior to registration or unless 
the medications can be properly monitored during the study.   
 
NOTE: If equivalent medication is not available, QTcF should be closely 
monitored. 
 
3.29k 
Known active hepatitis B (HBV) or hepatitis C (HCV) infections, known 
positive human immunodeficiency virus (HIV) antibody results, or acquired 
immunodeficiency syndrome (AIDS) related illness.  
 
NOTE: Subjects with a sustained viral response to HCV or immunity to prior 
HBV infection will be permitted. Subjects with chronic HBV that is adequately 
suppressed per institutional practice will be permitted.  
 
NOTE:  HBV, HCV, and/or HIV testing is not required prior to trial 
registration 
 
3.29l 
Any other acute or chronic medical or psychiatric condition, including recent 
(12 months of registration) or active suicidal ideation or behavior, or a 
laboratory abnormality that may increase the risk associated with study 
participation or investigational product administration or may interfere with the 
interpretation of study results and, in the judgment of the Investigator, would 
make the subject inappropriate for entry into this study.  
 
3.29m 
Inability or unwillingness to swallow ivosidenib or pemigatinib or have 
significant GI disorder(s) that could interfere with absorption, metabolism, or 
excretion.  
 
NOTE: Gastroesophageal reflux disease under medical treatment is allowed 
(assuming no drug interaction potential).  
 
3.29n 
Have been committed to an institution by virtue of an order issued either by the 
judicial or administrative authorities.  
 
3.29o 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 


13 
ACCRU-ICRN-1701 
4.0 
Test Schedule 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 *Footnotes on the following page 
 
 
 
 
 
 
Tests and procedures 
GD\V 
prior to 
registration 
Cycle 1 
(+/- 2 days) 
 
Day 1 of each 
new cycle 
(+/-3 days) 
 
 
Cycle 4 
Day 1 
and 
every 9 
weeks  
(+/- 2 
days) 
End of 
Treatment 
(At PD, 
withdrawal, or 
removal) 
 (30 Days after 
End of 
Treatment)11 
 
Day 
1 
Day 
8 
Day 
15 
 
 
 
 
History and exam, vitals (blood pressure, 
pulse, temp),  weight, ECOG PS1 
X 
X 
X 
X 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Adverse event assessment9 
X 
X 
X 
X 
X 
 
X 
  X 
Hematology2: CBC with differential, 
CEA, CA19-9 
X 
X 
X 
X 
X 
 
X 
X 
CMP2: with Mg and phos 
X 
X 
X 
X 
X 
 
X 
X 
Tumor measurement3 
X 
 
 
 
 
X 
X 
 
EC G5,R 
X 
X 
X 
X 
X 
 
 
 
Serum pregnancy test6 
X 
X 
 
 
X 
 
 
 
Ophthalmologic testing10 
X 
 
 
 
 
X 
X 
 
Mandatory blood sample (2-HG testing)7,R 
X 
 
 
 
 
X 
 
 
Patient Medication Diary8 
 
X 
X 
X 
X 
 
X 
 
 


 
14  
ACCRU # 
 
1. History, physical examination, vital signs, weight, and ECOG PS to be performed at baseline and weekly throughout Cycle 1 (DLT period), 
then on Day 1 of each subsequent cycle. This is considered standard of care except for evaluations on C1D8 and C1D15 during the DLT 
period. 
2. CBC with differential and chemistry panel to be performed at baseline and weekly throughout C1 (DLT period), then on D1 of each 
subsequent cycle. This is considered standard of care. 
3. Chest, abdomen and pelvis cross-sectional imagining required at baseline and per table 4.0 above for response evaluation. Imaging modality 
according to investigator preference; options include CT C/A/P with IV contrast, MRI abdomen + pelvis + chest CT, MRI abdomen + pelvis + 
CXR. PET/CT and FDG-PET/CT are allowed as long as CT portion is of diagnostic quality and includes IV contrast. Same imaging modality 
to be used throughout the study. 
4. 6FUHHQLQJLPDJLQJUHTXLUHG21 days prior to registration; considered research-funded if previous imaging outside 21-day window. 
5. ECG-Obtain ECG on ALL study subjects (ARM A & ARM B) at Screening. Then, for subjects assigned to ARM A (taking ivosidenib). ECG 
done on days 1, 8, & 15 in Cycle 1 and Day 1 of each new cycle (+/- 3 days), as well as when clinically indicated. 
6. For women of childbearing potential only. Must be done d7 days prior to registration and on D1 of each cycle. 
7.   Arm A patients only (patients receiving ivosidenib): 2-hydroxyglutarate (2-HG) levels will be drawn GD\VSULRUWRUHJLVWUDWLRQDQGDW
Cycle 4, day 1 (+/- 2 days) with first restaging scan. 
8. The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating 
institution OR compliance must be documented in the medical record by any member of the care team. Refer to Appendix I. 
9.   Any Adverse event assessment within 30 days of end of treatment will be recorded on the adverse event assessment form in the last cycle of 
treatment. 
10. Ophthalmologic testing - Obtain eye exams on ALL study subjects (ARM A & ARM B) at Screening.    Then, for subjects assigned to ARM B 
(taking Pemigatinib) - A comprehensive ophthalmological examination including OCT every 3 cycles (i.e., every 9 weeks) while a patient is 
receiving pemigatinib. After the first 6 months, ophthalmological exams for patients still on treatment with pemigatinib may be conducted 
every 3 months.  
11. All solicited, and any other reportable AEs, that occurred within 30 days after EOT should be included on the Adverse Events: Solicited and 
Adverse Events: Other forms in the last Treatment folder. 
R Research funded (see Section 19.0) 
 
 


 
15  
ACCRU-ICRN-1701 
5.0  
Grouping Factor 
 
5.1       Mutation Status: IDH1 vs. FGFR/FGF     
 
6.0  
Registration Procedures 
 
6.1 
Safety Run-in  
 
Prior to discussing protocol entry with the patient, call the ACCRU Registration 
Office (507-284-4130) for dose level and to ensure that a place on the protocol is 
open for the patient.  
 
6.2  
Registration Procedures (Safety Run-In and Expansion Cohort) 
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. 
 
6.21 
Correlative Research 
 
A mandatory correlative research component is part of this study. The patient 
will be automatically registered onto this component (see Sections 3.0 and 14.0). 
 
6.22 
Prior to accepting the registration, the registration/randomization application will 
verify the following: 
 
x 
IRB approval at the registering institution 
x 
Patient eligibility 
x 
Existence of a signed consent form 
x 
Existence of a signed authorization for use and disclosure of protected health 
information 
 
6.23 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients.  
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
  If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
 
Submission of annual IRB approvals is required until the study has been closed 
through your IRB. 
 
6.24 
At the time of registration, the following will be recorded: 
 
x 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn about, prevent, or treat cancer 
 


 
16  
ACCRU-ICRN-1701 
x 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn, prevent, or treat other health problems (for example: 
diabetes, Alzheimer’s disease, or heart disease) 
 
x 
Patient has/has not given permission for ACCRU to give his/her sample(s) to 
outside researchers 
 
6.25 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of a medical oncologist 
 
6.26 
Treatment cannot begin prior to registration and must begin 14 days after 
registration. 
 
6.27 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.28a All required baseline symptoms (see Section 10.0) must be documented and 
graded. 
 
6.28b Study drug is available on site. 
 
6.28c Blood draw kit is available on site. 
 
7.0 
Protocol Treatment 
 
7.1 
Treatment Schedule - Use actual weight or estimated dry weight if fluid retention 
 
7.11 
Pretreatment medication  
 
No premedication required for ivosidenib or pemigatinib required. Premedication 
for gemcitabine + cisplatin should be administered per institutional practice. 
 
7.12 
Treatment medication 
 
Arm 
Agent 
Dose Level 
Route 
Day(s) 
ReRx 
A 
Ivosidenib 
Per current dose 
level (Max of 
500mg) 
Oral 
1-21 
(once 
daily) 
Every 21 days 
 
B 
Pemigatinib 
Per current dose 
level (Max of 
13.5mg) 
Oral 
1-21 
(once 
daily) 
Every 21 days 
A, B 
Cisplatin 
25 mg/m2 
IV 
D1 & D8 
Every 21 days 
A, B 
Gemcitabine 
1000 mg/m2 
IV 
D1 & D8  
Every 21 days 
 
7.2 
Patients can be instructed in administration techniques and granted treatment 
independence with nursing staff approval.  See section 15 for details of study drug 
administration. 
 
7.3 
For this protocol, the patient must return to the consenting ACCRU institution for 
evaluation at least every 21 days (+/- 3 days) during treatment.  


 
17  
ACCRU-ICRN-1701 
7.4 
Phase I – determination of Maximum Tolerated Dose (MTD)  
 
7.41 
Dose De-escalation 
 
Dose level 
                  ivosidenib 
                 pemigatinib 
-2 
HOLD 
4.5 mg 
-1 
250 mg  
9 mg  
   0* 
500 mg  
13.5 mg  
*starting dose level   
 
7.411 
Treatment by a local medical doctor is not allowed.  
 
7.412  
Six patients will be treated at each dose level and observed for a 
minimum of 21 days to assess toxicities before new patients are 
treated. Doses will not be escalated in any individual patient. 
 
7.413 
Investigators are to contact the ACCRU Operations Office 
as soon as any dose-limiting toxicity (DLT) occurs. 
 
7.414     Dosing will be de-escalated (as described in “study flow”) if >/=2 
DLTs at any given dose; if >/= 2 DLTs is seen at lowest dose level, 
consideration will be given to terminate the trial vs further dose 
reduction.  A temporary enrollment hold will be enforced after each 6 
patient cohort has been enrolled to evaluate for excessive toxicity. .  If 
at any time the decision is made to pursue a further dose reduction 
other than as stated in the protocol, this will be addressed with a 
protocol amendment. 
 
7.42 
Definitions of DLT 
 
An event is considered a dose limiting toxicity (DLT) if it meets the following 
criteria:  
             Occurs during the 3 weeks (during initial first cycle of combined therapy) after 
starting the study, and is assessed as having a possible causal relationship with 
AG120 or pemigatinib (possibly, probably or definitely related) AND Meets any 
of the following criteria: 
 
x 
Grade 3 thrombocytopenia with bleeding.   
 
x 
Grade 4 thrombocytopenia. 
 
x 
Grade 3, 4 febrile neutropenia.  
 
x 
Grade 4 neutropenia without fever lasting more than 7 days. 
 
x 
Grade 4 anemia 
 
x 
$Q\JUDGHQRQ-hematologic toxicity with the following exceptions: 
 


 
18  
ACCRU-ICRN-1701 
x 
Grade 3 hypomagnesemia RUK\SHUSKRVSKDWHPLDZKLFKODVWGD\VZLWK
adequate supportive care for arm B only. 
 
x 
*UDGHQDXVHDYRPLWLQJRUGLDUUKHDODVWLQJGD\VZLWKDGHTXDWH
antiemetic and other supportive care 
 
x 
$Q\LQWROHUDEOHJUDGHWR[LFLW\ZDUUDQWLQJDGRVHUHGXFWLRQ 
 
Grade 3 or 4 QTcF prolongation 
 
x 
+\¶V/DZî8/1HOHYDWLRQRIWUDQVDPLQDVHVDQGFRQFRPLWDQWî8/1
elevation of bilirubin without alternative etiology) 
 
x 
Failure to receive at least 80% of the expected doses of AG120 or 
Pemigatinib. due to toxicity 
 
x 
Uncontrolled hyperphosphatemia even with binders while taking Pemigatinib 
 
8.0 
Dosage Modification Based on Adverse Events  
 
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained. Thereafter, these modifications should be regarded as guidelines to 
produce mild-to-moderate, but not debilitating, side effects. If multiple adverse events are seen, 
administer dose based on greatest reduction required for any single adverse event observed. 
Reductions or increases apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose. 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
8.1  
Dose Levels (Based on Adverse Events in Tables 8.3 and 8.4) 
 
Dose levels for gemcitabine + cisplatin should be per institutional practice. 
 
Dose Level 
Ivosidenib 
Pemigatinib 
0* 
500 mg 
13.5 mg 
-1 
250 mg 
9 mg 
-2 
HOLD 
 4.5 mg 
* Dose level 0 refers to the starting dose. 
 
8.2 
Dose Modifications 
 
Dose modifications for adverse events felt to be due to gemcitabine + cisplatin allowed 
per institutional practice. 
 
Patients who stop chemo for reasons other than progression may continue on study drug 
until progression. 
 
For any AE felt attributable to the study drug (ivosidenib or pemigatinib), including AEs 
not specifically mentioned below, the Investigator may decide to delay dosing or modify 
the dose of study drug based on clinical judgment. These decisions should be reviewed 


 
19  
ACCRU-ICRN-1701 
with the study chair or co-chair prior to implementation. 
 
Dose modifications of ivosidenib from 500 mg to 250 mg or pemigatinib from 13.5 
mg to 9 mg to 4.5 mg will be permitted on study for management of AEs.  
 
If more than one AE occurs that would require a dose modification, upon resolution of all 
AEs to baseline or Grade 1, study drug should be dose reduced to dose level -1 (Table 
8.1). If the patient experiences a significant adverse event requiring a dose reduction at 
the start of the next cycle, then the dose will remain lowered for that entire subsequent 
cycle. If that cycle is completed with no further adverse events >Grade 2, then 
reescalation may be allowed, one level at a time, in the following cycles with approval 
from the study chair or co-chair. There will be no dose re-escalation if the patient has a 
DLT or a serious toxicity at the higher dose. 
Dose delays for reasons other than management of AEs are discouraged. Dose 
delays up to 28 days will be permitted at the discretion of the Investigator for 
reasons including management of AEs and for mitigating circumstances (e.g., 
planned procedures.)  Palliative biliary decompression procedures and/or palliative 
paracentesis will be permitted on study and will not require interruption of study 
drug.  
 
Adverse events requiring a dose-reduction step for any or all drugs beyond the two 
dose-reduction steps (levels –1 and –2) will be at the discretion of the treating 
physician after discussion with the study chair or co-chair, if the decision is made 
for the patient to be kept on study. These dose reductions must be clearly recorded 
in reported clinical data. 
 
If the subject cannot resume ivosidenib or pemigatinib within 28 days,, the subject 
should be discontinued from study medication.  If study drug is discontinued, the 
subject will complete the EOT and continue to be followed as outlined in Protocol 
Sections 4.0 and 13.0.  
 
Exemptions for patients holding study drug for >28 days may be considered for 
those subjects who are determined by the study chair or co-chair to have received 
clinical benefit from treatment.  
 
If study drug is delayed for the management of an AE but chemotherapy is 
continued, the subject should resume study drug after resolution of AEs to baseline 
or Grade 1 at the next planned visit without changing current dosing cycle (e.g., if 
the subject did not start dosing at C3D1 due to management of an AE but may 
resume treatment with C3D8 or at any other time during the course of that given 
cycle. Resuming treatment will continue according to current cycle (i.e. if 
pemigatinib is resumed on C3D8, treatment break will continue as scheduled 
beginning on C3D15). 
 
 
 
 
 
 
 


 
20  
ACCRU-ICRN-1701 
8.3 Table 1:  
Dose Modifications for Ivosidenib 
 
Adverse Event 
Action 
Grade 2 nausea 
or vomiting 
(related or 
unrelated) 
·         Consider holding dose of ivosidenib until resolution of 
$(WR*UDGHZLWKLQGD\VRIVXSSRUWLYHWKHUDS\ 
·         Manage with supportive therapy according to the 
institutional standard of care.  
·         May resume ivosidenib at same dose 
Grade 3 adverse 
events (related, 
first event) 
·        Hold dose of iYRVLGHQLEXQWLOUHVROXWLRQWR*UDGHRU
baseline within 28 days of supportive therapy and then 
resume dose.  
·        Manage with supportive therapy according to the 
institutional standard of care.  
·        If the Grade 3 AE recurs (a second time), consider 
reducing ivosidenib to 250 mg in consultation with the 
study staff. Reescalation may be permitted after 
discussion with the study chair or co-chair  
·        If the Grade 3 AE recurs (a third time) despite dose 
reduction of ivosidenib, then consider discontinuing 
ivosidenib in consultation with study chair or co-chair 
Grade 4 adverse 
events (related, 
first event) 
·        Hold ivosidenib. 
·        Manage with supportive therapy according to the  
         institutional standard of care.  
·        ,IWKH$(UHVROYHVWR*UDGHRUEDVHOLQHZLWKLQ
days, then restart ivosidenib dosing at 250 mg in 
consultation with the study chair or co-chair.  
·        ,IWKH$(GRHVQRWUHVROYHWR*UDGHRUEDVHOLQHZLWKLQ
28 days, consider discontinuing study treatment in 
consultation with the study chair or co-chair.  
·        If the Grade 4 AE recurs (a second time), despite dose 
reduction, ivosidenib should be discontinued in 
consultation with the study chair or co-chair. 
 
 
NOTE:  If PML is suspected, regardless of relationship to ivosidenib, dose should be 
held until final diagnosis is confirmed.  If PML is confirmed as a diagnosis, then 
ivosidenib should be discontinued.  If Guillain-Barre is confirmed as a diagnosis, 
ivosidenib should be discontinued. 
 
8.31      QT prolongation in patients receiving ivosidenib 
 
Prolongation of heart-rate corrected QT (QTc) interval has been observed 
in monkeys at relatively high doses of ivosidenib as well as in patients 
while receiving ivosidenib.  Please refer to the current ivosidenib 
Investigator’s Brochure for detailed information. 
 
Subjects may be at increased risk for the development of QT prolongation 
when treated with ivosidenib combination with fluoroquinolones, azole 
antifungal agents, or serotonin (5-HT3) antagonists. Investigators need to 


 
21  
ACCRU-ICRN-1701 
be vigilant regarding concomitant medications associated with QT 
prolongation, and if no other therapeutic options are available, monitor 
subjects receiving ivosidenib with the combination of these drugs, and 
evaluate ECG and electrolytes (including potassium, magnesium, and 
calcium) particularly in subjects presenting with nausea, vomiting, or 
diarrhea. 
 
Subjects who experience prolongation of the heart-rate corrected QT 
interval, Fridericia’s correFWLRQ47F)WR!PVHF*UDGHZKLOH
treated with ivosidenib, should be promptly evaluated for causality of the 
QTc prolongation and managed according to the following guidelines and 
Table 2: 
 
• Levels of electrolytes (potassium, calcium, and magnesium) should be checked 
and supplementation given to correct any values outside the normal range. 
• Concomitant therapies should be reviewed and adjusted as appropriate for 
medications with known QT prolonging effects. 
• If no other cause is identified and the Investigator believes it is appropriate, 
particularly if QTcF remains elevated (after above measures have been 
implemented, or as determined by the Investigator), study treatment may be 
interrupted, and an ECG should be rechecked in approximately 1 week after the 
QTcF prolongation was first observed or more frequently as clinically indicated. 
If QTcF has recovered or improved and the Investigator believes it is safe to do 
so, re-challenge with study treatment should be considered if held. 
• ECGs should be conducted at least weekly (eg, at every scheduled visit) for 2 
weeks following QTcF reduction </=480 msec. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
22  
ACCRU-ICRN-1701 
Table 2: 
 
Management of QT Prolongation by CTCAE Grade 
 
 
CTCAE Grade 
Management 
Grade 2 
 
x 
The dose of study may be reduced to 250 
mg QD without interruption of dosing.  
The dose of study treatment may be re-
HVFDODWHGWRWKHSULRUGRVHLQGD\V
after QT prolongation has decreased to 
Grade 1. 
Grade 3 
 
x 
Hospitalization for continuous cardiac 
monitoring and evaluation by a cardiologist 
should both be considered. 
x 
Dosing with study treatment will be 
interrupted.  If QTcF returns within 30 
msec of baseline or < 450 msec for males 
and < 470 msec for females within 14 days, 
treatment must be resumed at a reduced 
dose of 250 mg. 
x 
The dose of study treatment cannot be re-
escalated following dose reduction for 
Grade 3 QTcF prolongation unless the 
prolongation was associated with an 
electrolyte abnormally of concomitant 
medication.  
Grade 4 
 
x 
Subjects should be admitted to a hospital 
for continuous cardiac monitoring and 
discharged only after review by a 
cardiologist. 
x 
Dosing with study treatment should be 
permanently discontinued.   
 
 
8.4        Dose modifications for pemigatinib. Dose interruptions and modifications may 
occur for individual study subjects.  The occurrence of toxicities (related or 
unrelated to study drug) will guide decisions for treatment interruptions and 
discontinuation for individual subjects. 
 
 
 
 


 
23  
ACCRU-ICRN-1701 
Table 3:  Guidelines for Interruption and Restarting of Pemigatinib 
 
Adverse Event 
Action   
Transaminitis:  AST 
or ALT >5.0 x ULN 
NOTE: In subjects 
with liver metastasis-
related elevations at 
baseline, contact the 
sponsor to discuss 
clinical management 
and possible dose 
reductions. 
Step 1:  Interrupt study drug up to 4 weeks (28 days) until 
toxicity resolved to </= Grade 1  
Step 2:  Restart study drug at same dose.  If assessed as related 
to study drug, restart study drug at next lower dose and monitor 
as clinically indicated. 
Other toxicity (not 
transaminitis): 
 
Any other Grade 1 or 
Grade 2 toxicity  
Continue study drug and treat toxicity, monitor as clinically 
indicated.   
Any Grade 3 toxicity 
if clinically 
significant and not 
manageable by 
supportive care 
Step 1:  Interrupt study drug up to 4 weeks (28 days) until 
toxicity resolved to </= Grade 1  
Step 2:  If toxicity assessed as related to study drug, restart 
study drug at next lower dose and monitor as clinically 
indicated. 
Any recurrent Grade 
3 toxicity after 2 
dose reductions 
Discontinue study drug and follow up per 
protocol.  (Exceptions require approval of chair or co-chair) 
Any other grade 4 
toxicity 
Discontinue study drug and follow up per protocol 
 
Due to the fact subjects may enter the study with extensive pretreatment toxicities, the dose 
reduction rules are provided as guidelines 
 
For dose adjustments, it is recommended that a maximum of 2 dose level reductions: 
subjects administered 13.5 mg can decrease to 9 mg, and if additional dose reduction is 
required, subjects can decrease to 4.5 mg.  Dose reductions below 4.5 mg are not allowed.  
The frequency of administration remains the same (once daily).  
 
$GYHUVHHYHQWVWKDWKDYHDFOHDUDOWHUQDWLYHH[SODQDWLRQLIWUDQVLHQWKRXUVDEQRUPDO
laboratory values without associated clinically significant signs or symptoms may be exempt 
from dose – reduction rules. 
 
8.5 
Management of Hyperphosphatemia in patients receiving pemigatinib 
 
Hyperphosphatemia is an expected on-target pharmacologic effect of FGFR 
inhibition.  Hyperphosphatemia should be managed with diet modifications, 
phosphate binders and diuretics, or dose reduction per recommendations below: 
 
 
 
 
 


 
24  
ACCRU-ICRN-1701 
Recommended approach for Hyperphosphatemia Management: 
 
Serum 
Phosphate 
Level 
Supportive Care 
Guidance for 
Interruption/Discontinuation 
of INCB054828 
Guidance for 
Restarting 
INCB054828 
>5.5 mg/dL 
and PJG/ 
Initiate a low-
phosphate diet 
 
No action. 
 
Not applicable. 
>7 mg/dL and 
PJG/ 
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 
DQGJPG/ZLWK
concomitant phosphate-
binding therapy for 2 
weeks, or if there is 
recurrence of serum 
phosphate level in this 
range, interrupt 
INCB054828 for up to 2 
weeks (not including the 
planned dose interruption 
per treatment cycle). 
Restart at the 
same dose when 
serum phosphate 
level recurs at > 
7 mg/dL, restart 
study drug with 
dose reduction. 
> 10 mg/dL 
Continue to 
maintain a low-
phosphate diet, 
adjust phosphate-
binding therapy, 
and start/continue 
phosphatidic 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 interrupt 
study drug. If there is 
recurrence of serum 
phosphate level in this range 
following 2 dose reductions, 
permanently discontinue 
INCB054828. 
Restart study 
drug at reduced 
dose with 
phosphate 
binders when 
serum phosphate 
is < 7mg/dL. 
 
8.6 
Criteria for Permanent Discontinuation of the Study Drug: 
 
 
The occurrence of unacceptable toxicity not caused by the underlying malignancy 
will be presumed to be related to study drug treatment and will require that the 
study drug be permanently discontinued.  Unacceptable toxicity is defined as 
follows: 
x 
Occurrence of an AE that is related to treatment with the study 
drug that, in the judgement of the investigatory, compromises the 
subject’s ability to continue study-specific procedures or is 
considered to not be in the subjects best interest, 
x 
An AE requiring more than 2 dose reductions. 
 
 


 
25  
ACCRU-ICRN-1701 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the American Society of Clinical Oncology (ASCO). 
Recommendations for the Use of WBC Growth Factors: American Society of Clinical 
Oncology Clinical Practice Guideline Update. J Clin Oncol 2015;33:3199-3212.  
 
9.3 
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. All blood products and concomitant medications such 
as antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the 
medical records. 
 
9.4 
Diarrhea: This could be managed conservatively with loperamide. The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea 
free (maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and other antidiarrheals.  
 
If diarrhea is severe and associated with fever or severe neutropenia (grade 3 or 4), broad-
spectrum antibiotics must be prescribed. Patients with severe diarrhea or any diarrhea 
associated with severe nausea or vomiting should be carefully monitored and given 
intravenous hydration and correction of electrolyte imbalances. Consider hospitalization  
 
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. 
 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following:  
 
x 
Any suspected adverse reaction that is both serious and unexpected.  
x 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity.  
x 
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.  
x 
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).  
 
 
 
 


 
26  
ACCRU-ICRN-1701 
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.   
 
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). 
 
NOTE: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
 
 
 


 
27  
ACCRU-ICRN-1701 
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 medical 
treatment suggest there is evidence to indicate a causal relationship between the 
drug/device and the adverse event.  
 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agents 
on the SAME Arm (Combination) 
 
When commercial agents are used on the same treatment arm as an 
investigational agent, the entire combination (arm) is then considered an 
investigational intervention for reporting. These AEs should be assessed as 
specified in the appropriate IND/IDE reporting guidelines in Section 10.4 
 
10.32 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: 
x 
Hospitalizations for respite care 


 
28  
ACCRU-ICRN-1701 
x 
Planned hospitalizations required by the protocol or to administer protocol 
directed treatment (i.e. 131I therapy) 
x 
Hospitalization planned before informed consent (where the condition 
requiring the hospitalization has not changed post study drug administration) 
x 
Hospitalization for administration of study drug or insertion of access for 
administration of study drug 
x 
Hospitalization for routine maintenance of a device (e.g., battery 
replacement) that was in place before study entry 
 
10.33 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.  
 
10.34 Report an expected event that is greater in severity or specificity than expected as 
an expedited event 
 
10.35 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. 
 
10.36 Death 
 
10.361 
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. 
 
10.362 
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. 
 
10.363 
Reportable categories of Death  
 
x 
Death attributable to a CTCAE term. 
x 
Death Neonatal:  A disorder characterized by cessation of life 
during the first 28 days of life. 
x 
Death NOS:  A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
x 
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. 
 
 


 
29  
ACCRU-ICRN-1701 
x 
Death due to progressive disease should be reported as Grade 5 
“Disease Progression” under the (SOC) General Disorders and 
Administration Site Conditions. Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted. 
 
10.37 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: 
 
x 
Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
x 
Myelodysplastic syndrome (MDS) 
x 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
10.38 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy).  Second malignancies require 
ONLY routine reporting. 
 
10.39 Pregnancy 
 
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 ACCRU Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the 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. 
 


 
30  
ACCRU-ICRN-1701 
10.4 
Expedited Adverse Event Reporting Requirements 
 
10.41 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 hosSLWDOL]DWLRQIRU
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 
ResultLQJLQ+RVSLWDOL]DWLRQKUV. 
7 Calendar Days 
24-Hour; 3 Calendar Days 
1RWUHVXOWLQJLQ+RVSLWDOL]DWLRQKUV. 
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: 
x 
All Grade 3, 4, and Grade 5 AEs 
 
Expedited 7 calendar day reports for: 
x 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
Effective Date:  May 5, 2011 
 
 
 


 
31  
ACCRU-ICRN-1701 
10.411 
Special Instructions 
 
x 
In addition to the reporting  requirements outlined in this protocol, sites 
are responsible for following site-specific reporting guidelines 
x 
Submit the ACCRU Adverse Expedited Report Form to the ACCRU 
SAE Coordinator via email: 
The ACCRU 
SAE Coordinator will forward to: 
 
Agios:   
The PI is responsible for sending expedited reports to Agios Medical Safety and Risk Management 
(MSRM) at 
 immediately but no later than 24 hours after regulatory 
submission. 
 
The PI is responsible for emailing pregnancy and overdose reports to Agios Medical Safety and Risk 
Management (MSRM) at 
 within 10 calendar days of sponsor awareness. 
 
Safety Reporting to Agios 
 
A listing of all SAEs should be reported to Agios on a quarterly basis. Any adverse event requiring 
expedited reporting (serious, unexpected event suspected of being related to ivosidenib) should be cross-
reported to Agios at the same time as submission to the authorities (within 24 hours of the site’s 
awareness of the event). 
 
Should the site become aware of a pregnancy or drug miss-dose/overdose, this should be reported to the 
Sponsor within 24 hours of becoming aware. 
 
Reports should be submitted to: 
  
 
SAE Reporting to Incyte 
Incyte: 
 
 
Incyte needs to be notified within 24 hours of learning of an 
event. Incyte also needs to be provided a completed SAE form 
via email. SAE reporting for each subject begins the day the 
informed consent is signed by the patient and within 30 days 
after subject has completed or discontinued from the study or has 
taken last dose of the study drug, or as described in the IST 
protocol. 
SAEs, occurring using Incyte Study drug, are reported in 
accordance with the effective protocol.  SAEs occurring with any 
another commercial drug are reported to manufacturer of that 
drug in accordance with regulations and protocol.  
Initial Serious Adverse events (SAEs) and/or subsequent follow-
up reports should be reported via email to: 
  SAE 
reports should be for a single subject. SAE forms will be e-
mailed with a cover sheet and any additional attachments to the 
IST email address: 
 
 
 


 
32  
ACCRU-ICRN-1701 
Reporting of Pregnancy to Incyte 
An “Initial Pregnancy Report” or equivalent must be completed 
in full and emailed to 
within 24 hours of discovery of a pregnancy of a 
subject who has taken the Incyte product or the pregnancy of a 
partner for a subject who has taken the Incyte product.  The 
“Follow-up Pregnancy Report Form” or equivalent must be 
completed and emailed to 
 
within 30 days after delivery, so that Incyte is 
provided with information regarding the outcome of the 
pregnancy.  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. 
 
x 
The ACCRU SAE Coordinator will forward to the ACCRU IND 
Coordinator 
as appropriate. The 
ACCRU IND Coordinator will assist the sponsor-investigator in 
notifying the FDA if required. 
 
The Sponsor is responsible for sending expedited reports to Agios 
Medical Safety and Risk Management (MSRM) at 
immediately but no later than 24 hours after 
regulatory submission. 
 
The Sponsor is responsible for emailing pregnancy <<and overdose 
reports>> to Agios Medical Safety and Risk Management (MSRM) at 
within 10 calendar days of 
sponsor awareness. 
 
10.5 
Adverse Events of Special Interest (AESI) 
 
AEs of Special Interest are defined by Agios and Incyte as a potential safety problem 
identified as a result of ongoing safety monitoring of their products. As such, surveillance 
for the AESIs noted in Section 10.51 MUST be undertaken at each treatment evaluation. 
'HYHORSPHQWRIRQHRIWKHVH$(6,V*UDGHXQOHVVRWKHUZLVHQRWed) MUST be 
reported in terms of CTCAE v 5.0 grade and attribution in the manner and timeframe 
outlined in Section 10.6. 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
33  
ACCRU-ICRN-1701 
10.51 AEs of Special Interest 
 
 Ivosidenib: 
 
 
System Organ 
Class (SOC) 
 
Adverse event 
Grade Severity 
to report 
QT interval 
prolongation 
Investigations 
Electrocardiogram QT 
corrected interval prolonged 
Grade 2 or 
higher 
 
 
Pemigatinib: 
 
 
System Organ 
Class (SOC) 
 
Adverse event 
Grade Severity 
to report 
Eye Disorders  
Blurred vision, optic nerve 
disorder, retinal detachment  
Grade 2 or 
higher 
Eye Disorder-
other 
retinal pigment epithelium 
detachment, serous retinal 
detachment 
Grade 2 or 
higher 
 
QT prolongation 
Prolongation of heart-rate corrected QT (QTc) interval has been observed in monkeys at relatively high 
doses of ivosidenib as well as in patients while receiving ivosidenib.  Please refer to the ivosidenib 
Investigator’s Brochure for detailed information. 
 
Subjects may be at increased risk for the development of QT prolongation when treated with ivosidenib in 
combination with fluoroquinolones, azole antifungal agents, or serotonin (5-HT3) antagonists. 
Investigators need to be vigilant regarding concomitant medications associated with QT prolongation, and 
if no other therapeutic options are available, monitor subjects receiving ivosidenib with the combination 
of these drugs, and evaluate ECG and electrolytes (including potassium, magnesium, and calcium) 
particularly in subjects presenting with nausea, vomiting, or diarrhea. 
 
Subjects who experience prolongation of the heart-rate corrected QT interval, Fridericia’s correction 
47F)WR!PVHF*UDGHZKLOHWUHDWHGZLWK ivosidenib, should be promptly evaluated for 
causality of the QTc prolongation and managed according to the following guidelines: 
x 
Levels of electrolytes (potassium, calcium, and magnesium) should be checked and 
supplementation given to correct any values outside the normal range. 
x 
Concomitant therapies should be reviewed and adjusted as appropriate for medication with 
known QT prolonging effects. 
x 
If no other cause is identified and the investigator believes it is appropriate, particularly if QTc 
remains elevated (after above measures have been implemented, or as determined by the 
investigator), investigational product may be interrupted, and an ECG should be rechecked in 
approximately 1 week after the QTc prolongation was first observed, or more frequently as 
clinically indicated. 
x 
If QTc has recovered or improved and the investigator believes it is safe to do so, re-challenge 
with ivosidenib should be considered if held. ECGs should be conducted at least weekly (e.g., at 
every scheduled visit) IRUZHHNVIROORZLQJ47FUHGXFWLRQPVHF 


 
34  
ACCRU-ICRN-1701 
x 
If Grade 2 the dose of ivosidenib may be reduced without interruption of dosing. The ivosidenib 
dose may be re-HVFDODWHGWRWKHSULRUGRVHLQGD\VDIWHU47SURORQJDWLRQKDVGHFUHDVHGWR
Grade 1. 
x 
If Grade 3 when QTc prolongation is first observed hospitalization for continuous cardiac 
monitoring and evaluation by a cardiologist should both be considered. Dosing with ivosidenib 
will be interrupted. If QTc returns to within 30 msec of baseline or < 450 msec within 14 days, 
treatment may be resumed at a reduced dose. The ivosidenib dose cannot be re-escalated 
following dose reduction for Grade 3 QTcF prolongation unless the prolongation was associated 
with an electrolyte abnormality or concomitant medication. 
x 
If Grade 4 subjects should be admitted to hospital when QTc prolongation is first observed for 
continuous cardiac monitoring and be discharged only after review by a cardiologist. Dosing 
with ivosidenib should be permanently discontinued. 
 
10.6 
Other Required Reporting 
 
10.61 Reporting Timelines and Mechanisms 
 
Adverse Event 
Form(s) 
Needed 
Site 
timeline to 
report to 
ACCRU 
ACCRU timeline to 
report to Agios and 
Incyte 
Non-Serious 
Adverse Event 
 
Adverse Events 
form (see CRF 
packet) 
At each 
evaluation 
Quarterly 
Adverse Events 
of Special 
Interest (Section 
10.51)* 
Adverse Events 
of Special 
Interest Form** 
At each 
occurrence  
Within 1 business day of 
receipt 
Adverse Events 
form (if criteria 
in 10.5 is met) 
Quarterly 
Pregnancy 
(Section 10.39) 
ACCRU 
Adverse Event 
Expedited 
Report Form** 
At each 
occurrence 
Within 1 business day of 
receipt 
Adverse Events 
form (if criteria 
in 10.5 is met) 
 
Quarterly 
Serious Adverse 
Events (Section 
10.4)* 
ACCRU 
Adverse Event 
Expedited 
Report Form** 
At each 
occurrence 
Within 1 business day of 
receipt 
Adverse Events 
form (see CRF 
packet) 
Quarterly 
* 
If an adverse event meets the criteria for both an AE of Special Interest and a 
Serious Adverse Event, please report only as a Serious Adverse Event. 
**  The Adverse Events of Special Interest Form and ACCRU Adverse Event 
Expedited Report Form are available on the ACCRU web site 
  


 
35  
ACCRU-ICRN-1701 
 
10.62 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. 
 
10.63 Baseline and Adverse Event 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. If CTCAE v5.0 grading is not used, note the grading scale used in the 
table below 
 
 


 
36  
ACCRU-ICRN-1701 
                                     Both Arms 
 
 
 
                                  
 
 
 
 
System Organ 
Class (SOC) 
Adverse event/ 
Symptoms 
Baseline 
Each 
evaluation 
Grading scale 
(if not CTCAE) 
Blood and 
lymphatic 
system 
disorders 
White blood cell 
decreased 
 
X 
 
X 
 
Blood and 
lymphatic 
system 
disorders 
Platelet count 
decreased 
 
 
X 
 
X 
 
Blood and 
lymphatic 
system 
disorders 
Anemia 
 
 
X 
 
X 
 
Blood and 
lymphatic 
system 
disorders 
Neutropenia 
 
 
X 
 
X 
 
Investigations 
AST Increased 
 
X 
 
X 
 
Investigations 
ALT Increased 
 
X 
 
X 
 
Investigations 
AlkPhos Increased 
 
X 
 
X 
 
Gastrointestinal 
disorders 
Diarrhea 
 
 
 
 
X 
 
Number of stools per 
day 
 
X 
 
Gastrointestinal 
disorders 
Nausea 
 
 
X 
 
X 
 
Gastrointestinal 
disorders 
Vomiting 
 
 
X 
 
X 
 
Metabolism 
and nutrition 
disorders  
 
Anorexia 
 
 
X 
 
X 
 
General 
disorders and 
administration 
site conditions  
 
Fatigue 
 
 
X 
 
X 
 


 
37  
ACCRU-ICRN-1701 
 For Arm B only (INCB54828) 
System Organ 
Class (SOC) 
Adverse event/ 
Symptoms 
Baseline 
Each 
evaluation 
Grading scale 
(if not 
CTCAE) 
metabolism and 
nutrition 
disorders 
Hyperphosphatemia1 
X 
X 
 
gastrointestinal 
disorders 
mucositis oral1 
X 
X 
 
gastrointestinal 
disorders 
Dry Mouth1 
X 
X 
 
Skin and 
subcutaneous 
tissue disorders 
Alopecia1 
 
X 
X 
 
 
Stomatitis1 
X 
X 
 
 
Decreased appetite1 
X 
X 
 
Nervous system 
disorders 
Dysgeusia1 
X 
X 
 
gastrointestinal 
disorders 
Abdominal Pain1 
X 
X 
 
Investigations 
Aspartate 
aminotransferase 
increased1 
X 
X 
 
Metabolism and 
nutrition 
disorders 
Hypophosphatasemia1 
X 
X 
 
Metabolism and 
nutrition 
disorders 
Dehydration1 
X 
X 
 
Eye disorders 
Dry Eye1 
X 
X 
 
Musculoskeletal  
And connective 
tissue disorders 
Pain in extremity1 
X 
X 
 
Investigations 
Alanine 
aminotransferase 
increased1 
X 
X 
 
Respiratory, 
thoracic and 
mediastinal 
disorders 
Cough1 
X 
X 
 
Eye disorders 
Blurred vision1 
X 
X 
 
 
Weight decreased1 
 
 
 


 
38  
ACCRU-ICRN-1701 
 
 
 
 
 
 
 
 
 
 
 
 
 
                      
 
 
 
 
 
 
 
 
 
1. For patients in Arm A, check “Adverse event not evaluated”. 
 
10.64 Case Report Forms - Academic and Community Cancer Research United (ACCRU) 
Submit the following AEs not specified in Section 10.4 (paper or electronic, as applicable) 
 
10.641 
Grade 1 and 2 AEs deemed possibly, probably, or definitely related to 
the study treatment or procedure. 
 
10.642 
Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure 
 
10.643 
Grade 5 AEs (Deaths) 
 
10.6431 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the 
study treatment or procedure requires the submission of an 
Expedited Adverse Event report (see Section 10.4). 
 
