Feasibility IB Trial of Paclitaxel/Carboplatin + Galunisertib (a Small Molecule Inhibitor of the Kinase Domain of Type 1 TGF-B Receptor) in Patients With Newly Diagnosed, Persistent or Recurrent Carcinosarcoma of the Uterus or Ovary
Phase: PHASE1
Conditions: Carcinosarcoma, Ovarian
Sponsor: University of Oklahoma

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CLINICAL STUDY PROTOCOL 
 
Study Title: Feasibility IB Trial of Paclitaxel/Carboplatin + Galunisertib.  (A Small 
Molecule Inhibitor of the Kinase Domain of Type 1 TGF-B Receptor) in 
Patients with Newly Diagnosed, Persistent or Recurrent Carcinosarcoma of 
the Uterus or Ovary  
 
Sponsor: 
 
 
Stephenson Cancer Center 
 
 
 
 
The University of Oklahoma Health Sciences Center 
 
 
 
 
800 NE 10th Street 
 
 
 
 
Oklahoma City, OK 73104 
 
Study Products: 
 
Galunisertib 
Funding Collaborator: 
Eli Lilly and Company (Funder ID: H9H-MC-E001) 
IND Number: 
 
133833 
NCT Number: 
 
NCT03206177 
 
STUDY CHAIRS 
Principal Investigator: 
Kathleen Moore, MD 
Stephenson Cancer Center 
800 NE 10th Street, Oklahoma City, OK 73104 
 
 
 
 
E-mail: Kathleen-Moore@ouhsc.edu  
Translational Scientist: 
Resham Bhattachraya, PhD 
Bio-Statistician: 
 
Kai Ding PhD 
 
 

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This clinical trial will be conducted in compliance with the protocol, International Conference on Harmonization Good 
clinical Practice Guidelines E6 (ICH-GCP), other applicable regulatory requirements and with the Declaration of 
Helsinki and its amendments. 
Investigator Signature Page 
 
Investigational Product 
 
Galunisertib (IND No.: 133833) 
 
I have read and understood the protocol and agree to implement the study in accordance with the 
procedures set forth in the protocol and in accordance with the sponsor's guidelines and all 
applicable government regulations and the International Conference on Harmonization Good 
Clinical Practice Guidelines E6 (ICH-GCP) and Good Clinical Practices (GCP) as described in the 
United States Code of Federal Regulations (CFR) – 21 CFR parts 50, 54, 56, and 312, and in 
accordance with ethical principles that have their origin in the Declaration of Helsinki. 
 
I will provide adequate protocol training to my associates, colleagues, and employees assisting in 
the conduct of the study. 
 
I will obtain Institutional Review Board (IRB)/Ethics Committee (EC) approval of the Protocol 
and Patient Informed Consent Form prior to enrollment of patients in the study. I understand that 
any modifications to the protocol made during the course of the study must first be approved by 
the Institutional Review Committee (or equivalent) and IRB/EC except when such modification is 
made to remove an immediate hazard to the patient. 
 
I will ensure that a fully executed Patient Informed Consent is obtained from each patient prior to 
initiation of any study procedures. 
 
I assume responsibility to report Suspected Unexpected Serious Adverse Reactions (SUSAR) to 
FDA and IRB/EC per the requirement contained in 21 CFR 312.64 and fax those cases to Eli Lilly 
and Company at 866-644-1697. 
 
I will allow the sponsor, Lilly and its agents, as well as the United States of America (USA) Food 
and Drug Administration (FDA) and other regulatory agencies, to inspect study facilities and 
pertinent records at reasonable times and in a reasonable manner, ensuring patient confidentiality. 
If I am notified that this study is to be inspected by a regulatory agency, I will notify the sponsor 
and study monitor as soon as possible thereafter (no later than 1 week). 
 
_______________________________________ 
 
 
___________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
_______________________________________ 
Investigator’s Name 
 
_______________________________________ 
Investigator’s Institutional Affiliation 
 

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Sponsor Signature Page 
 
Feasibility IB Trial of Paclitaxel/Carboplatin + Galunisertib.  (A Small Molecule Inhibitor 
of the Kinase Domain of Type 1 TGF-B Receptor) in Patients with Newly Diagnosed, 
Persistent or Recurrent Carcinosarcoma of the Uterus or Ovary 
 
Sponsor: 
 
 
Stephenson Cancer Center 
Investigational Product: 
Galunisertib (IND No.: 133833) 
 
Approved by: 
____________________________ 
 
Title:  
 
____________________________ 
 
Signature: 
 
____________________________ 
 
Date:  
 
____________________________ 
 
 

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Safety Lead In: A 3-6 patient safety lead in will precede the schema below.  Patients with the same 
eligibility criteria will receive 80mg po BID of Galunisertib along with the starting dose of 
paclitaxel and carboplatin based on prior exposure to pelvic radiation.  The dose limiting toxicity 
period is cycle 1 (28 days).  If 0/3 patients experience a DLT, the schema below will be activated 
for 20 patients.  If 1/3 patients experiences a DLT, the safety lead in will be expanded to 3more 
patients.  If 1/6 patients experiences a DLT, the below schema will be activated.  If 2/3 patients 
have a DLT, the study will be suspended for reassessment. If 2 or more of the 6 patients experience 
a DLT, the study will be suspended for reassessment. 
Day 1: Paclitaxel 175mg/mg2 IV & 
Carboplatin AUC 6 + Galunisertib 
150mg BID  (d 4-17) 28 day cycles. 
Galunisertib maintenance 150mg BID 
may be considered in event of CR or 
PR at investigator’s discretion 
Gynecologic 
cancer: 1o dx or 
recurrence who 
is eligible for 
paclitaxel 
& 
carboplatin 
chemotherapy 
For patients with history of prior 
pelvic radiation: 
Day 1: Paclitaxel 135mg/mg2 IV & 
Carboplatin AUC 5 + Galunisertib 
150mg BID  (d 4-17) 28 day cycles. 
Galunisertib maintenance 150mg BID 
may be considered in event of CR or 
PR at investigator’s discretion 
Progressive 
Disease 
or 
Toxicity 
= 
Treatment 
discontinuation 
Complete 
or 
Partial Response 
may 
consider 
maintenance 
Galunisertib 
until progression 
Tissue Collection 
from surgery or 
IR guided biopsy 
(if 
measurable 
disease) 

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Table of Contents 
1 HYPOTHESES AND OBJECTIVES ....................................................................................... 7 
1.1 
Objectives ....................................................................................................................... 7 
1.2 
Endpoints ........................................................................................................................ 7 
2 BACKGROUND AND RATIONALE ..................................................................................... 7 
2.1 
Inclusion of Women and Minorities ............................................................................. 10 
3 PATIENT ELIGIBILITY AND EXCLUSIONS .................................................................... 10 
3.1 
Study Population ........................................................................................................... 10 
3.2 
Inclusion Criteria .......................................................................................................... 10 
3.3 
Exclusion Criteria ......................................................................................................... 11 
4 SUBJECTS REGISTRATION AND ENROLLMENT.......................................................... 11 
4.1 
Required Protocol Specific Regulatory Documents ..................................................... 11 
4.2 
Patient Registration and Enrollment ............................................................................. 12 
5 STUDY MODALITIES .......................................................................................................... 12 
5.1 
Carboplatin (Paraplatin® - NSC #241240) ................................................................... 12 
5.2 
Paclitaxel (NSC #673089) ............................................................................................ 13 
5.3 
Galunisertib ................................................................................................................... 14 
6 TREATMENT PLAN ............................................................................................................. 16 
6.1 
Treatment Plan .............................................................................................................. 16 
6.2 
Method of Paclitaxel/Carboplatin Chemotherapy Administration ............................... 16 
6.3 
Administration of Galunisertib ..................................................................................... 17 
7 TREATMENT MODIFICATIONS ........................................................................................ 18 
7.1 
Paclitaxel* Dose Levels ................................................................................................ 18 
7.2 
Carboplatin Dose Levels ............................................................................................... 19 
7.3 
Galunisertib Dose Levels .............................................................................................. 19 
7.4 
Dose Modifications-Hematologic ................................................................................. 19 
7.5 
Dose Modifications-Non-Hematologic Toxicity .......................................................... 21 
8 STUDY PARAMETERS ........................................................................................................ 23 
8.1 
Observations and Tests ................................................................................................. 23 
8.2 
Pharmacokinetics .......................................................................................................... 24 

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8.3 
Tissue Biopsy for Pharmacodynamics .......................................................................... 24 
9 EVALUATION CRITERIA ................................................................................................... 24 
9.1 
Parameters of Outcome–RECIST 1.1 Criteria .............................................................. 24 
9.2 
Subjective Parameters ................................................................................................... 26 
9.3 
Definition of Evaluable Patients ................................................................................... 26 
10 DURATION OF STUDY ..................................................................................................... 26 
11 STUDY MONITORING AND REPORTING PROCEDURES .......................................... 26 
11.1 
Reporting of Serious Treatment Emergent Adverse Events ..................................... 27 
11.2 
MedWatch 3500a Reporting Guidelines ................................................................... 27 
11.3 
Assessing Causality .................................................................................................. 28 
11.4 
SAFETY REPRORTING REQUIREMENTS FOR IND HOLDERS ..................... 28 
11.5 
Collection and Recording Adverse Events ............................................................... 29 
12 STATISTICAL CONSIDERATIONS.................................................................................. 31 
12.1 
Data Analysis Plan .................................................................................................... 31 
12.2 
Interim Analysis ........................................................................................................ 33 
13 DATA AND SAFETY MONITORING PLAN ................................................................... 33 
13.1 
DSMC Auditing ........................................................................................................ 34 
14 DATA HANDLING AND RECORD KEEPING ................................................................ 34 
14.1 
Data Quality Assurance ............................................................................................ 34 
14.2 
Electronic Case Report Forms .................................................................................. 34 
14.3 
Record Retention ...................................................................................................... 34 
15 ETHICAL AND REGULATORY CONSIDERATIONS .................................................... 34 
15.1 
Ethical Conduct of the Study .................................................................................... 34 
15.2 
Informed Consent...................................................................................................... 35 
15.3 
Institutional Review Board or Ethics Committee ..................................................... 35 
15.4 
Confidentiality .......................................................................................................... 35 
16 BIBLIOGRAPHY ................................................................................................................. 36 
 
