Trial Information

Open-label,Random.,Controlled,Multicenter Phase II Study Investigating 2 Cilengitide Regimens in Combination w/ Cetuximab & Platinum-based Chemotherapy Compared to Cetuximab & Platinum-based Chemotherapy Alone as 1st-line Treatment for Patients w/ Advanced NSCLC

Schedule of visits and assessments:

Pre-screening Visit (Within 2 weeks prior to screening):

In an initial step subjects with newly diagnosed NSCLC (suspected or already established
diagnosis) will be offered to have their tumor assessed locally for EGFR expression. After
giving specific written informed consent to this analysis, they will be formally registered
and the tissue will be analyzed.

Signing of informed consent for local IHC-based EGFR expression determination; EGFR
expression testing in local pathology laboratory using archived tumor material;
Demographics, i.e. subject initial, date of birth, gender, ethnicity/race, height;
Allocation of subject number; Date of initial diagnosis; Tumor characteristics (histology,
localization, metastasis, Tumor-Nodes-Metastases (TNM) classification).

Screening Visit (Within 3 weeks prior to randomization):

Signing of informed consent for study participation (only if pre-screening positive and with
an EGFR expression ≥ 200); Archived tumor material for biomarker analysis including EGFR,
k-ras, b-raf, pathology and possible additional biomarker research including mutation
testing; Relevant medical history; Prior treatment of underlying tumor; Physical examination
including vital signs (including body weight, without BSA); ECOG-performance status; Central
12-lead ECG; Pulmonary function test; Baseline imaging within 4 weeks prior to randomization
(RECIST): At least chest + abdomen CT (or MRI if there are contraindications to CT);
Documentation of concomitant medications and AEs; Safety laboratory assessments (hematology
including coagulation parameters and biochemistry); Blood sampling for HACA assessment;
Serum pregnancy test for women of childbearing potential within 7 days to the start of study
medication; In-/exclusion criteria review; Randomization, (to be performed ≤7 days before
start of therapy); Optional: additional written informed consent for pharmacogenetics
testing and optional: blood sampling for pharmacogenetics testing (only applicable for
randomized study part).

Day 1 of Each Cycle (Start of Cycle Visit) (At start of each chemotherapy cycle) Before
start of first cycle: randomization should be performed ≤7 days before start of therapy;
Physical examination including vital signs (including body weight and BSA); Assessment of
cardiovascular specific symptoms; Documentation of AEs; Concomitant medication; Safety
laboratory assessments (hematology including coagulation parameters and biochemistry) must
be available before start of chemotherapy; Central Holter ECG before start of treatment
until the end of infusion of cilengitide (for Group C subjects until the 1 hour after the
end of infusion of cetuximab) on Day 1 of the first cycle only; Central standard ECG Cycles
2-6; ECOG-performance status; Administration of cilengitide (Groups A and B); Administration
of cetuximab (all subjects); Administration of cisplatin/vinorelbine or
cisplatin/gemcitabine (all subjects; first 6 cycles only); Blood sampling for plasma
circulating markers (only on Day 1 of Cycle 1 at pre-dose and at the end of the cisplatin
infusion); Additional blood sampling for CTC/CEC assessment (only pre-dose on Day 1 of Cycle
1 and Cycle 2); Blood sampling for cilengitide PK (6-10 subjects of Group B only; Cycle 1
only; see Section 7.4.1 for details) (at dedicated sites only); Blood sampling for cetuximab
PK (all subjects of Group A only; Cycles 1 and 2 only; see Section 7.4.1 for details); Blood
sampling for vinorelbine PK (6-10 subjects of Groups B and C; Cycle 1 only; see Section
7.4.1 for details) (at dedicated sites only).

DAYS 4, 11 and 18

Days 4, 11, and 18 of Each Cycle (Group B only) Vital signs (without BSA/body weight);
Administration of cilengitide.

Days 4 and 11 (additional examinations during the first 2 weeks of first cycle of safety
run-in): safety laboratory assessments (hematology including coagulation parameters and
biochemistry).

DAYS 8 and 15

Days 8 and 15 of Each Cycle: Vital signs (without BSA/weight); assessment of cardiovascular
specific symptoms; documentation of AEs; concomitant medication; administration of
cilengitide (Groups A and B); administration of cetuximab; administration of vinorelbine or
gemcitabine (all subjects; Day 8 of the first 6 cycles only); blood sampling for proBNP
(Cycle 1 Day 8 only); blood sampling for cetuximab PK (all subjects of Group A only; Days 8
and 15 of Cycle 1 and Day 8 of Cycle 2 only); blood sampling for plasma circulating markers
(all subjects; Days 8 and 15 of first cycle only at pre dose, for each subsequent cycle on
Day 8 only).

Days 8 and 15 (additional examinations during safety run-in): safety laboratory assessments
(hematology including coagulation parameters and biochemistry) must be available before
start of chemotherapy.

Once weekly safety lab evaluation during safety run-in (after end of chemotherapy): safety
laboratory assessments (hematology including coagulation parameters and biochemistry).

6-weekly Evaluation Visit (Every 6 weeks +/- 2 days after randomization until final tumor
assessment (FTA) visit): Physical examination including vital signs (without BSA/weight);
assessment of cardiovascular specific symptoms; documentation of AEs; concomitant
medication; ECOG-performance status; central standard ECG after cycle 6 only; CT scan or
MRI; safety laboratory assessments (hematology including coagulation parameters and
biochemistry); serum pregnancy test for women of childbearing potential. Blood sampling for
plasma circulating markers during maintenance treatment only, and for CTC/CEC (only once
after 6 cycles of chemotherapy).

Final Tumor Assessment Visit (At occurrence of PD and/or before start of any other systemic
anti-tumor therapy): Physical examination including vital signs (without BSA); documentation
of AEs; concomitant medication; ECOG-performance status; CT scan or MRI; safety laboratory
assessments (hematology including coagulation parameters and biochemistry); blood sampling
for plasma circulating markers and CTC/CEC; serum pregnancy test.

End-of-Study (EoS) Visit (Around 28 days after the last investigational medicinal product
[cilengitide or cetuximab] administration, or before other anticancer treatment starts, but
not before the FTA visit): Physical examination including vital signs (without BSA);
documentation of AEs. If a subject begins a subsequent anticancer therapy, the AE reporting
period for non-serious AEs will end at the time the new treatment starts; ECOG-performance
status; concomitant medication; safety laboratory assessments (hematology including
coagulation parameters and biochemistry); blood sampling for HACA assessment; central
12-lead ECG; reason for discontinuation.

Survival Follow-up (Every 2 months after EoS visit): Each subject's survival status and any
further anti-cancer treatments will be documented every 2 months after the end of study
visit until death, loss to follow-up, or consent withdrawal.

All subjects will be treated with platinum-based chemotherapy for a maximum of 6 cycles
(i.e. 18 weeks), until PD or death, unacceptable toxicity, or until the subject withdraws
consent. Subjects who do not experience PD after 6 cycles of platinum-based treatment will
continue treatment with cilengitide (Groups A and B) and cetuximab (Group A, B and C).
Subjects who discontinue treatment without PD will remain on study. Response assessment will
continue every 6 weeks until PD or until other anti-tumor treatment is started. Upon this
occurrence, all study medication should be discontinued and a final tumor assessment (FTA)
visit will be carried out. The end-of-study visit should be performed around 4 weeks after
the last investigational medicinal product administration but not before the FTA visit.