10.6432 
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 with an Expedited 
Adverse Event report (see Section 10.4). 
 
10.65 Late Occurring Adverse Events 
 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
Investigations 
alkaline phosphatase 
increased1 
X 
X 
 
Metabolism and 
nutrition 
disorders 
Hyperglycemia1 
X 
X 
 
Musculoskeletal 
and connective 
tissue disorders 
Back pain1 
X 
X 
 
 
Onycholysis1 
X 
X 
 
Infections and 
Infestations 
Paronychia1 
X 
X 
 
Musculoskeletal 
and connective 
tissue disorders 
Arthralgia1 
X 
X 
 
Metabolism and 
nutrition 
disorders 
Hyponatremia1 
X 
X 
 
Skin and 
subcutaneous 
tissue disorders 
Nail discoloration1 
X 
X 
 


 
39  
ACCRU-ICRN-1701 
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, 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 4 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 t2.0 cm with chest x-UD\RUDVFPZLWK
CT scan, CT component of a PET/CT, or MRI.  
 
11.212 
A superficial non-nodal lesion is measurable if its longest diameter is 
FPLQGLDPHWHUDVDVVHVVHGXVLQJFDOLSHUVHJVNLQQRGXOHVRU
imaging. In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is 
recommended. 
 
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 considered 
measurable disease under the following conditions: 
 
x 
Evidence of progression exists following completion of 
radiation therapy 
 
11.22 Non-Measurable Disease 
 
11.221 
All other lesions (or sites of disease) are considered non-measurable 
GLVHDVHLQFOXGLQJSDWKRORJLFDOQRGHVWKRVHZLWKDVKRUWD[LVWR
<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 


 
40  
ACCRU-ICRN-1701 
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:  
 
x 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
 
x 
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 1 cm to <2 cm CT imaging 
must be used for both pre- and post-treatment tumor assessments.  
 
x 
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:  
 
x 
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.  
 
x 
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 
acquisition protocol should be followed as closely as possible to prior scans. 
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
x 
PET-CT: If the site can document that the CT performed as part of a PET-CT 
is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  
 
x 
FDG-PET: FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' disease. 
A ‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid 
with an update greater than twice that of the surrounding tissue on the 
attenuation corrected image; otherwise, an FDG-PET scanned lesion is 
considered ‘negative.’ New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
 


 
41  
ACCRU-ICRN-1701 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
 
b.  No FDG-PET at baseline and a positive FDG-PET at follow-up:  
 
i. 
If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  
 
ii. If the positive FDG-PET at follow-up is not confirmed as a new site 
of disease on CT at the same evaluation, additional follow-up CT 
scans (i.e., additional follow-up scans at least 4 weeks later) are 
needed to determine if there is truly progression occurring at that site. 
In this situation, the date of PD will be the date of the initial abnormal 
PDG-PET scan.  
 
iii. If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the 
anatomic images, it is not classified as PD. 
 
11.33 Measurement at Follow-up Evaluation:  
 
x 
In the case of stable disease (SD), follow-up measurements must have met the 
SD criteria at least once after study entry at a minimum interval of 8 weeks 
(see Section 11.44). 
 
x 
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. 
 
x 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases (e.g., residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain.) 
 
11.4 
Measurement of Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
x 
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, 
there is no reason to perform additional studies beyond those specified in the 
protocol to discover new lesions.  
 
x 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, and in addition should 


 
42  
ACCRU-ICRN-1701 
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.  
 
x 
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.  
 
x 
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 
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. 
 
x 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and 
the PBSD. 
 
11.42  Non-Target Lésions & 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/PET-
CT 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. 
 
 
 
 
 


 
43  
ACCRU-ICRN-1701 
11.432 
Evaluation of Target Lesions 
 
x Complete Response (CR): All of the following must be true: 
 
a. Disappearance of all target lesions. 
b. Each target lymph node must have reduction in short axis to 
<1.0 cm. 
 
x 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). 
 
x 
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) 
DQGLQFUHDVHGWRFPVKRUWD[LVGXULQJIROORZ-up.  
 
b. 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.  
 
c. See Section 11.32 for details in regards to the requirements for 
PD via FDG-PET imaging. 
  
x 
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 
 
x 
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. 
 
x 
Non-CR/Non-PD: Persistence of one or more non-target lesions or 
non-target lymph nodes. 
 
x 
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 WR1.0 cm short axis during follow-up.  
 


 
44  
ACCRU-ICRN-1701 
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.)  
  
c. See Section 11.32 for details in regards to the requirements for 
PD via FDG-PET imaging. 
 
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:  
 
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 


 
45  
ACCRU-ICRN-1701 
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: 
 
x 
Worsening of tumor-related symptoms. 
x 
Decline in performance status of >1 level on ECOG scale. 
 
12.0 
Descriptive Factors  
 
12.1 
Cohort: Safety Run-In vs. Expansion  
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
 
 
13.1 
Patients who are CR, PR, or SD will continue treatment per protocol until disease 
progression. Subsequent treatment is at the discretion of their attending physician. 
 
13.2 
Patients who develop PD at any time should go to event monitoring. These patients 
should be treated with alternative therapy if their clinical status is good enough to allow 
further therapy at treating physician’s discretion. 
 
13.3     Patients who stop gemcitabine and/or cisplatin for reasons other than progression may 
continue on study drug until progression. 
 
 
13.4 
Event Monitoring is not part of the Active Monitoring phase of a study and is defined as 
the time period when the participant is no longer following the protocol test schedule. 
During Event Monitoring, the data collection schedule is dictated by the protocol but the 
visit schedule is determined by clinical practice at each participating site. During the 
Event Monitoring Phase of the study, the participant is being monitored for key study 
events such as progression, new primaries, and death. Event monitoring should occur 
every 6 months (± 30 days) until death or a maximum of 36 months from Registration. 
Phone,, or virtual visits are permitted during Event Monitoring. 
 
13.5 
Follow-up Decisions during Active Treatment 
 
Status During Treatment 
Go To… 
Complete response (CR), partial 
response (PR), stable disease 
(SD) 
Continue protocol treatment 
Off treatment for disease 
progression, alternative therapy, 
or withdrawal/refusal of treatment 
Survival  follow up/event monitoring 
Event Monitoring every 6 months (± 30 
days) until death or up to 60 months 
from Registration per Section 18.0 
Off treatment for any reason 
other than progression, 
alternative therapy, or 
withdrawal/ refusal of treatment 
Survival follow up / Event monitoring 6 
months (± 30 days) until death or up to 
60 months from Registration per Section 
18.0 
Death or withdrawal/refusal of 
follow-up 
No further follow-up 


 
46  
ACCRU-ICRN-1701 
13.6 
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).  
 
x 
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.  
 
13.7 
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. 
 
13.8 
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. 
 
14.0 
Body Fluid Biospecimens  
 
14. 1 
Blood/Blood Products Handling 
 
14.11 Kits will not be provided for this study. 
 
 NOTE: Below are acceptable use cryovials for the repository.  The site is 
responsible for ordering the cryovials. 
 
 
Storage Conditions: -80°C & LN2 
Manufacturer (Cat#): 
Capacity: 
Expected Sample 
Type(s): 
Manufacturer’s 
specifications: 
Corning (430659) 
2 mL 
Calls, Plasma, Serum 
2 mL Cryo 
(External Thread) 
Corning (430488) 
2 mL 
Cells, Plasma, Serum, 
Tissue 
2 mL Cryo (Internal 
Thread) 
Sarstedt (72.694.107) 
2 mL 
DNA, Plasma, Serum, 
Whole Blood, WBC 
2 mL Micro Tube 
Thermo Scientific 
(5000-0020) 
2 mL 
Cells, Plasma, Serum, 
Whole blood 
Cryogenic tubes 
Fisher Scientific (02-
707-361) 
2 mL 
CSF, Plasma, Serum, 
WBC, Whole blood 
2 mL Micro Tube 
 
 
 
 
 


 
47  
ACCRU-ICRN-1701 
14.12 All samples must be collected Monday-Friday. 
 
14.13 Institution can use their own label. Specimen label must include the 
following unique identifiers: 
x 
Study # 
x 
Analyte Name (e.g., ivosidenib, 2-HG) 
x 
Subject ID,  
x 
Group, if applicable,  
x 
Nominal timepoint (cycle, day),  
x 
Nominal time, if serial collections occurred within one visit 
 
Generic label 
x 
If the generic label is acceptable and your institution requires no changes, 
please complete the “Investigator Sponsored Trial Label Approval Form” 
located on the ACCRU Website and return to Agios. Once accepted, 
immediate supply availability is subject to mutual agreement of 
timelines, quantities, and availability of study protocol. 
x 
If the generic label is not acceptable, please complete the “Investigator 
Sponsored Trial Label Approval Form” located on the ACCRU website 
and return to Agios in addition to the Sponsor’s specific label 
requirements. The Sponsor may provide their specific label requirements 
in three ways: 
x 
Specify within the “Investigator Sponsored Trial Label Approval Form”, 
Section B. 
x 
Make adjustments within the attached word version with track changes 
enabled.  
x 
Or if the sponsor has their own required label text document, Agios can 
review this on a case by case as well. 
 
NOTE: It can take up to 8 weeks for a new label to be made if the generic label is 
not acceptable to your institution. 
 
NOTE: A sample inventory form / requisition form must accompany the samples 
and shall also include the nominal and actual date and time of each blood sample 
drawn as well as contact information, should the lab have questions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
48  
ACCRU-ICRN-1701 
14.14 
Collect and process all blood/blood products according to the table 
below. 
 
14.141 
Summary Table of Research Blood/Blood Products to Be 
Collected for This Protocol  
 
Applicable 
Arms 
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 
 
days 
prior to 
registra
tion 
and 
Cycle 4 
Day 1 
and 
every 9 
weeks  
(+/- 2 
days) 
Additional 
processing 
required 
at site 
after blood 
draw? 
Storage 
/shipping 
conditions1 
ivosidenib 
and 2-HG 
Analysis 
Mandatory 
K2 EDTA 
(purple 
top) 
6 mL 
(1) 
plasma 
X 
Yes 
Freeze (-80 C)dry 
ice 
1. After all samples have been processed, ship all specimens per processing and shipping 
instructions. 
Processing Instructions: 
1) Blood will be collected in each K2EDTA tube by direct venipuncture.  Gently invert the tube 
approximately 8-10 times.  
2) The date and time of each blood sample drawn will be recorded on the sample requisition.  
3) The blood is required be processed in a timely manner. The time from collection to centrifuge 
should not exceed 60 minutes.       
4)   Blood samples will be cooled by an ice bath or equivalent until processed and centrifuged at   
approximately 1500g at 2-8°C for approximately 15 minutes5)   If plasma cannot be separated 
immediately into cryovials, they can be placed into an ice bath or equivalent.       
5)   Using a pipette, the plasma will be evenly divided into two 2 mL labeled cryovials for each analyte 
(one primary and one backup each for PD sample(s)) and maintained in the ice bath. Preferred 
volume is approximately 0.5 mL of plasma in each aliquot tube. If there is a short blood draw, please 
fill primary cryovials first. 
6)   Plasma samples will then be stored and frozen at -80 °C ± 10 °C until shipment to BAP labs. 
7)   The time between sample collection and placement in freezer should not exceed 120 minutes. 
 
14.2 
Shipping 
 
14.21 Verify ALL sections of the Blood Specimen Submission Form (see Forms 
Packet), Requisition Form (provided in kit), and specimen collection labels are 
completed and filled in correctly. 
 
All sample shipments should be preceded by an email, phone call or fax prior to 
their receipt. All HIV positive or other known infectious sample shipments must 
be preceded by a phone call or facsimile prior to their receipt. 
 
NOTE:  Detailed sample inventory information must accompany the samples.  


 
49  
ACCRU-ICRN-1701 
Lack of paperwork or illegible information will delay sample login and project 
initiation. Samples that are unclearly or incompletely labeled may not be able to 
be analyzed. Submission of sample inventory information in electronic form is 
encouraged. 
 
14.22 Specimens must be shipped the Monday through Wednesday ONLY. 
 
14.23 Ship Plasma aliquots tubes via Priority Overnight service frozen on dry ice.   
 
14.24 Ship specimens via Priority Overnight service, Monday-Wednesday to PPD 
Receiving according to kit instructions. Do not send samples on weekends or 
just prior to federal holidays. 
 
Ship samples to: PPD 
 
 
 
 
 
 
 
14.3 
Study Methodology and Storage Information 
 
14.31 Blood/blood product samples will be collected for the following research  
 
14.311 2-HG will be measured from plasma samples obtained in K2EDTA tubes. 
Analysis of 2-HG will be performed using a qualified LC-MS/MS (liquid 
chromatography tandem mass spectrometry) method. ivosidenib will be 
measured from plasma samples obtained in K2EDTA tubes. Analysis of 
ivosidenib will be performed using a validated LC-MS/MS method. 
 
14.4 
Return of Genetic Testing Research Results 
 
 
No genetic specimens will be collected from non-slid tissue (body fluid) biospecimens 
for this study. If future genetic testing is being requested for stored specimens, patient 
reconsent is required. 
 
15.0 
Drug Information 
 
 
IND number 144189 
Investigator brochures: Investigator brochures for both agents are available on the ACCRU web 
site under study ACCRU-ICRN-1701. 
 
15.1 Ivosidenib (AG-120):  
 
15.11  Background: Ivosidenib (AG-120; also formerly known as AGI-16678) is a 
potent, selective, orally active small molecule inhibitor of mutated isocitrate  
dehydrogenase 1 (IDH1). Isocitrate dehydrogenase is a critical enzyme in the 
citric acid cycle catalyzing the oxidative decarboxylation of isocitrate to produce 
carbon dioxide (CO2) and alpha-NHWRJOXWDUDWHĮ-KG). 


 
50  
ACCRU-ICRN-1701 
15.12 Formulation: Ivosidenib is supplied as 50 mg, 200 mg, and 250 mg strength 
uncoated tablets, and as 250 mg strength film-coated (blue) tablets for oral 
administration.  Ivosidenib 50 mg, 200 mg, and 250 mg tablets contain the 
inactive ingredients hypromellose acetate succinate, microcrystalline cellulose, 
croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and 
magnesium stearate.  Ivosidenib 250 mg film-coated tablets also include the 
inactive ingredient Opadry® II Blue.  
 
15.13 Preparation and storage:  The recommended storage conditions and expiry 
(where required) are stated on the product label. 
 
15.14 Administration:  Subjects may take ivosidenib tablets with or without food.  To 
minimize the effects of a high-fat meal on ivosidenib exposure, subjects should 
avoid consuming a high-fat meal when ivosidenib is administered with food.  All 
subjects will also be advised to avoid grapefruit and grapefruit products. 
 
 
15.15 Pharmacokinetic information: 
Absorption:  Ivosidenib was rapidly absorbed following both single and multiple 
dosing (median Tmax from 1.92 to 4.0 hours on C2D1 of dose escalation) across 
the dose range studied. After reaching a peak, mean concentrations of ivosidenib 
declined in a bi-exponential manner, with a mean t½ of 71.8 to 138 hours after 
single dosing in Study AG120-C-001. 
Metabolism:  Predominantly metabolized by CYP3A4.  Following 
administration with itraconazole, ivosidenib exposure was increased ~2.6-
fold. 
 
Excretion:  Fecal excretion appeared to be the predominant route of 
elimination of the administered radioactive dose with an observed mean recovery 
of total radioactivity in urine and feces of 16.9% and 77.4%, respectively, over 
15 days post dose in Study AG120-C-003. 
 
15.16 Potential Drug Interactions:   
In vitro studies showed that ivosidenib is predominantly metabolized by 
CYP3A4 and therefore, coadministration with inhibitors or inducers of CYP3A4 
has the potential to affect ivosidenib exposure. Co-administration of 250 mg 
ivosidenib with a strong CYP3A4 inhibitor 
(itraconazole) increased single-dose AUC of ivosidenib by 169% with no change 
in Cmax. Based on physiologically-based pharmacokinetic (PBPK) simulations, 
coadministration with ivosidenib and a strong CYP3A4 inhibitor (itraconazole) 
or moderate CYP3A4 inhibitor (fluconazole) is predicted to increase ivosidenib 
steady-state Cmax by up to 52% and AUC by up to 90%.  Increased ivosidenib 
plasma concentrations may increase the risk of QTc interval prolongation. 
Consider alternative therapies that are not strong or moderate CYP3A4 inhibitors 
during treatment with ivosidenib. If concomitant use of strong or moderate 
CYP3A4 inhibitors (e.g., strong inhibitors such as: posaconazole, voriconazole, 
itraconazole, erythromycin, clarithromycin, and moderate inhibitors such as: 
fluconazole, erythromycin, isavuconazole, diltiazem, and grapefruit juice) is 
unavoidable, monitor subjects for increased risk of QTc interval prolongation. 
Based on a PBPK simulation, coadministration of ivosidenib with a strong 
CYP3A4 inducer (rifampin) is predicted to decrease ivosidenib steady-state AUC 
by 33% and Cmax by 19%. Avoid coadministration of strong CYP3A4 inducers 
with ivosidenib. 


 
51  
ACCRU-ICRN-1701 
 
Ivosidenib is an inducer of CYP3A4 and may also induce CYP2B6, CYP2C8, 
and CYP2C9. Coadministration of ivosidenib with narrow therapeutic index 
drugs that are extensively metabolized by CYP3A4 (e.g., cyclosporine, fentanyl, 
everolimus, tacrolimus, sirolimus) or 
CYP2C9 (e.g., phenytoin, warfarin) may result in decreased concentrations of 
these drugs.  Investigators should consider alternative therapies that are not 
sensitive substrates of CYP3A4 or CYP2C9 during treatment with ivosidenib. 
Subjects should be monitored for loss of therapeutic effect of these medications if 
coadministration with ivosidenib cannot be avoided. International normalized 
ratio (INR) levels should be monitored more frequently in subjects receiving 
warfarin (a CYP2C9 substrate) during initiation or discontinuation of ivosidenib. 
Coadministration of ivosidenib may decrease the concentrations of 
hormonal contraceptives.  
 
 
15.17 Known potential toxicities: 
 
Adverse Events Occurring in >10% of Subjects Overall in Study 
AG120-C-001: 
Diarrhea, fatigue, nausea, leukocytosis, febrile neutropenia, dyspnea, 
anemia, oedema peripheral, QT prolongation, pyrexia, cough, decreased 
appetite, arthralgia, constipation, hypokalemia, vomiting, dizziness, back 
pain, epistaxis, thrombocytopenia, pneumonia, headache, 
hypomagnesemia, rash, asthenia, abdominal pain, hypotension, IDH 
differentiation syndrome, hyperuricemia, pain in extremity, insomnia, 
stomatitis, chest pain, pleural effusion and pruritis. 
Adverse Events Occurring in >10% of Subjects Overall in Study 
AG120-C-002: 
Fatigue, nausea, diarrhea, vomiting, headache, decreased appetite, 
abdominal pain, oedema peripheral, anemia, constipation and back pain. 
Adverse Events Occurring in >10% of Subjects Overall in 
Study AG120-881-C-001: 
Diarrhea, hypocalcemia, anemia, hyperglycemia, pruritus, constipation, 
dysarthria, dysphagia, headache, hypokalemia, nausea, rash, seizure, 
tremor and WBC count decreased. 
Adverse Events Occurring in >10% of Subjects in Study AG120-C-005 After 
Crossover to ivosidenib: 
Diarrhea, nausea, anemia, ascites, fatigue, constipation, cough, decreased 
appetite and oedema peripheral. 
 
15.18 Drug procurement:   
Agios will supply ivosidenib to McKesson Specialty Pharmacy’s Clinical 
Research Services. Each participating ACCRU treating location will order the 
drug from McKesson Specialty Pharmacy’s Clinical Research Services.  Fax or 
email the Drug Order Request Form (found on the ACCRU web site) to:  
  
 
 
Each participating ACCRU treating location will be responsible for monitoring 
the supply of ivosidenib and will use the Drug Order Request Form to order 
additional supplies as needed.  


 
52  
ACCRU-ICRN-1701 
 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
 
15.19 Nursing Guidelines  
 
15.191 Ivosidenib has many drug to drug interactions. Assess patient’s 
concurrent medications, including OTC medications and supplements 
15.192 Gastrointestinal toxicity is the most commonly seen class of side effects 
with ivosidenib. Treat symptomatically and assess for effectiveness. 
 
15.193 Patients with hematologic malignancies were more likely to experience 
grade 3 or higher toxicity versus those with solid tumors. 
 
15.194 Hematologic toxicities were common. Monitor CBC w/diff. Instruct 
patient to report any unusual bruising or bleeding and/or signs/symptoms 
of infection to the study team. 
 
15.195 Patients may experience QT prolongation.  Monitor ECG per protocol 
recommendations. Use caution with other agents that may prolong the 
QTc interval. 
 
15.196 Rarely patients may experience Guillain-Barre Syndrome or 
leukoencephalopathy. Instruct patients to report any new neurologic 
symptoms to the study team immediately. 
 
15.197 Patients can experience dehydration with electrolyte abnormalities. 
Monitor chemistry panel as ordered per protocol.  
15.2 Pemigatinib (INCB054828):  
 
15.21  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. 
 
15.22 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. 
 
15.23 Preparation and storage:  Pemigatinib should be stored as detailed on the 
investigational product labeling. 
 


 
53  
ACCRU-ICRN-1701 
15.24 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.  
 
15.25 Pharmacokinetic information: 
Time to peak, serum:  0.5 - 6 hours  
Clearance:  11.2 L/hour 
Distribution:  Volume of distribution – 151 L    
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):  20.2 hours 
 
 
15.26 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%.%. Thus, concomitant 
use of moderate CYP3A4 inducers and potent CYP3A4 inducers or inhibitors are 
prohibited. The use of moderate CYP3A4 inhibitors are not prohibited but should 
involve careful monitoring. 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 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. 
 
 
15.27 Known potential toxicities: 
Summary of Treatment-(PHUJHQW$GYHUVH(YHQWV5HSRUWHGLQRI
Participants in Studies INCB 54828-101, INCB 54828-201 and INCB 54828-
202: Hyperphosphatemia, fatigue, dry mouth, alopecia, constipation, stomatitis, 
diarrhea, nausea, decreased appetite, dysgeusia, anemia, abdominal pain, 
vomiting, dry eye, weight decreased, arthralgia. 
Common (1 to < 10%): nail toxicity 
 
 
15.28 Drug procurement:   
Incyte will supply the drug order form for pemigatinib (INCB054828) to 
participating sites.  Sites are to complete the Investigational Supplies Shipment 
and Receipt Verification Form and email to: 
 


 
54  
ACCRU-ICRN-1701 
 
Each participating ACCRU treating location will be responsible for monitoring 
the supply of pemigatinib (INCB054828) and will use the Drug Order Request 
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. 
 
15.29b Nursing Guidelines 
 
15.291  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. 
15.292 Gastrointestinal side effects can be seen including nausea, vomiting, 
constipation, and diarrhea. Treat symptomatically and monitor for 
effectiveness. 
15.293   Monitor LFT’s.  Report elevated LFT’s to the treating provider.  
15.294  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. 
15.295  Patients may report fatigue, monitor hemoglobin as anemia can be seen. 
Instruct patients on energy conserving lifestyle.  
15.296 Pemigatinib may be administered with or without food. 
 
15.3 
Cisplatin (Platinol®) 
 
Please refer to the FDA-approved package insert for cisplatin for product information, 
extensive preparation instructions, and a comprehensive list of adverse events. 
 
15.31 Background 
 
Cisplatin inhibits DNA synthesis by the formation of DNA cross-links; denatures 
the double helix; covalently binds to DNA bases and disrupts DNA function; 
may also bind to proteins. Cisplatin can also bind two adjacent guanines on the 
same strand of DNA producing intrastrand cross-linking and breakage. 
 
15.32 Formulation 
 
Commercially available for injection as: Solution [preservative free]: 1 mg/mL 
(50 mL, 100 mL, 200 mL) 
 
15.33 Preparation, Storage, and Stability 
 
Refer to package insert for complete preparation and dispensing instructions. 
Store intact vials at room temperature and protect from light. Do not refrigerate 
solution, a precipitate may form. Further dilution stability is dependent on the 
chloride ion concentration and should be mixed in solutions of sodium chloride 
concentrations at least 0.3% NaCl. Further dilutions in 0.9% NaCl, D5/0.45% 
NaCl, or D5/0.9% NaCl to a concentration of 0.05-2 mg/mL are stable for 72 
hours at 4ºC to 25ºC. The infusion solution should have a final sodium chloride 
concentration equal to or greater than 0.2% NaCl. 
 


 
55  
ACCRU-ICRN-1701 
15.34 Administration 
 
Refer to the treatment section for specific administration instructions. When 
administered as sequential infusions, observational studies indicate a potential for 
increased toxicity when platinum derivatives (carboplatin, cisplatin) are 
administered before taxane derivatives (docetaxel, paclitaxel). Pretreatment 
hydration with 1-2 L of fluid is recommended prior to cisplatin administration; 
adequate hydration and urinary output (> 100 mL/hour) should be maintained for 
24 hours after administration. Hydration may be accomplished by adding the 
appropriate dose of cisplatin to 750 mL 0.5 D5/0.45% NaCl with 25 grams of 
Mannitol (approximating 1000 mL final volume) and infused over 2 hours. The 
IV rate of administration has varied from a 15- to 120-minute infusion, 1 
mg/minute infusion, 6- to 8-hour infusion, 24-hour infusion, or per protocol; 
maximum rate of infusion of 1 mg/minute in patients with CHF. 
 
15.35 Pharmacokinetic Information 
 
Distribution: Rapidly into tissue; high concentrations in kidneys, liver, ovaries, 
uterus, and lungs 
 
Protein binding: >90% 
 
Metabolism: Nonenzymatic; inactivated (in both cell and bloodstream) by 
sulfhydryl groups; covalently binds to glutathione and thiosulfate 
 
Half-life elimination: Initial: 20-30 minutes; Beta: 60 minutes; Terminal: ~ 24 
hours; Secondary half-life: 44-73 hours 
 
Excretion: Urine (>90%); feces (10%) 
 
15.36 Potential Drug Interactions 
 
Increased Effect/Toxicity: Delayed bleomycin elimination with decreased 
Glomerular filtration rate. When administered as sequential infusions, 
observational studies indicate a potential for increased toxicity when platinum 
derivatives (carboplatin, cisplatin) are administered before taxane derivatives 
(docetaxel, paclitaxel). 
 
Decreased Effect: Sodium thiosulfate and amifostine theoretically inactivate 
drug systemically; have been used clinically to reduce systemic toxicity with 
administration of cisplatin. 
 
Herb/Nutraceutical Interactions: Avoid black cohosh, dong quai in estrogen-
dependent tumors. 
 
15.37 Known Potential Adverse Events 
 
Consult the package insert for the most current and complete information.  
 
Common known potential toxicities, > 10%:   
Central nervous system: Neurotoxicity: Peripheral neuropathy is dose and 


 
56  
ACCRU-ICRN-1701 
duration dependent 
Dermatologic: Mild alopecia 
Gastrointestinal: Nausea and vomiting  
Hematologic: Anemia, leukopenia (nadir day 18-23, recovery by day 39, dose 
related), thrombocytopenia (nadir day 18-23, recovery by day 39, dose related) 
Hepatic: Liver enzymes increased 
Renal: Nephrotoxicity (acute renal failure and chronic renal insufficiency) 
Otic: Ototoxicity, manifested as high frequency hearing loss; ototoxicity is 
especially pronounced in children 
 
Less common known potential toxicities, 1% - 10%:  
Local: Tissue irritation 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Alopecia, ageusia, anaphylaxis, aortic thrombosis, autonomic neuropathy, 
bradycardia, cardiac arrhythmia, cardiac failure, cerebrovascular accident, 
extravasation, hemolytic anemia (acute), hemolytic-uremic syndrome, hiccups, 
hypercholesterolemia, hyperuricemia, hypocalcemia, hypokalemia, 
hypomagnesemia, hyponatremia, hypophosphatemia, increased serum amylase, 
leukoencephalopathy, myocardial infarction, neutropenic enterocolitis, optic 
neuritis, pancreatitis, papilledema, peripheral ischemia (acute), phlebitis, SIADH, 
tachycardia, thrombotic thrombocytopenic purpura 
 
15.38 Drug Procurement 
 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal 
commercial supply chain or wholesaler. 
 
15.39 Nursing Guidelines 
 
15.391 
May react with aluminum IV set, forming a black precipitate and 
losing its potency. 
 
15.392 
Assess laboratory values prior to drug administration, especially CBC, 
platelets, creatinine. 
 
15.393 
Patient should be hydrated before administration. Stress post infusion 
hydration maintenance to reduce risk of nephrotoxicity. 
 
15.394 
Administer aggressive antiemetic therapy pre- and post-treatment. 
 
15.395 
Monitor for signs of neurotoxicity and ototoxicity. Instruct patient to 
report any numbness, burning, or tingling in hands and feet to health 
care team. Also instruct patient to report any changes in hearing or 
ringing in the ears to health care team. 
 
15.396 
Monitor magnesium and potassium levels, and for signs and symptoms 
of hypomagnesemia and hypokalemia, supplements may be needed. 
15.397 
Instruct patient about alopecia. 
 


 
57  
ACCRU-ICRN-1701 
15.398 
Use cautiously with loop diuretics as these may increase the risk of 
ototoxicity. 
 
15.39a 
Monitor for signs and symptoms of allergic reactions. Treat according 
to institutional practice. 
 
15.39b 
Monitor renal function tests. 
 
15.4 
Gemcitabine (Gemzar®) 
 
Please refer to the FDA-approved package insert for gemcitabine for product information, 
extensive preparation instructions, and a comprehensive list of adverse events. 
 
15.41 Background 
 
Gemcitabine is a pyrimidine antimetabolite that inhibits DNA synthesis by 
inhibition of DNA polymerase and ribonucleotide reductase, specific for the S-
phase of the cell cycle. Gemcitabine is phosphorylated intracellularly by 
deoxcytidine kinase to gemcitabine monophosphate, which is further 
phosphorylated to active metabolites gemcitabine diphosphate and gemcitabine 
triphosphate. Gemcitabine diphosphate inhibits DNA synthesis by inhibiting 
ribonucleotide reductase; gemcitabine triphosphate incorporates into DNA and 
inhibits DNA polymerase. 
 
15.42 Formulation 
 
Commercially available for injection: 
Powder for reconstitution: 200 mg and 1 gram vials. 
Solution for injection: 38 mg/mL 200 mg, 1 gm, and 2 gm vials. MUST BE 
DILUTED BEFORE USE. 
 
15.43 Preparation, Storage, and Stability 
 
Powder for reconstitution 
Store intact vials at room temperature. Reconstitute the 200 mg vial with 
preservative free 0.9% NaCl 5 mL or the 1000 mg vial with preservative free 
0.9% NaCl 25 mL. Resulting solution is 38 mg/mL. Dilute with 50-500 mL 0.9% 
NaCl or D5W to concentrations as low as 0.1 mg/mL. Reconstituted vials are 
stable for up to 35 days and infusion solutions diluted in 0.9% NaCl are stable up 
to 7 days at 23ºC when protected from light; however, the manufacturer 
recommends use with 24 hours for both reconstituted vials and infusion 
solutions. Do not refrigerate. 
 
Solution for injection 
Store intact vials at refrigeration temperature between 2º to 8ºC (36º to 46ºF). Do 
not freeze. Each vial contains a gemcitabine concentration of 38 mg/mL. The 
appropriate amount of drug should be further diluted with 50-500 mL 0.9% 
NaCL or D5W to concentrations as low as 0.1 mg/mL. When prepared as 
directed, diluted gemcitabine solutions are stable for 24 hours at controlled room 
temperature.  
 


 
58  
ACCRU-ICRN-1701 
15.44 Administration 
 
Refer to the drug treatment section of the protocol for specific administration 
directions and infusion rates. Gemcitabine is normally infused IV over 30 
minutes. NOTE: Prolongation of the infusion time > 60 minutes has been shown 
to increase toxicity. Gemcitabine is being investigated in clinical trials for fixed 
dose rate infusion administration at doses from 1000 mg/m2 to 2200 mg/m2 at a 
rate of 10 mg/m2/minute. Prolonged infusion times increase the accumulation of 
the active metabolite, gemcitabine triphosphate. Patients who receive 
gemcitabine fixed dose rate infusions experience more grade three and four 
hematologic toxicities. 
 
15.45 Pharmacokinetic Information 
 
Distribution: Infusions <70 minutes: 50 L/m2; Long infusion times: 370 L/m2 
 
Protein binding: Negligible 
 
Metabolism: Metabolized intracellularly by nucleoside kinases to the active 
diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleoside metabolites 
 
Half-life elimination:  
*HPFLWDELQH,QIXVLRQWLPHPLQXWHV-94 minutes; infusion time 3-4 
hours: 4-10.5 hours 
Metabolite (gemcitabine triphosphate), terminal phase: 1.7-19.4 hours 
 
Time to peak, plasma: 30 minutes after completion of infusion 
Excretion: Urine (92% to 98%; primarily as inactive uridine metabolite); feces 
(<1%) 
 
15.46 Potential Drug Interactions 
 
Increased Effect/Toxicity: Gemcitabine may increase the levels/effects of 
fluorouracil. Gemcitabine may enhance the adverse pulmonary effects of 
bleomycin. 
 
Ethanol/Nutrition/Herb Interactions Ethanol: Avoid ethanol (due to GI 
irritation). 
 
15.47 Known Potential Adverse Events 
 
Consult the package insert for the most current and complete information.  
 
Common known potential toxicities, > 10%:   
Cardiovascular: Peripheral edema, edema 
Central nervous system: Drowsiness 
Dermatologic: Skin rash, alopecia 
Gastrointestinal: Nausea/vomiting, diarrhea, stomatitis 
Hematologic: Anemia, thrombocytopenia, neutropenia, hemorrhage Hepatic: 
Transaminases increased, alkaline phosphatase increased, bilirubin increased 
Infection:  Infection 


 
59  
ACCRU-ICRN-1701 
Renal: BUN increased 
Respiratory: Dyspnea, flu-like symptoms 
Miscellaneous: Fever 
Less common known potential toxicities, 1% - 10%:  
Central nervous system:  Paresthesia 
Local: Injection site reactions 
Renal: Creatinine increased 
Respiratory: Bronchospasm 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Adult respiratory distress syndrome, anaphylactoid reaction, anorexia, arthralgia, 
bullous skin disease, capillary leak syndrome, cardiac arrhythmia, cardiac failure, 
cellulitis, cerebrovascular accident, constipation, desquamation, digital vasculitis, 
gangrene of skin or other tissue, hemolytic-uremic syndrome, hepatic failure, 
hepatic veno-occlusive disease, hepatotoxicity (rare), hyperglycemia, 
hypertension, hypocalcemia, hypotension, increased gamma-glutamyl 
transferase, interstitial pneumonitis, myocardial infarction, neuropathy, 
petechiae, pulmonary edema, pulmonary fibrosis, radiation recall phenomenon, 
renal failure, respiratory failure, reversible posterior leukoencephalopathy 
syndrome, sepsis, supraventricular cardiac arrhythmia, thrombotic 
thrombocytopenic purpura  
 
15.48 Drug Procurement 
 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal 
commercial supply chain or wholesaler. 
 
15.49 Nursing Guidelines 
 
15.491 
Monitor CBC, differential, PLTs prior to each dose.  Myelosuppression 
is the principal dose-limiting factor.  Modification may be considered 
by physician when bone marrow suppression is suspected. 
 
15.492 
Evaluate hepatic and renal function prior to initiation of therapy and 
periodically thereafter.  Closely observe those patients with a history of 
preexisting mild renal impairment or hepatic insufficiency.  Encourage 
hydration. 
 
15.493 
GEMZAR clearance is affected by age and gender.  Grade 3/4 
thrombocytopenia has been more common in elderly women. 
 
15.494 
Antiemetics may be required for probable mild to moderate nausea and 
vomiting. Assess for their effectiveness. 
 
15.495 
Instruct patient in management of possible mild diarrhea and 
stomatitis. 
 
 
 
 


 
60  
ACCRU-ICRN-1701 
15.496 
GEMZAR may cause fever in the absence of clinical infection.  Fever 
can be accompanied by other flu-like symptoms.  Instruct patient to 
report fever or flu-like symptoms to healthcare team.  Treat symptoms 
as they occur. 
 
15.497 
Macular or finely granular maculopapular eruptions were experienced 
by 30% of patients tested.  Instruct patients to report any skin changes. 
 
15.498 
Instruct patient to report any respiratory changes. 
 
15.499 
Burning may occur at the injection site. May apply heat during 
infusion to minimize pain. 
 
16.0 Statistical Considerations and Methodology 
 
16.1 
Study Design:  
This phase Ib dose de-escalation study is designed to assess safety and tolerability of 
ivosidenib or pemigatinib in combination with cisplatin and gemcitabine in patients with 
advanced or metastatic cholangiocarcinoma. 
 
There will be a separate Phase Ib arm and safety run-in cohort for each group: patients 
with a known IDH1 R132 mutation (ivosidenib, gemcitabine, cisplatin - Treatment Arm 
A) and patients with FGFR genetic alteration (pemigatinib, gemcitabine, cisplatin - 
Treatment Arm B). The design of each of these Phase Ib arms is identical.  
16.11 Primary Endpoint:  
The primary endpoint of this trial is the safety and tolerability of the regimen as 
measured by the incidence of significant toxicity A significant toxicity (dose 
limiting toxicity, DLT) is defined in Section 7.53 that is possibly, probably, or 
definitely related to treatment ( ivosidenib or pemigatinib in combination with 
cisplatin and gemcitabine). 
16.12 Safety Run-In Cohorts: 
To ensure safety of treating patients with ivosidenib or pemigatinib in 
combination with cisplatin and gemcitabine, an initial 6 patients will be enrolled 
for each arm and treated for adverse events assessment. These patients will be 
enrolled in a cohort of 6+6 design. 
IDH1 R132 Mutation Arm (Ivosidenib):  
The first cohort of 6 patients for the IDH1 R132 mutation arm will receive 500 
mg ivosidenib (dose level 0). If less than 2 patients in this first cohort experience 
a DLT (See Section 7.53), then 500 mg of  ivosidenib (dose level 0) will be the 
recommended phase II dose and the study will continue to enroll to the accrual 
goal. 
If DLTs are observed in two or more patients in the initial cohort of 6 (at dose 
level 0) then an additional 6 patients will be enrolled to dose level -1 and will 
receive 250 mg of ivosidenib. If less than 2 patients enrolled at 250 mg of  
ivosidenib(dose level -1) experience DLTs then the recommended Phase II dose 
will be 250 mg of ivosidenib (dose level -1) and the study will continue to enroll 
to the accrual goal. If 2 or more patients enrolled at 250 mg ivosidenib (dose 


 
61  
ACCRU-ICRN-1701 
level -1) experience DLTs then the study team will temporarily suspend accrual 
and review the toxicity data.  
FGFR genetic Alterations Arm (Pemigatinib): The first cohort of 6 patients for 
the FGFR genetic alterations arm will receive 13.5 mg Pemigatinib (dose level 
0). If less than 2 patients in this first cohort experience a DLT (See Section 0), 
then 13.5 mg of Pemigatinib will be the recommended phase II dose and the 
study will continue to enroll to the accrual goal. 
If DLTs are observed in two or more patients in the initial cohort of 6 (at dose 
level 0), then an additional 6 patients will be enrolled to dose level -1 and will 
receive 9 mg of Pemigatinib. If less than 2 patients enrolled at 9 mg of  
Pemigatinib (dose level -1) experience DLTs then the recommended Phase II 
dose will be 9 mg of  Pemigatinib (dose level -1) and the study will continue to 
enroll to the accrual goal.  
If 2 or more patients enrolled at 9 mg of Pemigatinib (dose level -1) experience 
DLTs, then an additional 6 patients will be enrolled to dose level -2 and will 
receive 4.5 mg of Pemigatinib. If less than 2 patients enrolled at 4.5 mg of 
Pemigatinib (dose level -2) experience DLTs then the recommended Phase II 
dose will be 4.5 mg of Pemigatinib (dose level -2) and the study will continue to 
enroll to the accrual goal. If 2 or more patients enrolled at 4.5 mg of Pemigatinib 
experience DLTs, then the study team will temporarily suspend accrual and 
review the toxicity data.  
16.13 Sample Size:  
A total of 18 evaluable patients (6-12 accrued from run-in phase and continue to 
accrue until 18 patients) per arm will provide preliminary data to determine 
safety and tolerability. We anticipate enrolling an additional 2 patients per arm to 
account for ineligibilities, cancelations, major violations, and other reasons. 
Thus, the maximum accrual is 40 ((18+2) + (18+2)) patients in total.  
16.14 Accrual and Study Duration:  
The anticipated accrual rate is approximately 2 patients per month for each arm. 
Therefore, the accrual period for this study is expected to be approximately 3-6 
months for the safety run-in cohorts and an additional 3-6 months for the 
expansion cohort. The final analysis can begin approximately 17 months after the 
trial begins, i.e. as soon as the last patient accrued has been observed for 27 
weeks. 
16.2 
Data & Safety Monitoring:  
16.21 The study chair(s) and the study statistician will review the study at regular 
intervals to identify accrual, adverse event, and any endpoint problems that might be 
developing. The Mayo Clinic Data Safety Monitoring Board (DSMB) is responsible for 
reviewing accrual and safety data for this trial at least twice a year, based on reports 
provided by the Statistical Office. 
16.22 Adverse Event Stopping Rules:  The stopping rules specified below are based on 
the knowledge available at study development.  We note that the Adverse Event Stopping 
Rule may be adjusted in the event of either (1) the study re-opening to accrual 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.  


 
62  
ACCRU-ICRN-1701 
The study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
In addition to the stopping rules associated with the safety run-in cohort (see 
Section 7.53), accrual to the expansion cohort of either arm of this study will be 
temporarily suspended if at any time we observe events considered at least 
possibly related to study treatment (i.e. an adverse event with attribute specified 
as “possible”, “probable”, or “definite”) that satisfy either of the following: 
x 
Once accrual to the expansion cohort has begun (Phase II recommended 
dose determined), if 33% or more of AE evaluable patients from either 
the expansion cohort or patients still being treated at the recommended 
phase II dose from the safety run-in cohort experience a DLT (See 
Section 7.53) then the trial will be temporarily suspended and the study 
team will review the toxicity data. A decision will be made to either 
amend the protocol or permanently close the study.  Where AE evaluable 
is defined as any submission of Adverse Event Assessment data via 
CRFs and/or expedited reporting. 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
16.3 
Analysis Plans:  
 
The analysis plan outlined below will be applied independently to each arm. 
 
16.31 Primary Endpoint 
The primary endpoint for each arm of this phase Ib study is the incidence of 
significant toxicity at 3 weeks. A significant toxicity is defined as a Dose 
Limiting Toxicity (as defined in Section 7.53) that is possibly, probably, or 
definitely related to treatment. DLTs will be evaluated starting in the first cycle 
of combination treatment and up to 3 weeks of combination treatment. 
Toxicities will be assessed using the CTEP Active Version of the CTCAE. This 
data will be assessed in evaluating the tolerability of the regimen for future 
studies.  All patients meeting the eligibility criteria who have signed a consent 
form and have begun combination treatment will be considered evaluable for 
significant toxicity. Patients, who do not experience a DLT but withdraw from 
protocol therapy prior to 3 weeks, will not be evaluable for the primary 
endpoint. Incidence of significant toxicity at3  weeks will be estimated 
separately by arm and will be defined as the number of patients with significant 
toxicity within 3 weeks of combination treatment divided by the total number of 
evaluable patients. 
 
16.32    Definitions and Analyses of Secondary Endpoints 
The secondary objectives of this phase Ib study are exploratory and hypothesis-
generating in nature. These analyses will be purely descriptive. No formal 
analyses will be made comparing the two arms 
 
16.321 Overall Survival 
Survival time is defined to be the length of time from start of study 
therapy to death due to any cause. All patients meeting the eligibility 
criteria that have signed a consent form and begun treatment will be 


 
63  
ACCRU-ICRN-1701 
considered evaluable for estimation of the survival distribution. The 
distribution of overall survival for both arms of the study will be 
estimated separately using the Kaplan-Meier (Reference) method. 
 
16.322 Progression Free Survival 
Progression Free Survival time is defined as the time from the start of 
study therapy to documentation of disease progression. Patients who die 
without documentation of progression will be considered to have had 
tumor progression at the time of death. Patients who are still alive and 
have not progressed will be censored for progression at the time of the 
last disease evaluation. The time-to-progression distribution will be 
estimated separately for both arms, using the Kaplan-Meier method.  
Early efficacy signals via PFS endpoint will be assessed in an 
exploratory fashion.   
 
16.323 Adverse Events Profile 
The number and severity of all adverse events (overall, by dose-level, 
and by tumor group) will be tabulated and summarized in this patient 
population. The Grade 3+ adverse events will also be described and 
summarized in a similar fashion. This will provide an indication of the 
level of tolerance for this treatment combination in this patient group.  
 
16.324 Toxicity Profile  
The term toxicity is defined as adverse events that are classified as either 
possibly, probably, or definitely related to study treatment.  Non-
hematologic toxicities will be evaluated via the ordinal CTC standard 
toxicity grading. Hematologic toxicity measures of thrombocytopenia, 
neutropenia, and leukopenia will be assessed using continuous variables 
as the outcome measures (primarily nadir) as well as categorization via 
CTC standard toxicity grading.  
Overall toxicity incidence as well as toxicity profiles by dose level, 
patient and tumor site will be explored and summarized. Frequency 
distributions, graphical techniques and other descriptive measures will 
form the basis of these analyses.  
 
16.325 Response Profile 
Best Response is defined to be the best objective status recorded from the 
start of the treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements recorded 
since the treatment started). The patient’s best response assignment will 
depend on the achievement of both measurement and confirmation 
criteria. RECIST 1.1 criteria will be used for tumor evaluation and 
patients will be re-evaluated every prior to treatment in cycle 3 and then 
in odd subsequent cycles.  
Responses will be summarized by simple descriptive summary statistics 
delineating complete and partial responses as well as stable and 
progressive disease in this patient population (overall and by tumor 
group). The number of responses may indicate further evaluation for 
specific tumor types in a Phase II setting. 


 
64  
ACCRU-ICRN-1701 
16.33 Laboratory Correlates 
Exploratory analyses on plasma 2-hydoxglutarate (2-HG) levels will be 
conducted. The will be analyzed at baseline and after multiple doses of 
ivosidenib. As data permit, these data will be summarized by descriptive 
statistics, including mean, median and standard deviation. Correlations between 
these laboratory values and other outcome measures like response, and dose 
levels will be carried out in an exploratory manner. 
 
16.4 
Inclusion of Women and Minorities 
This study will be available to all eligible patients regardless of race, gender, or 
ethnic group.  
There is no information currently available regarding differential agent effects of 
either regimen in subsets defined by gender, race, or ethnicity, and there is no 
reason to expect such differences exist. Therefore, although the planned analyses 
will, as always, look for differences in treatment effect based on gender and 
racial groupings, the samples sizes are not increased in order to provide 
additional power for such subset analyses.  
To predict the characteristics of patients likely to enroll in this trial we have 
reviewed the Mayo registration classified by race and gender.  This revealed that 
roughly 3% of patients registered into cancer trials during the past five years 
could be classified as minorities and about 50% of patients were women.  . 
Expected sizes of racial by gender subsets are shown in the following table: 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
2 
2 
 
4 
Not Hispanic or Latino 
18 
18 
 
36 
Ethnic Category: Total of all subjects* 
20 
20 
 
40 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
 
0 
Asian 
0 
0 
 
0 
Black or African American 
1 
1 
 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
 
0 
White 
19 
19 
 
38 
Racial Category: Total of all subjects* 
20 
20 
 
40 
*These totals must agree.  Enter actual estimates (not percentages) 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 


 
65  
ACCRU-ICRN-1701 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (NOTE: Individuals from the Philippine Islands have been recorded as 
Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 
17.0  
Pathology Considerations/Tissue Biospecimens: None. 
 
 


 
66  
ACCRU-ICRN-1701 
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 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 Timetables 
 
NOTE: All reports must be de-identified, and labeled with study number, ACCRU 
patient ID number, and initials. 
 
 
 
 Initial Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
Institutional Contacts 
 
d 2 weeks after registration 
On-Study Form 
Adverse Events: Baseline  
On-Study: Prior Surgery1 
On-Study: Prior Radiation1 
On Study: Prior Systematic Therapy 
RECIST Measurements: Baseline 
Supporting Documentation: Baseline2 
Laboratory Tests and Results: Baseline 
Patient Status: Baseline 
Off Treatment 
Submit d2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
 
1. Submit only if applicable. 
2. Attach pathology report, imaging report, molecular testing result, and clinical note in 
RAVE on the Supporting Documentation: Baseline form.   
 
 


 
67  
ACCRU-ICRN-1701 
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) Form 
X 
X 
Treatment (Intervention):Dose modifications, 
Omissions, and Delays2 
X 
X 
Adverse Event: Solicited 
X 
X 
Adverse Events: Other2 
X 
X 
Dose Limiting Toxicities2, 3  
X 
 
RECIST Measurements 
X 
X 
Supporting Documentation1 
X 
X 
Specimen Submission: Blood 
X 
X 
Day 1 Laboratory Tests and Results 
X 
 
Day 8 Laboratory Tests and Results (Cycle 1 
Only)3 
X 
 
Day 15 Laboratory Tests and Results (Cycle 
1 Only)3 
X 
 
Patient Status: Treatment (Intervention) 
X 
X 
Off Treatment 
 
X 
Consent Withdrawal2 
X 
X 
Consent Withdrawal: Specimen Only2 
X 
X 
Consent Withdrawal: All Follow-Up2 
X 
X 
ACCRU Deviation Form2 
X 
X 
Notice of New Primary2 
X 
X 
 
1. Attach a copy of imaging report for restaging or progression in RAVE on the Supporting 
Documentation form if disease is evaluated.  
2. Submit only if applicable. 
3. For Cycle 1 only. 
 
