Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

All Drugs and Chemicals

Antineoplastic Agents

Lipid Regulating Agents

Antibodies

Antibodies, Monoclonal

Gemcitabine

Vinorelbine

Cetuximab

Cisplatin

Immunoglobulins

Fenofibrate

Antimetabolites

Antineoplastic Agents, Immunological

Tubulin Modulators

Antimitotic Agents

Cilengitide (Cil) will be administered at a dose of 1000 milligram (mg) as intravenous infusion twice weekly over 1 hour on Days 1 and 4.

Cilengitide

Cil will be administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4.

Cetuximab will be administered at a dose of 400 milligram per square meter (mg/m\^2) as intravenous infusion over 2 hours on Day 1.

Cisplatin (Cis) will be administered at a dose of 75 mg/m\^2 as intravenous infusion on Day 1.

Cis will be administered at a dose of 80 mg/m\^2 as intravenous infusion on Day 1.

Gemcitabine (Gem) will be administered at a dose of 1250 mg/m\^2 as intravenous infusion on Days 1 and 8.

Vinorelbine (Vin) will be administered at a dose of 25 mg/m\^2 as intravenous infusion on Days 1 and 8.

Cil will be administered at a dose of 2000 mg as intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle until progressive disease, death, unacceptable toxicity, or consent withdrawal.

Cil will be administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1, 4, 8, 11, 15, and 18 of each 3-week cycle followed by once weekly administration after end of chemotherapy until progressive disease, death, unacceptable toxicity, or consent withdrawal.

Cetuximab will be administered at a dose of 400 mg/m\^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by 250 mg/m\^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal.

Cis 80 mg/m\^2 intravenous infusion on Day 1 + Vin 25 mg/m\^2 or Cis 75 mg/m\^2 intravenous infusion on Day 1 + Gem 1250 mg/m\^2 intravenous infusion on Days 1 and 8 of each 3-week cycle will be administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

Chemotherapy

Medical Responsible

Primary objective of the study's Safety run-in:

- To determine the maximum tolerated dose (MTD) of cilengitide in combination with cetuximab, and platinum-based chemotherapy (cisplatin/vinorelbine or cisplatin/gemcitabine).

Primary objective of the study's Randomization Part:

- To assess the efficacy of cilengitide in combination with cetuximab and platinum-based chemotherapy (cisplatin/vinorelbine or cisplatin/gemcitabine) compared to cetuximab and platinum-based chemotherapy alone in terms of progression-free survival (PFS) time.

Study design and plan:

This is a multicenter, open-label, randomized, controlled Phase II study with a safety run-in part in subjects with advanced non-small cell lung cancer (NSCLC).

During the safety run-in, the regimen was intensified stepwise by cohort (cilengitide intravenous \[i.v.\] 1000 milligram \[mg\] to 2000 mg twice a week) in a classical 3+3 subjects (for each platinum-based chemotherapy regimens separately) approach with predefined dose- and schedule reduction rules.

In the safety run-in 12 subjects were included and evaluated for safety and feasibility of different escalating doses of cilengitide administered twice weekly in combination with cetuximab, cisplatin and vinorelbine or gemcitabine.

After completion of the safety run-in, the randomized part will be started, during which all subjects will receive cetuximab and platinum-based chemotherapy (cisplatin/vinorelbine or cisplatin/gemcitabine).

Subjects will be centrally randomized on a 1:1 basis to either Group A or C; Group B will be closed with implementation of Amendment No. 4 (dated 20 December 2010):

• Group A: Cilengitide 2000 mg once weekly (Days 1, 8, and 15 of every 3-week chemotherapy cycle) in combination with cetuximab and platinum-based chemotherapy that will consist of the following:

* Cetuximab once weekly (Days 1, 8, and 15), plus cisplatin on Day 1 and vinorelbine on Days 1 and 8 of every 3-week chemotherapy cycle, or
* Cetuximab once weekly (Days 1, 8, and 15), plus cisplatin on Day 1 and gemcitabine on Days 1 and 8 of every 3-week chemotherapy cycle.

The decision which of the 2 chemotherapy regimens will be applied for a given subject is at the discretion of the treating investigator.

• Group B: Cilengitide 2000 mg twice weekly (Days 1, 4, 8, 11, 15, and 18 of every 3-week chemotherapy cycle) in combination with cetuximab and platinum-based chemotherapy as described for Group A.

Group B will be closed with implementation of Amendment No. 4 (global, dated 20 December 2010). Subjects randomized to Group B before implementation of Amendment No 4 will continue to be treated as planned.

• Group C: Cetuximab and platinum-based chemotherapy as described for Group A

Chemotherapy will be given until radiographically documented progressive disease (PD) or unacceptable toxicity but for no more than 6 cycles.

Cilengitide and cetuximab will be given until radiographically documented PD or unacceptable toxicity.

Randomization will be performed centrally using an interactive voice/web response system (IXRS). A stratified block randomization procedure will be employed using chosen first-line chemotherapy (cisplatin/vinorelbine versus cisplatin/gemcitabine) as stratification criterion.

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 Epidermal Growth Factor Receptor (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 immunohistochemistry (IHC) based EGFR expression determination; EGFR expression testing in local pathology laboratory using archived tumor material; Demographics, that is, 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 body surface area \[BSA\]); ECOG-performance status; Central 12-lead electrocardiogram (ECG); Pulmonary function test; Baseline imaging within 4 weeks prior to randomization (RECIST): At least chest + abdomen computed tomography (CT) (or magnetic resonance imaging \[MRI\] if there are contraindications to CT); Documentation of concomitant medications and adverse events (AEs); Safety laboratory assessments (hematology including coagulation parameters and biochemistry); Blood sampling for Human anti-chimeric antibody (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 Common Toxicity Criteria (CTC)/circulating endothelial cell (CEC) assessment (only pre-dose on Day 1 of Cycle 1 and Cycle 2); Blood sampling for cilengitide pharmacokinetic (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); Blood sampling for vinorelbine PK (6-10 subjects of Groups B and C; Cycle 1 only) (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 pro-brain natriuretic peptide (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 (that is, 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.

Cilengitide and Cetuximab in Combination With Platinum-based Chemotherapy as First-line Treatment for Subjects With Advanced Non Small Cell Lung Cancer (NSCLC)

Open-label, Randomized, Controlled, Multicenter Phase II Trial Investigating 2 Cilengitide Regimens in Combination With Cetuximab and Platinum-based Chemotherapy (Cisplatin/Vinorelbine or Cisplatin/Gemcitabine) Compared to Cetuximab and Platinum-based Chemotherapy Alone as First Line Treatment for Subjects With Advanced NSCLC

The PFS time is defined as the duration from randomization to either first observation of progressive disease (PD) or occurrence of death due to any cause. Independent Read is the assessment of all imaging centrally by an Independent Review Committee (IRC).

The PFS time is defined as the duration from randomization to either first observation of progressive disease (PD) or occurrence of death due to any cause. Investigator read is the assessment of all imaging by the treating physician at the local trial site.

The OS time is defined as the time (in months) from randomization to death or last day known to be alive. Participants without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier.

The BOR rate is defined as the percentage of participants having achieved confirmed complete response (CR) or partial response (PR) as the best overall response, based on radiological assessments (based on response evaluation criteria in solid tumors \[RECIST\]) as assessed by Independent Review Committee (IRC): CR = disappearance of all target lesions; PR = at least 30% decrease in the sum of the longest diameter of target lesions.

Time to treatment failure was defined as the time from first administration of trial treatment until the date of the first occurrence of one of the events defining treatment failure: Progressive Disease (PD) assessed by the investigator, discontinuation of treatment due to PD, discontinuation of treatment due to an adverse event (AE), start of any new anticancer therapy, or withdrawal of consent or death within 60 days of the last tumor assessment or first administration of trial treatment. Time to treatment failure was assessed according to modified World Health Organization (WHO) criteria by Independent Review Committee (IRC).

Merck KGaA, Darmstadt, Germany

The analysis was performed on safety population, defined as all participants who received any dose of the trial treatment (cilengitide, cetuximab, or chemotherapy), whereby participants were analyzed according to the actual treatment they received.