 
 

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1 HYPOTHESES AND OBJECTIVES 
1.1 
Objectives 
1.1.1 Primary 
1. To determine the feasibility of delivering 4 cycles of carboplatin/paclitaxel (CT) in 
combination with galunisertib (GB) to patients with gynecologic carcinosarcoma 
1.1.2 Secondary 
1. To determine the frequency and severity of adverse events as assessed by the CTCAE v4 
2. To determine the progression free survival (PFS) and overall survival (OS) of patients 
receiving combination CT + GB. 
3. To ascertain the pharmacokinetic profile of GB when given in a combination regimen with 
CT. 
1.1.3 Exploratory/Correlative 
1. To determine if H-score criteria (% of cells and intensity) of IHC nuclear phospho-smad2/3 
levels after cycle 1 are associated with response to galunisertib therapy. 
2. To evaluate the mRNA expression Level of EMT markers along with the TGFβ1 in the GB 
pre-treated and post-treated patient samples 
 
1.2 
Endpoints 
1.2.1 Primary 
1. Completion of 4 cycles of CT + GB- completion of a cycle will be defined as receiving 
both carboplatin/paclitaxel and taking ≥75% of the doses of GB for the cycle. 
1.2.2 Secondary 
1. Adverse event occurrence and grade 
2. PFS- duration of time from enrollment to RECIST progression or death from any cause, 
censored at last disease assessment or loss to follow-up; and OS – duration of time from 
enrollment to death from any cause, censored at date last known alive or loss to follow-up 
3. Galunisertib plasma concentrations levels on Cycle 1 day 4, 8 and cycle 2 day 1 
1.2.3 Exploratory 
1. Correlate H-score of IHC nuclear phospho-smad2/3 before GB therapy with response rate 
(complete response + partial response). 
2. Compare H Score of psamd2/3 staining in pretreated and post-treated patient tumor 
samples then correlate with the patient therapy response 
2 BACKGROUND AND RATIONALE 
Uterine Carcinosarcoma (UCS) is a rare, aggressive malignancy accounting for 5% of uterine 
cancers. It is defined by the presence of both epithelial (carcinomatous) and mesenchymal 
(sarcomatous) malignant cells [1]. Carcinosarcomas (CS) have been reported in a variety of organ 
sites including the ovary, fallopian tube, peritoneum, prostate, and breast, with uterine origin being 
most common. The epithelial component of UCS may include endometrioid elements but 

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frequently has high grade features (serous, clear cell, grade 3). Clinically, UCS tumors have a high 
incidence of extra-uterine spread at diagnosis and high rates of recurrence manifesting as poor 
progression-free survival (PFS) and overall survival (OS)[2]. 
Standard of care treatment for patients with UCS includes hysterectomy, bilateral salpingo-
oophorectomy, and lymph node dissection. Adjuvant chemotherapy has emerged as the most 
active treatment. The GOG conducted a series of drug development trials with the goal of defining 
active regimens. Ifosfamide, cisplatin, and paclitaxel were identified as the most active single 
agents. Combination regimens further improved response rates, with variable effects on PFS and 
OS [3, 4].  A phase III trial comparing ifosfamide +/- paclitaxel in patients with advanced/recurrent 
UCS demonstrated an improved response rate (RR) (45% vs 29%), median PFS (5.8 vs 3.6 mo), 
and median OS (13.5 vs 8.4 mo) with the combination regimen [4]. A subsequent phase II trial of 
paclitaxel and carboplatin reported a RR of 54% (13% complete response), median PFS of 7.6 
months, and median OS of 14.7 months [5]. A subsequent phase III trial comparing ifosfamide + 
paclitaxel to carboplatin + paclitaxel is ongoing. In a parallel trial, stage I-IV patients with no 
residual disease were randomized to ifosfamide + cisplatin or whole abdominal radiation therapy 
[5]. The results demonstrated that a 22% reduction in the relative risk of recurrence and a 29% 
reduction in the risk of death with chemotherapy. In addition, the results of EORTC study 55874 
(observation vs pelvic radiation for stages I-II UCS and leiomyosarcoma) demonstrated better 
local control without impact on survival [6]. Despite these treatment improvements, <30% of 
patients with optimally resected, stage III-IV disease remain free of progression at 3 years [5]. For 
patients with bulky advanced/recurrent disease, ~15% of patients remain free of progression at 2 
years, and only 20% survive 2 years[7]. Improvement upon existing treatments is greatly needed.  
Historically, UCS was combined with other uterine sarcomas for treatment selection and clinical 
trial eligibility. There is increasing recognition that UCS are not sarcomas, but an extreme 
manifestation of de-differentiated endometrial cancer (EC). Several hypotheses have been 
advanced to explain the histiogenesis of UCS. One possible explanation for the phenotypic 
changes is that it may represent a model of epithelial-mesenchymal transition (EMT). EMT is a 
process whereby epithelial cells lose polarity and cell-cell contacts, have remodeled cytoskeletons, 
and acquire the ability to migrate [8-10]. These changes are associated with the activation of a 
mesenchymal like gene expression profile. Mesenchymal cells are able to detach, penetrate the 
basement membrane, infiltrate, and metastasize. Primary tumor cells undergo EMT to acquire 
invasive/metastatic capacity. In addition, EMT induces cancer stem-like properties and confers 
drug resistance to tumor cells [11, 12].  
A few studies have evaluated the role of EMT in uterine carcinosarcomas. Saegusa and colleagues 
compared 14 cases of UCS to 13 cases of endometrial cancers and demonstrated the complete 
shutdown of E-cadherin expression in the mesenchymal elements[13]. In addition pAkt and 
nuclear B-catenin levels were increased in mesenchymal cells. Romero-Perez and colleagues 
compared tumor DNA microarrays between 15 UCS and 23 EC samples and demonstrated changes 
in the expression of genes modulating EMT including the AT-hook 2 gene (embryonic nuclear 
factor that mediates EMT in some tumor models) and overexpression of HMGA2 gene (which 
favors EMT by cooperating with the TGF-beta/Smad pathway) [14].  
UCS represents an ideal model to study EMT. Morphologically, epithelial cells undergo EMT as 
reflected in the appearance of sarcomatous/mesenchymal populations of cells within UCS. The 
mesenchymal cells demonstrate many of the hallmarks (clinically and by IHC) of EMT. Metastatic 

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disease demonstrates epithelial components, perhaps suggesting the activation of mesenchymal to 
epithelial (MET) transition. However, the mechanisms underlying this EMT transformation are 
currently unknown.  
Several candidates that may interrupt EMT and inhibit cancer stem-like cells (CSC) have been 
identified [10, 15, 16]. Among several growth factors that can act as inducers of EMT, 
transforming growth factor beta (TFG-β) has been shown to play an important role in cancer 
progression and metastasis [15, 17-19]. TGFβ is a multifunctional cytokine that regulates EMT 
and suppresses growth and proliferation in epithelial cells. Aberrations in TGF-β signaling occur 
frequently during tumorigenesis allowing cancer cells to proliferate, invade, and metastasize 
beyond their tissue of origin. Active TGFβ binds to the TGFβ type II receptor subunit (TGFβR-
II), which then recruits and activates the type I receptor subunit (TGFβR-I). This active receptor 
complex phosphorylates and activates the receptor-activated Smads which then form complexes 
with Smad4, and translocates to the nucleus to modulate specific target gene expression[20].  Mani 
and colleagues were among the first to report a link between EMT and the acquisition of epithelial 
stem cell properties where TGFβ treatment of breast cancer stem cells initiated EMT and 
concomitant acquisition of tumor initiating and self-renewal properties[21]. TGFβ has also been 
shown to modulate E-cadherin expression and induce reversible epithelial to mesenchymal trans 
differentiation in epithelial cells [22].  
Komiyama and colleagues have reported that expression of TGFß1 and its receptors is associated 
with biological features of ovarian cancer and cancer sensitivity to paclitaxel/carboplatin [23]. 
Tissues of the primary tumor were collected from 24 patients with ovarian cancer, primary 
peritoneal cancer, or fallopian tube cancer who had undergone surgery and chemotherapy with 
paclitaxel/ carboplatin; and the expression of TGFß1, TßRI, and TßRII mRNA was evaluated. The 
authors found that a lower TGFß1 mRNA expression was associated with high sensitivity to 
paclitaxel and carboplatin [23]. In consistent with this report, studies on mice model have shown 
that increased TGF-β signaling could play an important role for paclitaxel-resistance and breast 
cancer recurrence [24].   
To test the role of TGFβ in UCS, researchers at the University of Oklahoma led by Dr. 
Bhattachraya utilized patient tumor samples to demonstrate that the components of the TGFβ 
pathway are expressed and functional in UCS[25, 26]. mRNA levels of TGFβ-I, TGFβ-II, TGFβR-
I and TGFβR-II were shown to be higher in recurrent compared to the non-recurrent UCS patient 
samples. 
Additionally, TGFβ induced significant phosphorylation of i) Smad 2/3 and ii) c-Jun N-terminal 
kinase (JNK), iiii) nuclear localization of nuclear factor of activated T cells 1 (NFAT1) and iv) 
cMyc transcription in UCS. While TGFβ induced proliferation through NFAT1/cMyc, regulation 
of migration/invasion and EMT are currently being explored. However the TGFβ receptor 1 
inhibitor (TGFβ R-1/ galunisertib.), efficiently blocks TGFβ induced proliferation, migration and 
EMT in UCS[15] . 
Galunisertib is a small molecule selective inhibitor of the TGFβR-I kinase domain. It has been 
evaluated in phase I testing and 300 mg/day, 14 days on/14days off was the suggested as the phase 
II dose [27, 28]. A randomized phase II study comparing 160 mg vs 300 mg/day in hepatocellular 
carcinoma patients demonstrated manageable toxicity, evidence for biomarker response, and 
Pk/PD data supporting the 300 mg/day dosing in future studies [29]. Furthermore, pre-clinical 
studies in mice model showed that galunisertib could prevent drug resistant to paclitaxel and 

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enhance chemotherapy effect for mouse xenografts of human breast cancer[24]. A phase Ib study 
with gemcitabine found no dose limiting toxicity, and the 300 mg/day dose was advanced into a 
phase II study in metastatic pancreatic cancer patients [29]. A phase II study of galunisertib plus 
lomustine, galunisertib monotherapy, or placebo plus lomustine found that combination with 
lomustine did not change the PKs of galunisertib [30]. Furthermore, patients treated with 
galunisertib (150-mg, PO, twice a day) alone had less frequency of drug-related grade 3/4 adverse 
events compared with lomustine-treated patients (10% vs 26%); and galunisertib did not increase 
the frequency of lomustine related adverse events [30].  
To date, the safety and anti-cancer effect of Galunisertib combined with paclitaxel/carboplatin 
regimen remains unclear. Based on the association of TGFβ signaling with EMT in UCS, we 
propose a Phase IB feasibility trial with this novel TGFβ inhibitor in combination with carboplatin/ 
paclitaxel (CT) in CS patients. In a phase II study evaluating CT in this population, 58% of patients 
were able to complete 6 or more cycles of CT therapy [7].  We anticipate that given the excellent 
tolerability of galunisertib in previous studies, and in the potential for improved disease control 
with this agent that 60% or more of patients will receive 4 cycles of therapy.  The trial would lend 
support for a randomized phase II trial of CT +/- galunisertib.   
2.1 
Inclusion of Women and Minorities 
The Stephenson Cancer Center will not exclude potential subjects from participating in this or any 
study solely on the basis of ethnic origin or socioeconomic status.  Every attempt will be made to 
enter all eligible patients into this protocol and therefore address the study objectives in a patient 
population representative of the entire gynecologic carcinosarcoma patient population.  
3 PATIENT ELIGIBILITY AND EXCLUSIONS  
3.1 
Study Population 
Women with a primary diagnosis of uterine, ovarian, fallopian tube or peritoneal carcinosarcoma, 
Stage I-IV or recurrent or progressive disease eligible for treatment with CT. 
3.2 
Inclusion Criteria 
1. Women ≥ 18 years old with a diagnosis of primary, recurrent or progressive uterine, 
ovarian, fallopian tube or peritoneal carcinosarcoma, for whom treatment with combination 
paclitaxel and carboplatin is recommended. 
2. Written informed consent/assent prior to any study-specific procedures 
3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2  
4. Tissue available for translational study. 
5. Adequate bone marrow, renal, and hepatic function as defined by ANC > 1500 cells/mcl, 
platelets > 100,000/mcl, creatinine < 2.0 x ULN, bilirubin < 1.5 times institutional normal, 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels < 2.5 x ULN  
6. No disease-modifying therapy, including investigational treatments, within 28 days prior 
to initiation of study treatment.  
7. Ability to swallow tablets 
8. For Women of child-bearing potential:  

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• Willingness to use a highly effective method of contraception during the study and for 
6 months  following the last dose of galunisertib. Negative beta human chorionic 
gonadotropin pregnancy test documented within 7 days prior to initiation of study drug. 
9. Patient must have measurable disease before the treatment 
3.3 
Exclusion Criteria 
1. Planned radiotherapy during or after the study chemotherapy prior to disease progression. 
2. Receipt of chemotherapy or radiation within 28 days of study treatment 
3. Have had a major surgical procedure or a significant traumatic injury within 28 days prior 
to study treatment; Minor procedures such as biopsy within 7 days prior to study treatment 
are allowed. 
4. Active infection that would preclude receipt of chemotherapy 
5. Moderate or severe cardiovascular disease with one of the following: 
• Myocardial infarction within 6 months prior to study entry, unstable angina pectoris, 
New York Heart Association Class III/IV congestive heart failure, or uncontrolled 
hypertension.  
• Major ECG abnormalities (e.g. Q-QS wave abnormalities, left ventricular hypertrophy, 
Wolff-Parkinson-White syndrome, complete bundle branch block, intraventricular 
block, atrial fibrillation, atrial flutter or major ST-T changes) not responding to medical 
treatments. Major abnormalities documented by ECHO with Doppler (for example, 
moderate or severe heart valve function defect) that is not stable for at least 6 months. 
Note:  Left ventricular [LV] ejection fraction <50% is allowed only if clinically stable 
for at least 6 months (evaluation based on the institutional lower limit of normal). 
• Predisposing conditions that are consistent with development of aneurysms of the 
ascending aorta or aortic stress (for example, family history of aneurysms, Marfan-
Syndrome, bicuspid aortic valve, evidence of damage to the large vessels of the heart 
documented by CT scan/MRI with contrast)  
6. Active pregnancy or lactation 
7. Second primary malignancy for which treatment during the study period would be 
recommended if this cancer were not also present.  
8. Prior malignancy requiring treatment within the last 3 years 
9. Use of another investigational product or device within 4 weeks of study entry or during 
study participation.  
4 SUBJECTS REGISTRATION AND ENROLLMENT   
4.1 
Required Protocol Specific Regulatory Documents 
This protocol, the Informed Consent document, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB by the Principal Investigator and 
reviewed and approved by the IRB before the study is initiated. 
 

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4.2 
Patient Registration and Enrollment 
Patients must have signed and dated all applicable consents and authorization forms. Patients who 
signed informed consent form will be registered in Velos eResearch database system, which is 
sponsored by OU-SCC. The subject ID number will be generated after registration.    
Patients must not start protocol treatment prior to registration. Patient will start protocol treatment 
only after pre-treatment evaluation is complete and eligibility criteria have been met 
5 STUDY MODALITIES   
5.1 
Carboplatin (Paraplatin® - NSC #241240) 
5.1.1 Formulation 
Carboplatin is supplied as a sterile, pyrogen-free, 10mg/mL aqueous solution in multi-dose vials 
containing 50mg/5mL, 150mg/15mL, 450mg/45mL, or 600mg/60mL of carboplatin.  
5.1.2 Storage 
Unopened vials of carboplatin are stable to the date indicated on the package when stored at 25°C 
(77°F). Excursions from 15 to 30°C (59 to 86°F) are permitted. Protect from light. Carboplatin 
multi-dose vials maintain microbial, chemical, and physical stability for up to 14 days at 25°C 
following multiple needle entries. 
5.1.3 Preparation 
Carboplatin aqueous solution can be further diluted to concentrations as low as 0.5mg/mL with 
5% Dextrose in Water or 0.9% Sodium Chloride for Injection, USP. When prepared as directed, 
carboplatin aqueous solutions are stable for 8 hours at room temperature (25°C / 77°F). Since no 
antibacterial preservative is contained in the formulation, it is recommended that carboplatin 
solutions be discarded 8 hours after dilution. 
Note that carboplatin dose will be recalculated if patient has weight change of greater than or equal 
to 10% from baseline.  
NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss of potency; 
therefore, needles or intravenous sets containing aluminum parts that may come in contact with 
the drug must NOT be used for the preparation or administration of carboplatin. 
5.1.4 Adverse Effects 
Consult the package insert for the most current and complete information. 
5.1.5 Supplier 
Commercially available both from Bristol-Myers Squibb Oncology as well as generic 
manufacturers. Consult the American Hospital Formulary Service Drug Information guide, Facts 
and Comparisons, or the package insert for additional information. 
5.1.6 Administration 
See Section 6.1. 
 

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5.2 
Paclitaxel (NSC #673089) 
5.2.1 Formulation 
Paclitaxel is supplied as a 6mg/mL non-aqueous solution in multi-dose vials containing 
30mg/5mL, 100mg/16.7mL, or 300mg/50mL of paclitaxel. In addition to 6mg of paclitaxel, each 
mL of sterile non-pyrogenic solution contains 527mg of purified Cremophor® EL 
(polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP. 
5.2.2 Storage 
Unopened vials of paclitaxel are stable to the date indicated on the package when stored between 
20 to 25°C (68 to 77°F). Protect from light. 
5.2.3 Preparation 
Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% Sodium Chloride 
for Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride 
Injection, USP; or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 1.2mg/mL. 
The solutions are physically and chemically stable for up to 27 hours at ambient temperature 
(approximately 25°C / 77°F) and room lighting conditions. 
NOTE: In order to minimize patient exposure to the plasticizer DEHP, which may be leached 
from PVC infusion bags or sets, diluted paclitaxel solutions should be stored in bottles (glass, 
polypropylene) or plastic (polypropylene, polyolefin) bags and administered through polyethylene 
lined administration sets. 
Paclitaxel should be administered through an inline filter with a microporous membrane not greater 
than 0.22 microns. Use of filter devices such as IVEX-2® or IVEX-HP®, which incorporate short 
inlet and outlet PVC-coated tubing, has not resulted in significant leaching of DEHP. 
All patients should be premedicated with corticosteroids, diphenhydramine, and H2 antagonists 
prior to paclitaxel administration in order to prevent severe hypersensitivity reactions. Patients 
who experience severe hypersensitivity reactions to paclitaxel should not be rechallenged with the 
drug. 
5.2.4 Adverse Effects 
Consult the package insert for the most current and complete information. 
5.2.5 Supplier 
Commercially available both from Bristol-Myers Squibb Oncology as well as generic 
manufacturers. Consult the American Hospital Formulary Service Drug Information guide, Facts 
andComparisons, or the package insert for additional information. 
NOTE: Docetaxel may be substituted if a patient is intolerant or has an allergic reaction to 
paclitaxel. 
Refer 
to 
the 
package 
insert 
for 
docetaxel 
(Taxotere, 
see 
http://products.sanofi.us/Taxotere/taxotere.pdf  ) for the most complete and current information 
for the followings: 
• Docetaxel Injection Concentrate 20 mg/mL is supplied in a single use vial as a sterile, 
pyrogen-free, non-aqueous solution. 
• Store docetaxel vials between 2°C and 25°C (36°F and 77°F). Retain in the original 
package to protect from light. Freezing does not adversely affect the product. 
• Using only a 21 gauge needle, aseptically withdraw the required amount of Taxotere 
injection concentrate (20 mg docetaxel/mL) with a calibrated syringe and inject via a single 

Version 8.0 (22-Apr-2021) 
14 
 
injection (one shot) into a 250 mL infusion bag or bottle of either 0.9% Sodium Chloride 
solution or 5% Dextrose solution to produce a final concentration of 0.3 mg/mL to 0.74 
mg/mL. If a dose greater than 200 mg of Taxotere is required, use a larger volume of the 
infusion vehicle so that a concentration of 0.74 mg/mL Taxotere is not exceeded. 
5.3 
Galunisertib 
5.3.1 Formulation 
The drug substance, galunisertib, is manufactured as a monohydrate and is also referred to using 
Lilly compound numbers LY2157299 monohydrate or LSN2232682. The nonproprietary name 
galunisertib can refer to the anhydrous or monohydrate form interchangeably. LY2157299 refers 
specifically to the anhydrous form. 
 
 
5.3.2 Physical and Chemical Characteristics 
Molecular weight: 387.4 
Molecular/Empirical formula: C22H19N5O∙H2O 
Description: White to practically white to light brown to light 
grey powder 
pKa: 
 
pKa1: 3.30 
pKa2: 4.43 
 
 
 
Determined in 0.15M KCl aqueous solution/1,4-dioxane co-solvent 
pH: 
 
Due to low solubility in deionised water, pH was not obtained. 
Stability:  
Drug substance is stable at room temperature 

Version 8.0 (22-Apr-2021) 
15 
 
Solubility:  
Practically insoluble in water and slightly soluble in ethanol at room 
temperature 
5.3.3 Drug Product 
Galunisertib is supplied for clinical trial use as nonfilm coated tablets and film coated tablets 
described below: 
Galunisertib tablets (nonfilm-coated) are composed of galunisertib and the inactive ingredients 
lactose monohydrate, microcrystalline cellulose, hydroxypropyl methylcellulose, pregelatinised 
starch, croscarmellose sodium, and magnesium stearate. Each tablet contains galunisertib 
equivalent to 80 mg or 150 mg of galunisertib (anhydrous). The drug product is stable when stored 
at room temperature. 
Galunisertib tablets (film-coated) are composed of galunisertib and the inactive ingredients 
mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium 
stearate, talc, lactose monohydrate, hypromellose, titanium dioxide, triacetin, iron oxide yellow, 
and iron oxide red. Each tablet contains galunisertib equivalent to 80 mg or 150 mg of galunisertib 
(anhydrous). The drug product is stable when stored at room temperature. 
5.3.4 Adverse Events 
Approximately 700 patients and 20 healthy volunteers have been treated with galunisertib.  At this 
time, no clear or definitive drug-related toxicity profile has emerged.  Based on galunisertib’s 
mechanism of action, the following toxicities could be expected: 
• Vascular degeneration 
• Aortic aneurysm 
• Decrease in blood pressure 
• Increase in heart rate 
• Cardiac insufficiency 
• Autoimmune reaction 
• Birth defects 
• Thrombocytopenia 
• Thromboembolic events 
5.3.5 Drug Supply 
Galunisertib will be supplied in 150mg and 80mg tablets by Lilly. 
 
 

Version 8.0 (22-Apr-2021) 
16 
 
6 TREATMENT PLAN  
An original, informed consent form, indicating prior approval by the institution’s Human Rights 
or Clinical Trials Committee for participation in this study, must be forwarded to the SCC CTO 
Office.  
6.1 
Treatment Plan 
6.1.1 Paclitaxel/Carboplatin plus Galunisertib 
• Paclitaxel** 175* mg/m2 over 3 hours, IV day 1 
• Carboplatin AUC 6* over 1 hour, IV day 1 (If no prior radiation therapy) 
• Galunisertib 150mg po BID day 4-17 (see section 6.3) 
• Cycles are 28 days 
* Or, in patients with history of prior pelvic radiation, Paclitaxel 135mg/m2 over 3 hours, IV day 
1; Carboplatin AUC 5* over 1 hour, IV day 1 (if no prior radiation therapy); Galunisertib 150mg 
po BID day 4-17 (see section 6.3). Cycles are 28 days.  
** Docetaxel starting at 75 mg/m2, IV day 1 may be substituted if a patient is intolerant or has an 
allergic reaction to paclitaxel.    
Patients will receive paclitaxel/carboplatin/galunisertib until unacceptable toxicity or progression.  
In the event of a complete clinical response or partial response for which the treating physician 
believes cytotoxic chemotherapy with paclitaxel/carboplatin may be safety suspended, patients 
will continue galunisertib 150mg po BID as maintenance monotherapy until progression or 
toxicity. 
6.2 
Method of Paclitaxel/Carboplatin Chemotherapy Administration 
6.2.1 Pre-medications for Paclitaxel 
Due to the risk of hypersensitivity reactions with paclitaxel, all patients should be pre-medicated 
with:  
AGENT 
DOSE/ROUTE 
DURATION 
Dexamethasone 
20 mg PO 
OR 
12 mg IV 
-12 and 6 hours prior to paclitaxel 
-30 minutes prior to paclitaxel 
 
Diphenhydramine 
50 mg IV 
30 minutes prior to paclitaxel 
Ranitidine 
Or  
equivalent alterative 
50 mg IV 
30 minutes prior to paclitaxel 
6.2.2 Antiemetics 
It is anticipated that nausea and vomiting may be a significant side effect. Based on an updated 
ASCO antiemetic guidelines, adult patients who are treated with carboplatin at AUC ≥ 4 should 
be offered a three-drug combination of an NK1 receptor antagonist (like fosaprepitant), a 5-HT3 
receptor antagonist, and dexamethasone[31]. Patients should receive fosaprepitant and either 
ondansetron, granisetron, or dolasetron prior to chemotherapy plus dexamethasone (10-20 mg IV). 

Version 8.0 (22-Apr-2021) 
17 
 
For some patients the addition of lorazepam (1-2 mg IV 30 minutes prior to chemotherapy) may 
also be appropriate.  
Note: Due to potential fosaprepitant drug interactions with oral dexamethasone[32], dose 
adjustment of dexamethasone should be considered.  
6.2.3 BSA Calculation 
If the body surface area is > 2.0m2 then drugs should be dosed at 2.0 m2.  
6.2.4 Post pre-medication 
After premedication, paclitaxel will be given at a dose of 175 mg/m2 as a 3-hour infusion or 
135mg/m2 as a 3-hour infusion for those patients with prior pelvic radiotherapy 
6.2.5 Paclitaxel/Carboplatin dose 
Carboplatin dosed to an AUC of 5 for patients receiving docetaxel rather than paclitaxel or with 
prior pelvic radiation; or AUC 6 for patients with prior radiation will be given IV over 30 minutes 
after paclitaxel.  
The dose of carboplatin will be calculated by the formula of Calvert et al. 
CALVERT FORMULA: 
Carboplatin dose (mg) = (Target AUC) X (GFR + 25) 
For the purposes of this protocol, GFR will be estimated based on the calculated creatinine 
clearance (Cockroft-Gault equation).  
Dosing of paclitaxel in patients with hepatic impairment is discussed in section 7.5.4 
The dose of carboplatin must be recalculated for each cycle if patient has weight change of greater 
than or equal to 10% from baseline. 
6.2.6 Regimen 
This regimen can be administered in an outpatient setting. 
Regimen will be repeated every 28 days until unacceptable toxicity or progression.  In the event 
of a complete clinical response or partial response for which the treating physician believes 
cytotoxic chemotherapy with paclitaxel/carboplatin may be safely discontinued, 4 cycles of 
combination therapy is recommended; treatment may be changed to monotherapy with galunisertib 
monotherapy with 28 day cycles with galunisertib alone on days 4-17. 
Recommended guidelines for dose reductions/discontinuation are described in section 7. 
6.3 
Administration of Galunisertib 
Studies must be conducted in accordance with ICH guidelines and protocols must be developed 
following section 6 of the ICH guidelines.  
6.3.1 Administration 
Galunisertib will be administered orally 150mg, bid, 14 days on and 11days off starting on day 4 
and ending on 17 of a 28 day cycle.   
A cycle (28 days) will be defined as an intermittent dosing regimen of 14 days of galunisertib 
followed by 11 days without galunisertib administration. Any missed doses should not be made 
up. No patient should receive more than 14 consecutive days of galunisertib dosing for safety 
reasons.  

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18 
 
To date, galunisertib at the IB defined dose is well tolerated in patients. If a toxicity is observed 
that may be related to galunisertib, a dose reduction to 80 mg BID is permitted.   
6.3.2 Recommended Guidelines for Dose Reductions/Discontinuation are as Follows: 
If a patient experiences any of the following events that are considered possibly related to 
galunisertib, galunisertib will be omitted until the event resolves:  
• Neutropenia with absolute neutrophil count (ANC) <0.5 x 109/L x 7 days, or ANC <1.0 x 
109/L with a single temperature of >101oF/38.3oC or a sustained temperature of 
>100.4oF/38oC for more than 1 hour, or thrombocytopenia with platelet count <50,000 x 
109/L  
• Hematologic toxicity must resolve to baseline or </= grade 1 prior to resumption of 
galunisertib therapy.  
• Non-hematologic toxicity must resolve to CTCAE Grade≤1 or baseline (with the exception 
of alopecia, fatigue, skin rash, nausea, vomiting, constipation, or diarrhea that can be 
controlled with treatment).  
6.3.3 Dose reduction 
If dosing is delayed for treatment-related AEs for more than 2 weeks, and the patient recovers 
within 28days, the patient may continue at a reduced dose of 80 mg BID (160-mg total daily dose). 
If recovery is >28 days, the patient must be withdrawn from study treatment. No patient will have 
his/her dose reduced more than once. Dose re-escalation to the previous dose is not permitted. 
7 TREATMENT MODIFICATIONS 
Dose modification is based on history of prior pelvic radiation therapy, interim nadir levels, and 
delays due to pre-treatment counts. No dose escalation will be permitted. Toxicity will be 
classified based on the current Common Toxicity Adverse Events (CTCAE) version 4.0 
7.1 
Paclitaxel* Dose Levels 
Dose level 
Dose (mg/m2/day) 
Indication 
-2 
110 
 
-1 
135 
Starting dose- History of prior radiation 
1 
175 
Starting dose- No prior radiation 
*Patients who experience hypersensitivity (allergic) reactions to paclitaxel may switched to 
docetaxel per the investigator’s discretion. 
Docetaxel Dose Levels 
Dose level 
Dose (mg/m2) 
Indication 
-2 
55 
 
-1 
65 
 
1 
75 
Starting dose 
 

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19 
 
7.2 
Carboplatin Dose Levels 
Dose level 
Dose (AUC) 
Indication 
-2 
4 
 
-1 
5 
Starting dose- for patients receiving 
docetaxel rather than paclitaxel or History 
of prior radiation 
1 
6 
Starting dose- No prior radiation 
7.3 
Galunisertib Dose Levels 
Dose level 
Dose  
Indication 
-2 
no 
second 
dose 
level 
reduction 
allowed 
 
-1 
80 mg po bid x 14 
days on, 11 days off 
( day 4-17) 
 
1 
150mg po bid x 14 
days on, 11 days off 
(day 4-17) 
Starting dose 
7.4 
Dose Modifications-Hematologic 
7.4.1 Interim Nadirs 
Dose reductions are for all subsequent cycles. 
Neutropenia 
First Occurrence 
Neutropenia 
CTCAE 
Grade  
0 
1 
2 
3 with fever 
4 x 7 days or with fever 
Carboplatin 
No 
Change 
No 
Change 
No 
Change 
Dose reduce to level -1 Dose reduce to level -1 
Paclitaxel 
No 
Change 
No 
Change 
No 
Change 
No Change 
No change 
Galunisertib 
No 
Change 
No 
Change 
No 
Change 
Hold dosing until ANC 
returns to grade 1 and 
then resume at same 
dose level 
 Hold 
dosing 
until 
ANC returns to grade 1 
and then resume at 
same dose level 
Patients who experience neutropenic fever or sepsis requiring antibiotics will undergo a dose level 
reduction, as above. 

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20 
 
Patients who have asymptomatic grade 4 toxicity at the lowest dose level may remain on protocol 
if counts recover on time and if platelet toxicity is grade 2 or less. 
Galunisertib should be held until counts meet criteria for resuming of chemotherapy. 
Second Occurrence 
Neutropenia 
CTCAE 
Grade  
0 
1 
2 
3 with fever 
4 x 7 days or with fever 
Carboplatin 
No 
Change 
No 
Change 
No 
Change 
Add G-CSF 
Add G CSF 
Paclitaxel 
No 
Change 
No 
Change 
No 
Change 
Dose level -1 
Dose level -1 
Galunisertib 
No 
Change 
No 
Change 
No 
Change 
Hold until ANC back 
to grade 1 and dose 
reduce to dose level -1 
Hold until ANC back 
to grade 1 and dose 
reduce to dose level -1 
Third Occurrence 
ANC Nadir 
Grade 
3rd  
Occurrence 
0 
1 
2 
3 with fever 
4 x 7 days or with fever 
Carboplatin 
No 
Change 
No 
Change 
No 
Change 
Dose level -2 
Dose level -2 
Paclitaxel 
No 
Change 
No 
Change 
No 
Change 
Dose level -2 
Dose level -2 
Galunisertib 
No 
Change 
No 
Change 
No 
Change 
Hold dosing until ANC 
returns to grade 1and 
then resume at same 
dose level 
Hold dosing until ANC 
returns to grade 1and 
then resume at same 
dose level 
If there is a 4th occurrence of grade 3 with fever or grade 4 ANC despite two dose level reductions 
of carboplatin, G-CSF and one dose level reduction of Galunisertib, the patient should be removed 
from protocol therapy 
Thrombocytopenia  
First Occurrence 
Thrombocyt
openia 
CTCAE  
Grade  
0 
1 
2 
3 with bleeding 
4  
Carboplatin 
No 
Change 
No 
Change 
No 
Change 
No Change 
No change 

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21 
 
Paclitaxel  
No 
Change 
No 
Change 
No 
Change 
Hold dosing until plts 
return to grade 1 and 
then resume at same 
dose level 
Hold dosing until plts 
return to grade 1 and 
then resume at same 
dose level 
Galunisertib 
No 
Change 
No 
Change 
No 
Change 
Reduce by dose level -
1 
Reduce by dose level -
1 
Second Occurrence   
Thrombocyt
openia 
Grade  
0 
1 
2 
3 bleeding 
4  
Carboplatin 
No 
Change 
No 
Change 
No 
Change 
Reduce carboplatin to 
dose level -1 
Reduce carboplatin to 
dose level -1 
Paclitaxel  
No 
Change 
No 
Change 
No 
Change 
No change 
No change 
Galunisertib 
No 
Change 
No 
Change 
No 
Change 
Hold dosing until plts 
return to grade 1and 
then resume at one 
dose level reduction 
Hold dosing until plts 
return to grade 1and 
then resume at one 
dose level reduction 
A third occurrence of grade 3 thrombocytopenia with bleeding or grade 4 thrombocytopenia will 
necessitate discontinuation of carboplatin chemotherapy.  Discussion regarding continuation of 
paclitaxel + galunisertib or galunisertib alone will be one a case by case basis with the study PI. 
No reduction below lowest dose level specified is allowed. If grade 4 neutropenia or 
thrombocytopenia is observed at the lowest dose levels, the Study Chair should be contacted and 
the patient will discontinue the study treatment. 
Dosing of galunisertib should be held until hematologic parameters are within range for treatment. 
If dosing is delayed for treatment-related AEs for more than 2 weeks, and the patient recovers 
within 28 days, the patient may continue at a reduced dose of 80 mg BID (160-mg total daily dose). 
If recovery is >28 days, the patient must be withdrawn from study treatment. No patient will have 
his/her dose reduced more than once. Dose re-escalation to the previous dose is not permitted. 
7.4.2 Pre-cycle Initiation Counts 
No subsequent course of therapy should be given until the ANC > 1500/mcl and the PLT count > 
75,000/mcl. If dose is held due to pre-treatment myelosuppression, recheck counts weekly. If 
therapy is delayed 3 weeks or longer from scheduled administration, the Study Chair should be 
notified and the patient should be removed from study treatment. 
7.5 
Dose Modifications-Non-Hematologic Toxicity 
7.5.1 Neurologic 
Neurotoxicity (paresthesia, neuropathy, toxicity)- as detected on pre-cycle initiation evaluation. 
Grade 0-1- No change, Grade 2- Hold paclitaxel until neuropathy improves to ≤ grade 1 level, then 
reduce paclitaxel by one dose level. Grade 3-4 requires removal of patient from study treatment. 

Version 8.0 (22-Apr-2021) 
22 
 
7.5.2 Gastrointestinal  
Nausea/vomiting: Increased antiemetic therapy, outpatient IV hydration, and hospital admission 
should be attempted prior to dose reduction.  
As reported greater than 48 hours following completion of chemotherapy cycle:  
Grade 0-3 toxicity- No change, Grade 4- reduce all drugs one dose level. 
Other toxicity: For any Grade 3-4 toxicity not mentioned above, protocol treatment should be 
withheld until patient recovers to ≤ Grade 1 status. Subsequent courses of therapy should be given 
with a one level dose reduction of agent(s) felt to be responsible. In general, unusual toxicities 
should be discussed with the Study Chair. 
If therapy is delayed 4 weeks or longer from scheduled administration, the Study Chair should be 
notified and the patient should be removed from study. 
7.5.3 Cardiac 
Given the cardiovascular toxicities that were observed in preclinical studies, monitoring must be 
performed as per the guidance below which is accordance with feedback obtained from the FDA. 
The specific cardiotoxicities seen in these preclinical studies were vascular degeneration and 
hemorrhage, resulting in development of valvular insufficiency and aneurysmal type changes in 
the large vessels at the base of the aorta or thoracic aorta. These changes occurred when treatment 
was administered continuously and at higher doses than used in humans.  If moderate or severe 
heart valve insufficiency or new aneurysms are observed, the patient must immediately be 
discontinued from the treatment and the adverse event reported to Lilly within 24 hours (SAE). 
General Guidance for Cardiotoxicity monitoring  
Prior to Enrollment 
•  MRI or CT scan (with contrast) of chest will be locally assessed for enrollment and safety 
decisions by a physician or a person who is qualified by experience or training. The 
objective of this evaluation is to assess for possible aneurysms of the ascending aorta and 
aortic arch. Should the patient have a previous history of abdominal aneurysm, an 
additional abdominal MRI or CT is required. NOTE: If a chest MRI or CT scan (with 
contrast) is performed as part of standard screening and on-treatment tumor assessment, 
this same scan may be used for safety evaluation, provided that it properly assesses the 
great vessels of the heart.  
During Study 
•  CT with contrast or MRI will be conducted at 6 cycles and then as clinically indicated. 
30-days follow-up visit 
• MRI or CT scan with contrast of chest to assess the large vessels of the heart: Perform if 
there was no previous post-treatment scan, if findings were observed on a previous scan, 
or if clinically indicated. 
7.5.4 Hepatic Function 
Dose adjustment of paclitaxel in patients with hepatic impairment include: 
3-hour infusion:  
• Transaminases <10 times ULN and bilirubin level ≤1.25 times ULN: 175 mg/m2 
• Transaminases <10 times ULN and bilirubin level 1.26 to 2 times ULN: 135 mg/m2 

Version 8.0 (22-Apr-2021) 
23 
 
• Transaminases <10 times ULN and bilirubin level 2.01 to 5 times ULN: 90 mg/m2 
• Transaminases ≥10 times ULN or bilirubin level >5 times ULN: Avoid use 
8 STUDY PARAMETERS 
8.1 
Observations and Tests 
1. Pre-study scans should be performed within 4 weeks prior to registration. 
2. Initial H&P and laboratory tests can be used for C1D1 if done within 72 hours 
The following observations and tests are to be performed and recorded on the appropriate form(s)6. 
PARAMETER 
Prior to 
Study 
Within 28 
days of 
enrollment 
Prior to 
Study 
Within 14 
days of 
enrollment 
Weekly 
Prior 
to 
each 
cycle 
Every 
other 
cycle 
30 
days 
after 
last 
dose 
Follow-
up 
History/ Physical/ 
Performance Status 
X 
X 
 
X 
 
 
 
Vital signs/ Weight 
 
X 
 
X 
 
 
 
CT CAP 1 
X 
 
 
 
X2 
X1 
 
CBC/Diff/ platelets 
 
X 
X3 
X 
 
 
 
Creatinine 
 
X 
 
X 
 
 
 
Urinalysis 
 
X 
 
X 
 
 
 
AST, ALT, 
Alkaline 
Phosphatase 
 
X 
 
X 
 
 
 
Eligibility Check 
 
X 
 
 
 
 
 
Con-med 
 
 
 
X 
 
 
 
Toxicity 
assessment 
 
 
 
X 
 
X 
 
Survival  
 
 
 
 
 
 
X4 
Biopsy 
X5 
 
 
 
 
 
 
 
1 MRI or CT scan with contrast of chest to assess the large vessels of the heart: Perform if there 
was no previous post-treatment scan, if findings were observed on a previous scan, or if 
clinically indicated. 
2 CT or MRI imaging and RECIST assessment will be repeated every other cycles during 
combination treatment, then every 4 cycles during maintenance treatment. 
3 CBC/Diff/ platelets exams will be repeated every week during combination treatment, then 
every cycles during maintenance treatment. 

Version 8.0 (22-Apr-2021) 
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4 The patient will be followed up every 3 month with phone check in after the last visit for 
duration of 2 years from date of registration. 
5 Each patient must have available tissue sample (include RNA, snap frozen and FFPE tissue) 
prior to treatment. For patients with a primary diagnosis, use of archival tissue from surgery 
or a new biopsy is acceptable. For patients with recurrence or progression, a new biopsy is 
required prior to receiving treatment. For patients with measurable disease, a second biopsy 
will be collected after cycle 1. 
6 During the COVID-19 crisis, protocol mandated visits may be performed via telemedicine or 
visits may be combined in order to prevent imminent safety risks to patients. Weekly 
laboratory visits during combination treatment with Paclitaxel/Carboplatin/Galunisertib are 
allowed to change to every 28 days. All such changes to the visit schedule must be clearly 
documented in the subject’s chart. Changes in study visit schedules or missed visits must be 
explained in the final clinical study report. 
8.2 
Pharmacokinetics 
For the first 6 subjects only, blood will be collected for PK testing of galunisertib levels on 
• Cycle 1 day 4 
o pre-dose (within 30 minutes of dose delivery time) 
• Cycle 1 day 8  
o pre-dose 
o Cycle 2 day 1 
o pre-dose 
Approximately 4ml of venous blood samples will be drawn into sodium heparinized tubes at each 
time-point for measurement of LY2157299. Plasma samples will be used to assay for LY2157299 
using a validated liquid chromatography-mass spectrometry (LC/MS) method [28, 33]. 
8.3 
Tissue Biopsy for Pharmacodynamics 
• Each patient must have available tissue sample (include RNA, snap frozen and FFPE 
tissue) prior to treatment. 
• For patients with a primary diagnosis, use of archival tissue from surgery or a new biopsy 
is acceptable.  
• For patients with recurrence or progression, a new biopsy is required prior to receiving 
treatment. 
• For patients with measurable disease, a second biopsy will be collected after cycle 1 
Please see lab manual for more detailed information of sample collection and shipping. 
9 EVALUATION CRITERIA   
9.1 
Parameters of Outcome–RECIST 1.1 Criteria  
9.1.1 Measurable Disease Definition 
Measurable disease is defined as at least one lesion that can be accurately measured in at least one 
dimension (longest dimension to be recorded). Each lesion must be ≥ 10 mm when measured by 
CT and MRI; or ≥ 20 mm when measured by conventional techniques, including plain x-ray.  
9.1.2 Baseline Documentation of “Target” and “Non-Target” lesions 
All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total 
representative of all involved organs should be identified as target lesions and will be recorded and 

Version 8.0 (22-Apr-2021) 
25 
 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest dimension) and their suitability for accurate repetitive measurements by one consistent 
method of assessment (either by imaging techniques or clinically). A sum of the longest dimension 
(LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline 
sum LD will be used as reference to further characterize the progression of the measurable 
dimension of the disease. Tumor within a previously irradiated field will be designated as “non-
target” lesions unless progression is documented or a biopsy is obtained to confirm persistence at 
least 90 days following completion of radiation therapy.  
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required and each of these lesions should be followed 
as stable (the persistence of a non-target lesion), complete response (the disappearance of a non-
target lesion) or progressive disease (the unequivocal progression of a non-target lesion).  
All baseline evaluations of disease status should be performed as close as possible to the start of 
treatment and never more than 4 weeks before the beginning of treatment.  
Measurement of the longest dimension of each target lesion size is required for follow-up. Change 
in the sum of these dimensions affords some estimate of change in tumor size and hence therapeutic 
efficacy. All disease must be assessed using the same technique as baseline.  
9.1.3 Definition of Disease Progression  
Progression for patients with measurable disease at baseline is defined as ANY of the following: 
• At least a 20% increase in the sum of LD target lesions taking as reference the smallest 
sum LD recorded since study entry; in addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm 
• In the case where the ONLY target lesion is a solitary pelvic mass measured by physical 
exam which is not radiographically measurable, a 50% increase in the LD is required taking 
as reference the smallest LD recorded since study entry  
• The appearance of one or more new lesions  
• Death due to disease without prior objective documentation of progression  
• Global deterioration in health status attributable to the disease requiring a change in therapy 
without objective evidence of progression  
• Unequivocal progression of existing non-target lesions, other than pleural effusions 
without cytological proof of neoplastic origin, in the opinion of the treating physician (in 
this circumstance an explanation must be provided)  
Progression for patients with non-measurable disease at baseline is defined as increasing clinical, 
radiological, or histological evidence of disease since study entry.  
9.1.4 Survival 
Survival is the observed length of life from the date of study entry to death or the date of last 
contact.  
9.1.5 Progression Free Survival 
Progression free survival is the period from the date of study entry until disease progression, death, 
or date of last contact.  

Version 8.0 (22-Apr-2021) 
26 
 
9.2 
Subjective Parameters 
The performance status, specific symptoms, and side effects are graded according to the CTCAE. 
Of particular interest will be ≥grade 3 adverse events. 
9.3 
Definition of Evaluable Patients 
Evaluable patients will be defined as patients who receive at least four cycle of study treatment. 
Patients who withdraw consent before completion of four cycles will be replaced. 
10 DURATION OF STUDY  
Treatment may continue as long as the patient is receiving clinical benefit and not experiencing 
excessive toxicity or disease progression.  If a complete clinical response is achieved or for patients 
who come on study with no measurable disease (e.g. post operative early stage) or achieve a 
durable partial response for which the treating physician feels discontinuation of cytotoxic 
chemotherapy is an option, 4 cycles of combination therapy is recommended with an option for 
maintenance therapy with galunisertib monotherapy until toxicity, progression.   
Follow-up is required as outlined in Section 8.1 In brief, patients will be seen every 28 days (prior 
to each cycle of therapy) while receiving active chemotherapy and/or galunisertib maintenance.  
CT scans to assess response will be performed prior to every odd cycle.  Patients will also be seen 
30 days after last study medication is issued. Required study procedures are based on the presence 
or absence of galunisertib related cardiac or other toxicities and are outlined in the footnotes of 
section 7. Additionally, birth control must continue for 6 months after discontinuation of 
galunisertib. After the last visit, the patient will be followed up with phone check in every 3 month 
for duration of 2 years from date of registration. 
A patient is considered off study therapy when the patient has progressed or died prior to 
completion of study therapy, a non-protocol drug or therapy (directed at the disease) is initiated or 
all study therapy is totally discontinued. Survival and progression data will continue to be 
collected.  
11 STUDY MONITORING AND REPORTING PROCEDURES   
In the event of an adverse event the first concern will be for the safety of the subject. Investigators 
are required to report to Lilly Drug Safety ANY serious treatment emergent adverse event 
(STEAE) as soon as possible.   
A STEAE is any sign, symptom or medical condition that emerges during treatment or during a 
post-treatment follow-up period that (1) was not present at the start of treatment and it is not a 
chronic condition that is part of the patient’s medical history, OR (2) was present at the start of 
treatment or as part of the patient’s medical history but worsened in severity and/or frequency 
during therapy, AND that meets any of the following regulatory serious criteria: 
• Results in death  
• Is life-threatening  
• Requires or prolongs inpatient hospitalization  
• Is disabling  
• Is a congenital anomaly/birth defect  

Version 8.0 (22-Apr-2021) 
27 
 
• Is medically significant or requires medical or surgical intervention to prevent one of the 
outcomes listed above. 
11.1 Reporting of Serious Treatment Emergent Adverse Events  
All STEAEs should be recorded on a Form and emailed or faxed to the Sponsor: 
Email: SCCIITreporting@ouhsc.edu 
Or 
Fax: 1-405-271-1416. 
AND 
Eli Lilly and Company 
Local Safety Representative 
Fax: 
866-644-1697 
(Please use the safety reporting fax cover sheet attached to this document for your fax 
transmission) 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed consent 
is obtained and initiation of study treatment and ends 30 days following the last administration of 
study treatment or study discontinuation/termination, whichever is earlier.  After this period, 
investigators should only report SAEs that are attributed to prior study treatment.  
The principal investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, are collected and reported to the FDA, appropriate IRB(s) and sponsor 
institute in accordance with CFR 312.32 (IND Safety Reports).  
All reportable events should be sent to the Sponsor via email/fax: 
Email: SCCIITreporting@ouhsc.edu 
Or 
Fax: 1-405-271-1416. 
In addition, the sponsor institute/principal investigator is responsible for notifying Eli Lilly and 
Company for AE/SAE related to Galunisertib in parallel of such events within 24 hours of the 
Sponsor/PI becoming aware of the event. The following reportable events must be submitted to 
Eli Lilly and Company 
• Serious Adverse Events 
• Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse event) 
11.2 MedWatch 3500a Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of the 
MedWatch 3500a form: 
• Treatment regimen (dosing frequency, combination therapy) 
• Protocol description (and number, if assigned) 

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• Description of event, severity, treatment, and outcome, if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
Follow-up information: 
Additional information may be added to a previously submitted report by any of the following 
methods: 
• Adding to the original MedWatch 3500a report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500a form  
• Summarizing new information and faxing it with a cover letter including subject identifiers 
(i.e. D.O.B. initial, subject number), protocol description and number, if assigned, suspect 
drug, brief adverse event description, and notation that additional or follow-up information 
is being submitted  (The subject identifiers are important so that the new information is 
added to the correct initial report) 
Occasionally Lilly may contact the reporter for additional information, clarification, or current 
status of the subject for whom and adverse event was reported.  
11.3 Assessing Causality 
Investigators are required to assess whether there is a reasonable possibility that galunisertib 
combined treatment caused or contributed to an adverse event.  The following general guidance 
may be used. 
Yes: 
if the temporal relationship of the clinical event to galunisertib administration makes a 
causal relationship possible, and other drugs, therapeutic interventions or underlying 
conditions do not provide a sufficient explanation for the observed event. 
No: 
if the temporal relationship of the clinical event to galunisertib administration makes a 
causal relationship unlikely, or other drugs, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 
11.4 SAFETY REPRORTING REQUIREMENTS FOR IND HOLDERS 
In accordance with 21 CFR 212.32, sponsors of studies conducted under an IND must comply with 
following safety reporting requirements:  
a. Expedited IND Safety Reports: 
7 Calendar-Day Telephone or Fax Report: 
The Sponsor is required to notify the FDA of any fatal or life-threatening adverse event that is 
unexpected and assessed by the investigator to be possibly related to the use of galunisertib.  An 
unexpected adverse event is one that is not already described in the Investigator Brochure.  Such 
reports are to be telephoned or faxed to the FDA and Lilly within 7 calendar days of first learning 
of the event.  Each telephone call or fax transmission (see fax number below) should be directed 
to the FDA new drug review division in the Center for Drug Evaluation and Research or in the 
product review division for the Center for Biologics Evaluation and Research, whichever is 
responsible for the review of the IND. 

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29 
 
15 Calendar-Day Written Report:   
The Sponsor is also required to notify the FDA and all participating investigators, in a written IND 
Safety Report, of any serious, unexpected AE that is considered possibly related to the use of 
galunisertib.  An unexpected adverse event is one that is not already described in the Investigator 
Brochure. 
Written IND Safety Reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32.  All safety reports previously filed with the IND concerning similar 
events should be analyzed.  The new report should contain comments on the significance of the 
new event in light of the previous, similar reports.   
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, Lilly 
Drug Safety, and all participating investigators within 15 calendar days of first learning of the 
event.  The FDA prefers these reports on a MedWatch 3500a Form but alternative formats are 
acceptable (e.g. summary letter). 
A log of the IND safety reports will be submitted annually to the OUHSC IRB at the time of 
Continuing Review.  
b. IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the Sponsor shall within 60 days of the 
anniversary date that the IND went into effect submit a brief report of the progress of the 
investigation.  Please refer to Code of Federal Regulations, 21 CFR § 312.32 for a list of the 
elements required for the annual report.  
11.5 Collection and Recording Adverse Events 
All adverse events (AEs) of any grade will be collected, identified using the MedDRA 
terminology, graded as to severity, assessed for causality, and followed until resolution. 
All AEs, regardless of the source of identification (eg, physical examination, laboratory 
assessment, ECG, reported by patient), must be documented in the eCRF and reported in the IND 
annual report. 
All AEs will be collected and recorded in the eCRF for each patient from the first day of dosing 
until 30 days after the last dose of study treatment. All AEs and SAEs experienced by a patient, 
irrespective of the suspected causality, will be monitored until the AE or SAE has resolved, any 
abnormal laboratory values have returned to baseline or normal levels, until there is a satisfactory 
explanation for the changes observed, until the patient is lost to follow-up, or until the patient has 
died. 
11.5.1 Definitions 
Adverse event: An adverse event is any untoward medical occurrence that occurs in a patient or 
clinical investigation subject administered a pharmaceutical product, and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including clinically significant abnormal laboratory findings), 
symptom, or disease temporally associated with the use of an investigational product, whether or 
not considered related to the product. 

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Adverse events may include the onset of new illness and the exacerbation of pre-existing medical 
conditions. An AE can include an undesirable medical condition occurring at any time, including 
baseline or washout periods, even if no study treatment has been administered. 
Treatment-emergent:  A treatment-emergent adverse event will be defined as any new AE that 
begins, or any preexisting condition that worsens in severity, after at least 1 dose of study treatment 
has been administered. 
Serious adverse event: A serious adverse event is defined as any untoward medical occurrence 
that, at any dose: 
• Results in death 
• Is life-threatening 
o Note: This means that the patient is at immediate risk of death at the time of the event; 
it does not mean that the event hypothetically might have caused death if it were more 
severe 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
o Any AE that prolongs hospitalization will be considered an SAE. 
o Exception: Planned hospitalization (eg, for observation, protocol compliance, elective 
procedures, social reasons, etc.) will not be considered an SAE; however, the reason 
for the planned hospitalization should be captured in medical history. 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event(s) 
o An important medical event may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or require intervention to prevent one 
of the above outcomes.  
11.5.2 Assessment of Adverse Events 
Each AE will be assessed by the Investigator with regard to intensity and causality with regard to 
study treatment as outlined in the following sections. 
Intensity 
Investigators should assess the severity of AEs according to CTCAE. In general, CTCAE (Version 
4) severity grades are: 
Grade 1:  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;        
intervention not indicated 
Grade 2:  
Moderate; minimal, local or noninvasive intervention indicated; limiting 
ageappropriate instrumental activities of daily living (ADL). (Instrumental ADL 
refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.) 
Grade 3:  
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL. (Self-care ADL refer to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden.) 
Grade 4:  
Life-threatening consequences; urgent intervention indicated 
Grade 5:  
Death related to AE 

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31 
 
A distinction should be made between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria above in Section 7.4 and 7.5. For example, a mild 
degree of gastrointestinal bleeding requiring an overnight hospitalization for monitoring purposes 
may be considered an SAE but is not necessarily severe. Similarly, an AE that is severe in intensity 
is not necessarily an SAE. For example, alopecia may be assessed as severe in intensity but may 
not be considered an SAE. 
Causality 
The Investigator will assess the causality/relationship between the study drug and the AE. One of 
the following categories should be selected based on medical judgment, considering the definitions 
and all contributing factors: 
• Related: A clinical event, including laboratory test abnormality, occurs in a plausible time 
relationship to treatment administration, and which concurrent disease or other drugs or 
chemicals cannot explain. The response to withdrawal of the treatment should be clinically 
plausible. 
• Possibly related: A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the treatment, unlikely to be attributed to concurrent 
disease or other drugs or chemicals. 
• Unlikely related: A clinical event, including laboratory test abnormality, with a temporal 
relationship to treatment administration which makes a causal relationship improbable, or 
in which other drugs, chemicals or underlying disease provide likely explanations. 
• Unrelated: A clinical event, including laboratory test abnormality, with little or no 
temporal relationship with treatment administration. Typically explained by extraneous 
factors (eg, concomitant disease, environmental factors, or other drugs or chemicals). 
12 STATISTICAL CONSIDERATIONS 
12.1 Data Analysis Plan 
(a) Definition of primary outcome/endpoint: 
1) Completion of 4 cycles- completion of a cycle will be defined as receiving both 
carboplatin/paclitaxel and taking ≥75% of the doses of GB for the cycle  
(b) Definition of secondary outcomes/endpoints: 
1) Adverse event occurrence and grade, as assessed by the CTCAE v4. 
2) PFS- duration of time from enrollment to RECIST progression or death from any cause, 
censored at last disease assessment or loss to follow-up; and OS – duration of time from 
enrollment to death from any cause, censored at date last known alive or loss to follow-
up 
3) Galunisertib serum concentrations levels on day 4, 8 and 29 (cycle 2 day 1) 
(c) Exploratory: 
Correlate mRNA levels of EMT markers (SNAI1, N-Cad) and TGFβ-I, TGFβR-I and 
TGFβR-II with response rate (complete response + partial response) and clinical benefit 
ratio (response rate + stable disease at 6 months) 
(d) Sample size and Analytic plan for primary objective: 

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The % of patients completing 4 cycles will be calculated and a 90% confidence interval 
constructed for the completion rate. With 25 patients and an expected completion rate of 
60%, the lower bound of the two-sided exact Clopper-Pearson 90% confidence interval 
(CI) would be 42%, which provides sufficient evidence that the combined regimen is 
feasible for inclusion in a randomized Phase II study. The following table provides 90% 
confidence intervals when the expected completion rate ranges from 60% to 80%, with a 
sample size of 25. Patients who come off the treatment for disease progression but did not 
experience toxicity requiring termination of treatment will be included among those 
patients completing the target goal of treatment of 4 cycles. Assuming 30% of the enrolled 
patients will drop out, we will enroll 36 patients to reach the targeted sample size (n = 25). 
# patients 
Expected rate of completing 4 cycles 
90% Confidence interval 
25 
60% 
42% - 76% 
 
70% 
52% - 85% 
 
80% 
63% - 92% 
 
(e) Analytic plan for secondary objectives: 
1) To determine the frequency and severity of adverse events as assessed by the CTCAE 
v4. 
• Frequency and severity of adverse events will be tabulated, by body system, type 
and maximum grade. 
2) To determine the PFS and OS of patients receiving combination CT + GB. 
• Median PFS and OS (and CIs) for patients who receive the combined regimen under 
study will be computed using the Kaplan-Meier curves and compared to a historical 
cohort of patients who received the standard care. 
3) To ascertain pharmacokinetic profile of GB when given in a combination regimen with 
CT. 
• Galunisertib levels will be drawn cycle 1 day 4: pre-dose and 2 and 6 hours post 
dose; Day 8 and day 29: pre-dose for the first 6 patients 
• Levels over time will be summarized descriptively, as quartiles and range, and 
graphically using boxplots for example.  These will be compared to previous phase 
I data describing the pharmacokinetics of galunisertib to determine if it is 
significantly impacts by co-administration of carboplatin/paclitaxel. 
4) To determine if mRNA levels of TGFβ-I, TGFβ-II, TGFβR-I and TGFβR-II are 
associated with response to galunisertib therapy including galunisertib. 
• The response rate (complete response + partial response) and clinical benefit ratio 
(response rate + stable disease at 6 months) will be tabulated according to high and 
low mRNA (divided by median mRNA levels observed) concentrations of TGFβ-
I, TGFβ-II, TGFβR-I and TGFβR-II. Because of the sample size, these analyses are 
hypothesis generating and hypothesis testing will not be conducted. 

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(f) Accrual 
25 patients will be enrolled over a period of 3 years. 
12.2 Interim Analysis 
If the main cohort is activated, an interim safety analysis will be conducted when 6 patients have 
received ≥ 3cycles of treatment. If a DLT occurs in 2 or more patient, the dose of GB will be 
decreased to a lower level (level -1) at 80mg, PO, BID and an additional analysis will then be 
conducted after 6 patients have completed ≥ 3cycles. DLT is defined as either hematologic or non-
hematologic toxicity (assessed in accordance with the CTCAE Version 4.0), which cause any of 
the following: 
Hematologic Toxicity: 
• Dose delay of greater than 3 weeks due to failure to recover counts. 
• Study treatment-related febrile neutropenia. 
• Grade 4 neutropenia lasting > 7 days. 
• Study treatment-related Grade 4 thrombocytopenia or bleeding associated with Grade 3 
thrombocytopenia. 
Non-Hematologic Toxicity: 
• Study treatment-related Grade 3 or Grade 4 non-hematological toxicity (excluding 
alopecia, fatigue, hypersensitivity reaction), (if controlled w/ medications exclude nausea, 
vomiting, constipation, diarrhea, hypokalemia, hypomagnesemia, hypocalcemia, 
hypophosphatemia) 
• Any drug-related death 
All AEs of the 6 patients will be listed. With 6 patients, there is high probability (>0.80) to observe 
at least one DLT, if the true DLT rate is at least 25% (Table 1). The probability of observing ≥2 
DLTs is high (≥0.77) if the true rate of DLTs is at least 40% (Table 1). 
Table 1 
True AE rate: 
5% 
10% 
15% 
20% 
25% 
30% 
40% 
50% 
Probability of 
observing ≥1 
DLT 
0.26 
0.47 
0.62 
0.74 
0.82 
0.88 
0.95 
0.98 
Probability of 
observing ≥2 
DLTs 
0.03 
0.11 
0.22 
0.34 
0.47 
0.58 
0.77 
0.89 
13 DATA AND SAFETY MONITORING PLAN 
Safety oversight will be performed by Stephenson Cancer Center’s (SCC) internal Data and Safety 
Monitoring Committee (DSMC). The DSMC is composed of individuals with the appropriate 
expertise in adult and pediatric hematology and medical oncology, radiation oncology, 
translational and correlative science, pharmacy, nursing and biostatistics. The DSMC operates 
under the rules of an approved data safety monitoring plan which complies with the National 
Cancer Institute (NCI) guidelines published as Essential Elements of a Data and Safety Monitoring 
Plan for Clinical Trials Funded by NCI as of January 2005 and the “NIH Policy for Data and 

Version 8.0 (22-Apr-2021) 
34 
 
Safety 
Monitoring,” 
NIH 
Guide 
for 
Grants 
and 
Contracts, 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html.  
The Data Safety Monitoring Committee is charged with oversight of participant safety, study 
conduct and the validity and integrity of data for clinical trials at SCC. While the focus of the 
DSMC is to monitor interventional investigator initiated trials (IITs) that are not subject to external 
monitoring, it has the authority to monitor any SCC protocol when potential concerns are 
identified. The DSMC also has the authority to suspend or close a study until the principal 
investigator addresses any issues that may cause harm or increase risks to subjects. The DSMC 
reports all findings to the Institutional Review Board (IRB).  
Under the direction of the DSMC chair, a full board meeting is convened on a quarterly basis to 
review the accumulated safety data, accrual information, and additional information as stated in 
the DSMC plan.  
13.1 DSMC Auditing  
In addition to monitoring, the DSMC oversees an internal auditing process to ensure subject safety and 
data quality. All cancer-related clinical trials active at the SCC are eligible for audit; however, priority 
is placed on those clinical trials that are not monitored or audited by an outside entity. If an external 
entity conducts an audit of a clinical trial at the SCC, then the findings of that audit are reported to the 
DSMC, either through the formal audit report provided by the external auditing entity, if available, or 
from the PI, who will report any findings communicated during the audit process. 
14 DATA HANDLING AND RECORD KEEPING 
14.1 Data Quality Assurance 
Stephenson Cancer Center (SCC) will be responsible for clinical monitoring all data for this study.   
14.2 Electronic Case Report Forms 
The Principal Investigator will develop electronic case report forms for study data entry.  All study 
data will be stored in a HIPAA-compliant database.  Only Investigator and assigned research staff 
will have access to study data.  The electronic case report forms will be available to sponsor, IRB 
or regulatory authorities in even of an audit.   
14.3 Record Retention  
Investigator will retain all research documents and case report forms at study site.   
15 ETHICAL AND REGULATORY CONSIDERATIONS 
15.1 Ethical Conduct of the Study 
The study will be conducted in full conformance with the ICH E6 guideline for Good Clinical 
Practice and the principles of the Declaration of Helsinki in addition to the requirements of the 
ICH E2A guidelines. This study will also comply with U.S. FDA regulations under a U.S. 
Investigational New Drug (IND) application in addition to local, state, and federal laws. 

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15.2 Informed Consent 
The informed consent document will be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements. The informed consent document used in this study, and any 
changes made during the course of the study, will be prospectively approved by the local IRB. 
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation. The investigator, or a 
person designated by the investigator, will obtain written informed consent from each patient 
before any study-specific activity is performed. The study site will retain the original of each 
patient’s signed consent document. 
15.3 Institutional Review Board or Ethics Committee 
This protocol, the Informed Consent document, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB by the Principal Investigator and 
reviewed and approved by the IRB before the study is initiated. 
The Principal Investigator is responsible for providing written summaries of the status of the study 
to the IRB annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB. Investigators are also responsible for promptly informing the 
IRB of any protocol amendments. 
In addition to the requirements for reporting all adverse events to the Sponsor, investigators must 
comply with requirements for reporting serious adverse events to the local health authority and 
IRB. 
15.4 Confidentiality 
The Sponsor and site will maintain confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. Patient medical information 
obtained by this study is confidential and may only be disclosed to third parties as permitted by 
the Informed Consent document (or separate authorization for use and disclosure or personal health 
information) signed by the patient, unless permitted or required by law. 
 
 

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