 
 


 
68  
ACCRU-ICRN-1701 
Follow-up Material(s)  
CRF 
Event Monitoring Phase/Survival Follow-Up1 
q. 6 
months 
until 
PD2 
At 
PD2 
After 
PD q. 
6 
mos. 
Death 
At Each Event 
Occurrence 
Patient Status: Survival 
and Disease 
Status  Follow-up/Event 
Monitoring 
X 
X 
X 
X 
 
Supporting 
Documentation2 
 
X 
 
 
 
Adverse Events: Late3 
X 
 
X 
X 
 
Consent Withdrawal 
(choose appropriate 
form)3 
x 
Consent 
Withdrawal: 
Specimen Only 
x 
Consent 
Withdrawal: All 
Follow-up 
X 
 
X 
 
 
Lost to Follow-up3 
X 
 
 X 
 
 
ACCRU Deviation3 
 
 
 
 
X 
Notice of New Primary3 
 
 
 
 
X 
1. 
Patients are followed in Event Monitoring for a maximum of 3 years from 
registration. 
2. 
Attach a copy in RAVE for documentation of progression on the 
Supporting Documentation Form.  
3. 
Submit only if applicable.  
 
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 
Tests to be research funded: Mandatory blood samples for correlative research. 
 
19.3 
Other budget concerns: 
 
19.31    Ivosidenib will be supplied by Agios.  Pemigatinib (INCB054828) will be 
supplied by Incyte.  Cisplatin and Gemcitabine will not be supplied, but is 
commercially available. 
 
 


 
69  
ACCRU-ICRN-1701 
 
20.0 
References 
 
 
ACS. Bile Duct Cancer (Cholangiocarcinoma). 2014: American Cancer Society. 
 
Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, et al. IDH1 and IDH2 mutations are 
frequent events in central chondrosarcoma and central and periosteal chondromas but not in other 
mesenchymal tumours. J Pathol. 2011;224(3):334-43. 
 
Ang C. Role of the fibroblast growth factor receptor axis in cholangiocarcinoma. J Gastroenterol 
Hepatol 2015;30:1116-1122. 
 
Arai Y, Totoki Y, Hosoda F, et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions 
define a unique molecular subtype of cholangiocarcinoma. Hepatology 2014;59:1427-1434. 
 
Baum M, Schiavi S, Dwarakanath V, Quigley R. Effect of fibroblast growth factor-23 on 
phosphate transport in proximal tubules. Kidney Int 2005;68:1148-1153. 
 
Bergquist A, von Seth E. Epidemiology of cholangiocarcinoma. Best Pract Res 
Clin Gastroenterol 2015;29:221-232. 
 
Blechacz BR, Gores GJ. Cholangiocarcinoma. Clin Liver Dis 2008;12:131-150. 
 
Borger DR, Tanabe KK, Fan KC, Lopez HU, Fantin VR, Straley KS, et al. Frequent mutation of 
isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broadbased 
tumor genotyping. Oncologist. 2012;17(1):72-9. 
 
Brieau B, Dahan L, De Rycke Y, Boussaha T, Vasseur P, Tougeron D, et al. Second-line 
chemotherapy for advanced biliary tract cancer after failure of the gemcitabine-platinum 
combination: A large multicenter study by the Association des Gastro-Enterologues Oncologues. 
Cancer. 2015;121(18):3290-7. 
 
Churi CR, Shroff R, Wang Y, et al. Mutation profiling in cholangiocarcinoma: prognostic and 
therapeutic implications. PLoS One 2014;9:e115383. 
 
Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, et al. The oncometabolite 2-
hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011;12(5):463-9. 
 
Clinical Trial Facilitation Group (CTFG). Recommendations related to contraception and 
pregnancy testing in clinical trials. September 15, 2014.  https://www.uni-
due.de/imperia/md/content/ethikkomission/kontrazeption.pdf.  Accessed Oct 8, 2018. 
Dailey L, Ambrosetti D, Mansukhani A, Basilico C. Mechanisms underlying differential 
responses to FGF signaling. Cytokine Growth Factor Rev 2005;16:233-247. 


 
70  
ACCRU-ICRN-1701 
 
Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated 
IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739-44. 
 
Eckman KR, Patel DK, Landgraf A, et al. Chemotherapy outcomes for the treatment of 
unresectable intrahepatic and hilar cholangiocarcinoma: a retrospective analysis. Gastrointest 
Cancer Res 2011; 4:155-160. 
 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247. 
 
Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. 
Cytokine Growth Factor Rev 2005;16:139-149. 
 
Farrow EG, White KE. Recent advances in renal phosphate handling. Nat Rev 
Nephrol 2010;6:207-217. 
 
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. 
 
Goyal L, Govindan A, Sheth RA, Nardi V, Blaszkowsky LS, Faris JE, et al. Prognosis and 
Clinicopathologic Features of Patients With Advanced Stage Isocitrate Dehydrogenase (IDH) 
Mutant and IDH Wild-Type Intrahepatic Cholangiocarcinoma. Oncologist. 2015;20(9):1019-27. 
 
Graham RP, Barr Fritcher EG, Pestova E, et al. Fibroblast growth factor receptor 2 translocations 
in intrahepatic cholangiocarcinoma. Human Pathology 2014;45:1630-1638. 
 
Guagnano V, Kauffmann A, Wohrle S, et al. FGFR genetic alterations predict for sensitivity to 
NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov 2012;2:1118-1133. 
 
Itoh N. Hormone-like (endocrine) Fgfs: their evolutionary history and roles in development, 
metabolism, and disease. Cell Tissue Res 2010;342:1-11. 
Javle M, Lowery M, Shroff RT, et al.  Phase II Study of BGJ398 in Patients with FGFR-
altered Advanced Cholangiocarcinoma.  J Clin Oncol 2018;36:276-282. 
 
Kipp BR, Voss JS, Kerr SE, Barr Fritcher EG, Graham RP, Zhang L, et al. Isocitrate 
dehydrogenase 1 and 2 mutations in cholangiocarcinoma. Hum Pathol. 2012;43(10):1552-8. 
 
Knights V, Cook SJ. De-regulated FGF receptors as therapeutic targets in cancer. Pharmacol 
Ther 2010;125:105-117. 


 
71  
ACCRU-ICRN-1701 
 
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. 
 
Lamarca A, Hubner RA, David Ryder W, and Valle JW. Second-line chemotherapy in advanced 
biliary cancer: a systematic review. Ann Oncol. 2014;25(12):2328-38. 
 
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. 
 
Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, et al. IDH mutation impairs 
histone demethylation and results in a block to cell differentiation. Nature. 2012;483(7390):474- 
8. 
 
Morganroth J. Focus on issues in measuring and interpreting changes in the QTc interval 
duration. Eur J Heart Suppl. 2001;3(Suppl K):K105-K111. 
 
National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events (CTCAE) 
Version https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-
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National Cancer Institute (NCI). SEER Stat Fact Sheets: Liver and Intrahepatic bile Duct 
Cancer.  2018.  https://seer.cancer.gov/statfacts/html/livibd.html.  Accessed Oct 8, 2018. 
 
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. 
 
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. 
 
Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. 
Gastroenterology 2013;145:1215-1229. 
 
Ross JS, Wang K, Gay L, Al-Rohil R, et al. New routes to targeted therapy of intrahepatic 
cholangiocarcinomas revealed by next-generation sequencing. Oncologist 2014;19:235-242. 
 
Saha SK, Parachoniak CA, Ghanta KS, Fitamant J, Ross KN, Najem MS, et al. Mutant IDH 
inhibits HNF-4alpha to block hepatocyte differentiation and promote biliary cancer. Nature. 
2014;513(7516):110-4. 


 
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ACCRU-ICRN-1701 
 
Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin 
D metabolism and phosphate homeostasis. J Bone Miner Res 2004a;19:429-435. 
 
Shimada T, Mizutani S, Muto T, et al. Cloning and characterization of FGF23 as a causative 
factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 2001;98:6500-6505. 
 
Shimada T, Urakawa I, Yamazaki Y, et al. FGF-23 transgenic mice demonstrate 
hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. 
Biochem Biophys Res Commun 2004b;314:409-414. 
 
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, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev 
Cancer 2010;10:116-129. 
 
Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus 
gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273-81. 
 
Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, et al. Targeted 
Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation. Science. 2013;In 
press. 
 
Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. The common feature 
of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting 
alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17(3):225-34. 
 
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. 
 
Wohrle S, Bonny O, Beluch N, et al. FGF receptors control vitamin D and phosphate 
homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone. 
J Bone Mineral Res 2011;26:2486-2497. 
 
Wu YM, Su F, Kalyana-Sundaram S, et al. Identification of targetable FGFR gene fusions in 
diverse cancers. Cancer Discov 2013;3:636-647. 
 
Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a 
competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 
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ACCRU-ICRN-1701 
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 
mutations in gliomas. N Engl J Med. 2009;360(8):765-73. 
 
Yanochko GM, Vitsky A, Heyen JR, et al. Pan-FGFR inhibition leads to blockade of FGF23 
signaling, soft tissue mineralization, and cardiovascular dysfunction. Toxicol Sci 2013;135:451- 
464 
 
Yen KE, Bittinger MA, Su SM, and Fantin VR. Cancer-associated IDH mutations: biomarker 
and therapeutic opportunities. Oncogene. 2010;29(49):6409-17. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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ACCRU-ICRN-1701 
APPENDIX I – PATIENT MEDICATION DIARY 
Instructions: 
 
x 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.  
x If you miss a dose, place a “0” under the date, but remember to take your prescribed dose at the next 
regularly scheduled time. 
x Bring all bottles and any unused study medication along with this diary when you return for your next 
appointment. 
 
 
 
 
 
 
Date:__________________      Participant’s Signature:___________________________________ 
Area Below Only To Be Completed by Coordinator 
 
Number of pills returned_____ 
 
 
 
Study Coordinator Initials_____ 
 
Date________  
 
 
 
 
 
Discrepancy Yes_____No_____ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date 
 
 
 
 
 
 
 
Ivosidenib 
 
 
 
 
 
 
 
pemigatinib 
 
 
 
 
 
 
 
Comments 
 
 
 
 
 
 
 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date 
 
 
 
 
 
 
 
Ivosidenib 
 
 
 
 
 
 
 
pemigatinib 
 
 
 
 
 
 
 
Comments 
 
 
 
 
 
 
 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Date 
 
 
 
 
 
 
 
Ivosidenib 
 
 
 
 
 
 
 
pemigatinib 
 
 
 
 
 
 
 
 
Comments 
 
 
 
 
 
 
 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Date 
 
 
 
 
 
 
 
Ivosidenib 
 
 
 
 
 
 
 
 
 
pemigatinib 
 
 
 
 
 
 
 
Comments 
 
 
 
 
 
 
 


 
75  
ACCRU-ICRN-1701 
Appendix II - list of eligible gene alterations 
 
ARM A:  Any R132C/L/G/H/S mutation 
 
ARM B:  FGFR1/2/3 and FGF alterations as listed below:  
 
1) FGFR1-3 fusions or FGFR2 rearrangements (only FGFR fusions or rearrangements with an 
intact kinase domain would be eligible) 
 
2) Known or likely activating mutations (excluding kinase domain) in FGFR1-3 (See Table 1) 
 
3) FGFR2 in frame insertions or deletions in the extracellular domain and FGFR2 truncating 
alterations in exon 18 based on emerging evidence (Table 2 for FGFR2 in frame insertions or 
deletions, and Table 3 for truncating alterations). 
 
4) Specifically, EXCLUDE FGFR amplifications, FGF amplifications or FGFR mutations in 
the kinase domain 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
76  
ACCRU-ICRN-1701 
Appendix III - Prohibited medications 
ARM A: 
 
 
 
  
 
 


 
77  
ACCRU-ICRN-1701 
Appendix IV 
New York Heart Association Classification 
 
Class 
Symptomatology 
I 
No limitation of physical activity.  Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain. 
II 
Slight limitation of physical activity.  Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, dyspnea, or anginal pain. 
III 
Marked limitation of physical activity.  Comfortable at rest, less than 
ordinary activity results in fatigue, palpitation, dyspnea, anginal pain. 
IV 
Unable to carry on any physical activity without discomfort.  Symptoms at 
rest.  If any physical activity is undertaken, discomfort is increased. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
78  
ACCRU-ICRN-1701 
Appendix V 
 
Fridericia's Formula: 
 
QTcF=QT/RR1/3  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
79  
ACCRU-ICRN-1701 
Appendix VI 
 
Medications Known to Prolong the QT Interval 
 
 
Amiodarone 
 
dofetilide 
 
grepafloxacin 
 
moxifloxacin 
 
quinidine 
Astemizole 
dolasetron 
halofantrine 
norfloxacin 
sevoflurane 
azithromycin 
domperidone 
 
haloperidol 
 
ofloxacin 
sotalol 
bepridil 
droperidol 
ibutilide 
ondansetron 
sparfloxacin 
chloroquine 
erythromycin 
itraconazole 
palonosetron 
terfenadine 
chlorpromazine 
escitalopram 
ketoconazole 
pentamidine 
thioridazine 
ciprofloxacin 
flecainide 
levofloxacin 
pimozide 
voriconazole 
citalopram 
gatifloxacin 
levomethadyl 
posaconazole 
clarithromycin 
gemifloxacin 
mesoridazine 
probucol 
disopyramide 
 
granisetron 
 
methadone 
 
 
procainamide 
 
 
*For a complete and updated (ongoing) list of medications, please use the following link: