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

NCT00842712 | Completed Phase 2 Results

• 2 other identifiers: EMR200037-014EudraCT Number: 2008-004148-35
• Study Type: interventional
• Target: 232
• Locations: 8 countries
• Sites: 44

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.

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

Outcome Measures

Primary Outcomes (2)

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

  Up to Week 3

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

  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).

  Time from randomization until disease progression, death or last tumor assessment, reported between day of first participant randomized, that is, Feb 2009 until cut-off date, (26 Jun 2013)

Secondary Outcomes (4)

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

  Time from randomization until disease progression, death or last tumor assessment, reported between day of first participant randomized, that is, Feb 2009 until cut-off date, (26 Jun 2013)

• Randomized Part: Overall Survival (OS) Time

  Time from randomization until death or last day known to be alive, reported between day of first participant randomized, that is, Feb 2009 until cut-off date,(26 Jun 2013)

• Randomized Part: Best Overall Response (BOR) Rate

  Time from randomization until disease progression, death or last tumor assessment, reported between day of first participant randomized, that is, Feb 2009 until cut-off date,(26 Jun 2013)

• Randomized Part: Time to Treatment Failure

  Time from randomization until treatment failure or last tumor assessment, reported between day of first participant randomized, that is, Feb 2009 until cut-off date,(26 Jun 2013)

Study Arms (7)

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

EXPERIMENTAL

Drug: Cilengitide; Drug: Cetuximab; Drug: Cisplatin; Drug: Gemcitabine

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

EXPERIMENTAL

Drug: Cilengitide; Drug: Cetuximab; Drug: Cisplatin; Drug: Vinorelbine

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

EXPERIMENTAL

Drug: Cilengitide; Drug: Cetuximab; Drug: Cisplatin; Drug: Gemcitabine

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

EXPERIMENTAL

Drug: Cilengitide; Drug: Cetuximab; Drug: Cisplatin; Drug: Vinorelbine

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

EXPERIMENTAL

Drug: Cilengitide; Drug: Cetuximab; Drug: Chemotherapy

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

EXPERIMENTAL

Drug: Cilengitide; Drug: Cetuximab; Drug: Chemotherapy

Randomized part: Cetuximab + Chemotherapy

ACTIVE COMPARATOR

Drug: Cetuximab; Drug: Chemotherapy

Interventions

Cilengitide DRUG

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.

Safety run-in part: Cil (1000 mg) + Cetuximab + Cis + Gem; Safety run-in part: Cil (1000 mg) + Cetuximab + Cis + Vin

Cetuximab DRUG

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.

Safety run-in part: Cil (1000 mg) + Cetuximab + Cis + Gem; Safety run-in part: Cil (1000 mg) + Cetuximab + Cis + Vin; Safety run-in part: Cil (2000 mg) + Cetuximab + Cis + Gem; Safety run-in part: Cil (2000 mg) + Cetuximab + Cis + Vin

Cisplatin DRUG

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

Safety run-in part: Cil (1000 mg) + Cetuximab + Cis + Gem; Safety run-in part: Cil (2000 mg) + Cetuximab + Cis + Gem

Gemcitabine DRUG

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

Safety run-in part: Cil (1000 mg) + Cetuximab + Cis + Gem; Safety run-in part: Cil (2000 mg) + Cetuximab + Cis + Gem

Vinorelbine DRUG

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

Safety run-in part: Cil (1000 mg) + Cetuximab + Cis + Vin; Safety run-in part: Cil (2000 mg) + Cetuximab + Cis + Vin

Chemotherapy DRUG

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.

Randomized part: Cetuximab + Chemotherapy; Randomized part: Cil (Once Weekly) + Cetuximab + Chemotherapy; Randomized part: Cil (Twice Weekly) + Cetuximab + Chemotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent obtained before undergoing any study-related activities.
• Male or female, at least 18 years of age
• Histologically confirmed NSCLC, Stage IIIb with documented malignant pleural effusion or Stage IV (according to staging system 6th edition)
• EGFR expression greater than or equal to (\>=) 200 on tumor tissue determined by local testing using the kit and testing procedures described in the study Manual of Operations (MOP)
• Archived tumor material sample for central histology and further biomarker research including mutational analysis of genes such as EGFR, k-ras, b-raf (material details described in the study MOP)
• At least 1 radiographically documented measurable lesion in a previously non-irradiated area according to evaluation criteria in solid tumors (RECIST), i.e. this lesion must be adequately measurable in at least 1 dimension (longest diameter \[LD\] to be recorded) as \>=2 centimeter (cm) by conventional techniques or ≥1 cm by spiral CT scan
• Eastern Cooperative Oncology Group (ECOG)-performance status 0-1
• Leukocyte count \>=3.0 x 10\^9 per liter (/L)
• Absolute neutrophil count (ANC) \>=1.5 x 10\^9/L
• Platelets \>=100 x 10\^9/L
• Hemoglobin \>=9 gram per deciliter (g/dL) (without transfusions)
• Bilirubin less than or equal to (\<=) 1.5 x upper limit of normality (ULN)
• Aspartate Aminotransferase (AST) \<=5 x ULN and Alanine Aminotransferase (ALT) \<=5 x ULN
• Serum creatinine \<=1.25 x ULN and/or creatinine clearance \>=60 milliliter per minute (mL/min)
• Prothrombin time (PT), international normalized ratio (INR) within normal limits and partial thromboplastin time (PTT) below upper limit of normal.

You may not qualify if:

• Prior treatment with an antibody or molecule targeting EGFR- and/or vascular endothelial growth factor receptor (VEGFR)-related signaling pathways
• Previous chemotherapy for NSCLC including prior adjuvant therapy
• History of or current brain metastasis and/or leptomeningeal disease (known or suspected)
• Radiotherapy (except localized radiotherapy for pain relief), major surgery or any intake of investigational drug in the 30 days before the start of study treatment entry
• Concurrent chronic immunosuppressive or hormone anti-cancer therapy (physiologic hormone replacement or corticosteroid treatment for chronic obstructive pulmonary disease \[COPD\] is allowed)
• Clinically relevant coronary artery disease (New York Heart Association \[NYHA\] functional angina classification III/IV), congestive heart failure (NYHA III/IV), clinically relevant cardiomyopathy, history of myocardial infarction in the last 12 months, or high risk of uncontrolled arrhythmia
• History of coagulation disorder associated with bleeding, recurrent or recent thrombotic events or history of hemoptysis related to bronchopulmonary cancer. Hemoptysis is defined as coughing more than a teaspoon of red blood per day
• Recent peptic ulcer disease (endoscopically proven gastric, duodenal or esophageal ulcer) within 6 months of study treatment start
• Presence of any contra-indication to treatment with cilengitide, cetuximab, cisplatin and vinorelbine or gemcitabine including:
• Known hypersensitivity to cilengitide, cetuximab, cisplatin, vinorelbine, or gemcitabine or to any of the excipients of these drugs
• Superior vena cava syndrome contra-indicating hydration
• Symptomatic peripheral neuropathy National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade \>=2 and/or ototoxicity NCI CTC AE Grade \>=2, except if due to trauma or mechanical impairment due to tumor mass
• Phenytoin (introduced to prevent the anticonvulsant effect of certain anticancer drugs) (contra-indication for cisplatin)
• Yellow Fever Vaccine, Live Attenuated Vaccines (contra-indications for cisplatin)
• Pregnancy or lactation period

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: lead

Study Sites (44)

Research Site

Antwerpen (Edegem), Belgium

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Brasschaat, Belgium

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Brussels, Belgium

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Gosselies, Belgium

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Leuven, Belgium

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Mons, Belgium

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Liberec, Czechia

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Usti Nach Labem, Czechia

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Bobigny, France

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Bordeaux, France

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Lille, France

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Lyon, France

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Marseille, France

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Nantes - Saint Herblain, France

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Paris, France

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Rennes, France

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Strasbourg, France

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Vandœuvre-lès-Nancy, France

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Aachen, Germany

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Berlin, Germany

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Darmstadt, Germany

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Frankfurt, Germany

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Freiburg im Breisgau, Germany

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Goch, Germany

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Halle-Dölau, Germany

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Hamburg, Germany

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Lübeck, Germany

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Mannheim, Germany

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Munich, Germany

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Offenbach, Germany

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Oldenburg, Germany

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Wiesbaden, Germany

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Dublin, Ireland

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Avellino, Italy

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Bologna, Italy

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Meldola, Italy

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Rome, Italy

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Lublin, Poland

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Otwock, Poland

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Poznan, Poland

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Warsaw, Poland

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Wodzisław Śląski, Poland

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Baracaldo Vizcaya, Spain

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Barcelona, Spain

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Related Publications (1)

• Vansteenkiste J, Barlesi F, Waller CF, Bennouna J, Gridelli C, Goekkurt E, Verhoeven D, Szczesna A, Feurer M, Milanowski J, Germonpre P, Lena H, Atanackovic D, Krzakowski M, Hicking C, Straub J, Picard M, Schuette W, O'Byrne K. Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: results of an open-label, randomized, controlled phase II study (CERTO). Ann Oncol. 2015 Aug;26(8):1734-40. doi: 10.1093/annonc/mdv219. Epub 2015 May 4.

  PMID: 25939894 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Metatropic dwarfism

Interventions

Cilengitide; Cetuximab; Cisplatin; Gemcitabine; Vinorelbine; Drug Therapy

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Therapeutics

Results Point of Contact

• Title: Merck KGaA Communication Center
• Organization: Merck Serono, a division of Merck KGaA

service@merckgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 10, 2009
• First Posted: February 12, 2009
• Study Start: February 1, 2009
• Primary Completion: July 1, 2013
• Study Completion: July 1, 2013
• Last Updated: January 13, 2017
• Results First Posted: September 30, 2014

Record last verified: 2017-01

Locations

BE (6); IE (1); DE (14); FR (10); PL (5); IT (4); ES (2); CZ (2)