Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: First-line treatment for subjects with advanced NSCLC, integrin receptor antagonist, EGFR chimerized monoclonal antibody, chemotherapy safety run-in + randomization part, MTD, PFS, Overall survival time, best overall response
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 232
Healthy volunteers: no

Brief summary:
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.

Detailed description:
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.

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None

Interventions: intervention 1: Cilengitide intervention 2: Cilengitide intervention 3: Cetuximab intervention 4: Cisplatin intervention 5: Cisplatin intervention 6: Gemcitabine intervention 7: Vinorelbine intervention 8: Cilengitide intervention 9: Cilengitide intervention 10: Cetuximab intervention 11: Chemotherapy
Intervention descriptions: intervention 1: 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. intervention 2: Cil will be administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4. intervention 3: 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. intervention 4: Cisplatin (Cis) will be administered at a dose of 75 mg/m\^2 as intravenous infusion on Day 1. intervention 5: Cis will be administered at a dose of 80 mg/m\^2 as intravenous infusion on Day 1. intervention 6: Gemcitabine (Gem) will be administered at a dose of 1250 mg/m\^2 as intravenous infusion on Days 1 and 8. intervention 7: Vinorelbine (Vin) will be administered at a dose of 25 mg/m\^2 as intravenous infusion on Days 1 and 8. intervention 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. intervention 9: 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. intervention 10: 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. intervention 11: 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.

Protocol document: