Clinical trial NCT02665143
Conditions: Relapsed/Refractory Acute Myeloid Leukemia
Keywords: acute myeloid leukemia
Sponsor: Yale University
Start date: 2016-07-21; Completion date: 2021-03-30
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine if a combination of nintedanib+ induction chemotherapy can be an effective strategy for patients where outcome of relapse/refractory acute myeloid leukemia (AML) is poor.

Detailed description:
This study will conducted as a Phase 1/Phase 2 trial.

The primary objective of Phase 1 is to determine the safety and tolerability of a combination of Nintedanib + induction chemotherapy in patients with acute myeloid leukemia.

The primary objective of Phase 2 is to determine the efficacy (rate of CR/CRp/CRi) of Nintedanib+ induction vs Placebo+ induction.

The secondary objectives of this study include: determining the overall response rate according to IWG AML 2003 criteria, the toxicity profile and safety of the combination, the percentage of patients bridging to transplantation, the overall survival, leukemia free survival including analysis with censoring at HSCT and rates of haematological improvement according to IWG MDS 2006 criteria. In addition, exploratory correlative studies will be conducted.

Arms: arm 1: The AML induction regimen combines Idarubicin 12mg/m2/d day 1 to 3 and Cytarabine 0.667g/m2/d CIV day 1 to 3. Based on the phase I dose, in the randomized phase II, the combination will be compared with chemotherapy+placebo. Nintedanib or placebo will be added at day 8 and continued until end of cycle .
Interventions: intervention 1: Nintedanib and AML induction
Intervention descriptions: intervention 1: The AML induction regimen combines Idarubicin 12mg/m2/d day 1 to 3 and Cytarabine 0.667g/m2/d CIV day 1 to 3. In the phase I part, all patients will receive the combination with Nintedanib 200mg bid begun at day 8 and continued until end of cycle. If a significant incidence of dose limiting toxicities is demonstrated, Nintedanib will be given at a lower dose level (150mg bid).

Protocol documents:
Prot_SAP_000.pdf: 
1 
A phase I-II randomized trial of a combination of 
Nintedanib/placebo in combination with induction 
chemotherapy for patients with refractory or first relapse 
acute myeloid leukemia 
NCT02665143 
Sponsored by:  Yale University 
Supported by: Boehringer Ingelheim, US 
Principal Investigator: 
Thomas Prebet, MD, PhD 
Internal Medicine Department (Hematology) 
Yale Comprehensive Cancer Center, 
333 Cedar St. PO Box 208028 
New Haven CT, 06520 
Pharmacodynamic Studies 
Thomas Prebet, MD, PhD 
Internal Medicine Department (Hematology) 
300 George Street, Room 785 
New Haven, CT, 06511 
Phone (203) 737-5531   Fax: (203) 785 7232 
Email: thomas.prebet@yale.edu 
Co- Investigator/Collaborating Center: 
Dr. Stephen A. Strickland Jr. MD, MSCI 
Vanderbilt Ingram Cancer Center 
1301 Medical Center Drive 
3927 The Vanderbilt Clinic 
Nashville, TN 37232 
Protocol Version 
Protocol Date 
Nintedanib AML version 7 
05.21.2019 


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Table of Contents 
1.1 
Trial summary ............................................................................................................ 4 
1.2 
Rational ....................................................................................................................... 8 
1.2.1 
Outcome of Acute Myeloid Leukemias after failure of frontline treatment ........... 8 
1.2.2 
Rational for targeting VEGF/VEGF-R pathway in AML .......................................... 8 
1.2.3 
Nintedanib, an oral VEGF inhibitor .......................................................................... 11 
1.2.4 
Combination of chemotherapy and Nintedanib in relapsed/refractory AML ...... 12 
1.3 
Objectives ................................................................................................................. 13 
1.3.1 
Primary objective ........................................................................................................ 13 
1.3.2 
Secondary Objectives ................................................................................................ 13 
1.3.3 
Exploratory objectives ................................................................................................ 14 
1.4 
Endpoints ................................................................................................................. 14 
1.4.1 
Primary endpoint ......................................................................................................... 14 
1.4.2 
Secondary endpoints.................................................................................................. 14 
1.5 
Treatment Plan ......................................................................................................... 15 
1.5.1 
Global treatment strategy .......................................................................................... 15 
1.5.2 
Drug Dose adjustments ............................................................................................. 18 
1.6 
Definition of dose limiting toxicities (DLT) during phase I ................................. 21 
1.7 
Statistical plan ......................................................................................................... 23 
1.8 
Patient selection ...................................................................................................... 25 
1.8.1 
Inclusion criteria .......................................................................................................... 25 
1.8.2 
Exclusion criteria ......................................................................................................... 26 
1.9 
Enrollment Procedure ............................................................................................. 28 
1.10 
Assessments ............................................................................................................ 29 
1.10.1 
Screening period ......................................................................................................... 29 
1.10.2 
Evaluation during treatment period .......................................................................... 31 
1.10.3 
Maintenance ................................................................................................................ 33 
1.10.4 
End of study treatment evaluation ............................................................................ 33 
1.11 
Concomitant treatments ......................................................................................... 34 
1.12 
Drug interactions ..................................................................................................... 35 
1.13 
Correlative studies .................................................................................................. 36 
1.14 
Study treatments ..................................................................................................... 39 
1.14.1 
Nintedanib .................................................................................................................... 39 
1.14.2 
Idarubicin ...................................................................................................................... 43 
1.14.3 
Cytarabine .................................................................................................................... 45 
1.15 
Premature discontinuation of treatment ............................................................... 46 
1.16 
Unblinding procedure ............................................................................................. 46 
1.17 
Criteria for terminating the study .......................................................................... 47 
1.18 
Follow-up .................................................................................................................. 48 
1.18.1 
Phase I: ........................................................................................................................ 48 
1.18.2 
Phase II: ....................................................................................................................... 48 
1.19 
Serious Adverse events .......................................................................................... 49 
1.19.1 
General definition ........................................................................................................ 49 
1.19.2 
Definition of an expected serious adverse event (SAE-E) ................................... 50 


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1.19.3 
Definition of an unexpected serious adverse event (SAE-U) ............................... 50 
1.19.4 
Intensity ........................................................................................................................ 50 
1.19.5 
Causal relationship between an adverse event (SAE/AE) and the study 
treatment ...................................................................................................................................... 51 
1.19.6 
What to do in the event of a serious adverse event .............................................. 51 
1.19.7 
Adverse events and laboratory values of special interest .................................... 52 
1.19.8 
Reporting to the IRB ................................................................................................... 53 
1.19.9 
Reporting to Boehringer Ingelheim .......................................................................... 54 
1.19.10 
Follow-up of SAEs .................................................................................................. 55 
1.20 
Multicenter management and coordination ......................................................... 56 
1.20.1 
Data Management ...................................................................................................... 56 
1.20.2 
Safety Evaluations ...................................................................................................... 57 
1.20.3 
Safety Monitoring ........................................................................................................ 57 
1.20.4 
Audit Plan ..................................................................................................................... 58 
1.20.5 Protocol Research Team Meetings ............................................................................. 58 
1.21 
Ownership of data and confidentiality .................................................................. 59 
1.22 
Publication ............................................................................................................... 60 
1.23 
Ethical and regulatory aspects .............................................................................. 61 
1.23.1 
Institutional Review Board (IRB) .............................................................................. 61 
1.23.2 
Competent Authority ................................................................................................... 61 
1.23.3 
Subject information and consent .............................................................................. 61 
1.23.4 
Responsibilities of the sponsor ................................................................................. 62 
1.23.5 
Responsibilities of investigators ............................................................................... 62 
1.24 
References ............................................................................................................... 64 
1.25 
Appendices .............................................................................................................. 66 
1.25.1 
Declaration of Helsinki ............................................................................................... 67 
1.25.2 
WHO PS ....................................................................................................................... 72 
1.25.3 
IWG response criteria ................................................................................................ 73 
1.25.4 
Common toxicity criteria for adverse events (CTCAE) ......................................... 74 
1.25.5 
Procedures for the follow-up of a potential DILI case in IIS with nintedanib ..... 75 
1.25.6 
Protocol Signature Page ............................................................................................ 78 
1.25.7 
Study Calendar ........................................................................................................... 79 
 
 
 


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1.1 Trial summary 
 
Title 
A phase I-II trial of a combination of Nintedanib, an oral VEGF inhibitor, in combination with 
induction chemotherapy for patients with refractory or first relapse acute myeloid leukemia 
Indication 
Treatment of patients with relapsed/refractory AML as defined by the WHO 
Design 
 Phase I- randomized II study 
Sponsor 
YALE UNIVERSITY 
 
Contact 
Thomas Prebet, MD PhD 
Phone:(203) 785 5531 
Fax:(203) 785 7232 
Email: thomas.prebet@yale.edu 
Products 
Nintedanib/ placebo, idarubicin, cytarabine 
Summary of Rationale 
Nintedanib is an oral VEGF inhibitor with a good tolerance profile. There is evidence of a potential 
clinical impact of VEGF inhibition in AML and some in vitro evidence of activity of Nintedanib 
against AML blasts. Given that outcome of relapse/refractory AML patient is poor and that no 
standard option is available for this group of patients, we anticipate that a combination of 
nintedanib+ induction chemotherapy may be an effective strategy for this group of patients. 
Treatment plan 
Phase I: Patients who meet eligibility criteria and sign informed consent will receive the following 
during an inpatient hospital stay; Idarubicin 12mg/m2/d IV Push over 10-15 minutes days 1 to 3, 
cytarabine 0.667g/m2/d (24 hr.) IV infusion day 1 to 3 and Nintedanib 200mg BID PO day 8-28.  
There will be no drug administered on days 4-7. Length of inpatient hospital stay is based on local 
site SOP.  
 
Phase II: Patients who meet eligibility criteria and sign informed consent will receive the 
following during an inpatient hospital stay; Idarubicin 12mg/m2/d IV Push over 10-15 minutes 
days 1 to 3, cytarabine 0.667g/m2/d (24 hr.) IV infusion day 1 to 3 and Nintedanib 200mg BID PO 
on day 8-28 OR placebo. There will be no drug administered on days 4-7. Length of inpatient 
hospital stay is based on local site SOP. 
 
For both Phase I and II, a maximum of 2 induction and 2 consolidation cycles may be given, cycles 
are 28 days.  
 
During Phase II, all Patients failing to achieve response based on IWG 2003 AML response criteria 
after cycle 1 will be unblinded, and all those who had been receiving placebo will be offered 
Nintedanib+ chemotherapy (cross over) for cycle 2. Patients in the Nintedanib arm can be given 
a second cycle of Nintedanib. 
 
Nintedanib maintenance treatment will be given to responding pts not eligible for Hematopoietic 
stem cell transplantation (HCT) for up to two years or until disease progression. Patients eligible 
for HSCT will be taken off study prior to HSCT.  


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Primary objective 
Phase I: To determine the safety and tolerability of a combination of Nintedanib + induction 
chemotherapy.  
Phase II: To determine the efficacy (rate of CR/CRp/CRi) of Nintedanib+ induction chemotherapy 
vs. Placebo+ induction chemotherapy 
Secondary objectives 
• 
Overall response rate according to IWG AML 2003 criteria 
• 
Toxicity profile and safety of the combination 
• 
Percentage of patients bridging to transplantation 
• 
Overall survival, leukemia free survival including analysis with censoring at HSCT 
• 
Rates of haematological improvement according to IWG MDS 2006 criteria 
• 
Correlative studies 
Inclusion criteria 
Patient must meet all of the following inclusion criteria to be eligible for the study 
1/  Patient aged  18y or older  
2/ Diagnosis of AML according to WHO 2008 criteria. Therapy related to AML may be included if off 
treatment for their prior malignancy for more than 2 years and in complete remission. AML arising after 
documented Myeloproliferative Disorder (MPD) is excluded. 
3/ Patient must meet one of the following 2 criteria:  
• 
Patient refractory (not responsive) to one or two standard induction regimens  
• 
Patients with a first untreated relapse within 2 years of documentation of complete 
remission. Patients relapsing after allogeneic stem cell transplantation are eligible if more 
than 6 months after transplantation and without signs of active Graft vs Host Disease 
(GVHD). 
4/ Patient may have been pre treated with intermediate to high dose cytarabine (More than 
1000mg/m2/d over 5d) if the day of the last infusion was at least 90 days before inclusion in the study. 
5/ ECOG performance status of 2 or less  
6/ Patient is willing to participate to the study, has the ability to adhere to the study visit schedule and 
other protocol procedures, and has the ability to understand and signs an informed consent form. 
7/ Women of childbearing potential must agree to use effective contraception without interruption through
the study and for 3 months after the end of treatment; 
8/ Men must agree to not conceive during the treatment and to use effective contraception during the 
treatment period (including periods of dose reduction or temporary suspension) and for 3 months after the 
of treatment if their partner is of childbearing potential. 
 
 


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Exclusion criteria 
Any of the following criteria excludes the patient from participating to the study.  
1/ Patient with documented acute promyelocytic leukemia and/or PML-RAR transcript. 
2/ Patient relapsing more than 2 years after initial remission. 
3/ Use of any active treatment for relapse/refractory AML including but not restricted to chemotherapy, targeted 
agents, hypomethylating agents or investigational drugs. Use of hydroxyurea up to 6g per day for cytoreduction is 
allowed for a maximum of 30 days prior treatment. 
4/ Patients with clinical evidence of active Central Nervous System (CNS) disease at enrollment 
5/ LVEF below 45% or lifetime exposure to anthracyclines over 350mg/m2 of daunorubicin equivalent 
6/ Liver function tests: AST ALT above 2.5 ULN, total bilirubin above 2.5 ULN in the absence of Hemolysis or diagnosis 
of Gilbert’s syndrome  
7/ Serum creatinine above 2.0mg/dl  
8/ Any sign of active uncontrolled disease including but not restricted to cardiac disease, infections, hepatitis. Any 
severe chronic disease potentially interfering with the protocol including HIV infection, active hepatitis B or C.  It 
includes major injuries and/or surgery within the past 4 weeks prior to start of study treatment with incomplete 
wound healing and/or planned surgery during the on-treatment study period. 
9/ Documented platelet refractoriness 
10/ Patient has a history of GI surgical procedures, non-surgical procedures or conditions that might interfere with         t
absorption or swallowing of the study drugs. 
11/ Women who are or pregnant, or who are currently breastfeeding 
12/ Prior treatment with nintedanib or any other VEGFR inhibitor. With the exception for treatment of prior 
malignancies with a VEGFR inhibitor. 
13/ Known hypersensitivity to nintedanib, any other trial drug, or their excipients 
14/ Persistence of any clinically relevant (CTCAE grade 2 or above) non -haematological toxicities from previous AML 
therapy 
15/ Active alcohol or drug abuse 
16/ Any other condition that, according to the investigator, may forbid the administration of the idarubicin+cytarabine 
regimen 
17/ Therapeutic anticoagulation with INR modifying drug or use of antiplatelet therapy (with the exception of low dose 
aspirin<325mg/d) 
18/ Any malignancies requiring active treatment within the past year other than basal cell skin cancer or carcinoma in si
of the cervix. Patients actively treated with hormone therapy for prostate cancer or breast cancer are eligible. 


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Planned of 
duration of the 
study 
2 years of accrual, 2 years of follow-up 
Number of 
patients  
22 to 60 patients according to the evaluation (see below statistical methods) 
Safety Analysis 
An independent safety review committee (SRC) assembled by the PI and comprised of one Investigator 
from both Yale, and Vanderbilt, two external AML experts and a statistician will meet, when required by 
the sponsor of the trial, and at least once after the inclusion of the first 6 patients, to analyze tolerance 
and adverse events and decide on any action to be taken. 
Statistical 
methods 
Phase I will use a classical 6+6 design. A n-1 dose level is schedule if DLTs are observed at initial dose level 
Phase II will use an adaptive randomized design. A minimum of 8 patients will be included in each arm and 
continuous reassessment method will be used after each patient to evaluate futility or success of each 
specific arm of treatment. 
Patient follow-up Phase I patients will be followed up to 60 days after the last study drug administration in order to 
determine if any DLTs are attributable to Nintedanib.  Patients will then be followed every 3 months +/- 7 
days for 24 months or until the patient begins receiving subsequent anti-cancer therapy or death, 
whichever comes first.   
Phase II patients will be followed every 3 months +/- 7 days 24 months or until the patient begins receiving 
subsequent anti-cancer therapy or death, whichever comes first.   
 
 
 
 


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1.2 Rational  
1.2.1 Outcome of Acute Myeloid Leukemias after failure of frontline treatment 
 
 Acute Myeloid Leukemia (AML) is an aggressive malignant disorder of the bone marrow, 
characterized by the accumulation of immature white cell precursors in the marrow and blood, 
ultimately resulting in bone marrow failure with infections and bleeding. Treatment with standard 
induction including an anthracycline and cytarabine results in complete response rate of 35% to 55% 
in patients with newly diagnosed AML 60 years old and older1 and 50% to 90% in younger patients. 
Despite the high rate of CR, most patients will eventually relapse.  
In first relapse, there is no single approach considered standard and treatment is selected based on 
the age of the patient and the duration of first CR. In patients 60 years old or older, intermediate 
dose cytarabine alone or in association with another cytotoxic agent (idarubicin, daunorubicin, 
mitoxantrone or etoposide) is commonly used. Despite substantial variability, the second CR rate 
generally exceeds 30%2,3. However the median overall survival is ≤ 6 months. The prognosis of 
relapsed AML remains poor, especially in elderly patients. Several investigational agents such as 
cloretazine, clofarabine, vosaroxin, and elacytarabine have been tested prospectively tested in 
randomized trial in the settings of patients with AML experiencing early relapse or refractoriness to 
induction. To date, none of them demonstrated a clear benefit on overall survival and there is no 
registered drug approved for this indication. Thus there is a strong unmet medical need for this 
situation  
 
1.2.2 
Rational for targeting VEGF/VEGF-R pathway in AML 
 
 
While multiple cytokines promote AML proliferation and survival, vascular endothelial 
growth factor (VEGF) likely plays an important role as a paracrine and/or autocrine mediator. Greater 
than 85% of bone marrow biopsies from patients with AML express VEGF significantly higher than 
normal bone marrows [reviewed in (Kampen, Ter Elst et al. 20134]. VEGF receptors are also 
commonly expressed on leukemic blasts from patients with AML4. In particular, VEGFR-2 protein 
levels are consistently higher than in normal bone marrow5,6. VEGF isoforms can be detected in the 
cytoplasm of AML blasts and can be secreted7,8.  
Elevated plasma concentrations of VEGF-A have been associated with lower complete remission 


Nintedanib AML Version 7 21 MAY 2019 
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rates and inferior survival in AML patients9-11. High VEGF-C expression has been associated with 
inferior ex vivo sensitivity to cytotoxic chemotherapy in AML blasts12. VEGF-C plasma concentrations 
have been demonstrated to have negative prognostic significance in pediatric and adult AML13.  
Both VEGF-A and VEGF-C stimulate AML blast proliferation and survival in vitro10,14,15. VEGF signaling 
in AML leads to activation of Bcl-2, HSP, MAPK and PI3K15. AML bone marrow biopsies often 
demonstrate increased micro-vessel density compared to normal bone marrow and AML in 
remission16-18. VEGF stimulates osteoblasts and osteoclasts and may lead to remodeling of the stem 
cell niche19-21; to what extent this impacts leukemia stem cells (LSC) is not clear.  
VEGF antagonists have demonstrated little clinical activity as monotherapy in relapsed or refractory 
AML16,22,23 or MDS24-26. However, VEGF antagonists may contribute significantly to outcomes in 
combination with cytotoxic drugs27-30. In timed sequential chemotherapy, AML patients receive a 
planned second exposure to chemotherapy shortly after their first exposure at a time point planned 
to coincide with the peak of cytokine-stimulated regrowth of residual leukemia cells. This approach 
led to superior leukemia-free survival in a pediatric population31 as well as in an adult population32 
(French). However, timed sequential therapy has led to longer aplasia duration than a single cycle of 
“seven plus three” (cytarabine plus anthracycline) and has not been widely adopted. Building on this 
model, Karp and colleagues30 studied a three day infusion of cytarabine in combination with 
mitoxantrone in patients with relapsed and refractory AML. Historical experience with this 
combination indicated that remissions were not likely with these drugs alone.  
The VEGF inhibitor bevacizumab was administered on day 8, in lieu of the second drug exposure in 
the timed sequence (Figure 1):  
 


Nintedanib AML Version 7 21 MAY 2019 
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Figure 1. VEGF inhibition in a timed sequential chemotherapy model of AML9 (Attached)  
 
Of 49 patients treated, 15 had primarily refractory disease, 12 were refractory to at least two 
induction regimens, or to reinduction after first relapse; 18 were in first relapse. Toxicities were as 
expected with intensive reinduction therapy; additional AEs attributed to the known toxicity profile 
of bevacizumab were observed. 7 patients experienced induction death.  
Importantly, residual leukemia was morphologically detectable in 38/48 patients on day 8 prior to 
bevacizumab. On Day 15 (one week following bevacizumab), 28/48 patients had cleared morphologic 
leukemia. 16 patients achieved complete remission, including 2/3 newly diagnosed poor-risk AML, 
9/18 patients in first remission, and 5/27 patients with primary refractory disease. 7 patients 
achieved PR, for an overall response rate of 48% following one cycle of treatment. VEGF receptor 
FLT-1 on bone marrow cells was greater than in normal bone marrow in 12/13 patients examined. On 
day 8, blasts continued to express FLT-1 in 8/10 patients. Serum free-VEGF was detectable in 14/21 
patients prior to treatment (median concentration 12 pg/mL). Day 8 concentrations were higher than 
on day 0 in 11 patients including 4 patients in whom VEGF had been undetectable, while VEGF 
concentration had decreased in 6.  


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Among 15 patients in whom serum was sampled two hours following bevacizumab infusion, 10 had 
complete suppression of detectable VEGF, while 4 patients had VEGF concentrations ranging from 24 
– 82% of the pre-bevacizumab baseline. Sequential examination of bone marrow microvessel density 
revealed significant decreases in 8/11 patients.  
This study confirmed the widespread expression of VEGF in patients with relapsed and refractory 
AML, and suggested that effective VEGF inhibition could substitute for a toxic second administration 
of chemotherapy drugs in a timed sequential chemotherapy model, leading to a very promising 
response rate. This combination was not further developed due to lack of priority from the 
manufacturer of bevacizumab, despite great interest from the Johns Hopkins group and the Cancer 
Therapy Evaluation Program. (Personal communication).  
 
1.2.3 Nintedanib, an oral VEGF inhibitor 
 
Nintedanib33,34 is an orally bioavailable VEGFR inhibitor with an IC50 ranging from 100 – 300 nM. 
Nintedanib also inhibits the different isoforms of FGF and PDGFR. In a trial in lung cancer in 
combination with paclitaxel and carboplatin in non-small cell lung cancer35, mean Cmax was 63 
ng/mL, similar to that in monotherapy trials36-39 and in combination with docetaxel in prostate cancer 
patients. Nintedanib administration was associated with decrements in plasma soluble VEGFR2.  
Nintedanib is being investigated in several cancer indications40. Two completed phase III NSCLC35,41 
studies and one phase III in ovarian cancer is still ongoing; the development for colorectal cancer, 
renal cell carcinoma, and hepatocellular carcinoma is in phase II. Additionally, nintedanib is also 
registered for the non-cancer indication idiopathic pulmonary fibrosis (IPF) 42,43 (150mg bid). As of 15 
Apr 2014, a total of 3470 cancer patients, 143 healthy volunteers and 1529 patients with IPF have 
been treated with nintedanib. Among the cancer patients, 672 were treated with monotherapy, 1255 
with combination of nintedanib and various backbone therapies, 162 with the combination of 
afatinib44, an EGFR/HER2 inhibitor, approved in the treatment of patients with NSCLC carrying EGFR 
mutation and 30 patients with the combination of volasertib, a PLK1 inhibitor.  1351patients were 
treated with either nintedanib or nintedanib-matching placebo in ongoing blinded studies.  
Based on the phase I dose escalation trials36-39, the MTD (maximum tolerated dose) was determined 
to be 250 mg bid for twice daily dosing in Caucasians and 200 mg bid in Japanese patients45 with a 


Ni nt e d a ni b A ML V ersi o n  7 2 1 M A Y 2 0 1 9 
1 2  
 
m a n a g e a bl e s af ety pr ofil e i n a dv a nc e d c a nc er p ati e nts. T h e pr e d o mi n a nt a dv ers e e v e nts w er e 
n a us e a, di arr h e a, v o miti n g, a b d o mi n al p ai n a n d f ati g u e o f m ostly l o w t o m o d er at e s ev erity. D os e 
li miti n g t oxiciti es ( DL T) w er e m ai nl y c o nfi n e d t o r e v ersi bl e h e p atic e nzy m e el ev ati o ns ( A S T, AL T, -
G T) w hic h i ncr e as e d d os e -d e p e n d e ntl y. M ost c as es occ urri n g at d os es of 2 5 0 m g a n d a b o v e, a n d a 
v ery l o w i nci d e nc e at  d os es b el o w 2 0 0 m g a n d w er e r ev ersi bl e aft er disc o nti n u ati o n of ni nt e d a ni b 
tr e at m e nt. All a dv ers e e v e nts o bs er v e d aft er si n gl e a d mi nistr ati o n of si n gl e d os es of ni nt e d a ni b t o 
h e alt hy v ol u nt e ers w er e o nl y of C T C A E gr a d e 1 s e v erity a n d f ull y r e v ersi bl e.  
 
1. 2. 4  
C o m bi n ati o n of c h e m ot h er a p y a n d Ni nt e d a ni b  i n r el a p s e d/r efr a ct or y 
A M L  
 
T h e av ail a bilit y of a n or ally bi o a v ail a bl e V E G F i n hi bit or wit h t ol er a bl e t oxicit y pr ofil e pr ovi d es a n 
o p p ort u nity t o f oll o w t h e si g n al fr o m t h e b e v aciz u m a b st u dy i n t h e d ev el o p m e nt of V E G F i n hi biti o n 
i n r ei n d ucti o n t h er a py.  T h e t ol er a bility of t h e c o m bi n ati o n will b e c o nfir m e d i n a s h ort p h as e I b 
f oll o w e d by a r a n d o miz e d p h as e II st u dy ev al u ati n g t h e p ot e nti al b e n efit of s uc h a c o m bi n ati o n as 
c o m p are d t o c o nv e nti o n c ar e. A n a d a p ti v e d esi g n will b e us e d f or t h e r a n d o miz e d p art. T his will 
all o w t o q uic kl y c o ncl u d e o n t h e p ot e nti al l ac k of effic ac y of a ny of t h e ar m of t h e st u dy as c o m p ar e d 
t o hist oric al c o ntr ols. 
 
 


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1.3 Objectives 
1.3.1 Primary objective 
 
Phase I: To determine the safety and tolerability of Nintedanib in combination with intensive AML 
chemotherapy; Idarubicin and cytarabine after 1 cycle of treatment 
Randomized Phase II: To determine the complete remission rate (CR+ CRp) of chemotherapy ; 
Idarubicin and cytarabine + nintedanib compared to chemotherapy Idarubicin and cytarabine 
+placebo after 1 cycle of treatment 
 
1.3.2 Secondary Objectives 
 
To determine overall response rate of nintedanib+ chemotherapy as compared to placebo + 
chemotherapy 
To determine the overall survival and leukemia free survival of patients treated with 
nintedanib+chemotherapy as compared to placebo+chemotherapy.  
To determine the percentage of patients bridging to allogeneic transplantation as well as time to 
transplantation after nintedanib+chemotherapy as compared to placebo+chemotherapy 
To determine hematological response rate of the nintedanib+ chemotherapy as compared to placebo 
+ chemotherapy 
Phase II: To determine the safety and tolerability of nintedanib+chemotherapy as compared to 
placebo+chemotherapy 
 
 


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1.3.3 Exploratory objectives 
 
To determine the role and correlate biomarkers of nintedanib activity in relapse/refractory AML (see 
below) 
1.4 Endpoints 
1.4.1 Primary endpoint 
 
Phase I:  Safety evaluated according to NCI CTCAE V4.03 criteria 
Phase II: Complete remission rate (including CR and CRp) evaluated according to IWG AML 2003 
criteria after 1 cycle of treatment 
 
1.4.2 Secondary endpoints 
 
Overall response rate will be defined according to IWG 2003 criteria46 and includes: CR, CRp, CRi, PR, 
and marrow leukemia free state (MLFS). Rates of hematological improvements (as defined by IWG 
2006 Myelodysplastic syndromes criteria47) will also be recorded. 
Overall Survival will be defined from time of treatment initiation to the time of last follow-up or 
death. Survival with censoring patients at the time of transplantation will also be evaluated. 
Leukemia free survival will be defined from time of documentation of complete remission 
(CR+CRp+CRi) to the time of last follow-up, relapse, or death of any cause. Survival with censoring 
patients at the time of transplantation will also be evaluated. 
 
 
 


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1.5 Treatment Plan 
1.5.1 Global treatment strategy 
 
Phase I:  This is an initial exploratory phase to confirm the safety and tolerability of the combination 
of Nintedanib+chemotherapy The AML chemotherapy induction and consolidation regimen occur at 
an inpatient hospital stay typically averaging 5 weeks and is Standard of Care (SOC) per local hospital 
policy. The induction and consolidation regimen combines Idarubicin 12mg/m2/d IV push over 10-15 
minutes days 1 to 3 and Cytarabine 0.667g/m2/d (24 hr. IV infusion) day 1 to 3. During Phase I, all 
patients will receive the combination chemotherapy in addition to Nintedanib 200mg bid starting at 
Day 8 through day 28 (end of cycle). If a significant incidence of dose limiting toxicities is 
demonstrated, Nintedanib will be given at a lower dose level (150mg bid). Patients may be 
discharged based on local site SOC and re-admitted prior to the start of the next cycle however, 
some patients will stay in the hospital continuously (especially between the first two induction 
cycles).  Induction cycle 2 can begin as early as study day 29 regardless of count recovery status if the 
investigator believes it would be clinically beneficial.  Patients can be given a “break” between cycles 
of induction based on investigator’s clinical judgement and clinical response.  Count recovery is 
necessary before a consolidation cycle can begin. If count recovery is not achieved 60 days after 
Cycle 1 Day 1, the patient is removed from the study.  
Phase II: Based on the phase I dose, in the randomized phase II, the combination of chemotherapy + 
Nintedanib will be compared with chemotherapy+placebo. The AML chemotherapy induction and 
consolidation regimen occur at an inpatient hospital stay typically averaging 5 weeks and is Standard 
of Care (SOC) per local hospital policy. The induction and consolidation chemotherapy regimen for 
Phase II are identical to that in Phase I and combines Idarubicin 12mg/m2/d IV push over 10-15 
minutes days 1 to 3 and Cytarabine 0.667g/m2/d (24 hr. IV infusion) day 1 to 3. In Phase II, patients 
will be randomized to receive the combination chemotherapy in addition to Nintedanib (dose 
determined in Phase I) at Day 8 through day 28 (end of cycle) or placebo at Day 8 until day 28 (end of 
cycle). . Patients may be discharged based on local SOC and re-admitted prior to the start of the next 
cycle however, some patients will stay in the hospital continuously (especially between the first two 
induction cycles). Induction cycle 2 can begin as early as study day 29 regardless of count recovery 
status if the investigator believes it would be clinically beneficial.  Patients can be given a “break” 
between cycles of induction based on investigator’s clinical judgement and clinical response.  Count 
recovery is necessary before a consolidation cycle can begin. If count recovery is not achieved 60 
days after Cycle 1 Day 1, the patient is removed from the study. Figure 2. describes the overall 


Nintedanib AML Version 7 21 MAY 2019 
16 
 
strategy of the Phase II portion of the study. All patients will be evaluated for response based upon 
count recovery or following day 45, whichever comes first. Patients without count recovery and 
without signs of bone marrow leukemia at day 45 will be followed up to day 60. If no recovery is 
observed at day 60, patients will be removed from protocol and considered a failure. 
In phase I, patients who fail to achieve CR or CRp based on IWG 2003 AML response criteria (pg. 77) 
after first cycle of treatment may receive a second cycle of treatment using Nintedanib+ 
chemotherapy. Patients who achieve CR or CRp after one or two induction cycles may receive up to 2 
cycles of consolidation using the same regimen. 
In phase II, patients failing to achieve response based on IWG 2003 AML response criteria after cycle 
1 will be unblinded, and all those who had been receiving placebo will be offered a cycle of 
Nintedanib+ chemotherapy (cross over). Patients in the Nintedanib arm may receive a second 
induction cycle of Nintedanib. Based on clinical judgement, patients can receive up to 2 cycles of 
consolidation after induction cycle (s) are complete. 
Patients are eligible for allogeneic transplantation as soon as remission is achieved and a donor is 
identified.  All transplant procedures occur off study.  For responding patients not eligible for 
transplantation, maintenance therapy with Nintedanib/Placebo will be provided until documented 
progression. 
Patients should NOT start Cycle 1 day 1 on a Thursday or Friday in order to facilitate sample 
collection, processing and shipment to Sponsor to avoid weekend deliveries.  
  


Nintedanib AML Version 7 21 MAY 2019 
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Figure 2. Global treatment strategy of the Phase II portion of the study 
NIN/PLA: Nintedanib/ Placebo, CR: complete response, CRp: CR with incomplete counts 
recovery.  Patients can receive up to 2 induction and 2 consolidation cycles. 
 
 
 


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1.5.2 Drug Dose adjustments 
 
1.5.2.1 Criteria for interruption of treatment with nintedanib/placebo 
 
Treatment with nintedanib must be interrupted if any of the criteria listed in Table1 is 
fulfilled and in the absence of alternative probable cause. 
Table 1: Criteria when to interrupt treatment with nintedanib /placebo due to an adverse 
event 
If one criterion is met, nintedanib/placebo must be interrupted 
□ nausea of CTCAE grade ≥ 3 despite supportive care 
□ vomiting of CTCAE grade ≥ 2 despite supportive care 
□ diarrhea of CTCAE grade ≥ 2 for more than 3 consecutive days despite supportive care 
□ AST and/or ALT elevations of > 2.5 x ULN in conjunction with bilirubin of > 1.5 x ULN 
persisting after repeat testing over a 24-hour period. AST and/or ALT elevations of > 5x ULN  
□ other non-hematological adverse event of CTCAE grade ≥ 3 considered drug-related 
 
 
1.5.2.2 Criteria to restart nintedanib/placebo treatment 
 
A patient is eligible to restart nintedanib (BIBF1120)/placebo if all criteria listed in table 2 are 
met. If a patient has to interrupt intake of nintedanib/placebo due to an adverse event for more than 
7 days, the decision to restart treatment with nintedanib (BIBF1120) needs to be discussed and 
agreed upon between the investigator and the sponsor. 
 
 
 
 
 
 
 


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Table 2: Criteria to assess eligibility to restart/continue nintedanib (BIBF1120)/placebo treatment  
All criteria must be met in order to restart nintedanib/placebo, meaning AEs have to return to 
Grade 1 or baseline, with the exceptions of the specific managements of the AE listed below 
□ nausea CTCAE grade ≤ 2 
□ vomiting CTCAE grade ≤ 1 
□ diarrhea CTCAE grade < 2 
□ AST and ALT < 2.5 x ULN; bilirubin < 1.5 x ULN   
□ no other non-hematological adverse event grade CTCAE ≥ 3 which is considered drug-related 
1.5.2.3 Dose adjustments during treatment 
After cycle 1, if the lifetime cumulative dose of anthracycline reaches 500mg/m2, idarubicin will be 
switched to etoposide 100mg/m2/d day 1 to 3.  
In case of severe hematologic or non-hematologic adverse events, dose of 
nintedanib/idarubicin/cytarabine could be adjusted for the subsequent cycles of treatment 
(IDA/CYTA) or when NINTEDANIB is restarted. Dose adjustment should be systematically discussed 
with coordinating investigator and may qualify for the definition of SAE and its related procedure.  
Given the toxicity profile of the different drugs it is likely that hematological toxicities will be related 
to idarubicin and/or cytarabine and dose adjustment will be done accordingly. Drugs are dose 
reduced independently and after discussion with the Protocol PI. Specific procedure should be 
applied in case of potential drug induced liver toxicity (see Appendices section).  
Table 3 
Drug 
Dose level 1 
Dose level -1 
Dose level -2 
Idarubicin (IV Push 
over 10-15 minutes 
Days 1-3 
12mg/m2/d 
8mg/m2/d 
Stop drug 
Cytarabine Daily (24 
hr.) IV infusion  
Days 1-3 
0.667 g/m2/d  
0.300 g/m2/d 
150mg/m2  
Nintedanib PO  
Days 8-28 
200mg bid 
150 mg bid 
100 mg bid 
For patients with a prior dose reduction, it could be discussed with the sponsor to re increase the 
dose of medication if the adverse event has fully resolved and if it was the first episode of this 
specific drug related AE.  
 
 


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Recommended dose adjustments for Nintedanib (BIBF1120) 
As an initial measure for the management of side effects treatment with nintedanib should be  
temporarily interrupted until the specific adverse reaction has resolved to levels that allow  
continuation of therapy. Nintedanib treatment may be resumed at a reduced dose. Dose  
adjustments in 100 mg steps per day (i.e. a 50 mg reduction per dosing) based on individual  
safety and tolerability are recommended as described in Table 4 shown below. In case of  
further persistence of the adverse reaction(s), i.e. if a patient does not tolerate 100 mg twice  
daily, treatment with nintedanib should be discontinued. 
 
Phase II dose reduction will be dependent on the MTD determined in Phase I. Dose  
reductions during phase II will be managed in 50mg increments to a minimum dose of  
100mg.  Patients who cannot tolerate the 100mg dose will be taken off treatment. 
 
Table 4: 
 
CTCAE* Adverse reaction 
Dose adjustment 
Diarrhea > grade 2 for more than 7 consecutive 
days despite anti-diarrheal treatment 
OR 
diarrhea > grade 3 despite anti-diarrheal treatment 
1st episode 
Reduce dose from 200 mg twice daily to  
150 mg twice daily 
 
2nd episode  
Reduce dose from 150 mg twice daily to  
100 mg twice daily   
 
3rd episode 
Stop treatment  
Vomiting ** > grade 2  
AND/OR 
Nausea > grade 3 despite anti-emetic treatment 
AST and/or ALT elevations of > 2.5 x ULN in      
conjunction with bilirubin of > 1.5 x ULN persisting 
after repeat testing over a 24-hour period.  OR AST 
and/or ALT elevations of > 5x ULN 
Dose adjustment/reduction will occur per dosing 
table 3 if Nintedanib is re-started after being held  
Other non-hematological adverse reaction of > 
grade 3 
Elevation of AST and/or ALT values to > 3 x ULN in 
conjunction with an increase of total bilirubin to ≥ 
2 x ULN and ALKP < 2 x ULN 
Unless there is an alternative cause 
established, Nintedanib should be 
permanently discontinued 
  
*CTCAE: Common Terminology Criteria for Adverse Events 


Nintedanib AML Version 7 21 MAY 2019 
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Patients should PERMANENTLY discontinue treatment with nintedanib (BIBF1120) in the event of: 
• Intolerable Adverse Events (CTCAE grade 3 or 4) that cannot be managed by dose 
reduction. 
• Withdrawal of informed consent. 
 
1.6 Definition of dose limiting toxicities (DLT) during phase I 
 
In order to determine safety of the combination, all adverse events will be recorded on the 
case report forms and graded using the NCI CTC criteria (version 4.03). Toxicities not listed on the 
CTC will be graded as mild, moderate, or severe. The local Investigator, in consultation with the 
clinical staff caring for the patient, and the Protocol PI will determine the relationship to study drugs 
(unrelated, unlikely, possibly related, probably related, related). Dose limiting toxicity (DLT) will be 
either as specified below; for organ systems not included, DLT will also include any Grade III or IV 
non-hematologic toxicity thought possibly or probably related to study drug administration.  
Specifically defined DLTs: Drug-related vomiting and nausea CTCAE grade >/= 2 for 5 or more 
consecutive days despite optimal supportive care. Drug-related diarrhea CTCAE grade >/= 2 
persisting for 8 or more consecutive days despite optimal supportive care. Drug-related hypertension 
CTCAE grade >/= 3 despite optimal supportive care or intervention.  
Drug-related transaminase elevation (ALT and/or AST) CTCAE grade >/= 3 or transaminase elevation 
CTCAE grade >/= 2 (ALT and/or AST) in conjunction with bilirubin CTCAE grade >1. All other drug-
related non-hematological toxicities of CTCAE grade >/= 3, except for isolated GGT increases. All 
other drug-related non-hematological toxicities of CTCAE grade 2 leading to an interruption of the 
BIBF 1120 treatment for >/=14 consecutive days  
Because all patients will be receiving cytarabine and idarubicin in conjunction with nintedanib, 
patients will not be evaluable for nintedanib- associated hematological toxicity.  
Patients will have bone marrow assessed at physician's discretion by day 35 of treatment. If blood 
counts have not recovered, but marrow is free of morphologic evidence of leukemia, patients may be 
followed clinically until day 45. If counts have not recovered by day 60 and there is no morphologic 
evidence of leukemia, this will be considered a nintedanib- associated hematologic DLT.  


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If <2/6 patients experience Nintedanib attributable dose limiting toxicity, we will proceed to the 
randomized Phase II trial. If >/= 2 patients experience attributable DLT, six additional patients will be 
treated with dose level - 1 of nintedanib (150 mg BID). Assuming that <2/6 patients experience 
Nintedanib attributable dose limiting toxicity at the reduced dose, we will proceed to the randomized 
Phase II trial -1 dose level of nintedanib.  
 


Nintedanib AML Version 7 21 MAY 2019 
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1.7 Statistical plan 
 
The feasibility phase is structured similar to a classic 3 + 3 Phase I study. The first six patients will be 
treated at the targeted dose. Like most Phase I studies, this dose will be considered feasible if <2/6 
patients experience attributable DLT. If at least two patients experience attributable DLT, six 
additional patients will be treated at dose level -1. If fewer than 2 patients experience attributable 
DLT, that dose will be used in the Randomized Phase II portion of the trial.  
The primary endpoint of the Randomized Phase II portion is the complete remission rate. The 
randomized phase II portion of the study utilizes a group sequential design to test the hypothesis 
that arm A (nintedanib+chemotherapy) will have a complete response rate of 40% after one cycle of 
treatment compared to 15% in arm B (Placebo+chemotherapy). Estey, Thall, and David reviewed the 
outcomes of salvage therapy for AML48. They stratified patients based on length of first remission 
(S1: if greater than 2 years) and whether the therapy was first or subsequent salvage (S2: first 
remission 1 – 2 years, S3: First remission 0- 1 year, first salvage: S4: First remission 0 – 1 year, 
receiving > first salvage). CR rates for S2, 3, and 4 were 47%, 14%, and 0. We will not be treating S1 in 
this protocol. Thus, a 40% response rate appears to be very robust for a mix of S2 to S4 patients. 
While it is highly unlikely that the control (placebo) arm will have a comparable CR rate, without the 
control arm the success of the addition of nintedanib will not be clear. Using the group sequential 
design we will minimize the number of patients receiving placebo. For example, if 0/8 patients in the 
placebo arm achieve remission, the arm will be stopped for futility. In contrast, if 5/11 patients in the 
nintedanib arm achieve CR, the study can be declared a success.   
For Phase II, OnCore will be used to randomize the patients by assigning a sequence number that will 
correspond to the treatment assignment. The list that includes the sequence number with the 
corresponding treatment assignment will be generated by the study statistician and released only to 
the research pharmacist at the site.  The group sequential design allows termination of either arm at 
early time points due to either futility or efficacy. In a randomized Phase II trial, each arm is 
compared to a historic control. The studies are not powered to officially compare the arms. Rather, 
they serve as “pick the winner” strategies. The null hypothesis is that each arm achieves a 15% 
response rate. The trial is powered to select an arm (presumably the experimental arm) which 
achieves a 40% response rate. At the point at which either arm can no longer demonstrate a 40% 
response rate, the arm is terminated for futility. Each arm is monitored following each accrual 
beginning with patient 8. The design assumes overall Type I error of 10% (1-sided) and 80% power. 


Nintedanib AML Version 7 21 MAY 2019 
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The following table demonstrates the number of responses at each accrual which would stop the trial 
for either futility (third column) or efficacy (fourth column):  
Analysis 
Number of included 
patients 
Number of 
responses to stop 
for futility  
Number of 
responses to stop 
for efficacy 
1 
8 
0 
4 
2 
9 
1 
4 
3 
10 
1 
5 
4 
11 
1 
5 
5 
12 
2 
5 
6 
13 
2 
5 
7 
14 
2 
6 
8 
15 
2 
6 
9 
16 
3 
6 
10 
17 
3 
7 
11 
18 
3 
7 
12 
19 
3 
7 
13 
20 
4 
7 
14 
21 
4 
8 
15 
22 
4 
8 
16 
23 
4 
8 
17 
24 
5 
8 
 
While this is a randomized Phase II study and each arm is ultimately statistically compared to the 
historical control, the response rates will be qualitatively compared between the two arms in order 
to get a sense whether the positive signal in the nintedanib arm is strong enough to warrant further 
development in larger trials.   
 


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1.8 Patient selection 
1.8.1 Inclusion criteria 
 
Patient must meet all of the following criteria to be eligible for the study 
1/ Patient aged 18y or older 
2/ Diagnosis of AML according to WHO 2008 criteria49. Therapy related AML may be included if in 
complete response and off treatment for their prior malignancy for more than 2 years. AML arising 
after documented MPD are excluded. 
3/ Patient must meet one of the following criteria:  a/ patient refractory to one or two standard 
induction regimen b/ patients with a first untreated relapse within 2 years of documentation of 
clinical remission. Patients relapsing after allogeneic stem cell transplantation are eligible if more 
than 6 months after transplantation and without sign of active GVHD. 
4/ Patient may have been pretreated with intermediate to high dose cytarabine (more than 
1000mg/m2/d over 5d) if the day of the last infusion was at least 90 days before inclusion in the 
study. 
5/ ECOG performance status of 2 or less  
6/ Patient is willing to participate to the study, has the ability to adhere to the study visit schedule and 
other protocol procedures, and has the ability to understand and signs an informed consent form. 
7/ Women of childbearing potential must agree to use effective contraception without interruption 
throughout the study and for a further 3 months after the end of treatment; 
8/ Men must agree to not conceive during the treatment and to use effective contraception during the 
treatment period (including periods of dose reduction or temporary suspension) and for a further 3 
months after the end of treatment if their partner is of childbearing potential. 
 
 


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1.8.2 Exclusion criteria 
 
Any of the following criteria excludes the patient from participating to the study. 
1/ Patient with documented acute promyelocytic leukemia and/or PML-RAR transcript. 
2/ Patient relapsing more than 2 years after initial remission. 
3/ Use of any active treatment for relapse/refractory AML including but not restricted to 
chemotherapy, targeted agents, hypomethylating agents or investigational drugs. Use of 
hydroxyurea up to 6g per day for cytoreduction is allowed for a maximum of 30 days prior treatment.  
4/ Patients with clinical evidences of active CNS disease at inclusion  
5/ LVEF below 45% or lifetime exposure to anthracyclines over 350mg/m2 of daunorubicin 
equivalent 
6/ Liver function tests: AST ALT above 2.5 ULN, total bilirubin above 2.5 ULN in the absence of 
Hemolysis or diagnosis of Gilbert’s syndrome  
7/ Serum creatinine above 2.0mg/dl  
8/ Any sign of active uncontrolled disease including but not restricted to cardiac disease, infections, 
hepatitis. Any severe chronic disease potentially interfering with the protocol including HIV infection, 
active hepatitis B or C.  It includes major injuries and/or surgery within the past 4 weeks prior to start 
of study treatment with incomplete wound healing and/or planned surgery during the on-treatment 
study period. 
9/ Documented platelet refractoriness.  
10/ Patient has a history of GI surgical procedures, non-surgical procedures or conditions that might 
interfere with the absorption or swallowing of the study drugs. 
11/ Women who are pregnant, or who are currently breastfeeding 
12/ Prior treatment with nintedanib or any other VEGFR inhibitor, With the exception of treatment 
of prior malignancies with a VEGFR inhibitor.   
13/ Known hypersensitivity to nintedanib, any other trial drug, or their excipients 


Nintedanib AML Version 7 21 MAY 2019 
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14/ Persistence of any clinically relevant (CTCAE grade 2 or above) non-haematological toxicities from 
previous AML therapy  
15/ Active alcohol or drug abuse 
16/ Any other condition that, according to the investigator, may forbid the administration of the 
idarubicin+cytarabine regimen 
17/ Therapeutic anticoagulation with INR modifying drug of or use of antiplatelet therapy (with the 
exception of low dose aspirin<325mg/d) 
18/ Any malignancies requiring active treatment within the past year other than basal cell skin cancer or 
carcinoma in situ of the cervix. Patients actively treated with hormonotherapy for prostate cancer or 
breast cancer are eligible. 
 
 


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1.9 Enrollment Procedure 
 
Prior to obtaining signed consent from a patient, the site principal investigator or coordinator 
must email the project manager to inquire about study space availability. If a slot is available, the 
potential study participant will complete the consent process.  The informed consent process 
must be completed before any study screening procedures may begin.   Following consent 
patients will have all required screening procedures outlined in Section 10. The site principal 
investigator or other approved investigator must document that the patient has met all inclusion 
criteria and has none of the exclusion criteria. Following completion of eligibility testing, 
eligibility documents will be sent to the YCCI project manager. Examples of required documents 
are listed in the manual of operations.  
Upon review and approval by the Project Manager, the PM will send back the patients’ study ID # 
and dose assignment (for Phase II) to the study team via email. The study team will register the 
patient into the Clinical Trials Management System, OnCore. During the Phase II portion of the 
study, the study sites will use OnCore to randomize the patient and receive a sequence # that 
corresponds to the study arm.  
 
 
 


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1.10 Assessments  
 
Written informed consent will be obtained from the patient before any study specific procedure is 
undertaken and documented in the patients’ medical record.  
Patients will be informed about the study, both verbally and by reviewing the consent form with the 
study investigator. The patient must be given the opportunity to ask questions and given time to 
consider his or her participation. The investigator and the patient will both sign and personally date 
the consent form as confirmation of consent. A copy of the consent form will be given to the patient.  
The screening assessments and study procedures apply to both Phase I and Phase II.  
1.10.1 Screening period 
 
The screening period is the time preceding registration and includes the 14-day period for 
performing screening assessments.  
The following assessments will be completed within 2 weeks prior to the first dose of study drug:  
• 
Informed Consent 
• 
Medical history,   
• 
Complete physical examination,   
• 
Body weight, height and vital signs,   
• 
ECOG performance status,   
• 
EKG,   
• 
Chest X-ray,   
• 
assess left ventricular ejection fraction (LVEF); using 3D Echocardiogram or the 
biplane Simpson method. 
• 
Concomitant medication,   
• 
Hematology: Complete Blood Cell Count (CBC) with differential (differential done as 
per hospital standard of care) entire panel is required at screening 
• 
Serum chemistry: AST, ALT, alkaline phosphatase, total bilirubin, BUN, serum 
creatinine, glucose, calcium, sodium, potassium, magnesium, chloride, bicarbonate, 
total protein, albumin, uric acid, LDH, and Beta HCG (women of childbearing 
potential only) 


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• 
Hepatitis B and C, HIV1 and 2 serologies  
• 
Coagulation profile: prothrombin time, activated partial-thromboplastin time, 
fibrinogen,   
• 
 Additional examination when clinically indicated (lumbar puncture, CT-scan, PET CT 
scan).  
• 
Bone marrow evaluation including a new cytogenetic and molecular characterization 
at the time of relapse,   
• 
Pharmacodynamic assessment: collection of blood (5 x 4mL) and bone marrow 
samples (8mL).  
The following assessments will be performed just prior to treatment from day – 1 to 1:  If these tests 
are performed within 24 hours of the Cycle 1 Day 1 visit, prior to administration of study drug, they 
do not need to be repeated on Cycle 1 Day 1, unless otherwise determined by the Principal 
Investigator.  
• 
Physical examination,  
• 
Body weight,  
• 
ECOG performance status,  
• 
Hematology = CBC with differential (differential done per hospital standard of care) 
• 
Serum chemistry. It includes AST, ALT, alkaline phosphatase, total bilirubin, BUN, 
serum creatinine, glucose, calcium, sodium, potassium, magnesium, chloride, 
bicarbonate, total protein, albumin and LDH.  
• 
Coagulation profile: prothrombin time, activated partial-thromboplastin time, 
fibrinogen,  
• 
Bacterial, fungal and viral cultures of throat, stool and urine, if clinically indicated,  
• 
Pregnancy test (women of childbearing potential only) 
 
 
 


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1.10.2 Evaluation during treatment period 
The treatment period begins Cycle 1 Day 1 and can continues until up to 30 days after the last dose 
of Nintedanib. The treatment period can include a maximum of 2 (28 day) induction and 2 (28 day) 
consolidation cycles.  If Maintenance therapy is indicated, patients will be followed monthly for the 
first 12 months and then every three months for the following year (a maximum of 24 months).  
Number and type of cycle will vary by patient and according to local SOC procedures.  
Labs between day 8 and counts recovery can be done +/-2day 
The following assessments need to be completed:  
• 
Physical examination daily from day 1 to day 6 and then twice weekly during the 
induction cycle(s) 1 and 2 (if receiving a second cycle). During consolidation cycle(s) 1 
and 2 at day 1, then weekly, and at the end of each cycle.  
• 
ECOG performance status weekly during the first induction cycle and at the end of each 
cycle thereafter,  
• 
Any adverse event,   
• 
Concomitant medication,   
• 
CBC with differential daily from day 1 to day 5 and then every other day for the first 
cycle and three times weekly of each cycle thereafter, (differential done as per hospital 
standard of care) entire panel required at response evaluation 
• 
Serum chemistry daily from day 1-5.  Then at a minimum of twice weekly,3-4 days apart 
(+/- 2 days) during the first cycle and every other week each cycle thereafter. It includes 
AST, ALT, alkaline phosphatase, total bilirubin, BUN, serum creatinine, glucose, calcium, 
sodium, potassium, chloride, bicarbonate, total protein, albumin, LDH and magnesium  
• 
Pregnancy test prior the beginning of each new treatment cycle (women of childbearing 
potential only) 
• 
Coagulation profile daily from Day 1-5 of cycle 1 and then weekly during the first two 
cycles: prothrombin time, activated partial-thromboplastin time, fibrinogen,  
• 
Bone marrow evaluation will be performed in patients with complete clearance of blasts 
in the blood on Day 14 (+/- 1 day) and at the end of cycle 1 Day 28 (+/- 7 days) and 
decided by local investigator based on count recovery.  Threshold: ANC at 1 and PLT at 
50,   
• 
Assess LVEF before cycle 2; this can be done any time after Cycle 1 day 14 up to the start 
of cycle 2, ideally closer to cycle 2 Day 1 using 3D Echocardiogram or the biplane 
Simpson method. 


Nintedanib AML Version 7 21 MAY 2019 
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• 
Pharmacodynamic assessment: collection of blood (5 x 4mL) and bone marrow samples 
(5-6mL if a bone marrow aspirate is performed) at day 8, 14 (+/-1d) and at the end of 
the cycle (in patients with complete clearance of blasts in the blood). Day 8 bone 
marrow aspirate is optional and will be performed in patients who specifically 
consented. If patient consents to D8 optional BMBX, start Nintedanib/placebo on 
afternoon dose after BMBX and continue until D29 morning dose. 
 
 


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1.10.3 Maintenance 
 
If maintenance therapy is indicated, patients will continue to be followed monthly (+/-3d) for the first 
12 months and every 3 months for the following year (+/-7d), (a maximum follow-up of 24 months). 
Follow-up will include  
• 
Physical examination,  
• 
ECOG performance status 
• 
Adverse events,   
• 
Concomitant medication,   
• 
CBC with differential; monthly for the first 12 months than every other month for an 
additional 6 months (differential done as per hospital standard of care) 
• 
Serum chemistry monthly for 6 months then every other month. It includes AST, ALT, 
alkaline phosphatase, total bilirubin, BUN, serum creatinine, glucose, calcium, sodium, 
potassium, chloride, bicarbonate, total protein and albumin.  
• 
Pregnancy test prior to the beginning of each new treatment cycle (women of 
childbearing potential only)  
• 
Coagulation profile every other month for 6 months: It includes prothrombin time, 
activated partial-thromboplastin time, fibrinogen  
1.10.4 End of study treatment evaluation 
 
A clinical work-up is to be performed at the end of treatment with Nintedanib within 30 days after 
the last administration of Nintedanib:  
• 
Complete physical examination,   
• 
Weight,   
• 
ECOG performance status,   
• 
Vital signs,   
• 
Any adverse event,   
• 
EKG,   
• 
Assess LVEF, using 3D Echocardiogram or the biplane Simpson method, after Cycle 1 
EOT visit ONLY 
• 
 Concomitant medication,   
• 
Hematology: CBC with differential and hemoglobin,   


Nintedanib AML Version 7 21 MAY 2019 
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• 
Serum chemistry including AST, ALT, alkaline phosphatase, total bilirubin, BUN, 
serum creatinine, glucose, calcium, sodium, potassium, magnesium, chloride, 
bicarbonate, total protein, albumin, and LDH 
• 
Bone marrow evaluation will be performed in patients with complete clearance of 
blasts in the blood,   
• 
Pregnancy test up to 3 months after last dose of Nintedanib (women of childbearing 
potential only) 
• 
Pharmacodynamic assessment: collection of blood (5 x 4mL) and bone marrow 
samples (5-6 mL if a bone marrow aspirate is performed).    
1.11 Concomitant treatments 
 
Patients may not receive chemotherapy, radiation therapy, or any investigational antineoplastic 
agent. Immunosuppressive agents are prohibited during the course of trial participation. Systemic 
and chronic inhaled steroids may not be used during participation, with the exception of intermittent 
use of corticoids for the treatment of nausea and vomiting, or as part of an anti-emetic regime or as 
treatment of immunoallergic reactions during platelets or blood transfusions.  
During the induction cycles, G- and GM-CSF may be used only in case of prolonged neutropenia or 
neutropenic sepsis if non-blastic aplasia is obtained; there will be no such constraints in subsequent 
cycles.  Use of growth factors during consolidation and maintenance is allowed. 
Antibiotics and antifungals can be given according to institutional rules.  Antifungal prophylaxis with 
systemic azoles (fluconazole, voriconazole) should be avoided due to the risk of liver toxicity. For 
other drugs, See drug interaction paragraph below for details. 
Patients should receive all necessary supportive care, including blood product transfusions, 
erythropoietin, and pain medications. The related information will be reported in the CRF. Given the 
risk of bleeding shown with Nintedanib in previous studies, it is recommended to maintain platelet 
levels above 10^9/L. in the absence of platelet refractoriness. Moreover, the use of anticoagulation 
during treatment should be limited if possible and if therapeutic anticoagulation is mandatory, 
discontinuation of Nintedanib need to be discussed with principal investigator. 
All treatments given in addition to the study treatment(s) on entry to the study or at any time during 
the study are regarded as concomitant treatments and must be documented on the appropriate 
pages of the CRF. 


Nintedanib AML Version 7 21 MAY 2019 
35 
 
1.12 Drug interactions 
 
 
Nintedanib is a substrate of P-gp. Co administration with the potent P-gp inhibitor 
ketoconazole increased exposure to nintedanib 1.61 fold based on AUC and 1.83 fold based on Cmax 
in a dedicated drug-drug interaction study. In a drug-drug interaction study with the potent P-gp 
inducer rifampicin, exposure to nintedanib decreased to 50.3 % based on AUC and to 60.3 % based 
on Cmax upon co-administration with rifampicin compared to administration of nintedanib alone. If 
co-administered with nintedanib, potent P-gp inhibitors (e.g. ketoconazole or erythromycin) may 
increase exposure to nintedanib. In such cases, patients should be monitored closely for tolerability 
of nintedanib. Co administration with nintedanib should be carefully considered. 
Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John’s Wort) may decrease 
exposure to nintedanib. Co administration with nintedanib should be carefully considered.  
Cytochrome (CYP) enzymes: Only a minor extent of the biotransformation of nintedanib depends on 
CYP pathways. Nintedanib and its metabolites, the free acid moiety BIBF 1202 and its glucuronide 
BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes in preclinical studies. The likelihood of 
drug-drug interactions with nintedanib based on CYP metabolism is therefore considered to be low.  
 
 
 
 


Nintedanib AML Version 7 21 MAY 2019 
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1.13 Correlative studies 
 
Sampling flow chart 
Peripheral Blood (PB)=20 ml EDTA, bone Marrow Aspirate (BMA)= 8 ml baseline, 5-6 ml follow-up, Bone marrow biopsy 
(BMB), * potential significant hypoplasia 
• 
Baseline (day -14 to – 5):  PB, BMA, BMB 
• 
Day 8 (day 5 post chemo, day 0 of Nintedanib) = PB* 
• 
Day 8 OPTIONAL CONSENT (day 5 post chemo, day 0 of Nintedanib) = BMA 
• 
Day 14 (day 11 post chemo, day 6 of Nintedanib) = PB*, BMA*, BMB* 
• 
Day 28 (day 25 post chemo, day 20 of Nintedanib) = PB, BMA, BMB 
• 
End of Treatment= PB, BMA, BMB 
 
Correlative studies 
1/ Genomic profiling (baseline) 
There is a significant diversity in molecular profiling of relapse/refractory AML and specific 
aberrations may be associated with differential response to chemo/nintedanib. Moreover, it is 
anticipated that several of the pathways that will be evaluated by CyToF may already been triggered 
by activating mutations at baseline (e.g. FLT3 ITD and STAT). 
Objective: Determine the mutational landscape of the population. Correlate with response and 
pathway activation 
Methods: Whole exome sequencing/ Ion Torrent 490 gene panel / RNA sequencing 
 
2/ Bone Marrow microvessel density (Baseline, day 14, day 28) 
 
Microvessel density is a classical pharmacodynamic read out of VEGF inhibition. It can be evaluated 
on BM biospies routinely 
Objective: determine the density of microvessel on bone marrow biopsies and correlate it with 
Nintedanib exposure and response 
Methods: Immunostaining on BM trephine biopsy sample (VWF, CD31, CD34 staining) 
Optional= Stem cell niche evaluation 
 
 


Nintedanib AML Version 7 21 MAY 2019 
37 
 
3/ VEGF expression levels (Baseline, day 8, 14, and 28) 
VEGF can be secreted by bone marrow stroma and has been also described as potentially secreted by 
some AML blasts. Bone Marrow stress induced by chemotherapy can also trigger a VEGF response 
that may subsequently affect survival of AML blast and normal cells recovery pattern. VEGF inhibition 
by bevacizumab has been described as associated with an increase in VEGF levels.  
Objective: Determine patterns of VEGF expression before and during treatment. Evaluate the effect 
of Nintedanib on these patterns. Correlate it with Response 
Methods: Quantitative assessment by ELISA (Quantikine R&D).  
Optional: Aliquoted frozen serum will be stored and can be used to evaluate other cytokines related 
to Nintedanib (FGF, PDGF). 
 
4/ Nintedanib target receptors and downstream pathways analysis (Baseline, day 8, 14, and 
28) 
Nintedanib is inhibiting the 3 isoforms of VEGFR, (1 to 3) the 3 isoforms of FGF (1 to 3), and the 2 
isoforms of PDGFR (A and B). With the exception of FGFR2, all of these receptors have been 
described in subsets of AML. Downstream pathways are converging to PI3K/AKT, MEK/ERK, and STAT 
signaling. As previously mentioned some of these pathways may be constitutively active or triggered 
by other AML related pathways. 
Objective: Determine the expression pattern for the receptors and pathways (pAKT, pERK, pSTAT3, 
and pSTAT5 will be evaluated ) before and during treatment .  Correlate it with baseline molecular 
profile, Nintedanib exposure, and clinical response. 
Methods: CyToF (Viability, Gating, Pathways, apoptosis) 
Backup plan/ validation= IHC on BM trephine biospies (Flash frozen sample vs FFPE?) 
 
5/ Evaluation of Nintedanib impact in specific cell subsets (Baseline, day 8, 14, and 28) 
The effect of Nintedanib may be different according to the cell types and it may consequently 
influence response, toxicity, and risk of relapse. It seems interesting to evaluate Leukemic Stem Cells 
subpopulation (CD45+, CD34+, CD38-, CD123+, CD90-) marrow stromal cells (CD45-, CD31-, CD34-, 
CD73+, CD90+, CD105+) , peripheral blood/ marrow endothelial cells (CD45-, CD31+, CD34+, 
CD105+/-) lymphocytes (CD45+, CD3+ or CD19+), and potentially residual normal hematopoietic 
stem cells (CD45+, CD34+, CD38-, CD123+, CD90+) 
Objective: Evaluate the differences of impact of Nintedanib in AML cells vs the above mentioned 
subtypes (LSC, MSC, CEC, Lymphocytes) 
Methods: Cytof (Viability, Gating, pathways, apoptosis) 


Nintedanib AML Version 7 21 MAY 2019 
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Optional: Cell culture assays. When adequate cells are present, bone marrow mononuclear cells will 
be plated in methylcellulose for determination of CFU-L, a surrogate for leukemic stem cells. By 
comparing day 14 marrow CFU-L growth in patients on the two treatment arms, we can gain insight 
into whether nintedanib inhibits the proliferation and survival of leukemic stem cells (ie patients in 
chemo arm should grow more CFU-L on day 14 than patients in arm nintedanib+chemo). 


Ni nt e d a ni b A ML V ersi o n  7 2 1 M A Y 2 0 1 9 
3 9  
 
1. 1 4  St u d y tr e at m e nt s  
1. 1 4. 1  Ni nt e d a ni b  
 
Ni nt e d a ni b ( BI B F 1 1 2 0) is a p ot e nt s m all m ol ec ul e tri pl e r ec e pt or  tyr osi n e ki n as e i n hi bit or ( P D G F R  
[ pl at el et d eri v e d gr o wt h f act or r ec e pt or], F G F R 1-3 [fi br o bl ast gr o wt h f act or r ec e pt or], V E G F R 1 -3 
[v asc ul ar e n d ot h eli al gr o wt h f act or r ec e pt or]). V E G F R- 2 is c o nsi d er e d t o b e t h e cr uci al r ec e pt or 
i nv olv e d i n i niti ati o n of t h e f or m ati o n as w ell as t h e m ai nt e n a nc e of t u m o ur v asc ul at ur e. O n t h e 
m ol ec ul ar l e v el, ni nt e d a ni b is t h o u g ht t o i n hi bit t h e si g n ali n g c asc a d e m e di ati n g a n gi o g e n esis by 
bi n di n g t o t h e a d e n osi n e tri p h os p h at e ( A T P) bi n di n g p oc k et of t h e r ec e pt or ki n as e d o m ai n, t h us 
i nt erf eri n g wit h cr oss-activ ati o n vi a a ut o p h os p h or yl ati o n of t h e r ec e pt or h o m o di m ers. B esi d es 
i n hi biti o n of n e o-a n gi o g e n esis, t u m o ur r e gr essi o n m ay als o b e ac hi ev e d by i n d uci n g a p o pt osis of 
t u m o ur bl o o d v ess el e n d ot h eli al c ells. I n hi biti o n of r ec e pt or ki n as es m a y als o i nt erf er e wit h 
a ut ocri n e a n d p ar acri n e sti m ul ati o n of t u m o ur a n gi o g e n esis vi a acti v ati o n l o o ps i nv olvi n g V E G F, 
P D G F, a n d b F G F utiliz e d by p eri v asc ul ar c ells s uc h as p eric yt es a n d v asc ul ar s m o ot h m uscl e c ells. I n 
vitr o, t h e t ar g et r ec e pt ors ar e all i n hi bit e d by ni nt e d a ni b i n l o w n a n o m ol ar c o nc e ntr ati o ns. I n i n viv o 
n u d e m o us e m o d els, ni nt e d a ni b s h o w e d g o o d a nti -t u m o ur effic ac y at d os es of 5 0 – 1 0 0 m g/ k g, 
l e a di n g t o a s u bst a nti al d el a y of t u m o ur gr o wt h or ev e n c o m pl et e t u m o ur st asis i n x e n o gr afts of a 
br o a d r a n g e of diff eri n g h u m a n t u m o ur t y p es. Hist ol o gic al ex a mi n ati o n of tr e at e d t u m o urs s h o w e d a 
m ar k e d r e d ucti o n of t u m o ur v ess el d e nsit y by a p pr oxi m at ely 8 0 %.  
I n a ni m als, ni nt e d a ni b s h o w e d m o d er at e t o l o w bi o av ail a bilit y. I n t h e r e p e at ed d os e t oxicity st u di es, 
t h e n o a dv ers e eff ect l ev el ( N O A EL) w as 3 m g/k g i n t h e 1 3 w e ek st u dy i n C y n o m ol g us m o nk eys, 5 
m g/k g i n t h e 2 6 w e e k st u dy i n r ats, a n d 1 0 m g/k g i n t h e 5 2 w e e k st u dy i n R h es us m o n k eys. T oxiciti es 
at t h e n ext hi g h er d os e l ev els w er e m il d (i ncis or d e nt o p at hy i n r ats, g astr oi nt esti n al s y m pt o ms i n 
m o nk e ys). R el ev a nt hist o p at h ol o gic al fi n di n gs a b ov e N O A EL w er e o bs er v e d i n t h e g astr oi nt esti n al 
tr act, ki d n e ys, li v er, extr a h e p atic bil e d uct, ly m p h atic tiss u es, b o n e m arr o w, ex ocri n e gl a n ds, s ki n a n d 
c or p or a l ut e a. T hic k e ni n g of e pi p hys e al gr o wt h pl at e i n gr o wi n g a ni m als w as i nt er pr et e d as a ty pic al 
m ec h a nis m -r el at e d t oxicit y ass oci at e d wit h a V E G F R-2 i n hi bit or a n d w as s e e n acr oss s p eci es. Mil d 
c h a n g es of h a e m at ol o gic al a n d cli nic al c h e mistry p ar a m et ers (i ncr e as es of al d ol as e, -G T, AL T, A S T, 
L A P, GL D H) w er e s e e n i n r ats. Mi ni m al t o sli g ht c h a n g es i n i m m u n ot oxic ol o gic al p ar a m et ers a n d 
l y m p h oi d tiss u es m a y b e t h e c orr el at e t o t h e a d diti o n al i n hi biti o n of src f a mily n o n-r ec e pt or tyr osi n e 
ki n as es s u c h as l y m p h oc yt e s p ecific pr ot ei n ki n as e (lc k) a n d l y n. Ov er all, t h e hist o p at h ol o gic al 
fi n di n gs a n d c h a n g es of l a b or at or y p ar a m et ers w er e mil d t o m o d er at e a n d g e n er all y w er e c o nfi n e d 
t o t h e hi g h-d os e gr o u ps.  


Ni nt e d a ni b A ML V ersi o n  7 2 1 M A Y 2 0 1 9 
4 0  
 
Ni nt e d a ni b is n o n -m ut a g e nic, ev e n at hi g h d os es . As ex p ect e d, b as e d o n t h e m ec h a nis m of acti o n, 
t w o ex pl or at or y r e pr o d uctiv e t oxicit y st u di es i n r ats r ev e al e d a t er at o g e nic eff ect of ni nt e d a ni b wit h 
a st e e p d os e / eff ect r el ati o ns hi p a n d a n e arly o ns et of e m br y of et al d e at hs at l o w d os a g es.  
A s oft g el ati n c a ps ul e f or m ul ati o n of ni nt e d a ni b is us e d i n m a n. Aft er or al a d mi nistr ati o n, ni nt e d a ni b 
is a bs or b e d q uickl y. M axi m u m pl as m a c o nc e ntr ati o ns ( Cm ax ) g e n er all y occ ur 2 t o 4 h o urs aft er 
a d mi nistr ati o n. S o f ar, n o evi d e nc e f or a d evi ati o n fr o m d os e pr o p orti o n ality of t h e P K of ni nt e d a ni b 
h as b e e n o bs erv e d. St e a dy st at e is r e ac h e d l at est aft er o n e w e e k of d osi n g. T h e a bs ol ut e 
bi o av ail a bility of ni nt e d a ni b w as sli g htly b el o w 5 % aft er a d mi nistr ati o n as s oft g el ati n e c a ps ul e t o 
h e alt hy v ol u nt e ers. Aft er f o o d i nt a k e, a tr e n d t o w ar ds a n i ncr e as e d s yst e mic ex p os ur e ( ar o u n d 2 0 %) 
a n d a d el a y e d a bs or pti o n w as o bs erv e d c o m p ar e d t o a d mi nistr ati o n of ni nt e d a ni b u n d er f ast e d 
c o n diti o ns. Ni nt e d a ni b dis pl a y e d a hi g h v ol u m e of distri b uti o n d uri n g t h e t er mi n al p h as e ( Vz) a n d a 
hi g h t ot al pl as m a cl e ar a nc e; t h e t er mi n al h alf -lif e of ni nt e d a ni b is i n t h e r a n g e of 7 t o 1 9 h. 
Ni nt e d a ni b is m ai nly eli mi n at e d vi a f a ec es. O nly 0. 7 % of t ot al [ 1 4 C] r a di o activit y w as eli mi n at e d vi a 
t h e uri n e. T h e m aj or m et a b olit es ar e BI B F 1 2 0 2 a n d its gl uc ur o ni d e, w hic h is f or m e d by U G T 1 A 1 
(liv er a n d i nt esti n e) as w ell as U G T 1 A 7, U G T 1 A 8 a n d U G T 1 A 1 0 (i nt esti n e) e nzy m es. Ni nt e d a ni b is a 
s u bstr at e a n d a w e a k i n hi bit or of P-g p. C o -a d mi nistr ati o n wit h t h e p ot e nt P -g p i n hi bit or 
k et oc o n az ol e i n a d e dic at e d dr u g - dr u g i nt er acti o n st u dy i ncr e as e d ex p os ur e t o ni nt e d a ni b by a b o ut 
6 0 – 7 0 % f or A U C a n d by a b o ut 8 0 % f or C m ax c o m p ar e d t o a d mi nistr ati o n wit h o ut k et oc o n az ol e. C o - 
a d mi nistr ati o n wit h t h e P -g p i n d uc er, rif a m pici n, d ecr e as e d ex p os ur e t o ni nt e d a ni b t o a p pr oxi m at el y 
5 0 % b as e d o n A U C a n d t o a p pr oxi m at ely 6 0 % b as e d o n C m ax of t h e esti m at e aft er a d mi nistr ati o n 
wit h o ut rif a m pici n. P o p P K a n al ys es r e v e al e d r el ev a nt i nfl u e nc es of a g e, w ei g ht, r ac e, a n d s m o ki n g 
h a bits o n t h e P K of ni nt e d a ni b; eff ect siz es w er e m o d er at e. T h er e w as n o r el e v a nt dr u g -dr u g 
i nt er acti o n b et w e e n ni nt e d a ni b a n d p aclit ax el, d oc et ax el, c ar b o pl ati n, p e m etr ex e d, or m F OL F O X 6 ( 5-
F U/L V & Ox ali pl ati n) at cli nic all y us e d d os es.   
B as e d o n t h e p h as e I d os e esc al ati o n tri als, t h e M T D ( m axi m u m t ol er at e d d os e) w as d et er mi n e d t o 
b e 2 5 0 m g bi d f or t wic e d ail y d osi n g i n C a uc asi a ns a n d 2 0 0 m g bi d i n J a p a n es e p ati e nts wit h a 
m a n a g e a bl e s af ety pr ofil e i n a dv a nc e d c a nc er p ati e nts. T h e pr e d o mi n a nt a dv ers e e v e nts w er e 
n a us e a, di arr h e a , v o miti n g, a b d o mi n al p ai n a n d f ati g u e of m ostly l o w t o m o d er at e s ev erity. D os e 
li miti n g t oxiciti es ( DL T) w er e m ai nl y c o nfi n e d t o r e v ersi bl e h e p atic e nzy m e el ev ati o ns ( A S T, AL T, -
G T) w hic h i ncr e as e d d os e -d e p e n d e ntl y. M ost c as es occ urri n g at d os es of 2 5 0 m g a n d a b o v e, a n d a 
v ery l o w i nci d e nc e at d os es b el o w 2 0 0 m g a n d w er e r ev ersi bl e aft er disc o nti n u ati o n of ni nt e d a ni b 
tr e at m e nt. All a dv ers e e v e nts o bs er v e d aft er si n gl e a d mi nistr ati o n of si n gl e d os es of ni nt e d a ni b t o 


Nintedanib AML Version 7 21 MAY 2019 
41 
 
healthy volunteers were only of CTCAE grade 1 severity and fully reversible.  
Regarding the phase I trials combining nintedanib with pemetrexed, docetaxel, paclitaxel/ 
carboplatin, mFOLFOX or gemcitabine/cisplatin, the recommended dose of nintedanib is 200 mg bid. 
The pattern of the adverse events was comparable to the adverse event profile of the phase I 
monotherapy trials except for the chemotherapy related toxicities. There was no clinically relevant 
change in the pharmacokinetic parameters of nintedanib or in that of the cytotoxic compounds in the 
combined treatment. Dose limiting toxicity consisted mostly of liver transaminase elevations as in the 
monotherapy phase I trials with the exception of the combination of nintedanib with pemetrexed, 
where fatigue was the most relevant DLT. As in phase I monotherapy studies, CTCAE grade 3 
transaminase elevations occurred more frequently at doses of 250 mg bid than at doses of 200 mg 
bid or below. In these studies, encouraging signs of efficacy were observed including some complete 
and partial responses with single agent treatment.  
With respect to the phase II trials which have been concluded thus far and which all employed 
nintedanib as monotherapy, the pattern of the adverse events in patients with advanced solid 
tumours was similar to that observed in phase I monotherapy trials with gastrointestinal adverse 
events as the most frequent events. The majority of CTCAE grade 3 liver enzyme increases was 
reported in the higher dose group of 250 mg bid in phase II trials. They were reversible and occurred 
early after start of treatment. Overall in the phase I and II studies ALT increases were generally more 
frequent than AST increases. In patients with advanced NSCLC, nintedanib showed comparable signs 
of efficacy in Eastern Cooperative Oncology Group (ECOG) 0-1 patients compared to historical data of 
other VEGFR inhibitors in a similar patient population. Data from the randomised phase II trial 1199.9 
suggest signs of efficacy of nintedanib for ovarian cancer patients as well as in Asian patients with 
advanced hepatocellular carcinoma (1199.39), advanced colorectal cancer based on the data from 
phase II combination trial 1199.51with mFOLFOX6 and in Renal Cell Carcinoma (1199.26).  
Based on the overall safety profile, 200 mg bid of nintedanib is the recommended phase III dose for 
combination treatments with pemetrexed, docetaxel and paclitaxel/carboplatin. Available 
pharmacokinetic data indicate that the systemic exposure needed for biological activity can be 
achieved starting with doses of 100 mg qd nintedanib.  
With respect to the phase III trials, nintedanib in combination with docetaxel (1199.13) and in 
combination with pemetrexed (1199.14) in patients with advanced non-small-cell-lung- cancer 
(NSCLC), the safety of nintedanib in combination with either docetaxel or pemetrexed was in line 


Nintedanib AML Version 7 21 MAY 2019 
42 
 
with the known profile of nintedanib, with gastrointestinal AEs and liver enzyme elevations as the 
most frequent adverse events. Overall, adverse events were manageable in the majority of patients 
with symptomatic therapy and dose reductions. Nintedanib in combination with docetaxel 
significantly prolonged PFS in patients with stage IIIB/IV or recurrent NSCLC after failure of first-line 
chemotherapy. In the adenocarcinoma population, nintedanib plus docetaxel significantly prolonged 
centrally assessed PFS and OS. In the combination with pemetrexed, the addition of nintedanib to 
pemetrexed showed a relevant prolongation of PFS by central independent review, compared with 
placebo plus pemetrexed, although the trial was stopped prematurely.  
Additional precautions for nintedanib (BIBF1120) 
• Diarrhea  
Diarrhea was the most frequently reported gastro-intestinal event and appeared in close 
temporal relationship with the administration of docetaxel in the clinical trial LUME-Lung 1. 
The majority of patients had mild to moderate diarrhea. 6.3 % of the patients had diarrhea of 
grade ≥3 in combination treatment compared to 3.6 % treated with docetaxel alone. 
Diarrhea should be treated at first signs with adequate hydration and anti-diarrheal 
medicinal products, e.g. loperamide, and may require interruption, dose reduction or 
discontinuation of therapy with nintedanib.  
 
• 
Nausea and vomiting 
Nausea and vomiting, mostly of mild to moderate severity, were frequently reported 
gastrointestinal adverse events in the clinical trial LUME-Lung 1. Interruption, dose reduction 
or discontinuation of therapy with nintedanib (BIBF1120) may be required despite 
appropriate supportive care. Supportive care for nausea and vomiting may include medicinal 
products with anti-emetic properties, e.g. glucocorticoids, anti-histamines or 5-HT3 receptor 
antagonists and adequate hydration. In the event of dehydration, administration of 
electrolytes and fluids is required. Plasma levels of electrolytes should be monitored, if 
relevant gastrointestinal adverse events occur. 
 
Pharmaceutical/Drug Distribution  
 
Study drug will be supplied to each study site by Almac Clinical Services. Participating sites are 
responsible to ensure processes, procedures, and documentation are in place for storage, 
distribution, inventory control, and disposition.  
 
Accountability  
 
The study drug provided for this study is for use only as directed in the study protocol. It is the 
investigator/institution’s responsibility to establish a system for handling study treatments, including 
investigational medicinal products, so as to ensure that:  
 
1. Deliveries of such products from Almac are correctly received by a responsible person  


Nintedanib AML Version 7 21 MAY 2019 
43 
 
2. Such deliveries are recorded  
3. Study treatments are handled and stored safely and properly as stated on the label  
4. Study treatments are only dispensed to study patients in accordance with the protocol  
 
The study personnel will account for all study medications dispensed and returned. Certificates of 
delivery and return should be signed. At the end of the study, it must be possible to reconcile 
delivery records with records of usage and destroyed/returned stock. Records of usage should 
include the identification of the person to whom the study treatment was dispensed, the quantity 
and date of dispensing and unused study treatment returned to the investigator. This record is in 
addition to any drug accountability information recorded on the CRF. Any discrepancies must be 
accounted for Certificates of delivery and return must be signed, preferably by the investigator or a 
pharmacist, and copies retained in the investigator site file. 
 
1.14.2 Idarubicin 
 
Idarubicin hydrochloride is a DNA-intercalating analog of daunorubicin which has an inhibitory effect 
on nucleic acid synthesis and interacts with the enzyme topoisomerase II. The absence of a methoxy 
group at position 4 of the anthracycline structure gives the compound a high lipophilicity which 
results in an increased rate of cellular uptake compared with other anthracyclines. Its principal 
indication is the treatment of acute myeloid leukemia (frontline and relapse) in combination with 
other chemotherapeutic drugs, cytarabine in particular.  
General Pharmacokinetics: Pharmacokinetic studies have been performed in adult leukemia patients 
with normal renal and hepatic function following intravenous administration of 10 to 12 mg/m2 of 
Idarubicin daily for 3 to 4 days as a single agent or combined with cytarabine. The plasma 
concentrations of Idarubicin are best described by a two or three compartment open model. The 
elimination rate of Idarubicin from plasma is slow with an estimated mean terminal half-life of 22 
hours (range, 4 to 48 hours) when used as a single agent and 20 hours (range, 7 to 38 hours) when 
used in combination with cytarabine. The elimination of the primary active metabolite, Idarubicinol, 
is considerably slower than that of the parent drug with an estimated mean terminal half-life that 
exceeds 45 hours; hence, its plasma levels are sustained for a period greater than 8 days. 
Distribution: The disposition profile shows a rapid distributive phase with a very high volume of 
distribution presumably reflecting extensive tissue binding. Studies of cellular (nucleated blood and 
bone marrow cells) drug concentrations in leukemia patients have shown that peak cellular 
Idarubicin concentrations are reached a few minutes after injection. Concentrations of Idarubicin and 
Idarubicinol in nucleated blood and bone marrow cells are more than a hundred times the plasma 
concentrations. Idarubicin disappearance rates in plasma and cells were comparable with a terminal 


Nintedanib AML Version 7 21 MAY 2019 
44 
 
half-life of about 15 hours. The terminal half-life of Idarubicinol in cells was about 72 hours. The 
extent of drug and metabolite accumulation predicted in leukemia patients for Days 2 and 3 of 
dosing, based on the mean plasma levels and half-life obtained after the first dose, is 1.7- and 2.3-
fold, respectively, and suggests no change in kinetics following a daily x 3 regimen. The percentages 
of Idarubicin and Idarubicinol bound to human plasma proteins averaged 97% and 94%, respectively, 
at concentrations similar to maximum plasma levels obtained in the pharmacokinetic studies. The 
binding is concentration independent. The plasma clearance is twice the expected hepatic plasma 
flow indicating extensive extrahepatic metabolism. 
Metabolism: The primary active metabolite formed is Idarubicinol. As Idarubicinol has cytotoxic 
activity, it presumably contributes to the effects of Idarubicin. 
Elimination: The drug is eliminated predominately by biliary and to a lesser extent by renal excretion, 
mostly in the form of Idarubicinol. 
Hepatic and Renal Impairment: The pharmacokinetics of Idarubicin have not been evaluated in 
leukemia patients with hepatic impairment. It is expected that in patients with moderate or severe 
hepatic dysfunction, the metabolism of Idarubicin may be impaired and lead to higher systemic drug 
levels. The disposition of Idarubicin may be also affected by renal impairment. Therefore, a dose 
reduction should be considered in patients with hepatic and/or renal impairment 
Severe myelosuppression will occur in all patients given a therapeutic dose of this agent for 
induction, consolidation or maintenance. Careful hematologic monitoring is required. Deaths due to 
infection and/or bleeding have been reported during the period of severe myelosuppression. Pre-
existing heart disease and previous therapy with anthracyclines at high cumulative doses or other 
potentially cardiotoxic agents are co-factors for increased risk of Idarubicin-induced cardiac toxicity 
and the benefit to risk ratio of Idarubicin therapy in such patients should be weighed before starting 
treatment with Idarubicin. Myocardial toxicity as manifested by potentially fatal congestive heart 
failure, acute life-threatening arrhythmias or other cardiomyopathies may occur following therapy 
with Idarubicin.  So cardiac function should be carefully monitored during treatment in order to 
minimize the risk of cardiac toxicity of the type described for other anthracycline compounds. The 
risk of such myocardial toxicity may be higher following concomitant or previous radiation to the 
mediastinal-pericardial area or in patients with anemia, bone marrow depression, infections, 
leukemic pericarditis and/or myocarditis. Idarubicin was embryotoxic and teratogenic in the rat at a 
dose of 1.2 mg/m2/day or one tenth the human dose, which was nontoxic to dams. Idarubicin was 
embryotoxic but not teratogenic in the rabbit even at a dose of 2.4 mg/m2/day or two tenths the 
human dose, which was toxic to dams. There is no conclusive information about Idarubicin adversely 


Nintedanib AML Version 7 21 MAY 2019 
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affecting human fertility or causing teratogenesis.   
Drug interactions seems limited. 
 
1.14.3  
Cytarabine 
 
Cytarabine is considered to be the most effective drug in the treatment of AML (Döhner M., 2010). It 
is a cell-cycle specific anti-metabolite that is phosphorylated intracellularly and incorporated into 
DNA, resulting in the inhibition of DNA polymerases and DNA synthesis. For initial treatment of AML, 
cytarabine is typically administered by intravenous continuous infusion for 5-7 days at doses of 100-
200 mg/m2/day, usually in combination with an anthracycline. In the relapsed setting, cytarabine 
remains an option for treatment but is generally administered at higher doses either alone or in 
combination with other agents, and in a variety of schedules. Cytarabine is a well-known myelotoxic 
drug. High dose cytarabine (2 to 3 g/m2/day) regimens may cause severe non-hematologic adverse 
events, including the following: mucositis, diarrhea, ileus, abdominal pain, conjunctivitis, skin rash, 
anaphylaxis, non-cardiogenic pulmonary edema, cholestatic jaundice, elevations of transaminases 
and alkaline phosphatase, and cerebral and cerebrellar dysfunction. Because of those toxicities, 
intermediate-dose cytarabine (500 mg to 1 g/m2/day) regimens are generally used in patients 60 
years old or older [Milano G., 2002].  
Elimination of cytarabine is rapid with biphasic kinetics characterized by initial and terminal half- life 
of 15 minutes and from 1 to 3h respectively. It is a prodrug that must be converted in the cells into 
the 5’triphosphate ara-CTP to be active. In plasma, cytarabine is rapidly transformed by deamination 
through the cytidine deaminase in a inactive metabolite: Uracil arabinoside (Ara-U). Ara-U is the 
major metabolite and the only one detectable in plasma. This deamination mechanism is not 
saturated even at high dose (up to 3 g/m2/day) [Liliemark JO, 1985]. Given that cytarabine is 
activated intracellularly, no relationship is evidenced between cytarabine plasma concentrations and 
cytotoxic effects. In addition, there is no correlation between cytarabine plasma concentrations and 
Ara-CTP intracellular concentrations [Milano G., 2002]. Indeed, the accumulation of Ara-CTP into cells 
appears to be saturated at plasma concentrations above a rate of administration of 250mg/m2/h 
[Milano G., 2002]. [Plunkett W., 1992].  
Given the unique metabolism pathway of cytarabine involving specific enzyme (cytidine deaminase) 
and the rate limited accumulation of intracellular Ara-CTP, any clinically relevant interaction of 
Nintedanib on the PK of cytarabine is unlikely. To date no publication has documented such an 
interaction effect when cytarabine is combined with other cytotoxics.  


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1.15 Premature discontinuation of treatment 
 
The treatment may be discontinued prematurely for the following reasons: 
- toxicity, 
- disease progression, 
- refusal to continue the trial, 
- withdrawal of consent, 
- patient lost to follow up, 
- major protocol violation. 
Where possible, patients who have discontinued their treatment prematurely will receive the same 
follow-up as other patients. 
 
1.16 Unblinding procedure 
 
Unblinding will be considered for a specific patient  
1/ if he/she is not achieving response after first cycle of treatment (crossover) or  
2/ in case of unexpected serious adverse event potentially related to the study drug.  In case of an 
unexpected serious adverse event potentially related to the study drug, the investigator will request 
the sponsor to unblind the study. In all cases and until the procedure of unblinding has been fully 
discussed and completed, the drug/placebo should be suspended. If the unblinding is done, the 
patient will continue to be followed according to the protocol recommendations, including a 
potential premature discontinuation of treatment if appropriate. 
 


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1.17 Criteria for terminating the study 
 
The trial can be suspended or terminated by the sponsor after consultation with the review Board 
(IRB), or other regulatory body for the following reasons: 
- an unexpectedly high frequency and/or severity of toxicity, 
- insufficient patient recruitment, 
- insufficient quality of data collection. 
 
 


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1.18 Follow-up 
1.18.1 Phase I:  
 
Phase I patients will be followed up to 60 days after the last study drug administration in order to 
determine if any DLTs are attributable to Nintedanib.  When counts have not recovered by day 60 
and there is no morphological evidence of leukemia it is considered a Nintedanib associated 
hematologic DLT Sixty days is the maximum length of time to wait for someone to recover before 
they are removed from the study.   
Patients will then be followed every 3 months +/- 7 days for 24 months or until the patient begins 
receiving subsequent anti-cancer therapy or death, whichever comes first. The following information 
will be collected; first subsequent anti-cancer therapy (if applicable), documentation of last disease 
progression/relapse, and date of death. Patients or their caregivers will be contacted by phone. 
1.18.2 Phase II:  
 
Phase II patients will be followed every 3 months +/- 7 days for 24 months or until the patient begins 
receiving subsequent anti-cancer therapy or death, whichever comes first.  The following information 
will be collected; Information regarding the first subsequent anti-cancer therapy (if applicable), 
documentation/date of last disease progression/relapse, and date of death. Patients or their 
caregivers will be contacted by phone.  
 
