Conditions: Ovarian Cancer Fallopian Tube Cancer Peritoneal Cancer
Keywords: Recurrent epithelial ovarian carcinoma Persistent epithelial ovarian carcinoma Bevacizumab resistant epithelial ovarian carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
The main purpose of this study is to see if BIBF 1120 can increase the number of women with bevacizumab resistant, persistent, or recurrent epithelial ovarian cancer who do not progress for at least six months.

Detailed description:
Ovarian cancer patients with platinum-resistant and refractory disease have the lowest response rates to relapse chemotherapy: various chemotherapeutic agents, such as paclitaxel, liposomal doxorubicin, topotecan, docetaxel, platinum, etoposide, ifosfamide, gemcitabine, and vinorelbine are available but result in response rates of 7-40%. Unfortunately, relapse therapy is not curative and treatment is only palliative. Recently two phase II trials demonstrated that anti-angiogenic therapy with bevacizumab alone or in combination with chemotherapy in women with recurrent disease had response rates ranging from 16-24% with an acceptable toxicity profile. However, resistance can develop to VEGF inhibition. Therefore other novel anti-angiogenic agents, such as BIBF 1120, should be evaluated in the treatment of ovarian cancer.

Arms:
arm 1: BIBF 1120 will be administered at a daily oral dose of 200 mg BID until disease progression or adverse effects prohibit further therapy.

Interventions: intervention 1: BIBF 1120
Intervention descriptions: intervention 1: PO 200mg BID

Protocol document:
Prot_SAP_000.pdf: 
 
BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
   Version Date 16 August 2018 
 
 
PHASE II EVALUATION OF NINTEDANIB (BIBF 1120) IN THE TREATMENT OF 
BEVACIZUMAB-RESISTANT PERSISTENT OR RECURRENT EPITHELIAL OVARIAN, 
FALLOPIAN TUBE, OR PRIMARY PERITONEAL CARCINOMA (NCT01669798) 
 
 
  
 
 
STUDY PRINCIPAL INVESTIGATOR 
NURSE CONTACT 
ANGELES ALVAREZ SECORD, MD 
JENNIFER MEWSHAW, NP 
DUKE UNIVERSITY MEDICAL CENTER 
DUKE CANCER INSTITUTE 
ROOM 25172, MORRIS BUILDING 
30 DUKE MEDICINE CIRCLE 
ROOM 15117, WHITE ZONE, DUKE SOUTH 
DURHAM, NC 27710 
DURHAM, NC 27710 
PHONE: 919-684-3765 
PHONE: 919-684-3780 
FAX: 919-684-8719 
FAX: 919-681-7689 
EMAIL: secor002@mc.duke.edu 
EMAIL: jennifer.mewshaw@duke.edu 
 
 
STATISTICIANS 
 
 
 
DATA MANAGEMENT 
YUAN WU, PhD 
MICHAEL LEONARD 
DUKE CANCER INSTITUTE 
DUKE CANCER INSTITUTE 
2424 ERWIN RD 
2424 ERWIN RD 
DURHAM, NC 27705 
DURHAM, NC 27705 
PHONE: (919) 681-5018 
PHONE: (919) 681.1620 
EMAIL: yuan.wu@dm.duke.edu 
EMAIL: michael.leonard@dm.duke.edu 
 
 
GLORIA BROADWATER, MS 
DCI SAFETY DESK 
 
 
 
DUKE CANCER INSTITUTE 
MARLA JORDAN, RN, BSN 
2424 ERWIN RD 
DUKE CANCER INSTITUTE 
DURHAM, NC 27705 
2424 Erwin Rd, suite 7021 
PHONE: (919) 681-5045 
DUMC Box 2723 
EMAIL: gloria.broadwater@duke.edu  
Durham, NC 27705 
 
PHONE: (919) 681-2351 
CLINICAL RESEARCH COORDINATOR  
 
MEGAN HOUPE 
 
DUKE CANCER INSTITUTE 
 
30 DUKE MEDICINE CIRCLE 
ROOM 15118, WHITE ZONE, DUKE SOUTH 
 
DUMC BOX 3079 
 
DURHAM, NC 27710 
 
PHONE: (919) 684-9074 
 
EMAIL: megan.bouma@duke.edu 
 
 
 
 
 
 
 
SCHEMA 
Nintedanib will be administered at a daily oral dose of 200 mg BID until disease progression or 
adverse effects prohibit further therapy. One cycle is defined as 28 days of treatment. 
 
This is an open label multi-center study with Duke University Medical Center serving as the 
coordinating center. 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
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Table of Contents 
 
1.0 
OBJECTIVES 
3 
2.0 
BACKGROUND & RATIONALE 
4 
3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS 
12 
4.0 
STUDY MODALITIES 
16 
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 
21 
6.0 
TREATMENT MODIFICATIONS 
22 
7.0 
STUDY PARAMETERS 
27 
8.0 
EVALUATION CRITERIA 
29 
9.0 
DURATION OF STUDY 
37 
10.0 
ADVERSE EVENTS, STUDY MONITORING & REPORTING PROCEDURE 
37 
11.0 
STATISTICAL CONSIDERATIONS 
55 
12.0 
BIBLIOGRAPHY 
58 
 
APPENDIX I. Percent of Normal Bone Marrow Irradiated Using Standard Radiation Ports 
APPENDIX II. Patient Nintedanib Capsule Diary 
APPENDIX III. Investigator Signature Page   
APPENDIX IV. Financial Disclosure Form 
APPENDIX V. Specimen Tissue Transmittal Form – Biomarker Form 
APPENDIX VI. Specimen Tissue Transmittal Form – Paraffin-Embedded Tumor Form 
APPENDIX VII. Protocol Deviation Form 
APPENDIX VIII. Model Informed Consent 
APPENDIX IX. Eligibility Checklist 
APPENDIX X. Subject Registration Form 
APPENDIX XI. Rank Preferences and Relative Concern Exercises 
APPENDIX XII. NFOSI-18 & FACT-GOG-Ntx 
 
 


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1.0 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To assess the activity of Nintedanib as measured by the proportion of 
patients who survive progression-free for at least 6 months after initiating 
study therapy in patients with bevacizumab-resistant, persistent or 
recurrent epithelial ovarian, fallopian tube, or primary peritoneal 
carcinoma.  
 
1.2 
Secondary Objectives 
 
1.2.1 To determine the proportion of patients who have objective tumor 
response (complete or partial) based on RECIST 1.1.  
1.2.2 To determine the proportion of patients who have objective tumor 
response (complete or partial) based Gynecologic Cancer InterGroup 
(GCIG) CA-125 criteria. 
1.2.3 To determine the frequency and severity of adverse events as assessed 
using NCI Common Toxicity Criteria version 4. 
1.2.4  To characterize the duration of progression-free survival and overall 
survival. 
1.2.5 To elicit patient preferences for outcomes of ovarian cancer treatment. 
1.2.6 To characterize baseline quality of life and cancer-related symptoms. 
 
1.3 
Translational Research Objectives 
 
1.3.1 To measure baseline levels of VEGF and correlate with treatment 
outcome. 
1.3.2  To measure baseline and on treatment levels of additional growth factors 
(listed in section 2.5) that may be co- or counter- regulated with VEGF 
and correlate with response to treatment.  
1.3.3 To measure baseline and on treatment levels of coagulation and 
endothelial cell activation markers that may predict for thrombotic or 
bleeding risks related to treatment. 
 
 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
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2.0 
BACKGROUND & RATIONALE 
 
2.1 
Ovarian Cancer  
 
Ovarian cancer patients with platinum-resistant and refractory disease have the 
lowest response rates to relapse chemotherapy: various chemotherapeutic agents, 
such as paclitaxel, liposomal doxorubicin, topotecan, docetaxel, platinum, 
etoposide, ifosfamide, gemcitabine, and vinorelbine are available but result in 
response rates of 7-40% [1, 2]. Unfortunately, relapse therapy is not curative and 
treatment is only palliative. Recently two phase II trials demonstrated that anti-
angiogenic therapy with bevacizumab alone or in combination with 
chemotherapy in women with recurrent disease had response rates ranging from 
16-24% with an acceptable toxicity profile [3, 4]. However resistance can 
develop to VEGF inhibition. Therefore other novel anti-angiogenic agents, such 
as Nintedanib, should be evaluated in the treatment of ovarian cancer.  
 
2.2      Background Information and Experience with Anti-Angiogenic agents in Ovarian 
Cancer 
 
The most commonly used anti-angiogenic agent is bevacizumab, a monoclonal 
antibody that targets vascular endothelial growth factor (VEGF). Several clinical 
trials have evaluated bevacizumab in recurrent ovarian cancer. In a GOG phase II 
study that evaluated bevacizumab in patients who had failed prior chemotherapy, 
Burger and colleagues reported a response rate of 21% and a median response 
duration of 10 months with 40.3% of patients remaining progression-free at 6 
months [3]. Another phase II trial evaluated the efficacy of combination 
bevacizumab and low-dose cyclophosphamide and demonstrated a response rate 
of 16%, a median PFS was 4.4 months with 27.8% of patients remaining 
progression free at 6 months [4]. In these two trials the most common adverse 
events (AEs) were proteinuria, hypertension, and arterial thrombotic events [3-5]. 
In view of the promising results with bevacizumab in the treatment of ovarian 
cancer seen in the phase II setting, there are four phase III trials examining 
whether the addition of this anti-angiogenic therapy to carboplatin-based 
chemotherapy improves clinical outcome in the primary and recurrent settings. 
The results of these trials have recently been presented and demonstrated a PFS 
benefit for concurrent followed by maintenance therapy as part of the first-line 
treatment of ovarian cancer [6, 7]. We anticipate increased use of bevacizumab in 
patients with newly diagnosed advanced stage ovarian, peritoneal, and tubal 
cancers.  
 
2.3      Resistance to VEGF Inhibition 
 
Despite an initial response to bevacizumab, the development of resistance against 
bevacizumab induced VEGF-blockade may occur. The development of resistance 
is not via the classic mechanisms noted for conventional cytotoxic agents. Tumor 
vascular endothelial cells are part of the tumor microenvironment but not the 
malignant clone and therefore are not prone to mutation. Rather the tumor 
endothelial cells adapt to VEGFR inhibition by recruitment of vasculature using 


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multiple secondary signaling pathways, such as those mediated by PDGF, basic 
FGF, or other cytokines. However, since VEGF is the primary angiogenic 
pathway, there may be an advantage to continue VEGF-blockade, and this has 
been demonstrated clinically. In a phase II trial, 40 patients with metastatic 
colorectal cancer (mCRC) who had previously been treated with bevacizumab 
(PMH Phase II Consortium Trial) were treated with aflibercept (VEGF Trap). Of 
the 24 evaluable patients there was 1 partial response, 17 with stable disease, and 
7 with stable disease at 16 weeks. Nine patients were not yet evaluable for 
response. The 4 month PFS rate and median PFS were 29% and 3.4 (1.9-NR), 
respectively, and were similar compared to those patients who were bevacizumab 
naïve [8]. Furthermore, in a prospective observational study, 1,445 of 1,953 
previously untreated patients with mCRC who were enrolled in the BRiTE study 
and whose disease progressed were classified into three groups. The groups were 
separated based on whether they received any treatment or bevacizumab beyond 
first progression (BBP): (1) no post-progressive disease (PD) treatment (n=253); 
(2) post-PD treatment without bevacizumab (no BBP; n=531); and (3) BBP 
(n=642). The median OS rates were highest in the BBP group (31.8 months vs. 
12.6 vs. 19.9), in the no post-PD treatment and no-BBP groups, respectively. In 
multivariate analyses, compared with no BBP, BBP was strongly and 
independently associated with improved survival (HR, 0.48; P < .001). These 
findings strongly suggest that continued VEGF inhibition, in this case with 
bevacizumab, beyond initial PD may have utility in the management of 
previously bevacizumab-treated patients [9]. Theoretically, an agent, such as 
Nintedanib, that can simultaneously inhibit the VEGF pathway as well as the 
alternate pro-angiogenic pathways, may prevent tumor resistance to VEGFR 
inhibition and enhance anti-tumoral effects.  
 
2.4 
Background Information and Experience with Nintedanib 
 
Nintedanib is a potent small molecule multi receptor tyrosine kinase inhibitor 
(PDGFR α/β (platelet derived growth factor receptor), FGFR 1/3 (fibroblast 
growth factor receptor), VEGFR 1-3 (vascular endothelial growth factor 
receptor))[10]. On the molecular level, Nintedanib is thought to inhibit the 
signaling cascade mediating angiogenesis by binding to the adenosine 
triphosphate (ATP) binding pocket of the receptor kinase domain, thus 
interfering with cross-activation via autophosphorylation of the receptor 
homodimers. Besides inhibition of neo-angiogenesis, tumor regression may also 
be achieved by inducing apoptosis of tumor blood vessel endothelial cells. 
Inhibition of receptor kinases may also interfere with autocrine and paracrine 
stimulation of tumor angiogenesis via activation loops involving VEGF, PDGF, 
and bFGF utilized by perivascular cells such as pericytes and vascular smooth 
muscle cells. In vitro, the target receptors are all inhibited by Nintedanib in low 
nanomolar concentrations. In in vivo nude mouse models, Nintedanib showed 
good anti-tumor efficacy at doses of 50 – 100 mg/kg, leading to a substantial 
delay of tumor growth or even complete tumor stasis in xenografts of a broad 
range of differing human tumor types including SKOV3 ovarian cancer 
xenografts [11].  


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Safety of Nintedanib: A total of 2092 patients have been treated with Nintedanib 
or placebo for oncological indications, of which more than 1400 patients 
(numbers estimated for ongoing studies involving blinded controls) have 
received the verum compound. In total, 433 patients have received Nintedanib as 
monotherapy in phase I and phase II studies, 195 patients received Nintedanib 
(verum) in combination with cytotoxic chemotherapy mostly in phase I dose 
escalation trials, and of the 1338 patients who have been included in the ongoing 
phase III trials 1199.13, 1199.14 and 1199.15, it is estimated that 698 patients 
have received Nintedanib in combination with the cytotoxic chemotherapy that is 
standard for the respective indication [10]. Despite targeting three kinases 
involved in angiogenesis there was not an exacerbation of expected toxicities 
associated with anti-angiogenic therapies. The predominant AEs were nausea, 
diarrhea, vomiting, abdominal pain and fatigue of mostly low to moderate 
intensity. Dose limiting toxicities (DLT) were mainly confined to reversible 
hepatic enzyme elevations (AST, ALT, and γ-GT) which increased dose-
dependently [10].  
The results from phase I monotherapy trials indicated that the MTD was 250 mg 
bid Nintedanib in the studies including Caucasian patients, and 200 mg bid 
Nintedanib in Japan. 
 
The predominating dose limiting AEs of Nintedanib were increases of liver 
enzymes that were rapidly reversible upon cessation of therapy. Hepatic 
transaminase elevations of grade > 2 were absent at doses below the MTD, 
occurred occasionally at the MTD dose, and increased in frequency at doses 
above the MTD. 
 
The safety profile overall appeared largely similar between Caucasian and 
Japanese patients, with the sole exception that the propensity to experience liver 
enzyme increases may be higher in Japanese patients. The lower MTD for bid 
dosing in Japanese patients was primarily due to a higher incidence of reversible 
liver enzyme increases of grade > 2, which started to occur at the dose of 200 mg 
bid, whereas in trials including primarily Caucasian patients, liver enzyme 
increases of grade > 2 were only observed starting at a dose of 250 mg bid. 
 
According to data from trials 1199.1-3, splitting the cumulative daily dose into 
two doses increased the tolerability of Nintedanib: at a total daily dose of 500 mg 
of Nintedanib (250 mg bid), 25% of the patients had dose limiting toxicities 
compared to more than 60% of the patients treated with once daily 450 mg of 
Nintedanib (1199.1-1199.3). 
 
The phase I data indicate that continuous treatment with 250 mg bid of 
Nintedanib in Caucasians and 200 mg bid in Japanese patients have an 
acceptable and manageable safety profile in patients suffering from advanced 
cancer. Gastrointestinal AEs were the predominate AEs of Nintedanib and were 
mostly of low to moderate severity.  AEs commonly considered as class effects 
of small molecule antiangiogenic receptor tyrosine kinase inhibitors such as 
hypertension, proteinuria or thromboembolic events occurred at low frequencies 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
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in the phase I monotherapy trials which may not be distinct from the background 
incidence in advanced cancer patients. 
 
Safety in pooled Phase I and II monotherapy trials with starting doses of 100 mg 
bid to 250 mg bid, also including all respective patients from phase I trials treated 
at these doses in addition to the data from the phase II trials. The overview 
includes data of 334 patients: 81 patients from phase I trials, and 253 patients 
from the phase II trials. Patients who have not received Nintedanib in these trials 
(e.g., placebo-treated patients from trial 1199.9) are not considered.  
 
Gastrointestinal side effects and liver enzyme increases represented the leading 
AEs. Gastrointestinal AEs rarely were of CTCAE grade > 2, and the frequency 
did not obviously increase with increased doses of Nintedanib up to 250 mg bid. 
 
Similar to the phase I studies, liver enzyme increases of grade > 2 were only 
observed in the high dose group of 250 mg bid, and across all trials the only 
exception were Japanese patients (phase I trial 1199.19), and Asian patients with 
hepatic impairment (1199.39, Asian patients with hepatocellular cancer). As in 
the phase I trials, increases of liver enzymes occurred within the first two months 
of treatment. Liver enzyme increases of grade > 2 were less frequent at a dose of 
200 mg bid Nintedanib. Among the phase II trials using 250 mg bid Nintedanib 
as starting dose, the frequency of liver enzyme increases grade > 2 exceeded 
33%. 
 
This frequency was higher than observed in other phase II trials for the same 
dose. In view of this observation, the absence of grade > 2 liver enzyme increases 
at 200 mg bid in Caucasian patients and the MTD of 200 mg bid in Japanese 
patients, the dose currently recommended for Nintedanib monotherapy is 200 mg 
bid. 
 
Experience with Nintedanib in ovarian cancer: With respect to the phase II trials 
in ovarian cancer, Nintedanib was evaluated as maintenance therapy in patients 
with relapsed ovarian cancer that had responded to a preceding line of 
chemotherapy (Study 1199.9) [10]. Eighty-four patients were randomized to 
either Nintedanib or placebo. The median treatment duration was 116 days with 5 
patients randomized to Nintedanib completing 9 months of therapy compared to 
none of those in the placebo group. The dose was 250 mg twice daily. The 36-wk 
PFS rates were 15.6% (95% confidence interval (CI)): 3.8 - 27.3) for Nintedanib 
and 2.9% (95% CI: 0.0, 8.4) for placebo. Although the trial was not powered for 
a direct comparison, the PFS hazard ratio was 0.68 (95% CI: 0.42, 1.09). Median 
time to progression based on RECIST criteria was 4.8 months for Nintedanib, 
and 2.8 months for placebo. Grade 3 and 4 AEs were reported in 54 and 7% 
compared to 25 and 3% in the Nintedanib and placebo groups, respectively. 
Expected grade 3 gastrointestinal toxicities as well as elevated liver enzymes 
occurred more frequently in the Nintedanib group (GI: 16% vs. 10%; elevated 
LFTs: 43% vs. 6.3%). The findings suggested that maintenance Nintedanib could 
delay disease progression in patients with ovarian cancer who had previously 
responded to chemotherapy [12]. A randomized placebo-controlled phase III 


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trial, LUME OVAR1, evaluating paclitaxel and carboplatin with or without 
Nintedanib has been developed and was activated in November 2009. This trial is 
evaluating a 200 mg po twice daily dosing schedule.  
 
In conclusion, based on the available preclinical and clinical data, Nintedanib 
displays a favorable safety profile and may have activity in a select patient 
population with ovarian cancer, such as those with bevacizumab-resistant 
disease. This proposed study will evaluate single-agent Nintedanib (200 mg po 
twice daily) in participants with bevacizumab-resistant recurrent or persistent 
ovarian, peritoneal, and tubal cancer. Patients will be treated to disease 
progression or toxicity.  
2.5 
Biomarker Discovery for Ovarian Cancer – Blood-based Angiome Profiling 
 
The Phase I Biomarker Laboratory at Duke University Medical Center acts as a 
molecular profiling laboratory for blood-based biomarkers of targeted therapies 
particularly targeted anti-angiogenic agents. Drs. Andrew Nixon and Herbert 
Hurwitz serve as co-directors of the facility and direct the overall research of the 
laboratory. The laboratory has quality control procedures in place to address 
many of the issues involved in clinical trials research including sample quantity, 
sample integrity, and sample heterogeneity.  
Additionally, the laboratory has been selected to act as a core facility for the 
oncology cooperative group, The Cancer and Leukemia Group B (CALGB). 
CALGB is a national clinical research group sponsored by the National Cancer 
Institute, with the Central Office headquartered at the University of Chicago and 
Statistical Center located at Duke University. The services offered align with 
their programmatic focus around the interrogation of blood and urine samples 
using multiplex or standard ELISA technologies. The multiplex design for this 
study addresses the specific drug target(s) for this drug as well as attempting to 
capture the relevant co- and counter-regulated proteins.  
All samples will have appropriate chain-of-custody documentation to ensure 
compliance with FDA and IRB regulations. The lab currently has systems in 
place detailing the location, transfer, and use of any and all human research 
subject samples. Any discrepancies or omissions in flow sheets and/or sample 
labels are resolved upon receipt of the sample in the lab. All sample and data 
handling procedures will be fully compliant with the Health Insurance Portability 
and Accountability Act of 1996 (HIPAA). Sample handling protocols will 
provide step-by-step details for sample isolation, sample handling, and sample 
receipt/shipment. Samples will be housed in ultra-low temperature freezers (-
80°C). The freezers are monitored daily and are equipped with an alarm system 
designed to alert laboratory personnel upon freezer malfunction. Additionally, 
secondary, independent alarm systems exist on all ultra-low freezers currently 
used to store all patient samples. Use of these redundant systems greatly reduces 
the chance of freezer failure, which could potentially result in the loss of 
irreplaceable samples from clinical trial patients.  
Blood-based Biomarkers:  In the past, the gold standard for detection of growth 
factors and cytokines in blood was the use of ELISAs; however, multiplex 


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technology offers an attractive alternative approach for cytokine and growth 
factor analysis. This novel technology allows for the measurement of multiple 
analytes simultaneously from a single sample. The advantages of multiplex 
technology compared to traditional ELISA assays are conservation of patient 
sample, increased sensitivity, and significant savings in cost, time and labor. 
Furthermore, all plate designs are validated in order to 1) limit cross-reactivity of 
the antibodies 2) optimize sensitivity and specificity and 3) maximize the 
linearity of the assay’s dynamic range. 
Several systems exist, the plate-based platforms being the Meso Scale Discovery 
(MSD) multiplex system and the SearchLight system, produced by Aushon 
Biosystems (formerly of Thermo Fisher Scientific). The assay design in both 
cases is similar to a sandwich ELISA, except multiple capture antibodies are pre-
spotted into individual wells of a 96-well plate. Samples or standards are added 
which bind to the specific capture antibodies and are detected using various 
outputs. Over the past 2 years, we have worked to optimize the design of 
customized multiplex ELISA plates via extensive collaborations with the 
SearchLight. We have devoted considerable effort to this and have developed an 
appropriately designed panel for the simultaneous evaluation of up to 40 
regulators of tumor and normal angiogenesis. The list of analytes that can be 
evaluated are shown in Table 1 below. Standard ELISA assays will also be 
included to evaluate soluble TGFbRIII and IGF-1 as additional blood markers.  
Biomarker Selection:  Since VEGF signaling is the fundamental pathway 
promoting angiogenesis, it will be informative to evaluate an array of VEGF and 
non-VEGF angiogenic factors. Since many angiogenic factors can be targeted 
with agents that are available or in development, information gained regarding 
mechanisms of resistance to anti-VEGF agents could direct novel combination 
therapies. Currently, it is not known which set of these factors will predict for 
baseline resistance to Nintedanib, which factors mediate acquired resistance to 
Nintedanib after initial response, and which factors may predict for greater or 
lesser risk of Nintedanib related toxicity. This lack of information represents a 
major gap in our understanding of the clinical mechanisms of efficacy, 
resistance, and toxicity for this agent. For bevacizumab, the fact that VEGF alone 
is not predictive of response likely reflects the complexity and redundancy of 
tumor angiogenesis, presumably mediated by multiple other angiogenic proteins. 
Given the limitations of preclinical modeling, it is critical that these mechanisms 
of clinical efficacy, resistance and toxicity be validated and prioritized in 
patients. 
Extracellular matrix (ECM) proteins interact with endothelial cells (EC) and 
serve as a scaffolding structure to support angiogenic sprouting. Matrix 
Metalloproteinase (MMP)-mediated remodeling of the ECM coordinates directly 
with VEGF-dependent angiogenesis. Therefore, information of matrix-derived 
angiogenic factors will take the microenvironment into consideration. 
Additionally, there are complex interactions between the coagulation system and 
the angiogenic process. For example, Tissue Factor (TF) is a principal initiator of 
coagulation; altered TF expression on EC membrane has been implicated in 
wound healing and angiogenesis, leading to VEGF upregulation. VEGF and TF 
levels are both increased by hypoxia in tumors and several studies suggest a 


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survival benefit in patients with malignant disease who have been treated with 
anticoagulation drugs. The growing recognition of the link between coagulation 
and angiogenesis led us to test coagulation biomarkers in anti-angiogenic 
therapies. 
All multiplex plate designs have been validated in order to limit cross-reactivity 
of the antibodies, optimized for sensitivity and specificity, and maximize the 
linearity of the assay’s dynamic range. The coefficient of variation (CVs) of the 
multiplex arrays is approximately 15-20%, depending on the particular assay. 
Any study samples that fall outside the linear portion of the standard curve are 
retested. Samples that read below the limit of detection are retested, if possible. 
Samples that read above the linear portion of the standard curve are serially 
diluted and retested to obtain accurate measurements. Any analyte that does not 
meet the aforementioned criteria will result in the sample being re-evaluated. 
Analytes of interest that are not available in our multiplex plates will be 
evaluated using commercial ELISA kits or ELISAs developed in the Biomarker 
Laboratory. 
Table 1. Plasma-based marker identification 
Soluble 
Angiogenic 
Factors 
Matrix-
Derived 
Angiogenic 
Factors 
Markers of 
Coagulation 
Markers of 
Vascular 
Activation and 
Inflammation 
bFGF 
MMP2 
Tissue Factor 
Gro- 
HGF 
MMP9 
PAI-1 Active 
IL-6 
PlGF 
TGF1 
PAI-1 Total 
IL-8 
VEGF-A 
TGF2 
CRP 
P-selectin 
VEGF-C 
Osteopontin 
D-dimer 
E-selectin 
VEGF-D 
TSP1 
Von 
Willebrand  
Factor 
SDF-1 
ANG-2 
TSP2 
ICAM-1 
PDGF-AA 
 
 
VCAM-1 
PDGF-BB 
 
 
MCP-1 
IGFBP1 
 
 
E-cadherin 
IGFBP3 
 
 
TNF- 
PEDF 
 
 
IFN- 
sVEGFR1 
 
 
NT-proBNP 
sVEGFR2 
 
 
 
 
2.6  
Inclusion of Women and Minorities 
 
The participating institutions 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 ovarian, fallopian tube, and primary 
peritoneal cancer population treated by participating institutions. 
 


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2.7       Background for quality of life and patient preferences addenda 
 
As clinical endpoints, neither OS nor PFS considers the rate of adverse events, 
quality of life (QOL), or other patient-reported outcomes (PROs) while on 
treatment. This context is critically important to frame survival metrics to better 
understand the implication of therapy.  In trials as well as in current practice, 
biologic therapies such as bevacizumab are now often continued as maintenance 
regimens following discontinuation of cytotoxic treatments, sometimes until 
disease progression.  The practice of continuing treatment over a prolonged 
period brings into focus the question of what effect such treatment has on quality 
of life.  At a minimum, it results in more trips for medical care and higher out of 
pocket expense on the part of both patients and caregivers.   
 
Development of a composite endpoint 
In phase III studies of ovarian cancer, quality of life is now often examined, 
usually as a secondary endpoint.  However, other patient-reported outcomes such 
as diverse symptoms, adverse event rates, and patient preferences have almost 
never been formally incorporated into primary trial endpoints for this disease. 
Our working group plans to develop a composite endpoint for ovarian cancer 
treatment trials that will incorporate PFS, severe adverse event rates, QOL and 
other PROs into the development of a composite endpoint for ovarian cancer 
trials.   
 
Patient preferences   
If a composite endpoint is to be considered, it is critical to ensure that the 
endpoint will successfully address the outcomes that are most important to 
patients. To this end, there is a need to determine how patients prioritize the 
factors and conditions that are most important to their treatment.  For example, 
surviving 5 years with severe peripheral neuropathy is not likely to be as 
desirable as surviving 5 years with no side effects.  Patients are likely to have 
opinions about how important each factor is and how it should be weighted when 
compared to the other factors.  The preferences of cancer patients concerning 
quality versus length of life have been reported(1, 2), but never specifically for 
women with ovarian cancer. 
 
The proposed pilot study will query women with ovarian cancer about their 
preferences for the possible effects of treatments on (1) progression-free survival, 
(2) overall survival, (3) development of severe side effects, (4) overall quality of 
life, and (5) ovarian-cancer specific health symptoms.  This study will allow us to 
determine the feasibility of assigning patient-determined weights to different 
individual endpoints for the future construction of a patient-centered composite 
endpoint.   Because preferences are often sensitive to the method of elicitation, 
multiple methods of elicitation will be used to assess the robustness of 
preferences.  Baseline quality of life and symptom index elicitation will allow 
examination of subjects’ preferences in relation to their current symptoms and 
well being. 
 


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3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS 
 
3.1   
Eligibility Criteria 
 
a) Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or 
primary peritoneal carcinoma. Histologic documentation of the original primary 
tumor is required via the pathology report. The following histologic epithelial cell 
types are eligible:  
o 
serous, endometrioid, mucinous, or clear cell adenocarcinoma;  
o 
undifferentiated, mixed epithelial or transitional cell carcinoma;  
o 
Brenner’s Tumor;  
o 
adenocarcinoma N.O.S. 
b) Patients must be considered bevacizumab-resistant, i.e., have a treatment-free 
interval following a response to bevacizumab (CR, PR, or SD) of less than 6 
months, or have progressed during treatment with a bevacizumab-containing 
therapy. 
c) Patients must have measurable disease or detectable (non-measurable) disease:  
o 
Measurable disease is defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded). Each 
lesion must be  10 mm when measured by CT, MRI, or caliper 
measurement by clinical exam; or  20 mm when measured by chest x-ray. 
Lymph nodes must be > 15 mm in short axis when measured by CT or 
MRI. Tumors 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. 
o 
Detectable disease in a patient is defined as one who does not have 
measurable disease but has at least one of the following conditions in the 
setting of a CA125 >2x ULN: 
 
Ascites and/or pleural effusion attributed to tumor 
 
Solid and/or cystic abnormalities on radiographic imaging that do 
not meet RECIST 1.1 definitions for target lesions 
d) For patients with measurable disease, patient must have at least one “target lesion” 
to be used to assess response on this protocol as defined by RECIST 1.1. Tumors 
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. 
e) Patients who must have a ECOG Performance Status of 0 or 1. 
f) Patients should be free of active infection requiring antibiotics (with the exception 
of uncomplicated UTI). 
g) Recovery from effects of recent surgery, radiotherapy, or chemotherapy 
o Any hormonal therapy directed at the malignant tumor must be discontinued at 
least one week prior to registration. Continuation of hormone replacement 
therapy is permitted. 
Any other prior therapy directed at the malignant tumor, including immunologic 
agents, must be discontinued at least three weeks prior to registration. If the 


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prior therapy was with bevacizumab then at least 4 weeks after treatment 
discontinuation must have elapsed prior to treatment on this study. 
h) Prior therapy 
o Patients must have had one prior platinum-based chemotherapeutic regimen for 
management of primary disease containing carboplatin, cisplatin, or another 
organoplatinum compound. This initial treatment may have included 
intraperitoneal therapy, high-dose therapy, consolidation, non-cytotoxic agents 
or extended therapy administered after surgical or non-surgical assessment. 
o Patients are allowed to receive, but are not required to receive, two additional 
cytotoxic regimens (a total of 3 cytotoxic regimens) for management of 
recurrent or persistent disease according to the following definition: 
 Patients who have received only one prior cytotoxic regimen (platinum-
based regimen for management of primary disease), must have a platinum-
free interval of less than 12 months, or have progressed during platinum-
based therapy, or have persistent disease after a platinum-based therapy. 
Patients must NOT have received any non-cytotoxic therapy for 
management of recurrent or persistent disease other than bevacizumab-
containing regimens. Patients are allowed to receive, but are not required to 
receive, biologic (non-cytotoxic) therapy as part of their primary treatment 
regimen. 
i) Patients must have adequate: 
o Bone marrow function: Absolute neutrophil count (ANC) greater than or equal 
to 1,500/mcl, equivalent to NCI Common Toxicity Criteria version 4.0 (CTCAE 
v4.0) grade 1. Platelets greater than or equal to 100,000/mcl.  Hemoglobin (Hb) 
greater than or equal to 9.0 g/dL. 
o Renal function: Creatinine less than or equal to 1.5 x institutional upper limit of 
normal (ULN), equivalent to the active version of the NCI AE grade 1.   
o Hepatic function: Bilirubin should be within normal limits (CTCAE v4.0, grade 
1). ALT/AST, should be less than or equal to 1.5 x ULN (CTCAE v4.0 grade 1). 
For patients with liver metastases, ALT/AST should be less than or equal to 2.5 
x ULN. Alkaline phosphatase should be less than or equal to 2.5 x ULN 
(CTCAE v4.0 grade 1). 
Neurologic function: Neuropathy (sensory and motor) less than or equal to 
CTCAE v4.0 grade 1. 
j) Blood coagulation parameters: PT such that the international normalized ratio (INR) 
is < 1.5 x ULN and a PTT < 1.5 x ULN.  Prophylactic heparin or low molecular 
weight heparin (enoxaparin or alternative anticoagulants (other than warfarin)) are 
acceptable.  
k) Patients must have signed an approved informed consent and authorization 
permitting release of personal health information. 
l) Patients of childbearing potential must have a negative serum pregnancy test prior to 
the study entry and be practicing an effective form of contraception up until three 
months after of receiving the last drug treatment. 
m) Patients may have undergone a major or minor surgical procedure as long as the 
following apply: 


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o Major surgical procedure, open biopsy or significant traumatic injury greater 
than 28 days prior to the first date of study therapy. 
o Core biopsy or IV Port placement greater than 7 days prior to the first date of 
study therapy. 
n) Patient must be at least 18 years of age. 
 
 
3.2 
Ineligibility Criteria 
 
a) Patients who have had previous treatment with Nintedanib. 
b) Patients who are pregnant or breastfeeding. 
c) Patients who have received radiation to more than 25% of marrow-bearing areas 
(See Appendix I). 
d) Patients with a history of other invasive malignancies, with the exception of non-
melanoma skin cancer, are excluded if there is any evidence of other malignancy 
being present within the last three years. Patients are also excluded if their previous 
cancer treatment contraindicates this protocol therapy. 
e) Patients who have received prior radiotherapy to any portion of the abdominal 
cavity or pelvis OTHER THAN for the treatment of ovarian, fallopian tube, or 
primary peritoneal cancer within the last three years are excluded. Prior radiation for 
localized cancer of the breast, head and neck, or skin is permitted, provided that it 
was completed more than three years prior to registration, and the patient remains 
free of recurrent or metastatic disease.  
f) Patients who have received prior chemotherapy for any abdominal or pelvic tumor 
OTHER THAN for the treatment of ovarian, fallopian tube, or primary peritoneal 
cancer or localized breast cancer within the last three years are excluded. Patients 
may have received prior adjuvant chemotherapy for localized breast cancer, 
provided that it was completed more than three years prior to registration, and that 
the patient remains free of recurrent or metastatic disease. 
g) Patients with a history of abdominal or tracheal-esophageal fistula, or 
gastrointestinal perforation are not eligible. Patients with a history of intra-
abdominal abscess within 6 months of enrollment.  
h) Patients with serious, uncontrolled, concomitant disorder(s) such as diabetes 
mellitus.  
i) Patients with clinically significant cardiovascular disease including: uncontrolled 
hypertension defined as systolic > 150 mm Hg or diastolic > 90 mm Hg; unstable 
angina or who have had a myocardial infarction within the past six months prior to 
registration; NYHA grade II or greater congestive heart failure; serious cardiac 
arrhythmia requiring medication (this does not include asymptomatic atrial 
fibrillation with controlled ventricular rate); or CTCAE v4.0 grade 2 or greater 
peripheral vascular disease (peripheral ischemia), defined as having at least brief (< 
24 hour) episodes of ischemia managed non-surgically and without permanent 
deficit. 
j) Patients with serious non-healing wound, ulcer, or bone factor. Patients with 
granulating incisions healing by secondary intention with no evidence of fascial 
dehiscence or infection are eligible but require weekly wound examinations. 


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k) Patients with active bleeding or pathologic conditions that carry high risk of 
bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major 
vessels. 
l) Patients with history or evidence upon physical examination of CNS disease; 
seizures not controlled with standard medical therapy; any brain metastases; or 
history of CVA, TIA, or subarachnoid hemorrhage within 6 months of the first date 
of treatment on this study. Patients diagnosed with primary brain tumors within the 
last three years are also excluded. 
m) Patients with central pulmonary metastases or recent hemoptysis (≥ 1/2 tsp. of red 
blood) within 28 days of registration. 
o Patients with clinically significant proteinuria (i.e. > Grade 1) or UPC ratio 
above 1.0. 
o Patients with suspicion of transmural tumor bowel involvement based on the 
investigator's discretion may not enroll on this study. 
n) Patients with clinical symptoms or signs of gastrointestinal obstruction and who 
require parenteral hydration and/or nutrition. 
o) Patients taking warfarin are not eligible. Patients on therapeutic doses of 
anticoagulants are excluded from study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.0 
STUDY MODALITIES 
 
4.1 
Drug Information: Nintedanib 
 
 
Investigator Brochure: The most recent version of the Nintedanib Investigator Brochure 
will be provided to each site. Please contact the Medical IIS Office at BIPI at 877-757-
7354 with questions regarding the Investigator Brochure. 
 
4.1.1 Formulation:  
 
 
Other Names: BIBF 1120, Nintedanib 
 
Classification: Tyrosine kinase inhibition 
 
Molecular Formula: C33H39N5O7S 
 
4.1.2    Mode of Action: Small molecule triple receptor tyrosine kinase inhibitor 
(PDGFR αβ (platelet derived growth factor receptor), FGFR 1/3 (fibroblast 
growth factor receptor), VEGFR 1-3 (vascular endothelial growth factor 
receptor)). 
 
4.1.3    How Supplied: Nintedanib is provided by Boehringer-Ingelheim 
Pharmaceuticals, Inc as soft gelatin capsules containing a suspension of milled 
active as the salt. It is available in two dose strengths corresponding to 100 mg 
(orange or peach, oblong capsules), 150 mg (orange or brown, oblong capsules). 
 
The capsule fill is composed of medium chain triglycerides, hard fat and lecithin 
in addition to the drug substance.  
 
Each bottle will be labeled in an open labeled fashion. Labels will contain, at a 
minimum, the following information: product name, tablet strength, batch 
number, directions for use, storage conditions, and appropriate caution 
statements. 
 
4.1.4 
Storage: The capsules are packaged in child resistant high density polyethylene 
(HDPE) bottles and have to be stored below 30°C.  
   
4.1.5 Stability: The current shelf life is 36 months. 
 
4.1.6 
Route of Administration: Oral. Missed doses will not be made up. Every effort 
should be made to take the capsules at the same time every day. If vomiting occurs 
the participant should not retake the dose and should be instructed to take the next 
dose at the next scheduled time.  
 
4.1.7 Rescue medication and additional treatments: Rescue medication to reverse the 
actions of Nintedanib is not available. Potential side effects of Nintedanib have 
to be treated symptomatically.  


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4.1.8 Incompatibilities:  
   
4.1.8.1 Potential Drug Interactions: After oral administration of [14C] Nintedanib 
to rats, radioactivity showed an early peak in blood (0.5 hours post dose) 
and in the liver (2 hours post dose). In most of the other tissues the 
concentration of radioactivity followed a time course with maximum at 8 
hours post dose. The highest exposure was seen in the liver, followed by 
the blood, lung and kidney. Nintedanib did not cross the blood brain 
barrier. In human liver microsomes, the cleavage of [14C] Nintedanib by 
esterase-catalyzed hydrolysis (formation of BIBF 1202) was the 
prevalent metabolic reaction (about 25 %). Metabolism of Nintedanib by 
CYP450 enzymes plays only a minor role (5%); CYP 3A4 was the 
predominant enzyme involved in the formation of hydroxylated 
Nintedanib and desmethylated Nintedanib. Nintedanib did not show 
relevant inhibition or induction of the major drug metabolizing 
cytochrome P450 enzymes and specifically no irreversible CYP 3A4 
inhibition. The main route of excretion was via feces. In Rhesus 
monkeys, cumulative fecal excretion was 85.6 % following intravenous 
and 88.9 % following oral administration. The median 168 hour 
cumulative urinary excretion was 5.21% following intravenous 
administration and 1.54% following oral administration. In the rat, the 
Rhesus-, and the Cynomolgus monkey, exposure to Nintedanib increased 
in essence linearly with the dose. 
 
With respect to the in vitro finding that the main metabolite of 
Nintedanib, BIBF 1202, is glucuronidated by UGT1A1 (liver and 
intestine) as well as UGT1A7, UGT1A8 and UGT1A10 (intestine), it 
may be speculated whether reduced UGT1A1 activity could result in 
increased levels of the non-conjugated metabolite. Pharmacogenetic 
investigations are currently ongoing (correlation of UGT1A1 genotype 
with PK parameters and clinical parameters) and patients will be 
genotyped for UGT1A1 in the phase III trials.  
 
Thus far, no relationship between reduced tolerability of Nintedanib and 
increases of bilirubin have been observed. Patients with increased 
bilirubin levels or increases of transaminases to > 2.5x ULN prior to start 
of therapy have been excluded in most trials conducted thus far and only 
patients with normal bilirubin will be enrolled in the phase III trials in 
NSCLC. Currently, there is no medical rationale to specifically exclude 
patients with slow metabolism genotype or reduced activity of the 
UGT1A1 enzyme since also UGT1A7, UGT1A8 and UGT1A10 are 
capable of glucuronidating BIBF 1202 (intestine). Combination of 
Nintedanib with agents metabolized via UGT1A1 such as irinotecan has 
not been tested thus far. Yet, the relevance of the possible interaction of 
Nintedanib with UGT1A1 for drug-drug interactions is not clear. 


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Specific dose reduction schemes for liver enzyme elevations are in place 
in all protocols. 
 
4.1.9 Reported Adverse Events and Potential Risks:  
 
4.1.9.1 Gastrointestinal adverse events: nausea, vomiting, diarrhea, anorexia and 
abdominal pain (upper and lower) were the most frequent adverse events 
and were mostly of CTCAE grades 1 and 2 intensities. The frequency of 
CTCAE grade 3 gastrointestinal events did not exceed 8% over all trials. 
Gastrointestinal side effects were the predominant reason for treatment 
interruption besides liver enzyme elevations and fatigue/asthenia. All 
events were fully reversible [8].  
 
4.1.9.2 Hepatic adverse events: The predominant dose limiting toxicity in phase 
I dose escalation trials was reversible elevation of hepatic transaminases, 
more pronounced for ALT than for AST. At doses below 200 mg bid no 
CTCAE grade 3+4 increases have been observed. According to phase II 
data, the probability to suffer from liver enzyme elevations of CTCAE 
grade 3 or 4 within the first two months of Nintedanib treatment is 10-
15% for patients treated with 250 mg bid of Nintedanib. An increase of 
transaminases was only rarely observed in Caucasian patients treated 
with 150 mg bid or 200 mg bid. An association with hyperbilirubinemia 
was rare, and was (if at all) represented by a low grade increase of 
bilirubin with only one exception in a patient with tumor stenosis of the 
ductus hepatocholedochus and grade 3 bilirubin increase two weeks after 
cessation of therapy. -GT elevations, either as isolated increases or in 
combination with transaminitis, were observed frequently. Enzyme 
elevations generally normalized upon dose reduction or discontinuation. 
No drug-related hepatic failure was reported [8]. 
 
The current dose of Nintedanib in all studies is limited to 200 mg bid 
and, all studies require monitoring of liver enzyme tests. In addition, all 
studies include specific dose reduction schemes regarding liver enzyme 
elevations [8]. 
 
4.1.9.3 Infection adverse events: Infections have been observed but were 
expected for advanced cancer populations and age group. Only a few 
were considered drug related. 
 
4.1.9.4 Thromboembolic and cardiac adverse events: In the combined phase I 
and II monotherapy trials (1199.1-3, 1199.9, 1199.10, 1199.11, 1199.16, 
1199.19), there were 13 patients (3.7%) with events from the “selected 
thrombotic events” category which included pulmonary embolism (3), 
deep vein thrombosis (2), myocardial infarction (2), transient ischemic 
attack (2), aphasia (1), hemiparesis (1), thrombophlebitis (1), and 
thrombosis (1). Five of these events (1.4%) were considered treatment 


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related: deep vein thrombosis (2) myocardial infarction (2), and transient 
ischemic attack (1). There were 66 patients (19%) with events from the 
“cardiac events” category which include the following: chest pain (24, 
6.9%), edema peripheral (9, 6.6%), sinus tachycardia (8, 2.3%), 
cardiovascular disorder (3, 0.9%), palpitations (3, 0.9%), arrhythmia (2, 
0.6%), cardiopulmonary failure (2 (1 fatal and not considered as 
treatment related), 0.6%), myocardial infarction (2, 0.6%), pericardial 
effusion (2, 0.6%), atrioventricular block second degree (1, 0.3%), 
cardiac failure (1, 0.3%), electrocardiogram ST segment (1, 0.3%), 
electrocardiogram change (1, 0.3%), heart rate decreased (1, 0.3%), heart 
rate irregular (1, 0.3%), pitting edema (1, 0.3%), sudden death (1 case 
considered as not treatment related, 0.3%), syncope (1, 0.3%), and 
ventricular arrhythmia (1, 0.3%). A total of 12 from these events (3.4%) 
were considered as treatment related: chest pain (2), myocardial 
infarction (2), peripheral edema (2), sinus tachycardia (2), arrhythmia 
(1), cardiac failure (1), electrocardiogram ST (1), electrocardiogram 
change (1), heart rate decrease (1), palpitation (1), tachycardia (1), and 
ventricular arrhythmia (1). In the placebo controlled unblinded phase II 
trial 1199.9 comparing 250 mg bid of Nintedanib to placebo in patients 
with ovarian cancer there was no difference in AEs from the SOC 
“Cardiac disorder” between both arms (Nintedanib: 1 (2-3%) versus 2 
(5%) for placebo).There was also no meaningful difference between both 
arms regarding “thrombotic events” (Nintedanib arm: 2 with deep vein 
thrombosis. Placebo arm: 1 with pulmonary embolism) and regarding 
“cardiac events” (Nintedanib arm: 5 (12.5%), placebo arm: 3 (6.8%)). 
 
In summary, the frequency of drug related thromboembolic events was 
low across all completed studies using Nintedanib monotherapy, and the 
frequency of thromboembolic adverse events regardless of relatedness 
did not exceed the expected rate in the patients with advanced solid 
tumors [8]. 
 
4.1.9.5 Hypertension adverse events: In the combined phase I and II 
monotherapy studies trials (1199.1-3, 1199.16, 1199.19, 1199.9, 
1199.10, 1199.11), 36 patients (10.3 %) had the AEs from the pool of 
‘hypertension’ events which include the following: 32 (9.2%) had 
hypertension, 3 (0.9 %) had blood pressure increased, and 2 (0.6 %) had 
systolic blood pressure increased. The majority of these events were 
considered as treatment related: 24 (6.9%) with hypertension, 3 (0.9%) 
with blood pressure increased, and 1 (0.3%) with systolic blood pressure 
increased. In a randomized study, in the combined trials, the frequency 
of reported hypertension adverse events was 2.6%-9.9%. Overall, the 
hypertensive potential of Nintedanib as an antiangiogenic compound is 
considered relatively low as compared to other compounds in the class 
[8]. 
 


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4.1.9.6 Dermatologic adverse events: In vitro studies suggested a theoretic risk 
of phototoxicity for patients treated with Nintedanib. However, it was 
estimated that the maximum concentration of Nintedanib in the human 
skin is about 4-fold lower than the threshold level of 0.5 µg/mL in the in 
vitro assay. Combined phase I and II Nintedanib monotherapy trials 
1199.1-3 1199.9, 1199.10, 1199.11, 1199.16 and 1199.19: a total of 72 
patients (20.7%) reported an AE from the user-defined category ‘skin 
events’. These AEs include following: pruritus (18, 5.2%), rash (18, 
5.2%), hyperhidrosis (17, 4.9%), erythema (14, 4%), skin lesion (5, 
1.4%), acne (4, 1.1%), skin irritation (3, 0.9%), sunburn (3, 0.9%), skin 
fissure (2, 0.6%), urticaria (2, 0.6%). Additionally, photosensitivity 
reaction, prurigo, pruritus generalized, rash macular, rash pustular, skin 
reaction, and skin ulcer occur each in less than 2 patients (0.3%). All 
events were grade 1-2 [8]. 
 
4.1.9.7 Other adverse events include fatigue or asthenia, metabolism and 
nutrition disorders, anorexia, and lab abnormalities. 
 
4.1.10  Availability: Nintedanib will be supplied by Boehringer Ingelheim  
 
 
 
 
 
4.1.11 Drug Ordering and Accountability:  
 Please see the following separate documents for information:  
 Drug Order Form  
 Investigational Agent Accountability Form 100mg capsules 
 Investigational Agent Accountability Form 150mg capsules 
 
 
 
 
 
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5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE  
 
Before patient screening begins, each site must submit the following documents to Duke 
University, Division of Gynecologic Oncology Clinical Trials via mail or email (Attn:  
Regulatory Department, Protocol BIBF 1120): 
 
 IRB approval. 
 IRB-approved informed consent. 
 IRB Membership list or FWA assurance letter. 
 Study-specific signed original FDA Form 1572 for institution PI.  
 Current CV (signed and dated within one year) for institution PI and sub-investigators listed 
on FDA Form 1572. 
 Medical license for institution PI and sub-investigators listed on the FDA Form 1572. 
 Lab license, certificates, and required Normal Lab Values (NLV) for labs listed on FDA 
Form 1572. 
 Signed original Signature Page for PI. 
 Signed original Financial Disclosure Form for all investigators listed on FDA Form 1572. 
 Delegation of Authority log. 
 Human Subject Protection Certificates for investigators and personnel who will be seeing 
and consenting study participants. 
 
Please allow 7-10 days for processing of regulatory documents before screening the first 
patient. All copies of the above should be filed into a study-specific regulatory binder at your 
institution. 
 
The initial supply of study drug cannot be shipped until all the regulatory documents have been 
reviewed and approved. Duke University may require copies of the regulatory documentation 
prior to any shipment of drug.  
 
5.1   
Patient Entry and Registration 
 
When a suitable candidate has been obtained for protocol entry, the following steps 
should be taken: 
 
5.1.1 An approved consent form must be signed by the patient or guardian. The 
consent must contain language permitting the release of personal health 
information. Current FDA and institutional regulations concerning informed 
consent will be followed. 
 
 
 
5.1.2 All eligibility requirements indicated must be satisfied. 
 
 
5.1.3 Eligibility Checklist data should be gathered and faxed to (919) 681-7689.  
 
 
5.1.4 Subject entry will take place after the fax is received and verification of the 
Eligibility Checklist data completed. Alternatively, a secure web-based process 
is available for subject registration, providing subject identifiers to the registrar, 


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as well as spawning a secure e-mail notification to coordinating center 
personnel. 
 
5.1.5 The institution will enter the patient's name into a Log Book to verify the 
patient's entry. 
 
            5.2 
Treatment Plan 
 
5.2.1 Patients to take 200 mg PO twice daily until disease progression or toxicity. 28 
days will be considered one cycle. Capsules will be swallowed unchewed with a 
glass of liquid of about one cup and with a dose interval of 12 hours. Patients 
will be instructed to take their medication at the same time every day, after food 
intake.  If a patient misses a dose, the missed dose will not be made up.  The 
patient should be instructed to take the next dose at the next scheduled time. 
 
5.3 
Criteria for removal from treatment 
 
5.3.1 Inability to tolerate Nintedanib at the lowest doses because of toxicity.  
 
5.3.2 Patients may choose to withdraw from the study at any time for any reason.  
 
5. 3.3 Patients with evidence of disease progression or significant side effects will be 
removed from study. 
 
5.3.4 Patients who become pregnant will be removed from the study. 
 
 
6.0 
TREATMENT MODIFICATIONS 
 
 
Study Drug  
2 Level reduction 
1 Level reduction 
Initial dose level 
 
Nintedanib 
100 mg BID 
1 100 mg capsule 
BID 
150 mg BID 
1 x 150 mg capsule 
BID 
200 mg BID  
2 x 100 mg 
capsules BID 
 
Please note that this section is referring to the active version of the NCI Common Toxicity 
Criteria Version 4.0 grading. 
 
 


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6.1 
Management of diarrhea 
 
CTCAE v4.0 Grade 
Action for Nintedanib and Anti-
diarrheal treatment 
Action for Nintedanib after 
recovery of diarrhea 1 
 
Grade 1  
Continue Nintedanib  
No Anti-diarrheal treatment 
No dose reduction of 
Nintedanib 
Grade 2 
      
Continue Nintedanib  
Anti-diarrheal treatment according 
to the local standard e.g., 
loperamide p.r.n. 
 
No dose reduction of 
Nintedanib 
 
Grade 2  ≥ 7 days despite optimal medical management or Grade ≥ 3 or 
any diarrhea independent of CTCAE grade leading to hospitalization of the patient 
First episode 
 
TEMPORALLY Nintedanib until 
recovery1 
AND 
Anti-diarrheal treatment according 
to the local standard e.g., 
loperamide p.r.n. 
Reduce Nintedanib dose to 
2 x 150 mg after recovery of 
diarrhea 1 
 
 
Second episode 
TEMPORALLY STOP 
Nintedanib until recovery1 
AND 
Anti-diarrheal treatment according 
to the local standard e.g., 
loperamide p.r.n. 
Reduce Nintedanib dose to 
2x 100 mg after recovery of 
diarrhea 1 
  
 
Third episode 
PERMANENTLY discontinue  
Nintedanib treatment 
AND 
Anti-diarrheal treatment according 
to the local standard e.g., 
loperamide p.r.n. 
PERMANENTLY discontinue 
Nintedanib treatment 
1Until resolution to less than or equal to the patient’s pre-therapy status at study enrollment. 
 
6.2 
Management of liver enzyme elevations:  If liver enzyme elevations are considered to 
be related to Nintedanib the following algorithm should be followed. This 
recommendation for the management of Nintedanib-induced liver toxicity is valid 
ONLY for patients with inclusion criteria: AST/ALT < 1.5 ULN and bilirubin ULN in 


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patients with no metastases in liver and, AST/ALT < 2.5 ULN and bilirubin ≤ ULN in 
patients with metastases in liver.  
ALT, AST and 
bilirubin 
elevation 
1st episode 
 
2nd episode  
 
3st episode  
ALT and/or AST 
≤ 5x ULN with 
bilirubin ≤ 1.5 
ULN 
Continue 
Nintedanib, No 
dose reduction 
Continue Nintedanib, No 
dose reduction 
Continue 
Nintedanib, No 
dose reduction 
ALT or AST > 2.5 
ULN in 
conjunction with 
bilirubin > 1.5 
ULN 
TEMPORARILY 
STOP Nintedanib 
until recovery*   
 
Then reduce 
Nintedanib dose1 
TEMPORARILY STOP 
Nintedanib until 
recovery*   
 
Then reduce Nintedanib 
dose1 
PERMANENT 
discontinuation of 
Nintedanib 
treatment 
ALT or AST > 5x 
ULN   
 
TEMPORARILY 
STOP Nintedanib 
until recovery*   
 
Then reduce 
Nintedanib dose1 
PERMANENT 
discontinuation of 
Nintedanib treatment 
PERMANENT 
discontinuation of 
Nintedanib 
treatment 
Bilirubin > 3.0 
ULN 
TEMPORARILY 
STOP Nintedanib 
until recovery*   
 
Then reduce 
Nintedanib dose1 
PERMANENT 
discontinuation of 
Nintedanib treatment 
PERMANENT 
discontinuation of 
Nintedanib 
treatment 
*ALT and or AST ≤ 2.5x ULN with bilirubin ≤ 1.5 ULN or baseline at study enrollment. 
1Nintedanib dose reductions : from 200 mg bid to 150 mg bid and from 150 mg bid to 100 mg bid 
 
Revised to change “ALT and/or AST ≤ 2.5x ULN with bilirubin ≤ 1.5 ULN” to “ALT and/or AST ≤ 5x ULN with bilirubin 
≤ 1.5 ULN” in order to provide direction for participants with an “ALT and/or AST > 2.5 but ≤ 5x ULN with bilirubin ≤ 1.5 
ULN”. 
 
Revised from “*CTCAE v4.0, grade ≤ 1 or baseline at study enrolment” to“*ALT and or AST ≤ 2.5x ULN with bilirubin ≤ 
1.5 ULN or baseline at study enrollment.” Change was made due to variations regarding hepatic toxicity in CTCAE v3.0 
and CTCAE v4.0. The Nintedanib modifications for hepatic toxicity were initially based on CTCAE v3.0.  CTCAE v 3.0 
defined grade 1 hepatic toxicity was defined as ALT and or AST ≤ 2.5x ULN.  However, CTCAE v 4.0 grade 1 hepatic 
toxicity is defined ALT and or AST ≤ 3.0x ULN.  Safety data up to date has used CTCAE v3.0.  For safety considerations 
in prior studies in these series the criteria for return to baseline was ALT and/or AST ≤ 2.5x ULN with bilirubin ≤ 1.5 ULN 
or returning to baseline at study enrollment. To improve patient safety we will use these parameters rather than CTCAE 
v4.0 study criteria. 
 
6.3  
Management of nausea and vomiting for trials investigating monotherapy of Nintedanib   


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In order to reduce the occurrence and the intensity of emesis the patients should be 
treated according to the following recommendations:   
CTCAE v4.0 
Grade 
Antiemetic treatment 
 
Dose of Nintedanib 
Nausea =1 
No antiemetic treatment 
No dose reduction 
Nausea 2 
and/or  
vomiting =1   
 
 
No Nintedanib treatment pause 
 
Antiemetic treatment according to local standard of 
care, e.g., metoclopramide or dimenhydrinate, or 
prochlorperazine  
 
If ineffective, patients should be treated according 
to treatment of vomiting > 2 or nausea CTCAE 
Grade ≥ 3. 
 
 
 
 
No dose reduction 
Vomiting  ≥2  
and/ or nausea 
≥ 3   
 
First episode 
 
 
 
 
 
Second episode 
 
 
 
Third episode 
 
 
 
 
 
Treatment with Nintedanib discontinued and 
resumed upon recovery1  
Antiemetic treatment according to local standard of 
care e.g., with 5-HT3 receptor antagonist* and/or 
corticosteroid  
 
Treatment with Nintedanib discontinued and 
resumed upon recovery1  
Treatment as above 
 
As above 
 
 
 
 
Nintedanib: dose 
reduction2  
 
 
 
Nintedanib: dose 
reduction2 
 
 
Nintedanib: 
discontinuation 
1CTCAE grade ≤ 1 or baseline at study enrolment. 
2Nintedanib dose reductions : from 200 mg bid to 150 mg bid and from 150 mg bid to 100 mg bid 
* Note: Tropisetron and dolasetron should be avoided due to genetically polymorphic metabolism by CYP2D6. 
 
 
 
 
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6.4 
Management of non-hematologic adverse events other than emesis, liver enzyme 
elevations, and diarrhea  
CTCAE v4.0   
Grade 3 or 4 
Nintedanib 
First Episode 
TEMPORARILY Stop Nintedanib treatment until recovery1  
Then Nintedanib dose reduction2 
Second Episode 
TEMPORARILY  Stop Nintedanib treatment until 
recovery1  
Then Nintedanib dose reduction2 
Third Episode 
PERMANENT Nintedanib treatment discontinuation 
1Until resolution to less than or equal to the patient’s pre-therapy value at study enrollment. 
2Nintedanib dose reductions : from 200 mg bid to 150 mg bid and from 150 mg bid to 100 mg bid 
 
 
6.5  
Patients should PERMANENTLY discontinue treatment with Nintedanib in the event 
of: 
 Intolerable Adverse Events (CTCAE v4.0 grade 3 or 4) that cannot be managed by 
dose reduction. 
 Nausea or vomiting CTCAE v4.0 grade 2 for 5 or more consecutive days despite 
optimal supportive care and dose reduction of study medication. 
 Diarrhea CTCAE v4.0 grade > 2 for 8 or more consecutive days despite optimal 
supportive care and dose reduction of study medication. 
 In the event that Nintedanib is withheld for > 21 consecutive days due to treatment-
related toxicity, Nintedanib will be permanently discontinued. 
 
6.6 
Dose escalations 
 
There will be no dose escalations or re-escalations on this study. 
 
 
 
 
 
 
 
 
 
 
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7.0 
STUDY PARAMETERS 
 
7.1 
The following observations and tests are to be performed and recorded on the 
appropriate form(s). Specimen requirements for translational research are 
provided in Section 7.3.  
 
Parameter 
Pre-
Therapy 
Weekly 
Prior to 
Each 
cycle 
Every  
Other  
Cycle 
Post 
Treatment 
Follow-up 
History & Physical 
X 1 
 
X 
 
X 
Performance Status 
X 1 
 
 
 
 
Clinical tumor measurement 
X 1 
 
X 2 
 
 
Toxicity Assessment  
X 3 
X 7 
X 
 
 
CBC/Differential/Platelets 
X 3 
 
X 4 
 
X 10 
Electrolytes, BUN, creatinine, Ca, 
Mg, PO4, Urinalysis 
X 3 
 
X 4 
 
X 10 
Bilirubin, SGOT, SGPT,  
Alkaline Phosphatase 
X 3 
 
X 4 
 
X 10 
INR/PT/PTT12 
X1 
 
 
X12 
 
Serum Pregnancy Test (for patients 
of childbearing potential) 
 X 9 
 
 
 
 
Chest imaging (X-ray or CT scan of 
the chest) 
X 1 
 
 
X 5 
 
Radiographic tumor measurement 
(RECIST) 
X 1, 6 
 
 
X 6 
X 6 
Electrocardiogram (ECG) 
X 1 
 
 
X13 
 
CA-125 
X 3 
 
X 4 
 
X 
Capsule Diary 
 
 
X 8 
 
 
Research samples 
X11 
 
 
X11 
X11 
Subject Preferences Tasks 
X14 
 
 
 
 
NFOSI-18 
X14 
 
 
 
 
FACT-GOG-Ntx 
X14 
 
 
 
 
 
Notes: 
1. Must be obtained within 28 days prior to initiating protocol therapy. 
2.  For those patients whose disease can be evaluated by physical examination (i.e. nodes, pelvic 
mass). 


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3. Must be obtained within 14 days prior to initiating protocol therapy. 
4. CBC/Differential/Platelets, liver function tests, creatinine,CA-125, and urinalysis must be 
obtained within 4 days before initiating the next cycle of treatment with protocol therapy. 
5. Repeat chest imaging if initially abnormal or if required, to monitor tumor response. 
6.   CT scan or MRI if used to follow lesion for measurable disease every other cycle for the first 
6 months; then every 3 months thereafter; and at any other time if clinically indicated based 
on symptoms or physical signs suggestive of progressive disease or rising serum tumor 
marker levels.  
7.  Nurse at site is to make weekly phone call to the patient during the first two cycles of 
treatment to inquire about any toxicity. The phone contact should be documented in the study 
participant’s chart.  
8. See Appendix II 
9. If the patient is of child-bearing potential the serum pregnancy test must be obtained within 7 
days prior to initiating protocol therapy. 
10. These tests are to be done as needed at the discretion of the study doctor. 
11. See section 7.3 for specimen requirements. Collect whole blood, serum, plasma, and urine 
pre-cycle #1, every other cycle (i.e. Cycle 3, 5, etc.), at the time of progression, and one 
month after study treatment is discontinued.  
12. Repeat every other cycle and more frequently as clinically indicated.  For patients with 
hepatic injury or elevated liver function tests repeat the INR/PT/PTT every cycle until the 
liver function tests return to baseline; then resume INR/PT/PTT every other cycle.    
13. Repeat every other cycle and more frequently as clinically indicated.   
14. Only for subjects enrolled at Duke 
 
7.2 
Pathology Requirements 
Stained pathology slides are not required for this protocol. Documentation of 
initial pathology will be performed by verifying the original pathology report.  
 
7.3 
Translational Research 
 
 
7.3.1   Specimen Requirements 
 
7.3.1.1 Blood Specimens 
 
For detailed instructions on processing and shipping please see 
Procedure Manual – Specimens SOP 
 
7.3.1.2 Urine Specimens 
 
For detailed instructions on processing and shipping please see 
Procedure Manual – Specimens SOP 
 
 
 
 
7.3.1.3 Tumor Specimens 
 
For detailed instructions on processing and shipping please see 
Procedure Manual – Specimens SOP 
 


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7.3.2 Biomarker processing and sample handling. 
 
For detailed instructions on processing and shipping please see Procedure 
Manual – Specimens SOP 
 
For any questions regarding biomarker processing, supplies and shipping, 
please call 919-684-4159. 
 
 
7.4 
Quality of Life 
The NCCN-FACT FOSI-18 and the FACT-Ntx will be collected at enrollment in 
conjunction with collection of patient preferences data.  These instruments will 
elicit patient-reported outcomes that complement and supplement the preferences 
data.  It is critical when examining preferences to have information on the current 
condition of those being queried. 
 
 
 
8.0 
EVALUATION CRITERIA 
 
8.1 
Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study using the new 
international criteria proposed by the revised Response Evaluation Criteria in 
Solid Tumors (RECIST) guideline (version 1.1) [13]. Changes in the largest 
diameter (unidimensional measurement) of the tumor lesions and the shortest 
diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
 
8.1.1 Disease Parameters 
 
Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as > 10 mm with CT scan, as > 20 mm by chest x-ray, or > 10 
mm with calipers by clinical exam. All tumor measurements must be 
recorded in decimal fractions of centimeters. 
 
Note: Tumor lesions that are situated in a previously irradiated area will 
not be considered measurable unless progression is documented or a 
biopsy is obtained to confirm persistence at least 90 days following 
completion of radiation therapy. 
 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 5 
mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
 


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Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter < 10 mm or pathological lymph nodes 
with ≥ 10 to < 15 mm short axis), are considered non-measurable disease. 
Leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal/pelvic masses (identified by physical exam and not CT or 
MRI), are considered as non-measurable. 
 
Notes:   
Bone lesions: Lytic bone lesions or mixed lytic-blastic lesions, with 
identifiable soft tissue components, that can be evaluated by CT or MRI 
can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. Blastic bone 
lesions are non-measurable. 
 
Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable 
nor non-measurable) since they are, by definition, simple cysts. “Cystic 
lesions” thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described 
above. However, if non-cystic lesions are present in the same patient, 
these are preferred for selection as target lesions. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, and in 
addition should be those that lend themselves to reproducible, repeated 
measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement, in which circumstance the 
next largest lesion which can be reproducibly measured should be 
selected. A sum of the diameters (longest for non-nodal lesions, short axis 
for nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
 
Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be 
identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 


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8.1.2 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a 
ruler or calipers. All baseline evaluations should be performed as closely 
as possible to the beginning of treatment and never more than 4 weeks 
before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during 
follow-up. Imaging-based evaluation is preferred to evaluation by clinical 
examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when 
they are superficial (e.g. skin nodules and palpable lymph nodes) and  10 
mm diameter as assessed using calipers (e.g. skin nodules). In the case of 
skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung. However, 
CT is preferable.  
 
Conventional CT and MRI: This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm 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. 
MRI is also acceptable in certain situations (e.g., for body scans), but 
NOT lung.  
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, 
and temporal resolution; however, there are many image acquisition 
variables involved in MRI, which greatly impact image quality, lesion 
conspicuity, and measurement. Furthermore, the availability of MRI is 
variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the 
modality used at follow-up should be the same as was used at baseline, 
and the lesions should be measured/assessed on the same pulse sequence. 
It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases. 
Ideally, subsequent image acquisitions should use the same type of 
scanner and follow the baseline imaging protocol as closely as possible. If 
possible, body scans should be performed with breath-hold scanning 
techniques. 
 


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PET-CT: At present, the low-dose or attenuation correction CT portion of 
a combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements. PET-CT scans are not always done with 
oral and IV contrast. In addition, the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or 
serially performed.  
 
FDG-PET: While FDG-PET response assessments need additional study, 
it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly 
possible “new” disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up 
is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD. If the positive FDG-PET at follow-up is 
not confirmed as a new site of disease on CT, additional follow-up CT  
scans are needed to determine if there is truly progression occurring at 
that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to 
a pre-existing site of disease on CT that is not progressing on the basis 
of the anatomic images, this is not PD. 
 
 Note:  A “positive” FDG-PET scan lesion means one that is FDG avid 
with an uptake greater than twice that of the surrounding tissue on the 
attenuation corrected image. 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a later 
date and, because they are operator dependent, it cannot be guaranteed 
that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the 
course of the study, confirmation by CT or MRI is advised. If there is 
concern about radiation exposure at CT, MRI may be used instead of CT 
in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective 
tumor evaluation is not advised. However, such techniques may be useful 
to confirm complete pathological response when biopsies are obtained or 
to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
 
CA-125 (Ovarian, fallopian tube and primary peritoneal cancer trials): 
CA-125 alone cannot be used to assess response. If CA-125 is initially 


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above the upper normal limit, it must normalize for a patient to be 
considered in complete clinical response. Specific guidelines for CA-125 
response (in recurrent ovarian cancer) have been published [14].  
 
Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases, e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain. 
 
It is mandatory to obtain cytological confirmation of the neoplastic origin 
of any effusion that appears or worsens during treatment when 
measureable disease has met criteria for response or stable disease. This 
confirmation is necessary to differentiate response or stable disease versus 
progressive disease, as an effusion may be a side effect of the treatment. 
 
8.1.3 Response Criteria 
 
Determination of response should take into consideration all target and 
non-target lesions and if appropriate, biomarkers. 
 
8.1.3.1 Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the baseline sum 
diameters 
 
 
 
Progressive Disease (PD): At least a 20% increase in the sum of 
the diameters of target lesions, taking as reference the smallest sum 
on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered 
progressions). 
 
 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, taking as reference the 
smallest sum diameters while on study. 
 
Not evaluable (NE): When at least one target lesion is not 
evaluated at a particular time point. 
 
 


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8.1.3.2 Evaluation of Non-Target Lesions 
 
 
 
Complete Response (CR): Disappearance of all non-target lesions. 
All lymph nodes must be non-pathological in size (< 10 mm short 
axis). 
 
 
 
 
 
 
 
 
 
Note: If CA-125 is initially above the upper normal limit, it must 
normalize for a patient to be considered in complete clinical 
response. 
 
 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)  
 
 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions. 
Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, 
not a single lesion increase. 
 
 
 
Not evaluable (NE): When at least one non-target lesion is not 
evaluated at a particular time point. 
 
Although a clear progression of only “non-target” lesions is 
exceptional, the opinion of the treating physician should prevail in 
such circumstances, and the progression status should be confirmed 
at a later time by the review panel (or Principal Investigator). 
  
8.1.3.3 Evaluation of Biomarkers 
 
If serum CA-125 is initially above the upper normal limit, it must 
normalize for a patient to be considered in complete clinical 
response.  
 
 
8.1.3.4 Evaluation of Best Overall (unconfirmed) Response 
 
The best overall response is the best time point response recorded 
from the start of the treatment until disease progression/recurrence 
(taking as reference for progressive disease the smallest sum 
recorded since baseline). The patient's best response assignment 
will depend on the achievement of both measurement and 
confirmation criteria in some circumstances. 
 
 
 
 


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Time Point Response for Patients with Measurable Disease at baseline (i.e., Target 
Disease)  
 
Target 
Lesions 
Non-Target 
Lesions 
Biomarker 
CA-125 
New 
Lesions* 
Time Point 
Response 
CR 
CR 
Within 
normal limits 
No 
CR 
CR 
Non-CR/Non-PD 
Any value 
No 
PR 
CR 
NE 
Any value 
No 
PR 
PR 
Non-PD or NE 
Any value 
No 
PR 
SD 
Non-PD or NE 
Any value 
No 
SD 
NE 
Non-PD 
Any value 
No 
NE 
PD 
Any 
Any value 
Yes or No 
PD 
Any 
PD** 
Any value 
Yes or No 
PD 
Any 
Any 
Any value 
Yes 
PD 
*See RECIST 1.1 manuscript for further details on what is evidence of a 
new lesion  
 
** In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
CR = complete response, PR = partial response, SD = stable disease, PD = 
progressive disease, and NE = inevaluable. 
 
8.1.3.5 Best Overall Confirmed Response  
 
Confirmation of CR and PR for determination of best overall 
response is required for studies with a primary endpoint that 
includes response. SD should also be confirmed. Responses (CR 
and PR) require confirmation at greater than or equal to 4 
weeks from initial documentation. For this study, the minimum 
criterion for SD duration is 6-8 weeks. 
 
 
Confirmed CR and PR for best overall confirmed response 
Time Point 
Response 
First time point 
Time Point 
Response 
Subsequent time 
point 
BEST overall 
confirmed response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR* 
CR 
SD 
SD provided minimum 
criteria for SD duration 
met, otherwise, PD 
CR 
PD 
SD provided minimum 
criteria for SD duration 
met, otherwise, PD 


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CR 
NE 
SD provided minimum 
criteria for SD duration 
met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD  
PR 
PD 
SD provided minimum 
criteria for SD duration 
met, otherwise, PD 
PR 
NE 
SD provided minimum 
criteria for SD duration 
met, otherwise, NE 
NE 
NE 
NE 
 
*If a CR is truly met at first time point, then any disease seen at a 
subsequent time point, even disease meeting PR criteria relative to 
baseline, makes the disease PD at that point (since disease must 
have reappeared after CR). However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely 
still present and in fact the patient had PR or SD, not CR at the first 
time point. Under these circumstances, the original CR should be 
changed to PR or SD and the best response is PR or SD.  
 
In non-randomized trials where response is part of the primary 
endpoint, confirmation of CR or PR is needed to deem either one 
the “best overall response.” Patients with a global deterioration of 
health status requiring discontinuation of treatment or who die 
without objective evidence of disease progression at that time 
should be reported to be off study treatment due to “symptomatic 
deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
8.1.4 CA125 Response Criteria  
 
A response according to CA 125 has occurred if there is at least a 50% 
reduction in CA 125 levels from a pretreatment sample. The response 
must be confirmed and maintained for at least 28 days. Patients can be 
evaluated according to CA125 only if they have a pretreatment sample 
that is at least twice the upper limit of normal and within 2 weeks prior to 
starting treatment [14]. 
 
8.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is 
measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or 


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progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is 
objectively documented.  
 
Duration of stable disease:  Stable disease is measured from study entry 
(date of registration) until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the treatment started, 
including the baseline measurements.  
 
8.1.6 Progression-Free Survival 
 
Progression-Free Survival (PFS) is defined as the duration of time from 
study entry to time of progression or death, whichever occurs first. 
 
8.1.7 Survival 
 
Survival is defined as the duration of time from study entry to time of 
death or the date of last contact. 
 
 
9.0  
DURATION OF STUDY 
 
9.0 
Patients will receive therapy until disease progression or intolerable toxicity 
intervenes. The patient can refuse the study treatment at any time. 
 
9.1  
All patients will be treated (with completion of all required case report forms) 
until disease progression or study withdrawal. Patients will then be followed (with 
physical exams and histories) every three months for the first two years and then 
every six months for the next year. Patients will be followed for OS for up to 3 
years after completing the study (due to either disease progression or study 
withdrawal). 
 
10.0     ADVERSE EVENTS, STUDY MONITORING & REPORTING PROCEDURE 
 
There must be adequate review, assessment, and monitoring of adverse events. All 
subjects will be closely monitored throughout the study for AEs. Investigators will assess 
the occurrence of AEs and serious adverse events (SAEs) at all subject evaluations and 
visits during the study. All AEs and SAEs whether volunteered by the subject, discovered 
by study personnel during questioning, or detected through physical examination, 
laboratory test, or other means will be recorded in the subject’s medical record and on the 
appropriate AE or SAE CRF page.   
 


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Any SAE due to any cause must be reported to the Duke Cancer Institute (DCI) Safety 
Desk at the Duke University by fax or email within 24-hours of learning of the event.  
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events), version 4.0 for Adverse Event (AE) and Serious Adverse Event (SAE) reporting.  
A copy of the CTCAE v4.0 can be downloaded from 
http://ctep.cancer.gov/reporting/ctc.html.    
 
10.1 
Safety  
 
For safety information on Nintedanib, refer to the most recent version of the 
investigator brochure.  
 
 
10.2 
Reporting Period 
 
Serious adverse events require immediate notification (within 24 hours of 
knowledge of the event) to Dr. Angeles Alvarez Secord of Duke University 
Medical Center or designated representative. The study period during which all 
AEs and SAEs must be reported begins after informed consent is obtained and 
initiation of study treatment on Cycle 1, Day 1. It ends 30 days following the last 
administration of study treatment, or if the patient initiates treatment with a new 
anti-cancer therapy, or study discontinuation/termination; whichever is earlier. 
Any SAEs occurring any time after this period should be promptly reported if a 
causal relationship to the investigational product is suspected; investigators 
should report only SAEs that are attributed to study treatment. 
 
SAEs that are observed or reported prior to initiation of study treatment should be 
recorded as SAEs on the CRF if they are associated with protocol-mandated 
interventions (e.g., invasive procedures such as biopsies, medication washout, or 
no treatment run-in). 
 
10.3 
Definitions   
 
 
10.3.1 An adverse event (AE) is any untoward medical occurrence, undesirable  
medical condition, recurrence or deterioration of a preexisting medical 
condition, or disease temporally associated with or subsequent to exposure 
to a pharmaceutical product/treatment or protocol-imposed intervention, 
regardless of attribution. This includes signs (including a clinically 
significant abnormal laboratory finding), symptoms or condition occurring 
at any dose independent of perceived causal relationship to the product or 
treatment.  AEs may or may not be formal medical diagnoses. Common 
examples include nausea, chest pain, tachycardia, enlarged liver, or 
electrocardiogram abnormalities. 
 
10.3.2 Inter-current illness or injuries should be regarded as adverse events.  


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Abnormal results of diagnostic procedures are considered to be adverse 
events if the abnormality: 
 Results in study withdrawal. 
 Is associated with a serious adverse event. 
 Is associated with clinical signs or symptoms. 
 Leads to additional treatment or to further diagnostic tests. 
 Is considered by the Investigator to be of clinical significance. 
 
10.3.3 A serious adverse event (SAE) as defined by the International Conference 
on Harmonization (ICH) is any adverse experience that at any dose meets 
any of the following conditions: 
 Results in death (i.e., the adverse event causes or leads to death).  
 Is life-threatening.  
 Requires inpatient hospitalization or prolongation of existing 
hospitalization. 
  
 Results in persistent or significant disability/incapacity. 
 Results in a congenital anomaly/birth defect. 
 An important medical event that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug reaction when, based upon appropriate medical 
judgment, they may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition above. Examples of such 
medical events includes allergic bronchospasms requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in impatient hospitalization, or the 
development of drug dependency or drug abuse. 
  
10.3.4 Life-threatening refers to immediate risk of death as the event occurred  
per the view of the investigator. A life-threatening experience does not 
include an experience, had it occurred in a more severe form, might have 
caused death, but as it actually occurred, did not create an immediate risk 
of death. For example, hepatitis that resolved without evidence of hepatic 
failure would not be considered life-threatening, even though hepatitis of a 
more severe nature can be fatal. Similarly, an allergic reaction resulting in 
angioedema of the face would not be life-threatening, even though 
angioedema of the larynx, allergic bronchospasm, or anaphylaxis can be 
fatal. 
 
10.3.5 Hospitalization is official admission to a hospital. Hospitalization or  
prolongation of a hospitalization constitutes criteria for an AE to be 
serious; however, it is not in itself considered an SAE. In absence of an 
AE, a hospitalization or prolongation of a hospitalization should not be 
reported as an SAE by the participating investigator. This is the case in the 
following situations: 


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 The hospitalization or prolongation of hospitalization is needed for a 
procedure required by the protocol (drug administration, protocol-
requiring testing, etc.). 
 The hospitalization or prolongation of hospitalization is part of a 
routine procedure followed by the center (e.g., stent removal after 
surgery). This should be recorded in the study file. 
 Social admissions (e.g., subject has no place to sleep). 
 Administrative admissions (e.g., for yearly physical examinations). 
 Admission for treatment of a preexisting medical condition not 
associated with the development of a new adverse event or with a 
worsening of the preexisting condition. 
 Optional admission not associated with a precipitating clinical adverse 
event (e.g., for elective cosmetic surgery). 
 
In addition, a hospitalization for a preexisting condition that has not 
worsened does not constitute an SAE. Hospitalization does not include the 
following: rehabilitation facilities, hospice facilities, respite care (e.g., 
caregiver relief), skilled nursing facilities, nursing homes, routine 
emergency room admissions, or same day surgeries. Diagnostic and 
therapeutic non-invasive procedures, such as surgery, should not be 
reported as adverse events. However, the medical condition for which the 
procedure was performed should be reported if it meets the definition of 
an adverse event. For example, an acute appendicitis that begins during 
the adverse event reporting period should be reported as the adverse event, 
and the resulting appendectomy should be recorded as treatment of the 
adverse event. 
 
10.3.6 Disability is defined as a substantial disruption in a person’s ability to  
conduct normal life functions. If there is any doubt about whether the 
information constitutes an SAE, the information is treated as an SAE. 
 
10.3.7 Congenital Anomaly/Birth Defect in a neonate/infant born to a mother  
exposed to the investigational or pharmaceutical product/treatment. 
 
10.3.8 A protocol-related AE is an AE occurring during a clinical study that is  
not related to the test article, but is considered by the investigator or the 
medical monitor (or designee) to be related to the research conditions, i.e., 
related to the fact that a subject is participating in the study. For example, 
a protocol-related AE may be an untoward event occurring during a 
washout period or an event related to a medical procedure required by the 
protocol. 
 
***All adverse events should be noted on the Adverse Reaction case 
report form (CRF), whether or not is felt to be related to study drug.   
 
10.3.9 Related/Associated (with the use of the drug): There is a reasonable  


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possibility (more likely than not) that the event may have been caused by 
the drug, device or research. Determining the possible cause of an event 
includes assessing temporal relationships, dechallenge/rechallenge 
information, association (or lack of association) with underlying diseases, 
and the presence (or absence) of a more likely cause. 
 
10.3.10 An unexpected adverse event means any adverse event that is not  
identified in nature, severity, or frequency in the current Investigator 
Brochure. 
 
10.3.11Overdose is defined as the accidental or intentional ingestion of any dose  
of a product that is considered both excessive and medically important. An 
overdose is defined as a dose increase of Nintedanib other than one 
prescribed by a health care professional or recommended by this protocol, 
whether accidental or intentional. For reporting purposes overdose does 
not need to be reported to Boehringer Ingelheim unless there is an SAE 
associated with the overdose. An overdose itself does not meet any criteria 
for reporting to BI (Safety) as an AE/SAE. If an SAE occurs due to 
overdose, the SAE should be reported and the information should be 
reported and the information should be reflected in the administration 
section of the SAE form. 
 
10.3.12 A pre-existing condition is one that is present at the start of the study,  
and should be recorded as an adverse event if the frequency, intensity, or 
the character of the condition worsens during the study period.   
 
10.3.13 Seriousness is a regulatory definition and is based on patient or event  
outcome or action criteria usually associated with events that pose a threat 
to a patient’s life or functioning. Seriousness (not severity) serves as the 
guide for defining regulatory obligations from the Sponsor to applicable 
regulatory authorities. 
 
10.3.14 Severity (or intensity) refers to the grade of a specific AE (e.g., mild  
(grade 1); moderate (grade 2); or severe (grade 3) myocardial infarction); 
see table for further details.          
 
**Severity and seriousness should be independently assessed when 
recoding AEs and SAEs on the CRF. 
 
10.3.15 Non-Serious AEs are any events that do not meet any of the criteria for  
Serious. 
 
10.4 
Adverse Events and Laboratory Values of Special Interest 
 
Adverse events of special interest are to be reported using the same time line as 
Serious Adverse Events, even if they do not meet any of the seriousness criteria: 


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1. Any gastrointestinal and non-gastrointestinal perforation, leakage, fistula 
formation, and abscess. In such case, the following additional information 
need to be collected, documented on the eCRF page and forwarded to 
Boehringer Ingelheim: 
 Location/extent of abdominal tumor magnifications. 
 Imaging and reports (CT, ultrasound, endoscopy, pathology, etc.). 
 Prior surgery (location, wound healing complications). 
 Concomitant diseases with GI involvement (e. g. Crohn’s, vasculitis, 
tuberculosis, diverticulitis). 
2. Elevated transaminases: based on laboratory values. 
(i) ALT and/or AST > 5x ULN without bilirubin elevation. 
(ii) ALT and/or AST > 3x ULN with bilirubin > 1.5x ULN. 
(iii) Occurrence of at least two (2) elevated results no more than 2 weeks apart 
that is not considered to be an adverse event.  
 
In such case, the following additional information needs to be collected, 
documented as an adverse event or medical history if applicable, and included on 
the Boehringer Ingelheim SAE reporting form:  
 Hepatic tumor involvement. 
 Gilbert syndrome. 
 Viral hepatitis (e.g., Hepatitis A; B; C; EBV; CMV). 
 Alcohol and/or autoimmune hepatitis. 
 Hepatobiliary disorders (e.g., gallstones). 
 Vascular hepatitis conditions (e.g., portal vein thrombosis, right heart failure). 
 Recent alcohol consumption. 
 Recent intake of hepatotoxic compounds (including steroids). 
 Other etiology. 
 
Medical evaluation of these results and clinical documentation should be 
provided. 
 
10.5  Medication Errors 
 
Generally, medication errors are the result of administration or consumption of 
the wrong product, by the wrong subject, per the wrong route, at the wrong time 
or at the wrong dosage strength, due to human error. FDA and EMEA have 
adopted risk management guidance documents suggesting collection and review 
of medication errors in pre-approval clinical trials. The purpose of collecting and 
reviewing medication errors occurring in pre-approval is mainly to determine 
whether medication errors can be prevented prior to or after market approval. 
That is, the reported medication errors should be analyzed to determine whether 
clearer labeling, dosing instructions or packaging might have prevented the 
medication error. Consequently, the intention is to ensure that the improvements 
in labeling, dosing and/or packing clarity are implemented in the marketed 


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version of the product. Medication errors are reportable only as defined in the 
protocol. Follow the guidance below.  
 
a. For studies with two or more treatment arms (e.g., double blind studies), the 
administration or consumption of the unassigned treatment is always a 
reportable medication error.  
b. Administration of an expired product should be considered as a reportable 
medication error when associated with an AE, or if otherwise appropriate, 
please define for your study. 
c. For parenteral products, define reportable errors involving rate of 
administration and reconstitution and dilution, including use of appropriate 
diluent and the time frame in which test article should be used after 
reconstitution and/or dilution. 
d. For vaccines and biologics, define in detail reportable errors related to storage 
or refrigeration requirements. 
 
All AEs and SAEs must be handled as specified in this protocol whether or not 
they are associated with a medication error. A medication error associated with an 
SAE (including overdose, inadvertent exposure, and/or accidental exposure) will 
be reported with the SAE on the SAE form. All other medication errors will be 
reported by faxing the Clinical Study Medication Error Incident Report form to 
the fax number indicated in the Emergency Contacts section under separate cover. 
 
10.6 
Progressive Disease 
 
Natural progression or deterioration of the malignancy under study (including 
new sites of metastasis and death due to disease progression) should be recorded 
as part of the efficacy evaluation and should not be reported as AEs or SAEs. 
 
Signs and symptoms clearly associated with the disease under study should NOT 
be reported as AEs unless they are any one of the following: 
 Newly emergent (i.e., not previously observed in the subject).  
 Judged by the investigator to be unusually severe or accelerated.  
 Judged by the investigator to represent exacerbation of disease-related signs 
and symptoms to be caused directly by the study drug. 
 
If there is reasonable uncertainty about an AE being caused by disease 
progression, it should be reported as an AE or SAE as appropriate. 
 
10.7 
Death on Study 
 
If a patient dies while on study, permission for autopsy will be sought by the treating 
doctor.  This information, when available, will be used in correlation with the clinical 
data.  
 
 


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10.8 
Other Reportable Information 
 
Certain information will be considered as SAEs for regulatory reporting purposes, 
and must be recorded, reported, and followed up as indicated for an SAE.  This 
includes exposure to the test medication in the following:  
 Pregnancy. If a pregnancy is confirmed, use of the test article must be 
discontinued immediately.    
 Lactation.  
 Overdose.  
 Inadvertent or accidental exposure  
 
10.9 
Pregnancy Guidelines 
 
During the course of the trial, all female patients of childbearing potential should 
be instructed to contact the treating physician immediately if they suspect they 
might have conceived a child. In addition, a missed or late menstrual period 
should be reported to the treating physician. If a female patient, or an investigator, 
suspects a pregnancy prior to administration of study drugs, the study drugs must 
be withheld until the results of a pregnancy test are available. If pregnancy is 
confirmed the patient must not receive study medications and must be withdrawn 
from the study. All supporters of the study will be informed if a pregnancy occurs. 
 
Throughout the entire pregnancy, additional contact should be made with the 
patient and in some cases with the healthcare provider, to identify spontaneous 
abortions and elective terminations, as well as any medical reasons for elective 
termination. In addition, the study investigator should include perinatal and 
neonatal outcome. Infants should be followed for a minimum of 8 weeks.  
 
If a male patient is suspected of having fathered a child while on study drugs, the 
pregnant female partner must be notified and counseled regarding the possible 
risk to the fetus. In addition, the treating physician must follow the course of the 
pregnancy, including prenatal and neonatal outcome. Infants should be followed 
for a minimum of 8 weeks.  
 
All serious adverse event reports relating to the pregnancy, including spontaneous 
abortion, elective abortion and congenital anomalies, should be forwarded to the 
FDA and a copy sent to all supporters. 
 
Any pregnancy that occurs during study participation should be reported.  To 
ensure patient safety each pregnancy must also be reported to Dr. Angeles Secord, 
the sponsor-investigator within 24 hours of learning of its occurrence. If the 
pregnancy is associated with a SAE then the pregnancy should be reported to BI 
Unique Entry Point within ten (10) calendar days upon receipt of the initial and/or 


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follow-up information.  The pregnancy should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of birth, and the 
presence or absence of any birth defects, congenital abnormalities or maternal and 
newborn complications. 
 
10.10  Recording Adverse Events   
 
Classification of Adverse Events  
**AEs that do not meet any of the criteria for serious should be regarded as 
non-serious AEs.  The terms “severe” and “serious” are not synonymous. 
Severity (or intensity) refers to the grade of a specific adverse event (e.g., mild; 
moderate; or severe).   
Ex. A severe rash is not likely to be an SAE. Likewise, a severe headache is not 
necessarily an SAE.  However, mild chest pain may result in a day’s 
hospitalization and thus is an SAE. 
  
 
“Serious” is a regulatory definition (see above) and is based on subject or event 
outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or functioning. Seriousness (not severity) serves as the guide for 
defining regulatory reporting obligations from the Sponsor to applicable 
regulatory authorities. Severity and seriousness should be independently assessed 
when recording AEs and SAEs on the CRF.  
 
Collection of complete information concerning SAEs is extremely important. Full 
descriptions of each event will be followed. Thus, follow-up information which 
becomes available as the SAE evolves, as well as supporting documentation (e.g., 
hospital discharge summaries and autopsy reports), should be collected 
subsequently, if not available at the time of the initial report, and immediately 
sent using the same procedure as the initial SAE report. 
 
The investigator must categorize the severity of each adverse event according to 
the following guidelines: 
 
Criteria: 
NCI toxicity criteria will be followed.  Special attention will be paid to 
gastrointestinal, non-gastrointestinal perforation, leakage, fistula formation, 
abscess, and elevated transaminases.   
 
Mild:    
 
Grade I NCI Common Toxicity 
Moderate:   
 
Grade II NCI Common Toxicity 
Moderately   
Severe:  Grade III Common Toxicity 
Severe:   
 
Grade IV NCI Common Toxicity 
Death:   
 
Grade V NCI Common Toxicity 
 
If the event is not found in the NCI Common Toxicity table, the adverse event 
will be scored using 5 grades: 


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Grade 1 
 
Causing no limitation of usual activities 
 
 
Grade 2 
 
Causing some limitation of usual activities 
 
 
Grade 3 
 
Causing some inability to carry out usual activities 
 
 
Grade 4 
 
Causing life-threatening or disabling toxicity 
 
 
Grade 5 
 
Causing death 
 
NCI Common Toxicity for Adverse Event Grading (Severity) Chart v4.0  
Grade 
Severity (Intensity) 
Alternative Description  
1 
Mild; asymptomatic or mild symptoms; 
clinical or diagnostic observations only; 
intervention not indicated. 
Transient or mild discomfort (< 48 hours); 
no interference with the subject’s daily 
activities; no medical intervention/therapy 
required 
2 
Moderate; minimal, local or noninvasive 
intervention indicated; limiting age-
appropriate instrumental ADL* 
Mild to moderate interference with the 
subject’s daily activities; no or minimal 
medical intervention/therapy required 
3 
Severe or medically significant but not 
immediately life-threatening; 
hospitalization or prolongation of 
hospitalization indicated; disabling; 
limiting self-care ADL** 
Considerable interference with the subject’s 
daily activities; medical intervention/therapy 
required; hospitalization possible 
4 
Life-threatening consequences; urgent 
intervention indicated. 
 
Extreme limitation in activity; significant 
medical intervention/therapy required, 
hospitalization probable 
5 
 Death related to AE 
Death related to AE 
 
Causal relationship of adverse event 
Medical judgment should be used to determine the relationship, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge 
or re-challenge, confounding factors such as concomitant medication, 
concomitant diseases and relevant history. Assessment of causal relationship must 
be recorded for each adverse event.  
Causality will be reported as either “Yes” or “No”. 
 
Yes: 
There is a reasonable causal relationship between the investigational 
product administered and the AE.  
No: 
There is no reasonable causal relationship between the investigational 
product administered and the  AE.  
 
10.11 Procedures For Reporting 
 
Reporting of Adverse Events: 
Upon inclusion into a trial, the patient’s condition is assessed (e.g., documentation 
of history/concomitant diagnoses and diseases), and relevant changes from 
baseline are noted subsequently. 


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All adverse events, serious and non-serious, occurring during the course of the 
clinical trial (i.e., from signing the informed consent onwards through the trial 
defined follow-up period) will be collected, documented and reported by the 
investigator. For each adverse event, the investigator will provide the onset date, 
end date, intensity, treatment required, outcome, seriousness, and action taken 
with the investigational drug. The investigator will determine the expectedness of 
the investigational drug to the AEs as defined in the Listed Adverse Events 
section of the Boehringer Ingelheim’s Investigator Brochure for the Product.  
Serious Adverse Events (SAEs) and unknown reactions or unexpected events that 
occur in the course of any patient’s treatment on study or within 30 days 
following cessation of treatment should be reported to the Principal Investigator 
and the lead site/Sponsor (Dr. Angeles Secord/Duke University) within 24 hours 
of learning of the event. SAEs must be recorded using the Boehringer Ingelheim 
SAE Reporting Form, found in the Procedure Manual.    
 
Additional information and/or corrections may be submitted as they are obtained.  
All SAEs must be followed through resolution or stabilization.  
 
All adverse events, regardless of severity, and whether or not ascribed to the study 
drug administration, will be recorded in the appropriate section of the Case Report 
Form. Patients withdrawn from the study due to AEs will be followed by the 
Investigator until the outcome is determined and, when appropriate, additional 
written reports and documentation will be provided. 
 
The DCI Safety Desk at Duke University should be contacted when reporting an 
SAE and should be faxed or emailed to the following: 
 
DCI Safety at Duke University (on behalf of Dr. Angeles Alvarez Secord) 
Phone:   (919) 681-9538 
Fax:   (919) 681-9357 
Email:  dcccsafe@dm.duke.edu 
 
If this person cannot be reached within 24 hours, the Principle Investigator and/or 
Chief Medical Officer should be contacted:  
 
Dr. Angeles Alvarez Secord 
Duke University Medical Center 
Room 25172, Morris Building 
Durham, NC 27710 
Phone:  (919) 684-3765 
Fax:      (919) 684-8719  
 
Pager    (919) 970-0087 
 
Minimum Criteria for Reporting: 
Information for final description and evaluation of a case report may not be 
available with the required time frames for reporting. Nevertheless, for regulatory 


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purposes, initial report shall be submitted within the prescribed time as long as the 
following minimal requirements are met:  
 
The initial report for each SAE should include at minimum the following 
information: 
 Protocol # and title. 
 Regulatory Seriousness criteria if applicable (i.e., death; life-threatening; 
hospitalization; etc.). 
 Patient initials, study identification number, sex, and age. 
 Date the event occurred (onset). 
 Severity (intensity) - see chart. 
 Description of the SAE. 
 Dose level and cycle number at the time the SAE occurred. 
 Description of the patient’s condition. 
 Indication whether the patient remains on study. 
 Causality (relationship of the event to the study medication). 
 
Follow-up information may include: 
 Severity (intensity) - see chart. 
 Duration of the event. 
 Treatment and/or medication(s) given for the event, if any. 
 Brief narrative summarizing the relevant details of the event.  
 Action taken to study medication. 
 Concomitant medications.  
 Event outcome with dates should be communicated to the Duke as soon as 
possible. 
 When applicable and requested, information from relevant hospital records 
(e.g., discharge summary, autopsy reports, etc.).  
 
Upon receipt of the Serious Adverse Event Report Form by Duke, DCI Safety 
will:  
a. Notify Dr. Secord of the event via email and obtain an assessment for each 
event via the SAE Review Form.  
b. Fax the form to Boehringer Ingelheim Global Pharmacovigilance Center US 
(GPV Centre US) at 1-203-837-4329  
 
All adverse events, regardless of severity, and whether or not ascribed to the study 
drug administration, will be recorded in the appropriate section of the Case Report 
Form. Patients withdrawn from the study due to AEs will be followed by the 
Investigator until the outcome is determined and, when appropriate, additional 
written reports and documentation will be provided. 
 
10.12 Regulatory (Expedited) Reporting 
 


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As per 21 CFR 312.2(a), this study must be conducted under an IND. Dr. Angeles 
Alvarez Secord of Duke University Medical Center will be the sponsor-
investigator for this study and will hold the IND. Thus, Dr. Secord will serve as 
both a principal investigator and the regulatory sponsor of this multi-center study. 
 
Per 21 CFR 312.32(c), the sponsor will notify the FDA and all participating 
investigators in a written IND Safety Report of: 
(A) Any adverse event associated with the use of the drug  
(B) That is both serious and unexpected (see above for definitions). 
 
 Each notification shall be made as soon as possible and in no event later than 
15 calendar days after the sponsor's initial receipt of the information. Each 
written notification may be submitted on FDA Form 3500A (MedWatch form) 
or in a narrative format. In each written IND safety report, the sponsor shall 
identify all safety reports previously filed with the IND concerning a similar 
adverse experience, and shall analyze the significance of the adverse 
experience in light of the previous, similar reports.  
 The sponsor shall also notify the FDA by telephone or by fax of any 
unexpected fatal or life-threatening experience associated with the use of the 
drug as soon as possible but no later than 7 calendar days after the sponsor's 
initial receipt of the information. 
 Follow-up information to a safety report shall be submitted as soon as the 
relevant information is available. 
 Additionally, adverse events will be reported to the FDA in an annual report 
according to annual report requirements.  Events will be reviewed and 
reported to the Duke IRB according to local IRB guidelines. 
 
10.13  Data and Safety Monitoring 
 
Audits and Inspections  
Authorized representatives of Duke University Health System (DUHS), the 
Institutional Review Board (IRB), and Cancer Protocol Committee (CPC) may 
perform audits or inspections, including source data verification. The purpose of 
such an audit or inspection is to systematically and independently examine study-
related activities and documents to determine whether these activities were 
conducted, and data were recorded, analyzed, and accurately reported according to 
the protocol, Good Clinical Practice (GCP), guidelines of the International ICH, 
and any applicable regulatory requirements.  
Study Monitoring Requirements  
This study will be monitored by the sponsor-investigator and will be independently 
monitored and assessed in accord with the Duke Cancer Institute (DCI), NCI-
approved Data and Safety Monitoring Plan.  
 
In terms of internal review, the sponsor-investigator is responsible for monitoring 
the protocol to ensure that the investigation is conducted in accordance with the 


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general investigational plan and protocol (21 CFR 312.50), and all applicable 
regulatory requirements. The sponsor-investigator will continuously monitor and 
tabulate adverse events and will also monitor the conduct, data, and safety of this 
study to ensure that:  
 Interim analyses occur as scheduled;  
 Stopping rules for toxicity and/or response are met;  
 Risk/benefit ratio is not altered to the detriment of the subjects;  
 Appropriate internal monitoring of adverse events and outcomes is done;  
 Over-accrual does not occur;  
 Under-accrual is addressed with appropriate amendments or actions;  
 Data are being appropriately collected in a reasonably timely manner.  
 
External review begins with the initial scientific review by the CPC. The CPC 
assigns the degree of monitoring to commensurate with the type of intervention, 
phase, endpoints, degree of risk, size, and complexity of the protocol. The 
primary site, Duke, will be monitored by the DCI Safety Oversight Committee 
and the DCI Monitoring Team. The minimum level of monitoring to be 
determined by the DCI Monitoring Team may include the following: routine 
monitoring after the first 3 subjects have been enrolled, followed by annual 
monitoring of 1-3 subjects until closed to enrollment or subjects are no longer 
receiving study drug or other interventions that are more than minimal risk. 
Additional monitoring may be prompted by findings from monitoring visits, 
unexpected frequency of serious and/or unexpected toxicities, or other concerns.  
CPC conducts annual progress reviews focusing on protocol prioritization, 
accrual and scientific progress while the study is open to enrollment, excluding 
pediatric protocols.  
 
DUMC will serve as the coordinating site for this multi-site study.   
The DUHS sponsor-investigator is responsible for providing data and safety 
monitoring oversight for participating external sites. The Duke Gynecologic 
Oncology team will be monitoring the external sites. A site monitoring visit will 
be planned after the first 3 subjects are enrolled. If a physical site visit is 
logistically impossible, a copy of redacted source documents will be obtained 
from the external site and the subject data will be monitored by designated 
personnel. Subsequent monitoring will be arranged based on pace of accrual, 
accrual status, and results of previous monitoring. 
 
The DCI Safety Oversight Committee (SOC) will conduct annual data and safety 
monitoring. SOC reviews data provided by the sponsor-investigator pertaining to 
safety data, toxicities and new information that may affect subject safety or 
efficacy.  All safety concerns are communicated to the sponsor-investigator and 
will be communicated to the IRB and CPC as necessary.  
 
10.14  Management Forms 
 


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The Duke Cancer Institute IT (DCI-IT) group will be responsible for the 
management of clinical data utilizing the caBIG-compliant platform, known as 
the Cancer Central Clinical Database (C3D), with local implementation at Duke. 
C3D is the Clinical Trials Database and a key component of NCI's Clinical Trial 
Suite (CTS). Oracle Clinical serves as the foundation of C3D by supporting 
clinical trial definition, data capture, multiple site reporting, data definition, and 
usage standardization. Trial definition is based on Common Data Elements (CDE) 
from an existing library of template Case Report Forms. Oracle Clinical's RDC 
Onsite system provides a user-friendly HTML-based interface that allows local 
and remote data entry and electronically confirms source data verification 
(electronic signature). C3D also provides researchers with web-based tools for ad-
hoc querying, reporting and analysis of clinical data. DCI-IT has been a C3D 
adopter (locally hosted) for several years, and is the home of the caBIG Clinical 
Trials Management Systems Knowledge Center. Through this enhanced 
relationship, DCI-IT will have access to a wide range of tools and resources, 
including case report form templates, the Common Data Elements dictionary, and 
other global library elements. This will enable us to construct the necessary data 
collection tools quickly. 
 
The process relies on the clinical site to originate data and correct any clinical 
data inconsistencies that are not included in the point of entry validation. A 
variety of quality control routines which are run regularly will spawn queries that 
will need to be addressed by the clinic in order for the record to be closed and 
made available for the analytic dataset. This cycle is key to the process, as 
depicted below: 
 
 
 
 
 
 
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Electronic Case Report Forms (eCRF) will be generated from NCI/CaBIG and 
other templates and Common Data Elements (existing and specifically curated), 
most of which already exist in the caBIG C3D library. 
 
Data entry via RDC Onsite is encrypted and secure. Communications between 
clinical sites that require this level of security will be handled via Tumbleweed’s 
MailGate product (a 128 bit encrypted and authenticated e-mail system), as 
encapsulated through Duke’s implementation of Microsoft’s Outlook/Exchange 
Server product. 
 
The eCRFs shown in Table 8 must be completed for all patients registered: 
 
Registration/
Enrollment
Oracle Clinical 
Remote Data 
Capture (RDC) 
System
Patient
Screening
Enrolled
Project Coord.
Review
Oracle Clinical 
Discrepancy 
Management
     Pass
        Fail
Analytic
Datasets
Statistics
Data Archive
Screening Log
(to Repository)
Data and Safety 
Monitoring Board
Steering
Committee
E-mail
Confirmation
Data 
Repository
Patient 
Tracking 
System


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Table 8. Required eCRFs per each patients 
Form and Reports 
Due within 
Copies 
Comments 
Weeks 
Event 
Initial On-Study Form 
4 
Registration 
3 
 
Pre-Treatment Summary 
Form 
4 
Registration 
3 
The “prior therapy” 
form does not need to 
be completed 
Solid Tumor Evaluation 
Form 
4 
Registration 
3 
 
Primary disease: 
Pathology Form 
Pathology Report  
Slides  
 
Recurrent or Persistent 
Disease: 
Pathology Form 
Pathology Report 
Slides  
 
6 
6 
6 
 
 
6 
6 
6 
 
Registration 
Registration 
Registration 
 
 
Registration 
Registration 
Registration 
 
3 
4 
 
 
 
3 
4 
 
 
 
 
 
 
 
 
Cycle Drug Dose Form 
2 
Completion of each 
cycle of therapy 
3 
 
Solid Tumor Evaluation 
Form 
2 
Clinical response 
assessment 
3 
 
Common Toxicity 
Reporting Form 
2 
Beginning of each 
subsequent cycle 
3 
 
 
Treatment Completion 
Form 
2 
Completion of study Rx 
and change in Rx 
3 
 
Follow-up Form 
2 
Disease progression; 
death; normal follow-up 
3 
Quarterly for 2 years, 
semi-annually for an 
additional year for a 
total of 3 years 
 


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10.15 Laboratory Data Management 
 
Samples will be tracked utilizing caTissue v1.2, an NCI caBIG-developed 
platform. caTissue has been installed at Duke, and has some pilot implementation 
projects underway.  Data from this system will provide a near real-time 
accounting of all samples, shipping and results from contracted lab, and provide 
views of the data that may be integrated with views from the eCRF for reporting 
purposes. As with other data in the system, expectations for the presentation of 
sample information will be set by the patient milestone (initiation and follow-up 
visit activity), flagging inconsistencies and missing sample information at regular 
intervals.  
 
10.16 Regulatory Compliance 
 
Both systems are built and deployed in accordance with HIPAA and 21 CFR Part 
11, with proper system testing and validation. Application development follows a 
strict Software Development Life Cycle (SDLC) model, ensuring accurate 
deployment of all data collection tools and systems. 
 
 
 
ANALYSIS
DESIGN
DEVELOPMENT
DEPLOYMENT
P R O G R A M S
UNIT TEST
Failure
Approval
SYSTEM 
TEST
Failure
Approval
Software Design 
Specification (SDS)
Program 
Specification
design 
changes
User Requirement 
Specification (URS)
Software Requirement 
Specification (SRS)
requirement 
changes
Test Specification
Defect Log
Unit Test Plan 
(UTP)
System Test Plan 
(STP)
Defect Log


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
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11.0     STATISTICAL CONSIDERATIONS 
 
The primary objective of this study to assess the activity of the study agent as measured 
by the proportion of patients who survive progression-free for at least 6 months after 
initiating study therapy in patients with bevacizumab-resistant persistent or recurrent 
epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.  
 
11.1 
The study plan is a single arm, non-randomized, 2-stage phase II clinical trial. 
 
11.2 
Parameters employed to evaluate treatment efficacy and toxicity are: 
 
11.2.1 Primary Endpoints: 
 
11.2.1.1The proportion of patients who survive progression-free for at 
least 6 months. 
 
11.2.2 Secondary Endpoints: 
 
11.2.2.1 The proportion of patients who have objective tumor response 
(complete or partial). 
11.2.2.2 Frequency and severity of adverse effects as assessed by the 
active version of the NCI Common Toxicity Criteria. 
11.2.2.3 Duration of progression-free survival and overall survival. 
 
11.2.3 Translational Endpoints: 
 
11.2.3.1To measure baseline levels of VEGF and correlate with treatment 
outcome. 
11.2.3.2 To measure baseline and on treatment levels of additional growth 
factors (listed in section 2.5) that may be co- or counter- regulated 
with VEGF and correlate with response to treatment.  
11.2.3.3 To measure baseline and on treatment levels of coagulation and 
endothelial cell activation markers that may predict for thrombotic 
or bleeding risks related to treatment. 
 
11.3 
A total of up to 56 will be accrued at the rate of about 5 patients per month. If the 
6-month progression-free survival rate is observed to be ≥ 0.20 the trial will be 
considered a success. Progression-free survival will be defined as the length of 
time from on-study to disease progression or death, whichever comes first. The 
study will use a 2-stage optimal design [15] to test the null hypothesis that the 6-
month PFS rate is ≤ 13% against the alternative hypothesis that this rate is ≥ 27%. 
The targeted accrual for the first stage will be 27 eligible and evaluable patients 
but permitted to range from 27 to 31 for PFS determination and administrative 
reasons. The critical value for the number of patients who survive progression-
free for 6 months will be based on the first 27 patients who are both eligible and 
evaluable for 6 month PFS. An interim analysis will be done after accrual of these 
patients (Stage 1). After the accrual of these patients, further accrual will be 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
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Page 56 of 78 
 
suspended until all patients have been followed for at least 6 months or until at 
least 4 patients (15%) are found progression-free at 6 months. If 3 or less of the 
patients are progression-free at 6 months, the therapy will be deemed ineffective. 
If 4 or more of the patients are progression-free at 6 months, another 29 patients 
will be accrued. If 10 or less of the 56 patients are progression-free at 6 months, 
the therapy will be deemed ineffective. If at least 11 patients (20%) are 
progression-free at 6 months, the therapy will be deemed effective and worthy of 
further research. These stopping rules are illustrated in the table below.  
 
Stage 
 Sample Size 
Minimum number of patients who must be progression-free 
at 6-months for therapy to be considered effective 
1 
27 
4 (15%) 
2 
56 
11 (20%) 
 
This design has a one-sided Type I error of 0.10, a power of 0.90. The 
probabilities of early termination given the null and the alternative are 0.54 and 
0.04, respectively. If exactly 11 responses are observed, the exact 80% confidence 
interval will be [0.13, 0.28]. If even one patient drops out or is lost-to-follow-up 
before progression, then we will not be able to tabulate the number of patients 
who are progression-free at 6 months. In this case, we will calculate the Kaplan-
Meier curve and focus on the probability of surviving to 6 months as calculated 
by the Kaplan-Meier method. We will call this trial a success only if the lower 
10% confidence bound of this probability is greater than 0.13.  
 
Statistical Analysis of Secondary Aims 
 
Secondary Aim 1 is to determine the proportion of patient who has an objective tumor 
response (complete or partial). To address this aim all responses will be tabulated: 
complete response, partial response, stable disease, progressive disease.  
 
Secondary Aim 2 is to determine the frequency and severity of adverse events. To 
address this aim, all toxicities will be tabulated by type and grade.  
 
Secondary Aim 3 is to estimate the distribution of PFS and overall survival (OS). PFS 
was defined above. OS is defined as the length of the interval from on-study to death due 
to any cause. Both PFS and OS will be estimated with the Kaplan-Meier curve. In 
addition, we will compare the PFS of patients who had prior bevacizumab resistance with 
that of patients who had prior bevacizumab and chemotherapy resistance. Specifically, 
within each of these two groups, we will describe PFS with a Kaplan-Meier curve and the 
6-month PFS rate (with its 80% confidence interval). We expect the latter group to have 
worse PFS than the former. 
 
Secondary Aim 4 is to elicit patient preferences for outcomes of ovarian cancer treatment. 
The distribution of rank preferences for each general attribute will be described using 
mean ranks as well as the proportions of times each concept was ranked as most 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
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Page 57 of 78 
 
important, second most important, third most important, fourth most important, and least 
important.  In the token ranking exercise, to describe the allocations of tokens across the 
general attributes, we will report means, standard deviations, and median numbers of 
tokens for each attribute.  To examine consistency between token allocations with rank 
preferences, we will reverse order the rank preferences such that higher ranks correspond 
to higher preferences and compute correlation coefficients.  We will test whether 
correlations between ranks and token counts differ between attributes using Spearman 
rank tests.  We will also examine the proportion of patients who provided the highest 
token counts to their most preferred attribute and vice versa. In the ratings exercise, to 
describe respondents’ ratings on the 5-point Likert scale representing level of concern 
with each attribute included in the DCE, we will report frequencies of ratings for each 
attribute as well as means to provide a summary measure.   
 
Secondary Aim 5 is to characterize baseline quality of life and cancer-related symptoms. 
We will use descriptive characteristics to summarize baseline characteristics for the study 
cohort enrolled at Duke.  These characteristics will include summary scores from the 
NFOSI-18 and the FACT-GOG-Ntx.  We will report means, medians, and standard 
deviations for continuous variables and counts and proportions for categorical variables.  
  
 
Statistical Analysis of Translation Research Objectives 
 
The association of PFS with baseline values of VEGF (continuous) will be tested with the 
proportional hazards model; VEGF will also be dichotomized at a clinically meaningful 
cut point and a Kaplan-Meier plot of PFS according to VEGF level will be made. An 
analogous procedure will be used to examine the association of PFS with baseline values 
of the growth factors listed Section 2.5.  
 
 
 
 
 
 
 
 
 
 
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BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
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12.0 
BIBLIOGRAPHY 
 
1. ten Bokkel Huinink, Gore M, Carmichael J, et al. Topotecan versus paclitaxel for the 
treatment of recurrent epithelial ovarian cancer. J Clin Oncol. 1997; 15: 2183-93. 
2. Kavanagh JJ, Kudelka AP, de Leon CG, et al. Phase II study of docetaxel in patients with 
epithelial ovarian carcinoma refractory to platinum. Clin Cancer Res. 1996; 2: 837-42. 
3. Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in 
persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a 
Gynecologic Oncology Group Study. J Clin Oncol.  2007; 25: 5165-7.  
4. Garcia AA, Hirte H, Fleming G, et al. Phase II clinical trial of bevacizumab and low-dose 
metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, 
Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol. 2008; 26: 76-
8. 
5. Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients 
with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007; 
25: 5180-6. 
6. Burger RA, Brady MF, Bookman MA, Walker JL, Homesley HD, Fowler J, Monk BJ, 
Greer BE, Boente M, Liang SX. Phase III trial of bevacizumab (BEV) in the primary 
treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), 
or fallopian tube cancer (FTC): a Gynecologic Oncology Group study J Clin Oncol. 
2010; 28: abstract LBA1. 
7. Perren T, Swartz AM, Pfisterer J, Ledermann J, Lortholary A, Kristensen G, Carey M, 
Beale P, Cervantes A, Oza A, on behalf of GCIG ICON7 collaborators. A phase III 
randomised gynaecologic cancer intergroup trial of concurrent bevacizumab and 
chemotherapy followed by maintenance bevacizumab, versus chemotherapy alone in 
women with newly diagnosed epithelial ovarian (EOC), primary peritoneal (PPC) or 
fallopian tube cancer (FTC). Ann Oncol 2010; 21: abstract LBA4. 
8. Tang P, Cohen SJ, Bjarnason GA, et al. Phase II Trial of aflibercept (VEGF Trap) in 
previously treated patients with metastatic colorectal cancer: A PMH Phase II 
Consortium Trial.  J Clin Oncol. 2008; 26 (May 20 Suppl; abstr 4027). 
9. Grothey A, Sugrue MM, Purdie DM, et al. Bevacizumab beyond first progression is 
associated with prolonged overall survival in metastatic colorectal cancer: results from a 
large observational cohort study (BRiTE) J Clin Oncol.  2008; 26: 5326-34. 
10. Boehringer Ingelheim GmbH Investigator’s Brochure. Doc. No: U02-1482-11 Project 
No. 1199.P1/1199.P2/1199.P4/1199.P5 Date of IB: 11 April 2011 Version No. 11. 
11. Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: Triple angiokinase inhibitor with 
sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008; 68: 4474-82. 
12. Ledermann JA, Rustin GJ, Hackshaw A, et al. A randomized phase II placebo-controlled 
trial using maintenance therapy to evaluate the vascular targeting agent BIBF 1120 
following treatment of relapsed ovarian cancer.  J Clin Oncol. 2011; 29: 3798-3804. 
13. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST Guideline (version 1.1). Eur J Cancer.  2009; 45: 228-47. 
14. Rustin GJS, Quinn M, Thigpen T, et al. New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors (Ovarian Cancer) J Natl Cancer Inst. 2004; 96: 487-8.  
15. Simon R.  Optimal two-stage designs for Phase II clinical trials. Controlled Clin Trials 
1989; 10: 1-10. 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
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16. Meropol NJ, Egleston BL, Buzaglo JS, Benson AB, 3rd, Cegala DJ, Diefenbach MA, et 
al. Cancer patient preferences for quality and length of life. Cancer 2008 Dec 
15;113(12):3459-66. 
17. Zafar SY, Alexander SC, Weinfurt KP, Schulman KA, Abernethy AP. Decision making 
and quality of life in the treatment of cancer: a review. Supportive care in cancer : official 
journal of the Multinational Association of Supportive Care in Cancer 2009 
Feb;17(2):117-27. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
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Appendix I    
Percent of Normal Bone Marrow Irradiated Using Standard Radiation Ports 
 
 
Anatomic Site  
 
 
 
 
% of Total Red Marrow 
 
 
 
Head  
 
 
 
 
 
 
 
13.1 
 
Cranium  
 
 
 
 
 
 
11.9 
 
Mandible  
 
 
 
 
 
 
1.2 
 
 
Upper Limb Girdle 
 
 
 
 
 
 
8.3 
 
2 Humeri (head and neck) 
 
 
 
 
1.9 
 
2 Scapulae  
 
 
 
 
 
 
4.8 
 
2 Clavicles 
 
 
 
 
 
 
1.6 
 
 
Sternum 
 
 
 
 
 
 
 
2.3 
 
 
Ribs 
 
 
 
 
 
 
 
 
7.9 
 
 
Vertebrae 
 
 
 
 
 
 
 
42.3 
 
Cervical 
 
 
 
 
 
 
 
3.4 
 
Thoracic  
 
 
 
 
 
 
14.1 
 
Lumbar 
 
 
 
 
 
 
 
10.9 
 
Sacrum 
 
 
 
 
 
 
 
13.9 
 
 
Lower Limb Girdle 
 
 
 
 
 
 
26.1 
 
 
2 Os Coxae 
 
 
 
 
 
 
22.3 
 
 
2 Femoral heads and necks 
 
 
 
 
  3.8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adapted from:  Ellis R.E. The distribution of active bone marrow in the adult. Phys Med Biol 
5:255, 1961. 
 


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Appendix II   
Patient Nintedanib Capsule Diary 
Subject ID #____________ 
Subject Initials____________ 
Cycle #___________ 
 
Date 
Study 
Day 
Morning 
dose 
Evening 
dose 
Comments1 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
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25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 1Changes to concomitant medications can be written in the comment section. 
 
Patient__________________________Reviewer_____________ 
 


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Appendix III    
Investigator Signature Page 
 
 
Product:  Nintedanib (BIBF 1120) 
 
Protocol: PHASE II EVALUATION OF NINTEDANIB (BIBF 1120) IN THE TREATMENT 
OF BEVACIZUMAB-RESISTANT PERSISTENT OR RECURRENT EPITHELIAL 
OVARIAN, FALLOPIAN TUBE, OR PRIMARY PERITONEAL CARCINOMA 
 
Investigator’s Agreement 
 
I have read the attached protocol entitled “PHASE II EVALUATION OF NINTEDANIB (BIBF 
1120) IN THE TREATMENT OF BEVACIZUMAB-RESISTANT PERSISTENT OR 
RECURRENT EPITHELIAL OVARIAN, FALLOPIAN TUBE, OR PRIMARY PERITONEAL 
CARCINOMA”, and agree to abide by all provisions set forth therein. 
 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice and applicable FDA regulations/guidelines set forth in 21 CFR Parts 11, 
50, and 56. 
 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation. 
 
 
______________________________    
Signature 
 
 
 
                                                                             
______________________________  
 
 
_______________________ 
Name of Principal Investigator 
 
 
 
 Date (DD Month YYYY) 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
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Page 64 of 78 
 
Appendix IV    
Clinical Investigator Financial Disclosure Form 
06/23/2010 
 
This information below is provided in accordance with 21 CFR Part 54 in regard to the following clinical study. 
 
Pharmaceutical Company:  
Boehringer Ingelheim  
 
Investigating Product:  
 
Nintedanib (BIBF 1120) 
 
Title of Study/Protocol:  
Phase II evaluation of Nintedanib (BIBF 1120) in the treatment of bevacizumab-
resistant or recurrent epithelial ovarian, fallopian tube, or primary peritoneal 
carcinoma.  
 
 
_________________________________ 
Investigator/Sub-Investigator (Please Print) 
 
Yes 
  
 
No 
 
Do you, your spouse or dependent children have a financial arrangement with Boehringer Ingelheim, 
whereby the value of compensation to you, your spouse or dependent children could be influenced by the 
outcome of the study? This includes compensation that could be greater for a favorable clinical result, 
compensation in the form of an equity interest in Boehringer Ingelheim or compensation tied to sales of 
the product tested in the above study such as a royalty interest. If yes, the nature of the financial 
arrangement is as follows: 
 
Yes 
 
 
No 
 
Do you, your spouse or dependent children have a proprietary interest in Nintedanib (BIBF 1120) such as 
patent rights or rights under a patent, trademark, copyright or licensing agreement? If yes, the nature of 
the proprietary interest is as follows: 
 
Yes 
 
 
No 
 
 
Do you, your spouse or dependent children, or any of you combined have a significant equity interest in 
Boehringer Ingelheim such as an ownership interest, stock options or any other financial interest whose 
value cannot be readily determined through reference to public prices, or any equity interest in Boehringer 
Ingelheim (if it is a publicly traded organization) exceeding $50,000, or any combination of these? If yes, 
the amount and nature of the equity interest is as follows: 
 
Yes 
 
 
No 
 
 
Have you, your spouse or dependent children, or any of you combined received payments from 
Boehringer Ingelheim in excess of $25,000, exclusive of the costs of conducting the clinical studies, such 
as honoraria, a grant or grants to fund ongoing research, compensation in the form of equipment, or 
retainers for ongoing consultation? If yes, the amount and nature of the payment is as follows: 
 
 
To the best of my knowledge, the information provided above is correct and complete. I understand that I am obligated 
to amend this statement and notify Angeles Alvarez Secord at Duke University Medical Center and Boehringer 
Ingelheim promptly if there is any change in this information during the conduct of the clinical studies listed above or 
during one year after the studies have been completed. 
 
 
 
__________________________________________________ 
Signature of Investigator 
 
 
 
________________________________ 
Date 


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    Appendix V    
 Specimen Tissue Transmittal Form 
Biomarker Flow Sheet 
 
Phase II evaluation of Nintedanib (BIBF 1120) in the treatment of bevacizumab-resistant 
persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.  
 
Insert copy of this completed form with shipment and fax to  
ATTN: DUKE – BIOMARKER at 919-668-3037 
 
Section 1: General Information 
SUBJECT 
INITIALS 
 
SUBJECT 
STUDY ID # 
 
SITE 
NAME 
Duke 
 
Section 2: Flow sheet 
DATE OF  
BIOMARKERS DRAWN 
 
CYCLE # 
 
DAY # 
 
 
EVENT 
TIME 
DRAWN 
TIME 
FROZEN 
NUMBER OF 
CRYOVIALS 
COMMENTS 
INITIALS 
Whole blood 
 
 
 
N/A 
 
 
Serum 
 
 
 
 
 
 
Plasma – EDTA 
 
 
 
 
 
 
Plasma – citrate 
 
 
 
 
 
 
Urine 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
Section 3: Shipment Information (for DUMC site, complete transfer log) 
 
DATE SHIPPED: 
 
 
_______________________________________________ 
TRACKING NUMBEROF SHIPMENT:  
 
_____________________________ 
NAME OF PERSON RESPONSIBLE FOR SHIPMENT: 
                   _____      
 
PHONE NUMBER OF PERSON RESPONSIBLE FOR SHIPMENT:  
__________  
 
 
Nintedanib (BIBF 1120) Biomarker Flow sheet v.24Jun2010 
 
 
 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
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Appendix VI    
 Specimen Tissue Transmittal Form 
Paraffin-Embedded Tumor 
 
Phase II evaluation of Nintedanib (BIBF 1120) in the treatment of bevacizumab-resistant 
persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.  
 
Insert copy of this completed form with shipment and fax to  
ATTN: DUKE – Shara Reihani at 919-684-8718 
 
Section 1: General Information 
SUBJECT 
INITIALS 
 
SUBJECT 
STUDY ID # 
 
SITE 
NAME 
 
 
Section 2: Flow sheet 
 
EVENT 
PARAFFIN-
EMBEDDED 
PRIMARY 
TUMOR 
PARAFFIN-
EMBEDDED 
METASTATIC 
TUMOR 
COMMENTS 
INITIALS 
DATE TISSUE 
INITIALLY 
OBTAINED 
 
 
 
 
INDICATE 
TISSUE BLOCK 
(TB) OR 
UNSTAINED 
SLIDES (US) 
 
 
 
 
 
If the specimen was not collected please indicate reason: (e.g., patient refused, not enough 
tumor for research, referring site won’t release tumor).______________________________ 
 
Signature: 
 
 
 
 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
Section 3: Shipment Information (for DUMC site, complete transfer log) 
 
DATE SHIPPED: 
 
 
_______________________________________________ 
TRACKING NUMBEROF SHIPMENT:  
 
___________________________ 
NAME OF PERSON RESPONSIBLE FOR SHIPMENT: 
 
 
 
 
 
PHONE NUMBER OF PERSON RESPONSIBLE FOR SHIPMENT:  
 
 
 
 
 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
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APPENDIX VII 
Protocol Deviation Form 
Protocol BIBF 1120 
 
 
Subject ID Number:   
 
 
Complete a new form for each deviation from the protocol. 
 
Date of Protocol Deviation (DD/MMM/YYYY):     
/ 
/ 
 
 
Description of Protocol Deviation: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reason for Protocol Deviation: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
What steps were taken to resolve this Protocol Deviation and prevent recurrence: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Does this deviation meet Duke IRB reporting requirements:    NO   
  Yes 
 
COMPLETED BY:   
 
 
 
  
 
/ 
/ 
 
 
 
 
 
 
 
 
 
       (DD/MMM/YYYY) 
Investigator’s Signature: 
 
 
 
  
 
/ 
/ 
 
 
 
 
 
 
 
 
 
       (DD/MMM/YYYY) 
 
Date Submitted To: 
 
 
 
  
  
       (DD/MMM/YYYY) 
 
  Duke IRB  
 
 
 
 
                          / 
/ 
 
 


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APPENDIX VIII  
 
See Attached Model Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX IX  
Study #: Pro00033060                                                                                                    Subject ID #: 
Inclusion Criteria 
Yes 
No 
N/A 
Patient signed approved Informed Consent & Authorization Form permitting release of personal 
health information. 
  
  
  
Patient is at least 18 years of age. 
  
  
  
Patient has recurrent/persistent: Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal 
Carcinoma. 
  
  
  
• Histologic documentation of the original primary tumor is required via the pathology report.  
  
  
  
The following histologic epithelial cell types are eligible: Serous, endometrioid, mucinous, or clear cell 
adenocarcinoma; Undifferentiated, mixed epithelial or transitional cell carcinoma; Brenner’s Tumor; 
Adenocarcinoma N.O.S. 
  
  
  
Patient is Bevacizumab-resistant: treatment-free interval following response to Bevacizumab 
(CR/PR/SD) of < 6 months, or progressed during treatment with Bevacizumab-containing therapy. 
  
  
  
Patient has either measurable disease, per RECIST 1.1 (at least 1 lesion, accurately measured in at least 
1 dimension) or detectable (non-measurable) disease (CA125>2x ULN + either ascites/pleural effusion 
attributed to tumor OR solid/cystic abnormalities that do not meet RECIST 1.1) 
  
  
  
• For patients with measurable disease: 
 Each lesion must be ≥ 10 mm when measured by CT, MRI, or caliper measurement by clinical 
exam. 
  
  
  
 Each lesion must be ≥ 20 mm when measured by chest x-ray.  
  
  
  
 Lymph nodes must be > 15 mm in short axis when measured by CT or MRI. 
  
  
  
For patients with measurable disease: patient has at least 1 target lesion (RECIST 1.1) to be used to 
assess response on this protocol.  
  
  
  
• Tumors in irradiated fields are non-target unless: progression documented, or biopsy confirms persistence 
≥ 90 days after completion of radiation. 
  
  
  
Patient has an ECOG Performance status of 0 or 1. 
  
  
  
Patients is free of active infection requiring antibiotics (Exception: Uncomplicated UTI). 
  
  
  
Patient has recovered from effects of recent surgery, radiotherapy, or chemotherapy. 
  
  
  
If patient had hormonal therapy directed at malignant tumor: discontinued ≥ 1 week before 
registration.  
  
  
  
• Continuation of hormone replacement therapy is permitted. 
  
  
  
If patient had therapy directed at malignant tumor (ex: immunologic agents): discontinued ≥ 3 weeks 
before registration. 
  
  
  
If patient received prior therapy with Bevacizumab: ≥ 4 weeks between discontinuation and 
treatment on this study. 
  
  
  
Patient has had 1 prior platinum-based chemotherapeutic regimen for management of primary 
disease containing Carboplatin/Cisplatin/organoplatinum compound.  May have included 
intraperitoneal therapy/high-dose therapy/consolidation/non-cytotoxic agents/biologic therapy/extended 
therapy administered after surgical/non-surgical assessment 
  
  
  
 
  
  
  
Patients are allowed to receive, but are not required to receive, two additional cytotoxic regimens (a 
total of 3 cytotoxic regimens) for management of recurrent or persistent disease Patients who have 
received only one prior cytotoxic regimen (platinum-based regimen for management of primary disease), 
must have a platinum-free interval of less than 12 months, or have progressed during platinum-based 
therapy, or have persistent disease after a platinum-based therapy. 
  
  
  
Patients must NOT have received any non-cytotoxic therapy for management of recurrent or 
persistent disease other than bevacizumab-containing regimens. Patients are allowed to receive, but are 
not required to receive, biologic (non-cytotoxic) therapy as part of their primary treatment regimen. 
 
 
 
Patient has adequate bone marrow function:  
  
  
  
• Absolute Neutrophil Count ≥ 1,500/mcl (equivalent to CTCAE v4.0 grade 1).   
  
  
  
• Platelets ≥ 100,000/mcl.  
  
  
  
• Hemoglobin ≥ 9.0 g/dL. 
  
  
  
Patient has adequate renal function: 
  
  
  
• Creatinine ≤ 1.5 x institutional upper limit of normal (equivalent to active version of NCI AE grade 1).   
  
  
  
Patient has adequate hepatic function: 
  
  
  
• Bilirubin is within normal limits (CTCAE v4.0  grade 1). 
  
  
  
• ALT/AST ≤ 1.5 x ULN (CTCAE v4.0 grade 1). If patient has liver metastases: ALT/AST ≤ 2.5 x ULN. 
  
  
  
• Alkaline phosphatase ≤ 2.5 x ULN (CTCAE v4.0 grade 1). 
  
  
  


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
   Version Date 16 August 2018 
 
Page 70 of 78 
 
Patient has adequate neurologic function: 
  
  
  
• Neuropathy (sensory and motor) ≤ CTCAE v4.0 grade 1. 
  
  
  
Patient has adequate blood coagulation: 
  
  
  
• Prothrombin: International Normalized Ratio < 1.5 x ULN & Partial Thromboplastin Time < 1.5 x 
ULN.   
  
  
  
• Prophylactic/low molecular weight Heparin (ex: Enoxaparin) is allowed (Exception: Warfarin is not 
allowed). 
  
  
  
If patient is of child-bearing potential: negative serum pregnancy test prior to study entry and be 
willing to practice an effective form of contraception up until three months after of receiving the last 
drug treatment.. 
  
  
  
If patient had major surgical procedure/open biopsy/significant traumatic injury: > 28 days before 1st 
day of treatment. 
  
  
  
If patient has undergone a core biopsy/IV Port placement: > 7 days prior to 1st date of study therapy. 
  
  
  
 
Study #: Pro00033060                                                                                                    Subject ID #: 
 
Exclusion Criteria 
Yes 
No 
N/A 
Patient is breastfeeding or pregnant. 
  
  
  
Patient had previous treatment with Nintedanib. 
  
  
  
Patient received radiation to > 25% of marrow-bearing areas. 
  
  
  
• Head: 13.1% (Cranium: 11.9%, Mandible: 1.2%) 
  
  
  
• Upper Limb Girdle: 8.3% (2  Humeri {head and neck}: 1.9%, 2 Scapulae: 4.8%, 2 Clavicles: 1.6%) 
  
  
  
• Sternum: 2.3% 
  
  
  
• Ribs: 7.9% 
  
  
  
• Vertebrae: 42.3% (Cervical: 3.4%, Thoracic: 14.1%, Lumbar: 10.9%, Sacrum: 13.9%) 
  
  
  
• Lower Limb Girdle: 26.1% (2 Os Coxae: 22.3%, 2 Femoral heads and necks: 3.8%) 
  
  
  
Patient has history of other invasive malignancies, & there is evidence of malignancy being present 
within last 3 years. 
  
  
  
Exception: Non-melanoma skin cancer. 
  
  
  
Patient's previous cancer treatment contraindicates this protocol therapy. 
  
  
  
Patient received prior radiotherapy to any portion of abdominal cavity/pelvis.  
  
  
  
Exception: Treatment of Ovarian, Fallopian Tube, or Primary Peritoneal Cancer within last 3 years. 
  
  
  
Exception: For localized cancer of breast/head & neck (Exception: CNS disease)/skin, if completed > 3 
years before registration & patient remains free of recurrent/metastatic disease. 
  
  
  
Patient received prior chemotherapy for any abdominal or pelvic tumor.  
  
  
  
Exception: Ovarian/Fallopian Tube/Primary Peritoneal Cancer or localized Breast Cancer within last 3 
years. 
  
  
  
Exception: Adjuvant chemotherapy for localized Breast Cancer, if completed > 3 years before registration 
& patient remains free of recurrent/metastatic disease. 
  
  
  
Patient has a history of abdominal or tracheal-esophageal fistula, or gastrointestinal perforation.  
  
  
  
Patient has a history of intra-abdominal abscess within 6 months of enrollment. 
  
  
  
Patient has a serious, uncontrolled, concomitant disorder (such as diabetes mellitus).  
  
  
  
Patient has clinically significant cardiovascular disease, including: 
  
  
  
• Uncontrolled hypertension: systolic > 150 mm Hg or diastolic > 90 mm Hg. 
  
  
  
• Unstable angina, or they had a myocardial infarction within the past 6 months prior to registration.  
  
  
  
• NYHA grade II or greater congestive heart failure. 
  
  
  
• Serious cardiac arrhythmia requiring medication (Exception: Asymptomatic atrial fibrillation with 
controlled ventricular rate.) 
  
  
  
• Peripheral vascular disease/Peripheral ischemia ≥ CTCAE v4.0 grade 2 
  
  
  
Patient has a serious non-healing wound, ulcer, or bone factor.  
  
  
  
• Exception: Granulating incisions healing by secondary intention with no evidence of fascial dehiscence or 
infection. Weekly wound examinations are required. 
  
  
  
Patient has active bleeding/pathologic condition with high risk of bleeding, such as: bleeding 
disorder/coagulopathy/tumor involving major vessels. 
  
  
  
Patient has history/evidence upon physical exam of CNS disease; seizures not controlled with 
standard medical therapy; brain metastases; or history of CVA/TIA/subarachnoid hemorrhage 
within 6 months of 1st date of treatment on this study. 
  
  
  
Patient has been diagnosed with primary brain tumors within the last 3 years. 
  
  
  
Patient has central pulmonary metastases, or recent hemoptysis (≥ 1/2 tsp. of red blood) within 28 
days of registration. 
  
  
  
Patient has clinically significant proteinuria (> Grade 1), or UPC ratio above 1.0. 
  
  
  


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
   Version Date 16 August 2018 
 
Page 71 of 78 
 
 
 
Patient is suspected of having transmural tumor bowel involvement (per investigator's discretion). 
  
  
  
Patient has clinical symptoms/signs of gastrointestinal obstruction, and requires parenteral hydration 
and/or nutrition. 
  
  
  
Patient is on therapeutic doses of anticoagulants, or is taking Warfarin. 
  
  
  
_________________________________________                                               _______________________________ 
            Signature of Coordinator/Research Nurse                                                                                        Date: 
______________________________________________                                                 _______________________________ 
          Signature of Investigator/Sub-Investigator                                                                                         Date: 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
   Version Date 16 August 2018 
 
Page 72 of 78 
 
APPENDIX X 
 
 Subject Registration Form 
Section 1:  SUBJECT INFORMATION 
 
First Initial: ________________________ Middle Initial: ____ Last Initial: _____________________________ 
Sex: 
 Male 
 Female   Date of Birth: ____ / ____ / _______   Duke MRN (if applicable): _______________ 
Date Consent Signed: ____ /____ / _______        Version Date of Site Consent: ____ /____ / _______ 
Type of Cancer Diagnosis:  ____________________________ Protocol Name: ___________________________ 
RACE: 
 White 
 Black or African American 
 Native Hawaiian or other Pacific Islander 
 Asian 
 American Indian or Alaska Native 
 Not Reported 
 Unknown 
 
ETHNICITY: 
 Hispanic or Latino 
 Non Hispanic or Latino 
 Not Reported 
 Unknown 
 
 
Section 2:  SITE INFORMATION 
 
Site Name: ______________________________________ Site Fax #: __________________________________     
Study Coordinator Name: __________________________ Phone #: _____________ Pager #: ______________ 
Study Coordinator Email: _____________________________________________________________________ 
Treating MD Name: _______________________________ Phone #: _____________ Pager #: ______________ 
Treating MD Email: __________________________________________________________________________ 
Section 3:  ELIGIBILITY 
 
    Subject meets all eligibility criteria.  (Please note:  If subject meets all eligibility criteria, please provide completed  
             eligibility checklist along with supporting source documentation to the Duke Team.) 
 
           Date of expected Cycle 1 Day 1:  ____ / ____ / _______ 
 
    Subject does not meet all eligibility criteria. 
 
          If subject does not meet eligibility, please explain below. 
         _______________________________________________________________________________________ 
 
Study Coordinator Signature: _________________________________________ Date: ____________________ 
  
Section 4:  TO BE COMPLETED BY DUKE STUDY TEAM 
------------------------------------------------------------------------------------------------------------------------------------------ 
 
Subject Study 
Number 
 
 
Cohort 
Number 
 
N/A 
 
 
Duke Investigator Signature and Date: 
 
 
 
 
 
 
 
 
 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
   Version Date 16 August 2018 
 
Page 73 of 78 
 
 
Appendix XI 
Rank Preferences and Relative Concern Exercises 
 
When researchers are testing new treatments for ovarian cancer, they have to decide ahead of time what 
kind of results they want to measure.  We would like to find out what kind of results patients think are 
most important.  Some of the outcomes researchers measure are listed below, with descriptions of what 
they mean. 
 
Overall quality of life.   This means how you are doing overall.  It includes your physical and emotional 
well-being and how well you can perform your normal daily activities. 
 
Side effects from treatment.  This means health effects that are caused by your cancer treatment.  
Examples of common side effects of cancer treatment are hair loss, neuropathy or numbness or tingling in 
your fingers and toes, nausea and vomiting. 
 
Symptoms from cancer.  Some common symptoms of ovarian cancer are abdominal fullness, pain or 
bloating, constipation, loss of appetite, and nausea. 
 
Progression-free survival.  This is the average length of time that a woman will spend without any sign of 
her cancer growing or coming back once she starts a new treatment. 
 
Overall survival.  This is the average length of time that a woman will live after starting a new treatment. 
 
 
A.  Relative Concern Exercise 
 
Now please indicate below how concerned you are about each of the following outcomes of your 
treatment. 
 
Quality of life 
Not 
concerned 
A little bit 
concerned 
Moderately 
concerned 
Very 
concerned 
Deeply 
concerned 
Symptoms of 
cancer 
Not 
concerned 
A little bit 
concerned 
Moderately 
concerned 
Very 
concerned 
Deeply 
concerned 
Side effects of 
treatment 
Not 
concerned 
A little bit 
concerned 
Moderately 
concerned 
Very 
concerned 
Deeply 
concerned 
Progression-
free survival 
Not 
concerned 
A little bit 
concerned 
Moderately 
concerned 
Very 
concerned 
Deeply 
concerned 
Overall 
survival 
Not 
concerned 
A little bit 
concerned 
Moderately 
concerned 
Very 
concerned 
Deeply 
concerned 
 
 
 
 
 
 
 
 
 
 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
   Version Date 16 August 2018 
 
Page 74 of 78 
 
 
B.  Rank Preferences 
 
Please rank the following outcomes we can measure in order from the MOST important (1) to the LEAST 
important (5) to you. 
 
 
_____________ Overall quality of life.  This includes your physical and emotional well-being and how 
well you can perform your normal daily activities. 
 
_____________ Side effects that are caused by the treatment. 
 
_____________ Symptoms that are caused by ovarian cancer. 
 
_____________ Length of time spent without the cancer growing. 
 
_____________ Total length of life remaining. 
 
(To avoid any potential bias introduced associated with the order the concepts are listed, the order will be 
randomized across participants.) 
 
 
 
C.  Token distribution exercise 
 
Now imagine that you have 100 coins or tokens.  We would like you to distribute the tokens to indicate 
how important each outcome is to you.  You could place all 100 tokens on one outcome if you only care 
about that outcome.  If you feel that all the outcomes are equally important, you will place 20 tokens on 
each outcome. 
 
_____________ Overall quality of life.  This includes your physical and emotional well being and how 
well you can perform your normal daily activities. 
 
_____________ Side effects that are caused by the treatment. 
 
_____________ Symptoms that are caused by ovarian cancer. 
 
_____________ Length of time spent without the cancer growing. 
 
_____________ Total length of life remaining. 
 
 
(To avoid any potential bias introduced associated with the order the concepts are listed, the order will be 
randomized across participants.) 
 
 
 
 
 
 
 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
   Version Date 16 August 2018 
 
Page 75 of 78 
 
 
Appendix XII 
 
NCCN-FACT FOSI-18 
Below is a list of statements that other people with your illness have said are important.  
Please circle or mark one number per line to indicate your response as it applies to  
the past 7 days. 
 
 
 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
 
 
 
 
 
 
GP1 
I have a lack of energy 
0 
1 
2 
3 
4 
GP4 
I have pain 
0 
1 
2 
3 
4 
GP6 
I feel ill 
0 
1 
2 
3 
4 
O3 
I have cramps in my stomach area 
0 
1 
2 
3 
4 
HI7 
I feel fatigued 
0 
1 
2 
3 
4 
Cx6 
I am bothered by constipation 
0 
1 
2 
3 
4 
O1 
I have swelling in my stomach area 
0 
1 
2 
3 
4 
C3 
I have control of my bowels 
0 
1 
2 
3 
4 
GF5 
I am sleeping well 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse 
0 
1 
2 
3 
4 
GP2 
I have nausea 
0 
1 
2 
3 
4 
B5 
I am bothered by hair loss 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment 
0 
1 
2 
3 
4 
O2 
I have been vomiting 
0 
1 
2 
3 
4 
BMT15 
I am bothered by skin problems 
0 
1 
2 
3 
4 
BMT5 
I am able to get around by myself 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now 
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
DRS-P=Disease-Related Symptoms Subscale – Physical 
DRS-E=Disease-Related Symptoms Subscale – Emotional 
TSE=Treatment Side Effects Subscale 
FWB=Function and Well-Being Subscale 
English (Universal) 
03 March 2010 
Copyright 2001 
 
D
R
S-
P 
T
S
E 
F 
W 
B 
D
R
S-
E 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
   Version Date 16 August 2018 
 
Page 76 of 78 
 
FACT/GOG-NTX (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
PHYSICAL WELL-BEING 
Not at 
all 
A little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
GP1 
I have a lack of energy 
0 
1 
2 
3 
4 
GP2 
I have nausea 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family 
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment 
0 
1 
2 
3 
4 
GP6 
I feel ill 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed 
0 
1 
2 
3 
4 
 
SOCIAL/FAMILY WELL-BEING 
 
Not at 
all 
A little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
GS1 
I feel close to my friends 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family 
0 
1 
2 
3 
4 
GS3 
I get support from my friends 
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness 
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my 
main support) 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer 
it, please mark this box        and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life 
0 
1 
2 
3 
4 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
   Version Date 16 August 2018 
 
Page 77 of 78 
 
 
FACT/GOG-NTX (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 
7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
 
GE1 
I feel sad 
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness 
0 
1 
2 
3 
4 
GE4 
I feel nervous 
0 
1 
2 
3 
4 
GE5 
I worry about  
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse 
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life 
0 
1 
2 
3 
4 
GF4 
I have accepted my illness 
0 
1 
2 
3 
4 
GF5 
I am sleeping well 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now 
0 
1 
2 
3 
4 
 
 


BIBF 1120 in the Treatment of Bevacizumab Resistant Ovarian Cancer 
   Version Date 16 August 2018 
 
Page 78 of 78 
 
 
FACT/GOG-NTX (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 
7 days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A 
little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
NTX
1 
I have numbness or tingling in my hands 
0 
1 
2 
3 
4 
NTX
2 
I have numbness or tingling in my feet 
0 
1 
2 
3 
4 
NTX
3 
I feel discomfort in my hands 
0 
1 
2 
3 
4 
NTX
4 
I feel discomfort in my feet 
0 
1 
2 
3 
4 
NTX
5 
I have joint pain or muscle cramps 
0 
1 
2 
3 
4 
HI12 
I feel weak all over 
0 
1 
2 
3 
4 
NTX
6 
I have trouble hearing 
0 
1 
2 
3 
4 
NTX
7 
I get a ringing or buzzing in my ears 
0 
1 
2 
3 
4 
NTX
8 
I have trouble buttoning buttons 
0 
1 
2 
3 
4 
NTX
9 
I have trouble feeling the shape of small objects when 
they are in my hand 
 
0 
 
1 
 
2 
 
3 
 
4 
An6 
I have trouble walking 
0 
1 
2 
3 
4 
 
 
English (Universal)                                                                                                                                                                                                                                                              16 November 2007 
Copyright  1987, 1997