A double-blind, randomised, placebo controlled Phase III study of
nintedanib plus best supportive care (BSC) versus placebo plus BSC in
patients with colorectal cancer refractory to standard therapies.

Colorectal cancer (CRC) has high incidence (about 2.6 million new cases/year)
and it is the second leading cause of cancer-related deaths in Western
countries. Even though most of the newly diagnosed patients initially underwent
surgery with curative intent and received adjuvant systemic treatment, about
half of patients eventually develop metastatic disease. 5-fluorouracil (5-FU)
has been the mainstay of treatment for metastatic CRC for several decades.
Modulation of 5-FU with folinic acid, modification of 5-FU scheduling, addition
of new chemotherapeutic agents as oxaliplatin irinotecan have all contributed
to a significant improvement in the overall survival of patients with
metastatic CRC.The addition of biologically targeted treatments (bevacizumab,
cetuximab, panitumumab, aflibercept) to chemotherapy regimens and recent
introduction of regorafenib has increased patients* survival further.

As indicated by bevacizumab and aflibercept clinical experience, angiogenesis
is highlyrelevant for CRC cancer growth and development of metastases. Vascular
Endothelial Growth Factor (VEGF) and its high affinity receptor VEGFR-2 are
crucial for the formation of new tumour vessels. In addition, there is
preclinical evidence that fibroblast growth factor (FGF) and platelet-derived
growth factor (PDGF) and their associated receptor tyrosine kinases
substantially contribute to tumour angiogenesis. The VEGF - VEGFR-2 axis,
besides promoting angiogenesis, may also be involved in stimulating growth of
tumour cells themselves via an autocrine growth factor loop. Therefore,
suppression of neoangiogenesis
via inhibition of VEGFR-2 and other pathways is a promising strategy for the
treatment of CRC. A substantial number of clinical trials with various
inhibitors of VEGF or VEGFRs performed recently in CRC demonstrated this
approach can convey clinical benefit, in particular in combination therapy with
standard chemotherapeutic drugs. Moreover recent data with a regorafenib Phase
III trial indicate that angiogenesis inhibition with small tyrosine-kinase
inhibitors may be also effective for CRC refractory to conventional
chemotherapies as well as biological agents including bevacizumab. Nintedanib
is a potent, orally available triple kinase inhibitor targeting VEGFRs, PDGFRs,
and FGFRs. The specific and simultaneous abrogation of these pathways results
in effective growth inhibition of both endothelial and, via PDGF- and
FGF-receptors of perivascular cells, which may be more effective than
inhibition of endothelial cell growth via the VEGF pathway alone. Furthermore,
signalling by FGF-receptors has been identified as a possible escape mechanism
for tumour angiogenesis when the VEGF pathway is disrupted Present trial will
investigate the efficacy and safety of nintedanib in patients with refractory
CRC after failure of standard chemotherapy drugs and biological agents
currently used for CRC.

The objective of this Phase III study is to evaluate the efficacy and safety of
nintedanib in patients with mCRC after failure of previous treatment with
standard chemotherapy and biological agents.

This is a Phase III multi-centre double-blind, randomised trial to evaluate the
efficacy and safety of nintedanib in combination with best supportive care
(BSC) in patients with mCRC after failure of standard drugs in comparison to
placebo plus BSC. The trial will be performed by investigators specialised in
the treatment of patients with colorectal cancer. Patients eligible for this
study will have best supportive care as the only remaining standard available
therapy for refractory CRC as specified in the inclusion criteria. After
completion of screening assessments, patients will be randomly assigned based
on a randomisation ratio 1:1 to receive either nintedanib + best supportive
care (BSC) (Arm A) or matching placebo +
BSC (Arm B). The randomised patients will be treated until unequivocal
progression or undue toxicity; no other anti-cancer treatment will be allowed
until study medication is discontinued (see Section 3.3.3). End of treatment,
regardless of the reason of EOT, will be followed by a Residual Effect Period
(REP) which starts from last treatment intake and ends 28 days later.

Patients who discontinue trial medication but did not progress on treatment
will have follow-up period for PD until PD, start of new anti-cancer treatment,
death, lost to follow-up or when the required OS events for the OS analysis
have been reached.

Safety parameters will be continuously followed-up during the duration of the
trial. Evaluation of tumour response will be assessed by imaging according to
RECIST (version 1.1) every 6 weeks. Decision on continuation of treatment will
be based on assessment of tumour response and progression by the investigator.
Independent blinded assessment of tumour images will also be performed by a
central imaging unit but will not be used for clinical decision by
investigator.

Addition of BIBF 1120 (nintedanib) or placebo to the standard therapy given
(best supportive care).

This study investigates the addition of BIBF 1120 or placebo to best supportive
care. The subjects have metastic colorectal cancer refractory to standard
therapies. A disease that is difficult to treat and has no other options for
therapy. BIBF 1120 has a favourable toxicity profile and can potentially
enhance survival of these patients.
The patient already would undergo a number of procedures (blood draw, vital
signs, CT scans), regardless of study participation. If he/ she thus would like
to participate and receive additional therapy, some additional assesments will
be performed (e.g.blood draws, vital signs and CT- scans) will be required for
this study.
In this study blood is drawn for pharmacokinetics and pharmacogenetic analysis.
The subject can refuse participation in the pharmacogenetic testing, but may
continue to participate in the main study.