Cilengitide (Cil) 1000 milligram (mg) intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 milligram per square meter (mg/m\^2) intravenous infusion over 2 hours on Day 1 + Cisplatin (Cis) 75 mg/m\^2 intravenous infusion on Day 1 + Gemcitabine (Gem) 1250 mg/m\^2 intravenous infusion on Days 1 and 8 for 3 weeks.

Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem

Cil 1000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m\^2 intravenous infusion over 2 hours on Day 1 + Cis 80 mg/m\^2 intravenous infusion on Day 1 + Vinorelbine (Vin) 25 mg/m\^2 intravenous infusion on Days 1 and 8 for 3 weeks.

Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Vin

Cil 2000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m\^2 intravenous infusion over 2 hours on Day 1 + Cis 75 mg/m\^2 intravenous infusion on Day 1 + Gem 1250 mg/m\^2 intravenous infusion on Days 1 and 8 for 3 weeks.

Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem

Cil 2000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m\^2 intravenous infusion over 2 hours on Day 1 + Cis 80 mg/m\^2 intravenous infusion on Day 1 + Vin 25 mg/m\^2 intravenous infusion on Days 1 and 8 for 3 weeks.

Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Vin

Cil 2000 mg intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle + Cetuximab 400 mg/m\^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 250 mg/m\^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cis 80 mg/m\^2 intravenous infusion on Day 1 + Vin 25 mg/m\^2 or Cis 75 mg/m\^2 intravenous infusion on Day 1 + Gem 1250 mg/m\^2 intravenous infusion on Days 1 and 8 of each 3-week cycle) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy

Cil 2000 mg intravenous infusion twice weekly over 1 hour on Days 1, 4, 8, 11, 15, and 18 of each 3-week cycle followed by once weekly administration after end of chemotherapy + Cetuximab 400 mg/m\^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 250 mg/m\^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cis 80 mg/m\^2 intravenous infusion on Day 1 + Vin 25 mg/m\^2 or Cis 75 mg/m\^2 intravenous infusion on Day 1 + Gem 1250 mg/m\^2 intravenous infusion on Days 1 and 8 of each 3-week cycle) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy

Cetuximab 400 mg/m\^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 250 mg/m\^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cis 80 mg/m\^2 intravenous infusion on Day 1 + Vin 25 mg/m\^2 or Cis 75 mg/m\^2 intravenous infusion on Day 1 + Gem 1250 mg/m\^2 intravenous infusion on Days 1 and 8 of each 3-week cycle) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

Randomized Part: Cetuximab + Chemotherapy

Cil 1000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m\^2 intravenous infusion over 2 hours on Day 1 + Cis 75 mg/m\^2 intravenous infusion on Day 1 + Gem 1250 mg/m\^2 intravenous infusion on Days 1 and 8 for 3 weeks.

Cil 1000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m\^2 intravenous infusion over 2 hours on Day 1 + Cis 80 mg/m\^2 intravenous infusion on Day 1 + Vin 25 mg/m\^2 intravenous infusion on Days 1 and 8 for 3 weeks.

Total

Less than 65 years

Greater than or equal to 65 years

Age, Customized

Gender

Intent-to-treat (ITT) population included all participants who were randomized to trial treatment.

Merck KGaA Communication Center

Cil 1000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 milligram per square meter (mg/m\^2) intravenous infusion over 2 hours on Day 1 + Cis 75 mg/m\^2 intravenous infusion on Day 1 + Gem 1250 mg/m\^2 intravenous infusion on Days 1 and 8 for 3 weeks.

DLT population included all participants who completed first 3 weeks of treatment (first chemotherapy cycle) or who discontinued treatment due to any DLT during the first 3 weeks of treatment in the safety-run-in part.

Safety run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs)

Randomized Part: Progression Free Survival (PFS) Time - Independent Read

ITT population included all participants who were randomized to trial treatment.

Spots Global Cancer Trial Database for integrin receptor antagonist, egfr chimerized monoclonal antibody, chemotherapy