  
 
 


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1.19 Serious Adverse events 
1.19.1 General definition 
 
An adverse event (AE) is any expected or unexpected harmful and unintended occurrence or exacerbation 
in a clinical trial subject, whether or not related to the trial or the investigational product. It can be a new 
intercurrent disease, exacerbation of a concomitant disease, an accident, or any other deterioration in the 
patient’s health, including abnormal laboratory findings. All AEs will be reported from the time that consent 
is obtained.  
Any medical condition that existed before the start of the study treatment and that remains unchanged or 
improves must not be recorded as an AE. If a medical condition worsens, it must be recorded as an AE. The 
diagnosis or syndrome rather than the individual signs or symptoms must be recorded on the AE pages of 
the case report form. 
An event is considered a serious adverse event (SAE) if it: 
 
Results in death; Death due to disease progression is excluded 
 
Is life-threatening, 
 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
 
Cause any persistent or significant disability/ incapacity, 
 
Causes a congenital anomaly, birth defect or abortion, 
 
Is a new cancer (that is not the condition of the study) 
 
Is associated with an overdose 
 
Is another medically significant event 
 
The terms disability and incapacity refer to any clinically significant physical or mental handicap, 
whether temporary or permanent, that affects the patient’s physical activity and/or quality of life. 
A medically significant event is any clinical event or laboratory finding considered by the investigator 
to be serious that does not meet the seriousness criteria defined above. It may pose a risk to the 
patient and require medical intervention to prevent one of the serious outcomes mentioned 
previously (e.g. an overdose, second cancer, pregnancy, and new information can be considered 
medically significant). 
The following are not considered as serious adverse events: 
 
Death due to disease progression  
 
Hospitalization for < 24 hours 
 
Hospitalization scheduled before the start of the trial and/or stipulated in the protocol (e.g. for 
biopsy or chemotherapy) 
 
The AE pages of the case report form and an SAE form should be completed for each AE considered serious. 
For each AE, the investigator shall provide information about the intensity, start and end dates, 
causality, the action taken, and the outcome 
 


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1.19.2 Definition of an expected serious adverse event 
(SAE-E) 
 
An expected SAE is an event already mentioned in the most recent version of the Investigator 
Brochure, or in the Summary of Product Characteristics (SmPC) for medicinal products that have 
already been granted marketing authorization (MA). This definition also applies to the trial drug when 
it is administered for the same population but for an unlicensed indication. 
 
1.19.3 Definition of an unexpected serious adverse event 
(SAE-U) 
 
Any adverse drug experience, the specificity or severity of which is not consistent with the current 
investigator brochure; or, if an investigator brochure is not required or available, the specificity or 
severity of which is not consistent with the risk information described in the general investigational 
plan.  “Unexpected” as used in this definition, refers to an adverse drug experience that has not been 
previously observed (e.g., included in the investigator brochure) rather than from the perspective of 
such experience not being anticipated from the pharmacological properties of the pharmaceutical 
product. [21CFR312.32(a)] 
1.19.4 Intensity 
 
The term intensity (severity) should not be confused with the term seriousness that serves as a guide 
for defining reporting obligations. 
 
The intensity of events shall be evaluated according to the excerpt from the CTC-AE classification, 
version 4.0 (Appendix 7). The intensity of adverse events not listed in this classification will be rated 
using the following terms: 
Mild (grade 1): does not affect the patient’s usual daily activities 
Moderate (grade 2): interferes with the patient’s usual daily activities 
Severe (grade 3): prevents the patient’s usual daily activities 
Very severe (grade 4): requires intensive care / is life-threatening 
Death (grade 5) 
 
 


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1.19.5 Causal relationship between an adverse event 
(SAE/AE) and the study treatment 
 
Assessment of attribution is made by consideration of all clinically relevant data prior to, during, and 
after occurrence of the event, including diagnostic tests to assess the cause of the event.  Clinically 
relevant data include, but are not limited to; underlying disease, past and present medical history (all 
concurrent non-malignant disease), concurrent medications, and timing between event and drug 
administration.  The mechanism of action and prior toxicology of the study drug should be 
considered. 
An adverse event is associated with the use of the drug when there is a reasonable possibility that 
the experience may have been caused by the drug. [21CFR312.32(a)] 
Attribution Standards per NCI – CTEP: 
Unrelated 
The Adverse Event is clearly not related to the investigational agent (s) 
Unlikely 
The Adverse Event is doubtfully related to the investigational agent(s) 
Possible 
The Adverse Event may be related to the investigational agent(s) 
Probable 
The Adverse Event is likely related to the investigational agent(s) 
Definite 
The Adverse Event is clearly related to the investigational agent(s) 
 
1.19.6   What to do in the event of a serious adverse 
event 
 
The investigator must report any Expected Serious Adverse Event (SAE-E) or Unexpected Serious 
Adverse Event (SAE-U) and adverse events of special interest (AESI) (see section 19.7) that occurs 
during the treatment period starting at the time consent is signed, or within 30 days after the last 
administration of the study drug, regardless of whether it is attributable to the study.  The event 
must be reported within 24 hours of learning of the event to the Yale Project Manager and Sponsor 
PI who will report to Boehringer Ingelheim.  Sites are responsible for reporting to their IRB per local 
policy.  All events will be forwarded by the PM to Boehringer Ingelheim as required.  
 
All SAEs should be entered into OnCore within 24 hours of the site becoming aware of the event.  
 
The Yale Project Manager shall provide SAEs and AESI to BI as per the method and timeline specified in 
section 1:19.9 
Any delayed serious adverse event (occurring after the 30-day period) that may reasonably be considered 
related to the treatment(s) described in the protocol or to the study must be reported, and no time limit 
applies to such adverse events. 


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For each event, the investigator shall complete the SAE reporting form provided at start-up. 
Additional information may be requested by the monitor (by fax, post, telephone, or during a visit). 
Nevertheless, any event that qualifies as expected but differs in its intensity, clinical course, or 
frequency will be considered as an unexpected event by the pharmacovigilance unit at Boehringer 
Ingelheim. 
 
1.19.7 Adverse events and laboratory values of special 
interest 
 
The following events are considered as Protocol-specified events of special interests: 
Any gastrointestinal- and non-gastrointestinal perforation, leakage, fistula formation, abscess 
• 
In such cases the following additional information needs to be collected, documented in the 
respective comment field of the CRF page and the respective narratives of the SAE form and 
emailed or faxed to the Yale Project Manager and Sponsor PI.  
• 
  Location of perforation, leakage, fistula, abscess 
• 
Location/extent of abdominal tumor manifestations, 
• 
Imaging & reports (CT, ultrasound, endoscopy, pathology, etc.) 
• 
Prior surgery (location, wound healing complications) 
• 
Concomitant diseases with GI involvement (e.g., M Crohn, vasculitis, tuberculosis, 
diverticulitis) 
• 
Thromboembolic events (or predisposition) 
Drug-induced liver injury is under constant surveillance by sponsors and regulators and is considered 
a protocol-specified adverse event of special interest (AESI). Timely detection, evaluation, and follow-
up of laboratory alterations of selected liver laboratory parameters to distinguish an effect of the 
investigational drug from other causes are important for patient safety and for the medical and 
scientific interpretation of the finding.  
The following are considered as protocol-specified AESI: 
• 
An elevation of ALT and / or AST > 5x ULN without bilirubin elevation measured in the same 
blood draw sample 
• 
An elevation of AST and/or ALT >2.5 fold ULN combined with an elevation of bilirubin to >1.5 
fold ULN measured in the same blood draw sample 
 
Patients showing above laboratory abnormalities need to be followed up until the protocol specific 
retreatment criteria have been met. 


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Protocol-specified AESI are to be reported in an expedited manner to by the PM to BI, similar to 
Serious Adverse Events, even if they do not meet any of the seriousness criteria.  
 
1.19.8 Reporting to the IRB 
 
Sites are responsible for reporting to their IRB per local policy.   
The PM will report to the Yale IRB all SAEs meeting the criteria for expedited reporting using HIC 
Form 710 FR 4: Unanticipated Problem Involving Risks to Subjects or Others (UPIRSOs), including 
Adverse Events (AEs) Reporting Form as per Yale IRB Policy 710.   
 
 
 


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1.19.9 Reporting to Boehringer Ingelheim 
 
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. 
All adverse events, serious and non-serious, that occur from the time of signing the informed consent 
through 30 days following cessation of Nintedanib will be collected and documented by the 
investigator.  
The Yale Project Manager shall report all SAEs and non-serious AEs which are relevant to a reported 
SAE by fax using BIs SAE form to BI Unique Entry Point as detailed below in accordance with the 
following timelines:  
• within five (5) calendar days upon receipt of initial and follow-up SAEs containing at least one fatal 
or immediately life-threatening event;  
• within ten (10) calendar days upon receipt of any other initial and follow-up SAEs.  
 
Boehringer Ingelheim Pharmaceuticals, Inc. 
900 Ridgebury Road 
Ridgefield, CT  06877 
Fax: 1-203-837-4329 
For each adverse event, the investigator will provide the onset date, end date, intensity, treatment 
required, outcome, seriousness, causal relationship and action taken with the investigational drug. 
The investigator will also determine the expectedness of each AE based on the listed adverse event 
section of Boehringer Ingelheim’s (BI’s) Investigator Brochure for the Product.  
The investigator does not need to actively monitor patients for adverse events once the clinical trial 
has ended. However, if the investigator becomes aware of an SAE(s) that occurred after the patient 
has completed the clinical trial (including any protocol specified follow-up period/Residual effect 
period), it should be reported to the PM if investigator considers it as relevant to the study drug. The 
PM will report to BI as required. 
 
 
 


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1.19.10 Follow-up of SAEs 
 
The investigator is responsible for providing appropriate medical follow-up for patients until the event 
has resolved or stabilized or until the patient's death. Sometimes this may mean that follow-up will 
extend beyond the patient’s withdrawal from the trial. 
The investigator shall send additional information to the Project Manager and Sponsor PI using the 
SAE report form provided at start-up specifying that this is a follow-up report and not an initial 
report) within 48 hours of receiving the information. The investigator must also send the final 
follow-up once the SAE has resolved or stabilized. 
 
The investigator shall keep the documents about the presumed adverse effect, in case anything 
needs to be added to the information previously sent. 
The investigator shall respond to requests for additional information in order to document the initial 
report. 
 
If an SAE is suspected of having been caused by Nintedanib, the Project Manager shall send the 
report to BI. 
 
 


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1.20 Multicenter management and coordination  
 
1.20.1 Data Management 
 
1.20.1.1 
Data Submission 
 
Data will be collected and managed in Yale’s web-based clinical trial management system, 
OnCore. The schedule for completion and submission of the electronic case report forms will be 
indicated within OnCore. The investigators are required to prepare and maintain adequate and 
accurate case histories designed to record all observations and other data pertinent to the 
investigation on each individual treated in the investigation. Data that are derived from source 
documents and reported on the eCRF must be consistent with the source documents or the 
discrepancies must be explained.  
 
1.20.1.2 
Monitoring 
 
The study principal investigator and YCCI are responsible for monitoring the performance of all of the 
participating sites. This will be performed by conducting a study site initiation visit, as well as 
regularly scheduled monitoring visits and/or remote monitoring throughout the life of the protocol. 
At the end of the trial, the monitor will then perform a study site close-out visit at all participating 
sites.  
YCCI will utilize their institution’s initiation, monitoring and close-out visit reports. Following each site 
visit, a visit report will be generated containing information on site activities, and a summary of 
pertinent points and action items together with a copy of the follow-up letter will be sent to each 
investigative site.  
During these monitoring visits, some of the items that will be reviewed are the following:  
• 
Training of the sites  
• 
Site personnel qualifications to participate in the trial  
• 
Confirmation that study related documents are current  
• 
Regulatory documents and compliance  
• 
Completion of informed consent by each subject  
• 
Compliance with the protocol 
• 
Confirm all SAEs and AEs have been reported to the local regulatory and Ethics/IRB 
Committees, BI and YCCI, as appropriate  
• 
Verify source documentation for completed CRFs  
• 
YCCI will document the required study monitoring activities in a Monitoring Plan.  


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1.20.2 Safety Evaluations 
 
Safety analysis will be conducted on all participants who have received at least one dose of therapy, 
and will include the frequency of all AEs and laboratory abnormalities as well as frequency of dose 
interruptions, dose reductions, and treatment discontinuation. Participants who receive one total 
cycle of treatment will be considered as having completed the evaluation for safety. Additional 
treatment cycles may be delivered if there are no safety concerns, there is no disease progression, 
and/or there is an indication of clinical benefit. Maintenance monitoring will occur on day 1 of every 
additional treatment cycle, unless indicated. 
 
Any safety concern or new information that might affect either the safety or the ethical conduct of 
this trial will be immediately forwarded to the principal investigator in written form. The principal 
investigator will be responsible for informing the IRB and Data and Safety Monitoring Committee 
(DSMC). If trends in toxicities are noted or stopping rules are met, the principal investigator will 
temporarily suspend enrollment while reviewing the episodes with the IRB and DSMC. Toxicity data 
must be submitted via OnCore at the end of each cycle of therapy. 
 
1.20.3 Safety Monitoring 
 
1.20.3.1 
Data and Safety Monitoring Committee 
 
The Yale Cancer Center Data and Safety Monitoring Committee (DSMC) will provide the 
primary oversight of data and safety monitoring.  The Yale DSMC will review and monitor 
compliance, toxicity and deviations from this study. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the study. 
Information that raises any questions about participant safety will be addressed with the Principal 
Investigator. 
 
The DSMC will review this protocol bi-annually, at a minimum. Information to be provided to the 
committee includes: a study narrative by the PI, a summary DSMC report produced by OnCore 
(which includes participant accrual, response, trial status history, SAEs, Adverse Events, Deviations 
and survival); audit results, and monitoring reports as applicable. Other information (e.g. scans, 
laboratory values) will be provided upon request.  
1.20.3.2 
Independent safety review committee (SRC) 
 
An independent safety review committee (SRC) assembled by the PI and comprised of one 
Investigator from both Yale, and Vanderbilt, two external AML experts and a statistician will meet, 
when required by the sponsor of the trial, and at least once after the inclusion of the first 6 
patients, to analyze tolerance and adverse events and decide on any action to be taken. 


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1.20.4 Audit Plan 
 
The YCCI Office of Quality Assurance and Training will audit the trial at least annually or as 
determined by the DSMC. The overall principal investigator, project manager and/or monitor may 
request access to all source documents and other study documentation for on-site or remote 
monitoring, audit or inspection. 
 
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the Principal 
Investigator or Yale. The purpose of these audits or inspections is to examine study-related activities 
and documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported in accordance with the protocol, institutional policy, and any 
applicable regulatory requirements. 
 
1.20.5 Protocol Research Team Meetings 
 
Scheduled meetings will be held via teleconference monthly, or more frequently depending on the 
activity of the protocol.  These meetings will include the protocol investigators and research staff 
involved with the conduct of the protocol. 
During these meetings the investigators will discuss: 
• 
Safety of protocol participants (adverse events and reporting) 
• 
Validity and integrity of the data (data completeness on case report forms and complete 
source documentation) 
• 
Enrolment rate relative to expectation of target accrual, (eligible and ineligible participants) 
• 
Retention of participants, adherence to the protocol and protocol violations 
• 
Protocol amendments 
 
 


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1.21 Ownership of data and confidentiality 
 
The investigator undertakes that he/she and anyone who monitors the conduct of the trial will ensure 
the confidentiality of all of the information until the trial results are published. This confidentiality 
requirement shall not apply to information that the investigator gives to patients in connection with 
their participation in the trial or to previously published information. 
The investigator undertakes not to publish, disclose, or use any trial-related scientific or technical 
information, in any way, either directly or indirectly.  
No written or verbal comments can be made about the trial without the sponsor's consent, since all 
of the information provided or obtained while the trial is being conducted legally belongs to the 
sponsor, which can use the information at its own discretion. 
 
 


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1.22 Publication 
 
All of the information arising from this trial shall be considered confidential, at least until completion 
of the appropriate analysis and subsequent checks by the trial sponsor, coordinating investigator, and 
statistician. 
 
Any publications, abstracts or presentations that include results from the trial must be submitted to 
the sponsor for approval. 
 
Any communications, articles, or presentations must also include a section mentioning the Yale 
University and the organizations that supported the research financially. 
 
The trial’s coordinating investigator will be the main (first or last) author. 
The first or last author (depending on the position given to the coordinating investigator) will be jointly 
selected by the sponsor and the CI. 
 
The investigators will be cited in order of the number of patients recruited for multicenter trials or 
based on their involvement in the protocol and/or the disease. The trial statistician will also be cited. 
 
Similarly, publications of ancillary results (biological studies) shall include the name of the person who 
carried out the ancillary study, as well as the names of anyone else involved in the ancillary study. 
 
 


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1.23 Ethical and regulatory aspects 
 
The clinical trial must be conducted in accordance with: 
- the ethical principles of the current version of the Declaration of Helsinki, 
- the guideline for Good Clinical Practice of the International Conference on Harmonization (ICH–E6, 
07/17/96), 
 
1.23.1 Institutional Review Board (IRB) 
 
Before conducting biomedical research on human subjects, sites are responsible for submission to 
their IRB per local policy, including amendments and renewals. 
 
1.23.2 Competent Authority 
 
Before conducting a clinical trial or having one conducted, the sponsor of the trial shall apply to the 
FDA for authorization. 
 
1.23.3 Subject information and consent 
 
Before biomedical research is conducted on a person, their voluntary, written, informed consent must be 
obtained, after they have been fully informed by the investigator during a consultation and given enough 
time to consider their decision. 
The consent form must be signed and dated personally by the trial subject and the investigator (the original 
copy shall be archived by the investigator, and one copy will be given to the trial subject). 
 
 
 
 
 
 


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1.23.4 Responsibilities of the sponsor 
 
The sponsor of the clinical trial is the individual or legal entity that takes the initiative for the 
biomedical research on human subjects, manages the trial, and ensures that provision has been made 
for its funding. 
The sponsor's main responsibilities are to: 
- request the opinion of the IRB on the initial project and substantial amendments, 
- request authorization for the initial project and substantial amendments from the IRB and regulatory 
authority, 
- provide information about the trial to the site directors, investigators, and pharmacists, 
- report any suspected unexpected serious adverse events related to any of the trial treatments to the 
regulatory authority, BI, and the trial investigators, 
- submit the annual safety report to the regulatory authority, 
- notify the regulatory authority of the start and end of the trial, 
- write the final clinical study report, 
- send the trial results to the regulatory authority and trial subjects, 
- archive essential trial documents in the sponsor's Trial Master File (TMF) folder for a minimum of 15 
years after the trial has ended. 
 
1.23.5 Responsibilities of investigators 
 
The principal investigator of each site undertakes to conduct the clinical trial in accordance with the 
protocol approved by the IRB 
The investigator must not make any changes to the protocol without the written authorization of the 
sponsor and unless the IRB has approved the proposed changes. 
It is the responsibility of the principal investigator at each site to: 
- provide the sponsor with his/her curriculum vitae as well as those of his/her co-investigators, 
- identify the members of his/her team who are participating in the trial and define their 
responsibilities, 
- recruit patients once authorized to do so by the sponsor. 
 


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It is the responsibility of each investigator to: 
- obtain informed consent, personally signed and dated by the subject, before carrying out any trial-
specific screening procedures, 
- regularly complete the case report form (CRF) of each patient enrolled in the trial and allow the 
clinical research assistant (CRA) to have direct access to source documents, so that the latter can 
validate the data on the CRF, 
- date, correct, and sign corrections on the CRF of each patient enrolled in the trial, 
- accept regular visits by the monitor, and any auditors appointed by the sponsor or inspectors from 
the regulatory authorities. 
 
All of the trial-related documentation (the protocol, consent forms, case report forms, investigator 
brochure, etc.) and source documents (laboratory results, X-rays, consultation reports, physical exam 
reports, etc.) are considered confidential and must be kept in a safe place. The principal investigator 
must store the data and a patient identification list for a minimum of 15 years after the end of the 
study. 
 
 


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1.24 References 
 
1. 
Ossenkoppele G, Lowenberg B. How I treat the older patient with acute myeloid leukemia. Blood 2015; 125(5): 767-74. 
2. 
Leopold LH, Berger MS, Cheng SC, Cortes-Franco JE, Giles FJ, Estey EH. Comparative efficacy and safety of gemtuzumab 
ozogamicin monotherapy and high-dose cytarabine combination therapy in patients with acute myeloid leukemia in first relapse. Clinical 
advances in hematology & oncology : H&O 2003; 1(4): 220-5. 
3. 
Leopold LH, Willemze R. The treatment of acute myeloid leukemia in first relapse: a comprehensive review of the literature. 
Leuk Lymphoma 2002; 43(9): 1715-27. 
4. 
Kampen KR, Ter Elst A, de Bont ES. Vascular endothelial growth factor signaling in acute myeloid leukemia. Cellular and 
molecular life sciences : CMLS 2013; 70(8): 1307-17. 
5. 
Hiramatsu A, Miwa H, Shikami M, et al. Disease-specific expression of VEGF and its receptors in AML cells: possible autocrine 
pathway of VEGF/type1 receptor of VEGF in t(15;17) AML and VEGF/type2 receptor of VEGF in t(8;21) AML. Leuk Lymphoma 2006; 47(1): 
89-95. 
6. 
Imai N, Shikami M, Miwa H, et al. t(8;21) acute myeloid leukaemia cells are dependent on vascular endothelial growth factor 
(VEGF)/VEGF receptor type2 pathway and phosphorylation of Akt. Br J Haematol 2006; 135(5): 673-82. 
7. 
Padro T, Bieker R, Ruiz S, et al. Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR 
(VEGFR-2) in the bone marrow of patients with acute myeloid leukemia. Leukemia 2002; 16(7): 1302-10. 
8. 
Hou HA, Chou WC, Lin LI, et al. Expression of angiopoietins and vascular endothelial growth factors and their clinical significance 
in acute myeloid leukemia. Leuk Res 2008; 32(6): 904-12. 
9. 
Aguayo A, Kantarjian HM, Estey EH, et al. Plasma vascular endothelial growth factor levels have prognostic significance in 
patients with acute myeloid leukemia but not in patients with myelodysplastic syndromes. Cancer 2002; 95(9): 1923-30. 
10. 
Ter Elst A, Ma B, Scherpen FJ, et al. Repression of vascular endothelial growth factor expression by the runt-related transcription 
factor 1 in acute myeloid leukemia. Cancer Res 2011; 71(7): 2761-71. 
11. 
Kruizinga RC, de Jonge HJ, Kampen KR, Walenkamp AM, de Bont ES. Vascular Endothelial Growth Factor A isoform mRNA 
expression in pediatric acute myeloid leukemia. Pediatric blood & cancer 2011; 56(2): 294-7. 
12. 
de Jonge HJ, Weidenaar AC, Ter Elst A, et al. Endogenous vascular endothelial growth factor-C expression is associated with 
decreased drug responsiveness in childhood acute myeloid leukemia. Clinical cancer research : an official journal of the American 
Association for Cancer Research 2008; 14(3): 924-30. 
13. 
de Jonge HJ, Valk PJ, Veeger NJ, et al. High VEGFC expression is associated with unique gene expression profiles and predicts 
adverse prognosis in pediatric and adult acute myeloid leukemia. Blood 2010; 116(10): 1747-54. 
14. 
Dias S, Choy M, Alitalo K, Rafii S. Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates 
leukemic cell proliferation, survival, and resistance to chemotherapy. Blood 2002; 99(6): 2179-84. 
15. 
Dias S, Shmelkov SV, Lam G, Rafii S. VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 
expression and apoptosis inhibition. Blood 2002; 99(7): 2532-40. 
16. 
Mesters RM, Padro T, Bieker R, et al. Stable remission after administration of the receptor tyrosine kinase inhibitor SU5416 in a 
patient with refractory acute myeloid leukemia. Blood 2001; 98(1): 241-3. 
17. 
Padro T, Ruiz S, Bieker R, et al. Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood 2000; 
95(8): 2637-44. 
18. 
Negaard HF, Iversen N, Bowitz-Lothe IM, et al. Increased bone marrow microvascular density in haematological malignancies is 
associated with differential regulation of angiogenic factors. Leukemia 2009; 23(1): 162-9. 
19. 
Tashiro K, Nonaka A, Hirata N, Yamaguchi T, Mizuguchi H, Kawabata K. Plasma elevation of vascular endothelial growth factor 
leads to the reduction of mouse hematopoietic and mesenchymal stem/progenitor cells in the bone marrow. Stem cells and development 
2014; 23(18): 2202-10. 
20. 
Rehn M, Olsson A, Reckzeh K, et al. Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic 
stem cell function in the low-oxygenic niche. Blood 2011; 118(6): 1534-43. 
21. 
Rahman N, Purpura KA, Wylie RG, Zandstra PW, Shoichet MS. The use of vascular endothelial growth factor functionalized 
agarose to guide pluripotent stem cell aggregates toward blood progenitor cells. Biomaterials 2010; 31(32): 8262-70. 
22. 
Fiedler W, Mesters R, Heuser M, et al. An open-label, Phase I study of cediranib (RECENTIN) in patients with acute myeloid 
leukemia. Leuk Res 2010; 34(2): 196-202. 
23. 
Roboz GJ, Giles FJ, List AF, et al. Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the 
treatment of acute myeloid leukemia and myelodysplastic syndrome. Leukemia 2006; 20(6): 952-7. 
24. 
Gupta P, Mulkey F, Hasserjian RP, et al. A phase II study of the oral VEGF receptor tyrosine kinase inhibitor vatalanib 
(PTK787/ZK222584) in myelodysplastic syndrome: Cancer and Leukemia Group B study 10105 (Alliance). Investigational new drugs 2013; 
31(5): 1311-20. 
25. 
Giles FJ, Bellamy WT, Estrov Z, et al. The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor 
prognosis acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Leukemia research 2006; 30(7): 801-11. 
26. 
Legros L, Slama B, Karsenti JM, et al. Treatment of myelodysplastic syndromes with excess of blasts by bevacizumab is well 
tolerated and is associated with a decrease of VEGF plasma level. Annals of hematology 2012; 91(1): 39-46. 
27. 
Ossenkoppele GJ, Stussi G, Maertens J, et al. Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: 
a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical 
Cancer Research (SAKK). Blood 2012; 120(24): 4706-11. 
28. 
Buckstein R, Kerbel R, Cheung M, et al. Lenalidomide and metronomic melphalan for CMML and higher risk MDS: a phase 2 
clinical study with biomarkers of angiogenesis. Leukemia research 2014; 38(7): 756-63. 
29. 
Barr P, Fu P, Lazarus H, et al. Antiangiogenic activity of thalidomide in combination with fludarabine, carboplatin, and topotecan 
for high-risk acute myelogenous leukemia. Leuk Lymphoma 2007; 48(10): 1940-9. 
30. 
Karp JE, Passaniti A, Gojo I, et al. Phase I and pharmacokinetic study of flavopiridol followed by 1-beta-D-
arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias. Clinical cancer research : an official journal of 
the American Association for Cancer Research 2005; 11(23): 8403-12. 


Nintedanib AML Version 7 21 MAY 2019 
65 
 
31. 
Woods WG, Kobrinsky N, Buckley J, et al. Intensively timed induction therapy followed by autologous or allogeneic bone marrow 
transplantation for children with acute myeloid leukemia or myelodysplastic syndrome: a Childrens Cancer Group pilot study. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 1993; 11(8): 1448-57. 
32. 
Castaigne S, Chevret S, Archimbaud E, et al. Randomized comparison of double induction and timed-sequential induction to a "3 
+ 7" induction in adults with AML: long-term analysis of the Acute Leukemia French Association (ALFA) 9000 study. Blood 2004; 104(8): 
2467-74. 
33. 
Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor 
efficacy. Cancer research 2008; 68(12): 4774-82. 
34. 
Roth GJ, Heckel A, Colbatzky F, et al. Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the 
discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120). Journal of medicinal chemistry 2009; 52(14): 4466-80. 
35. 
Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously 
treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. The Lancet Oncology 2014; 15(2): 
143-55. 
36. 
Kropff M, Kienast J, Bisping G, et al. An open-label dose-escalation study of BIBF 1120 in patients with relapsed or refractory 
multiple myeloma. Anticancer research 2009; 29(10): 4233-8. 
37. 
du Bois A, Huober J, Stopfer P, et al. A phase I open-label dose-escalation study of oral BIBF 1120 combined with standard 
paclitaxel and carboplatin in patients with advanced gynecological malignancies. Annals of oncology : official journal of the European 
Society for Medical Oncology / ESMO 2010; 21(2): 370-5. 
38. 
Ellis PM, Kaiser R, Zhao Y, Stopfer P, Gyorffy S, Hanna N. Phase I open-label study of continuous treatment with BIBF 1120, a 
triple angiokinase inhibitor, and pemetrexed in pretreated non-small cell lung cancer patients. Clinical cancer research : an official journal 
of the American Association for Cancer Research 2010; 16(10): 2881-9. 
39. 
Mross K, Stefanic M, Gmehling D, et al. Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid 
tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 2010; 16(1): 311-9. 
40. 
Torok S, Cserepes TM, Renyi-Vamos F, Dome B. [Nintedanib (BIBF 1120) in the treatment of solid cancers: an overview of 
biological and clinical aspects]. Magyar onkologia 2012; 56(3): 199-208. 
41. 
Reck M, Heigener D, Reinmuth N. Nintedanib for the treatment of patients with advanced non-small-cell lung cancer. Expert 
review of clinical pharmacology 2014; 7(5): 579-90. 
42. 
Raghu G, Selman M. Nintedanib and pirfenidone. New antifibrotic treatments indicated for idiopathic pulmonary fibrosis offer 
hopes and raises questions. American journal of respiratory and critical care medicine 2015; 191(3): 252-4. 
43. 
Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. The New England 
journal of medicine 2014; 370(22): 2071-82. 
44. 
Molife LR, Omlin A, Jones RJ, et al. Randomized Phase II trial of nintedanib, afatinib and sequential combination in castration-
resistant prostate cancer. Future oncology 2014; 10(2): 219-31. 
45. 
Okamoto I, Miyazaki M, Takeda M, et al. Tolerability of nintedanib (BIBF 1120) in combination with docetaxel: a phase 1 study in 
Japanese patients with previously treated non-small-cell lung cancer. Journal of thoracic oncology : official publication of the International 
Association for the Study of Lung Cancer 2015; 10(2): 346-52. 
46. 
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working Group for Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J 
Clin Oncol 2003; 21(24): 4642-9. 
47. 
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working 
Group (IWG) response criteria in myelodysplasia. Blood 2006; 108(2): 419-25. 
48. 
Antoniu SA. Nintedanib (BIBF 1120) for IPF: a tomorrow therapy? Multidisciplinary respiratory medicine 2012; 7(1): 41. 
49. 
Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid 
neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114(5): 937-51. 
 
 


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1.25 Appendices 
 
Declaration of Helsinki 
WHO performance status scale 
IWG response criteria 
Common toxicity criteria for adverse events (CTCAE) 
Drug Induced Liver Toxicity procedure 
Protocol Signature Page 
Study Calendar 
 
 


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1.25.1 Declaration of Helsinki 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI  
Ethical Principles for Medical Research Involving Human Subjects  
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 35th W M A General Assem bly, Venice, 
Italy, October 1983 41st W M A General Assem bly, Hong Kong, Septem ber 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 52nd W M A 
General Assembly, Edinburgh, Scotland, October 2000 53th W M A General Assem bly, W ashington 
2002 (Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 2004 (Note 
of Clarification on Paragraph 30 added) 59th W M A General Assem bly, Seoul, O ctober 2008 
A. INTRODUCTION  
• The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on 
identifiable human material and data. The Declaration is intended to be read as a w hole and 
each of its constituent paragraphs should not be applied without consideration of all other 
relevant paragraphs.   
• Although the Declaration is addressed primarily to physicians, the WMA encourages other 
participants in medical research involving human subjects to adopt these principles.   
• It is the duty of the physician to promote and safeguard the health of patients, including those 
who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty.   
• The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares 
that, “A physician shall act in the patient's best interest when providing medical care.”   
• Medical progress is based on research that ultimately must include studies involving human 
subjects. Populations that are underrepresented in medical research should be provided 
appropriate access to participation in research.   
• In medical research involving human subjects, the well-being of the individual research subject 
must take precedence over all other interests.   
• The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best current interventions 
must be evaluated continually through research for their safety, effectiveness, efficiency, 
accessibility and quality.   
• In medical practice and in medical research, most interventions involve risks and burdens.   


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• Medical research is subject to ethical standards that promote respect for all human subjects and 
protect their health and rights. Some research populations are particularly vulnerable and 
need special protection. These include those who cannot give or refuse consent for 
themselves  and those w ho m ay be vulnerable to coercion or undue influence.   
• Physicians should consider the ethical, legal and regulatory norms and standards for research 
 involving hum an subjects in their ow n countries as w ell as applicable international norm s 
and standards. No national or international ethical, legal or regulatory requirement should 
reduce or eliminate any of the protections for research subjects set forth in this Declaration. 
  
B. PRINCIPLES FOR ALL MEDICAL RESEARCH  
• It is the duty of physicians who participate in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of 
research subjects.   
• Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected.   
• Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment.   
• The design and performance of each research study involving human subjects must be clearly 
described in a research protocol. The protocol should contain a statement of the ethical 
considerations involved and should indicate how the principles in this Declaration have been 
addressed. The protocol should include information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest, incentives for subjects and provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation in 
the research study. The protocol should describe arrangements for post-study access by 
study subjects to interventions identified as beneficial in the study or access to other 
appropriate care or benefits.   
• The research protocol must be submitted for consideration, comment, guidance and approval to a 
research ethics committee before the study begins. This committee must be independent of 
the researcher, the sponsor and any other undue influence. It must take into consideration 
the laws and regulations of the country or countries in which the research is to be performed 
as well as applicable international norms and standards but these must not be allowed to 
reduce or eliminate any of the protections for research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No change to the protocol may be made without consideration and approval by the 
committee.   
• Medical research involving human subjects must be conducted only by individuals with the 
appropriate scientific training and qualifications. Research on patients or healthy volunteers 
requires the supervision of a competent and appropriately qualified physician or other health 


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care professional. The responsibility for the protection of research subjects must always rest 
with the physician or other health care professional and never the research subjects, even 
though they have given consent.   
• Medical research involving a disadvantaged or vulnerable population or community is only justified 
if the research is responsive to the health needs and priorities of this population or 
community and if there is a reasonable likelihood that this population or community stands 
to benefit from the results of the research.   
• 
Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved in 
the research in comparison with foreseeable benefits to them and to other individuals or 
communities affected by the condition under investigation.  
 
• 
Every clinical trial must be registered in a publicly accessible database before recruitment of 
the first subject.  
• Physicians may not participate in a research study involving human subjects unless they are 
confident that the risks involved have been adequately assessed and can be satisfactorily 
managed. Physicians must immediately stop a study when the risks are found to outweigh 
the potential benefits or when there is conclusive proof of positive and beneficial results.   
• Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the research subjects.   
• Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees.   
• 
Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on their 
physical, mental and social integrity.  
• In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential 
risks of the study and the discomfort it may entail, and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal. Special attention 
should be given to the specific information needs of individual potential subjects as well as to 
the methods used to deliver the information. After ensuring that the potential subject has 
understood the information, the physician or another appropriately qualified individual must 
then seek the potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally 
documented and witnessed.   
• For medical research using identifiable human material or data, physicians must normally seek 
consent for the collection, analysis, storage and/or reuse. There may be situations where 
consent would be impossible or impractical to obtain for such research or would pose a 
threat to the validity of the research. In such situations the research may be done only after 
consideration and approval of a research ethics committee.   


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• When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician 
or may consent under duress. In such situations the informed consent should be sought by 
an appropriately qualified individual who is completely independent of this relationship 
 
• For a potential research subject who is incompetent, the physician must seek informed consent 
from the legally authorized representative. These individuals must not be included in a 
research study that has no likelihood of benefit for them unless it is intended to promote the 
health of the population represented by the potential subject, the research cannot instead 
be performed with competent persons, and the research entails only minimal risk and 
minimal burden.   
• When a potential research subject who is deemed incompetent is able to give assent to decisions 
about participation in research, the physician must seek that assent in addition to the 
consent of the legally authorized representative. The potential subject’s dissent should be 
respected.  Research involving subjects w ho are physically or m entally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or mental 
condition that prevents giving informed consent is a necessary characteristic of the research 
population. In such circumstances the physician should seek informed consent from the 
legally authorized representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be 
obtained as soon as possible from the subject or a legally authorized representative.   
• Authors, editors and publishers all have ethical obligations with regard to the publication of the 
results of research. Authors have a duty to make publicly available the results of their research 
on human subjects and are accountable for the completeness and accuracy of their reports. They 
should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as 
positive results should be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest should be declared in the publication. Reports of 
research not in accordance with the principles of this Declaration should not be accepted for 
publication.   
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE  
• 
The physician may combine medical research with medical care only to the extent that the 
 research is justified by its potential preventive, diagnostic or therapeutic value and if the 
physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects.   
• 
The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best current proven intervention, except in the following circumstances: • The 
use of placebo, or no treatment, is acceptable in studies where no current proven 
 intervention exists; or Where for compelling and scientifically sound methodological reasons 
the use of placebo is necessary to determine the efficacy or safety of an intervention and the 
patients who receive placebo or no treatment will not be subject to any risk of serious or 
irreversible harm. Extreme care must be taken to avoid abuse of this option.  


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• 
At the conclusion of the study, patients entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 
access to interventions identified as beneficial in the study or to other appropriate care or 
benefits.   
• 
The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw 
from the study must never interfere with the patient-physician relationship.   
• 
In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the patient 
or a legally authorized representative, may use an unproven intervention if in the physician's 
judgement it offers hope of saving life, re-establishing health or alleviating suffering. Where 
possible, this intervention should be made the object of research, designed to evaluate its 
safety and efficacy. In all cases, new information should be recorded and, where appropriate, 
made publicly available.   
 
 
 
 


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1.25.2 WHO PS 
 
 
 
 


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1.25.3 IWG response criteria 
 
Primary endpoint will be based on IWG 2003 AML response criteria46  
• 
Morphologic complete remission (CR): ANC ≥ 1,000/mcl, platelet count ≥ 100,000/mcl, < 5% 
bone marrow blasts, no Auer rods, no evidence of extramedullary disease. (No requirements 
for marrow cellularity, hemoglobin concentration).  
 
• 
Morphologic complete remission with incomplete blood count recovery (CRi): Same as CR 
but ANC may be < 1,000/mcl but >500 mcl and/or platelet count < 100,000/mcl but 
>20,000/mcl 
 
• 
Partial remission (PR): ANC ≥ 1,000/mcl, platelet count > 100,000/mcl, and at least a 50% 
decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts < 5% with 
persistent Auer rods.  
 
• 
Marrow Leukemia Free State: < 5% bone marrow blasts, no Auer rods, no extra medullary 
disease. No requirement on cytopenias 
 
Secondary Endpoint will also include evaluation of hematological improvement based on IWG MDS 
2006 criteria47  
• 
Erythroid response (pretreatment <11 g/dL): Hgb increase at least by 1.5 g/dL. Relevant 
reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 
wk compared with the pretreatment transfusion number in the previous 8 wk. Only RBC 
transfusions given for a Hgb of below or equal to 9.0 g/dL pretreatment will count in the RBC 
transfusion response evaluation 
 
• 
Platelet response (pretreatment 100x109/L): Absolute increase of at least 30x109/L for 
patients starting with more than 20x109/L platelets. Increase from less than 20x109/L to 
more than 20x109/L and by at least 100% 
 
• 
Neutrophil response (pretreatment, <1.0x109/L) At least 100% increase and an absolute 
increase of at least 0.5x109/L 
 
 


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1.25.4 Common toxicity criteria for adverse events 
(CTCAE) 
 
Please refer to CTCAE v4.03, a new version of the CTEP, NCI CTC v4.0, includes Adverse Events applicable 
to all oncology clinical trials regardless of chronicity or modality: 
 
 


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1.25.5 Procedures for the follow-up of a potential DILI 
case in IIS with nintedanib 
 
Introduction 
 
Drug-induced liver injury 
Drug-induced liver injury (DILI) has been the most frequent single cause of safety-related 
drug marketing withdrawals for the past 50 years (e.g., iproniazid), continuing to the present 
(e.g., ticrynafen, benoxaprofen, bromfenac, troglitazone, nefazodone). Accordingly, detection 
of drug-induced liver injury of an investigational compound has become an important aspect 
of patient´s safety guarding in drug development. 
 
The US-FDA has published a Guidance for Industry entitled, “Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation” which outlines the detection, evaluation, follow-up and 
reporting of drug-induced liver injury in clinical trials. Drugs that have the potential for 
inducing severe liver injury may be identified by marked peak aminotransferase elevations 
(10x-, 15xULN), or the combination of hepatocellular injury (aminotransferase elevation 
≥3xULN) and altered liver function (hyperbilirubinemia ≥2xULN) which is defined as potential 
“Hy´s law case” if not explained by other causes including evidence of biliary obstruction (i.e., 
significant elevation of alkaline phosphatase, ALP, >2X ULN) or some other explanation of 
the injury (e.g., viral hepatitis, alcohol hepatitis, concomitant use of other known hepatotoxic 
drugs). This constellation predicts a poor outcome and although very rare, these potential 
cases have to be well characterized as soon as being identified as other confounding 
conditions may be the cause.   
 
In further consideration of this FDA Guidance, any potential “Hy’s Law case” has to be 
reported in an expedited manner to the FDA (i.e., even before all other possible causes of 
liver injury have been excluded) and be followed-up appropriately. The follow-up includes a 
detailed clinical evaluation and identification of possible alternative etiologies for the “Hy´s 
Law case” constellation such as concomitant diseases (e.g. Hepatitis B) and/or other 
concomitant therapies that might potentially be hepatotoxic.  
 
 


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Although rare, a potential for drug-induced liver injury is under constant surveillance by 
sponsors and regulators. Therefore, this study requires timely detection, evaluation, and 
follow-up of laboratory alterations of selected liver laboratory parameters to ensure patients´ 
safety. 
 
The concept below has been worked out by Boehringer Ingelheim (BI) in order to guard 
patient´s safety and to respond to regulatory requirements. It is the basis for all clinical 
studies and should be applied as appropriate. 
 
Definition 
The following changes in the laboratory values are considered to be a protocol-specific 
significant adverse event for all patients with normal values for ALT/AST at baseline: 
  
- 
an elevation of ALT and / or AST > 5x ULN without bilirubin elevation measured in the 
same blood draw sample 
- 
 an elevation of AST and/or ALT >2.5 fold ULN combined with an elevation of bilirubin 
to >1.5 fold ULN measured in the same blood draw sample.  
 
These definitions are in line with the current dose reduction recommendations as outlined in 
all study protocols for BIBF 1120. 
 
Patients showing these laboratory abnormalities need to be followed up until the protocol 
specific retreatment criteria have been met  
 
For patients with elevated ALT/AST values at baseline special considerations apply, if they 
are eligible for inclusion into the trial, e.g. if liver metastasis are present and do not qualify as 
exclusion criterion. For those special cases the BI contact person should be involved. 
 
 
 
 
 


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Procedures 
1. Protocol-specified significant events are to be reported in an expedited manner 
similar as Serious Adverse Events, even if they do not meet any of the seriousness 
criteria and documented in the eCRF 
 
 
2. Replication of the following laboratory tests for confirmation within 48 hours: 
 
- 
AST, ALT,  
- 
bilirubin measurement (total and direct bilirubin) 
- 
Alkaline Phosphatase 
- 
Haptoglobin 
- 
Complete blood count and cell morphology 
- 
Reticulocyte count 
- 
CK 
- 
LDH 
The results of these repeated laboratory tests must be documented on the eCRF 
/CRF forms and reported immediately via the SAE form to the Project Manager who 
will report it to BI. 
 
3. An evaluation of the patient within 48 hours with respect to but not limited to: 
 
- 
Abdominal ultrasound or clinically appropriate other imaging and 
investigations adequate to rule out biliary tract, pancreatic,  intra- or 
extrahepatic pathology, e.g. bile duct stones,  neoplasm, hepatic tumour 
involvement, biliary tract, pancreatic or intrahepatic pathology, vascular 
hepatic conditions such as portal vein thrombosis or right heart failure. 
These data need to be collected, documented in the respective field of the 
eCRF / CRF / additional documentation form, and the respective SAE form 
has to be updated and forwarded to BI 
 
- 
detailed history of current symptoms and concurrent diagnoses and 
medical history  
 
- 
detailed history of concomitant drug use (including non-prescription 
medications, herbal and dietary supplement preparations and eg steroids 
as concomittant suppportive treatment), alcohol use, recreational drug 
use, and special diets detailed history of exposure to environmental 
chemical agents 
 
4. In case that both imaging and laboratory value did not unequivocally confirm 
cholestasis as the reason of ALT / AST increase, in particular if AP < 2x ULN,  
then please complete the following laboratory tests: 
 
- 
Clinical chemistry 
alkaline phosphatase, cholinesterase (either plasma or red blood cell), 
albumin, PT or INR, CK, CK-MB, coeruloplasmin*, α-1 antitrypsin*, 


Nintedanib AML Version 7 21 MAY 2019 
78 
 
transferrin, ferritin, amylase*, lipase*, fasting glucose*, cholesterol, 
triglycerides 
- 
Serology 
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), 
Hepatitis C (Anti-HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, 
Anti-IgG)*, Hepatitis E (Anti-HEV, Anti-HEV IgM, RNA if Anti-HEV IgM 
positive)*, Anti-Smooth Muscle antibody (titer)*, Anti-nuclear antibody 
(titer)*, Anti-LKM (liver-kidney microsomes) antibody*, Anti-mitochondrial 
antibody*, Epstein Barr Virus (VCA IgG, VCA IgM), cytomegalovirus (IgG, 
IgM), herpes simplex virus (IgG, IgM), varicella (IgG, IgM), parvovirus (IgG, 
IgM)  
- 
Hormones,  
TSH* 
- 
Hematology 
Thrombocytes*, eosinophils* 
 
*If clinically indicated and in case that additional investigations are needed 
(e.g immunocompromised patients.) 
 
5. Initiate close observation of all patients with elevated liver enzyme and bilirubin 
elevations by repeat testing of ALT, AST,bilirubin (with fractionation into total and 
direct) and AP at least weekly until the laboratory values return to normal or to the 
values as defined in the protocol.  
 
6. In case that transaminases and/or bilirubin increase despite cessation of the 
experimental therapy, more frequent intervals will be warranted.  
Depending on further laboratory changes, additional parameters identified e.g. by 
reflex testing will be followed up based on medical judgement and Good Clinical 
Practices 
 


78 
 
 
1.25.6 Protocol Signature Page 
 
 
Acknowledgment of the Investigators 
 
PROTOCOL TITLE: A phase I-II randomized trial of a combination of Nintedanib/placebo in combination 
with induction chemotherapy for patients with refractory or first relapse acute myeloid leukemia 
Version 7; May 21, 2019 
  
 
1.) I have read this protocol and agree that the study is ethical  
  
2.) I agree to conduct the study as outlined and in accordance with all applicable regulations and 
guidelines  
  
3.) I agree to maintain the confidentiality of all information received or developed in connection with this 
protocol  
  
_____________________________________  
 
 
________________ 
Signature of Investigator:  
  
 
 
 
 
Date:    
  
_____________________________________ 
Name of Investigator (Printed or Typed


79 
 
1.25.7 Study Calendar 
Screening and Cycle 1 (Induction Therapy) 
 
Screening 
Day 
 
 
-14 
to -
5 
-1  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
END 
Of 
Treatment 
 
 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional exams (Lumbar 
puncture, CT, Pet-CT)b  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG, Cardiac Echo, and 
CXRm 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Hepatitis B, C, HIV1 & 
HIV2 serologies 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bacterial, fungal & viral 
cultures throat, stool & 
urine b 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Evaluation 
& Cytogenetics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies 
(Blood) 
x 
 
 
 
 
 
 
 
 
xl 
 
 
 
 
 
xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Correlative Studies (Bone 
Marrow) 
x 
 
 
 
 
 
 
 
 
xgl 
 
 
 
 
 
xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Concomitant 
Medicationsq 
x 
Ongoing basis  
Bone Marrow Biopsyk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
xp 
x 
Physical Exam c, 0 
x 
x 
xa 
x 
x 
x 
x 
x 
 
 
xh 
 
xh 
 
 
 
xh 
 
 
 
xh 
 
 
xh 
 
 
xh 
 
 
x 
x 
ECOG PS 
x 
x 
 
 
 
xi 
 
 
 
 
 
 
xi 
 
 
 
 
 
xi 
 
 
 
 
xi 
 
 
 
 
 
 
x 
CBC with differentialn  
x 
x 
xa 
x 
x 
x 
x 
 
xj 
 
xj 
 
xj 
 
xj 
 
xj 
 
xj 
 
xj 
 
xj 
 
xj 
 
xj 
 
xj 
 
x 
Serum chemistry d 
x 
x 
xa 
x 
x 
x 
x 
 
 
 
xh 
 
xh 
 
 
 
xh 
 
 
 
xh 
 
 
xh 
 
 
xh 
 
 
 
x 
Pregnancy testing  
x 
x 
xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation Profile e 
x 
x 
xa 
x 
x 
x 
x 
 
 
 
xi 
 
 
 
 
 
xi 
 
 
 
 
 
 
xi 
 
 
 
 
 
 
 
Idarubicin f 
 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytarabine 
 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
(nintedanib/placebo) 
 
 
 
 
 
 
 
 
 
Xg 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
AEs q 
 
 
Ongoing basis 


Nintedanib AML Version 7 21 MAY 2019 
80 
 
 
 
a: If these tests are performed within 24 hours of the Cycle 1 Day 1 visit, prior to administration of study drug, they do not need to be repeated on C1 D1, unless otherwise 
determined by the Principal Investigator.  
b: If clinically indicated 
c: Complete physical exam and vitals including, weight, blood pressure, pulse, temperature, respiratory frequency, height required at screening only 
d: Serum chemistry: AST, ALT, alkaline phosphatase, total bilirubin, BUN, serum creatinine, glucose, calcium, sodium, potassium, magnesium, chloride, bicarbonate, total protein, 
albumin, LDH, and uric acid at screening only 
e: Coagulation profile: prothrombin time, activated partial-thromboplastin time, and fibrinogen, 
f: Idarubicin may be dose reduced, replace, or omitted according to total dose of anthracycline received by the patient 
g: Day 8 Bone Marrow aspirate is optional. If patient consents to D8 optional BMBX, start Nintedanib/placebo on afternoon dose after BMBX and continue until D29 morning dose.  
h: Twice weekly  
i: Weekly 
j: Every other day 
k: Performed in patients with complete clearance of blasts in the blood 
l: (+/- 1 day)  
m: All three tests are required at screening, CXR not required at End of Treatment evaluation; 3d Echocardiogram or biplane Simpson method are acceptable methods for obtaining 
LVEF 
n: differential for CBC done as per hospital standard of care (Required at screening, response evaluation and end of treatment visit) 
p: (+/- 7 Days) and decided based on count recovery: Threshold: ANC at 1 and PLT at 50 
q: AEs and Concomitant Medications will be assessed on an ongoing basis. AE assessment should begin following C1D1 treatment, 
 


Nintedanib AML Version 7 21 MAY 2019 
81 
 
Cycles 2, 3 and 4 (Induction or Consolidation) * To be followed if Cycles, 2, 3 and 4 are Induction and/or consolidation cycles, if patient goes to Maintenance refer to 
Maintenance Calendar 
a: Induction cycle ONLY 
b: Weekly for a Consolidation cycle 
c: Complete physical exam and vitals including weight, blood pressure, pulse, temperature, respiratory frequency 
d: Serum chemistry: AST, ALT, alkaline phosphatase, total bilirubin, BUN, serum creatinine, glucose, calcium, sodium, potassium, magnesium, chloride, bicarbonate, total protein, 
albumin, LDH,  
e: Coagulation profile: prothrombin time, activated partial-thromboplastin time, and fibrinogen 
f: Idarubicin may be dose reduced, replace, or omitted according to total dose of anthracycline received by the patient 
g: Twice weekly for an Induction Cycle 
h: Weekly; Cycle 2 ONLY 
i: Three times weekly 
j: Prior to Cycle 2:  Any time after Cycle 1 day 14 up to the start of cycle 2; 3d Echocardiogram or biplane Simpson method are acceptable methods for obtaining LVEF  
k: Performed in patients with complete clearance of blasts in the blood 
l: Every other week 
m: differential for CBC will only be done as per hospital standard of care (Required at screening, response evaluation and end of treatment visit) 
o: AEs and Concomitant Medications will be assessed on an ongoing basis 
p: prior to the start if each new treatment cycle 
 
 
Day 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
END 
END 
Of 
Treatment 
Bidimensional 
Echography j 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds o 
Ongoing basis 
Physical Exam c  
x 
xa 
xa 
xa 
xa 
xa 
 
 
xg 
 
xg,b 
 
 
 
xg 
 
 
 
xg,b 
 
 
xg,b 
 
 
xg,  
 
 
x 
x 
ECOG PS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
CBC with differential m 
 
xi 
 
xi 
 
xi 
 
 
xi 
 
xi 
 
xi 
 
 
xi 
 
xi 
 
xi 
 
 
xi 
 
xi 
 
xi 
 
x 
Serum chemistry d 
 
 
 
 
 
 
 
 
 
 
xl 
 
 
 
 
 
 
 
 
 
 
 
 
xl 
 
 
 
x 
x 
Pregnancy testing p 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation Profile  e 
 
 
 
xh  
 
 
 
 
 
xh 
 
 
 
 
 
xh 
 
 
 
 
 
 
xh 
 
 
 
 
 
Idarubicin f 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytarabine 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
(nintedanib/placebo) 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
AEs o 
Ongoing basis 
x 
Correlative Studies 
(Blood& Bone Marrow) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Bone Marrow 
Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xk 


Nintedanib AML Version 7 21 MAY 2019 
82 
 
 
 Maintenance Cycle, End of Treatment & Follow Up  
 
a: Continuous/daily 
b: Complete physical exam and vitals including weight, blood pressure, pulse, temperature, respiratory frequency 
c: Serum chemistry: AST, ALT, alkaline phosphatase, total bilirubin, BUN, serum creatinine, glucose, calcium, sodium, potassium, chloride, bicarbonate, total protein, albumin,  
d: Coagulation profile: prothrombin time, activated partial-thromboplastin time, fibrinogen,  
e: Performed in patients with complete clearance of blasts in the blood (+/- 7 Days) 
f: differential for CBC will only be done as per hospital standard of care (Required at screening, response evaluation and end of treatment visit) 
g: 3d Echocardiogram or biplane Simpson method are acceptable methods for obtaining LVEF  
i: AEs and Concomitant Medications will be assessed on an ongoing basis 
j: Monthly at the beginning of each Maintenance cycle up until 3 months after last dose of Nintedanib  
 
 
Maintenance Therapy 
Monthly (+/- 3 days) for the first 12 months                    
then every 3 months (+/-7 Days) until disease progression or up to 2 years  
 
Every 3 months  
(+/-7 Days)  
up to 2 years  
Month 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
15 
16 
18 
20 
21 
22 
24 
End of 
Treatment 
Follow-Up 
Nintedanib a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x 
X 
 
 
Concomitant Medications i 
Ongoing basis 
 
Physical Exam b   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
x 
 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
x 
 
AEs i 
Ongoing basis  
 
CBC with differential f  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 
Serum chemistry c 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
x 
x 
 
Pregnancy Testing j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xj 
xj 
Coagulation Profile d 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG, Cardiac Echo g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Bone Marrow Evaluation e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Correlative Studies  
(Blood & Bone Marrow) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Hematology, CBC & hemoglobin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Subsequent anti-cancer therapy, 
documentation/date of last disease 
progression/relapse, date of death 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x