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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT00842712
First received: February 10, 2009
Last updated: September 29, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Carcinoma, Non-Small-Cell Lung
Drug: Cilengitide
Drug: Cetuximab
Drug: Cisplatin
Drug: Gemcitabine
Drug: Vinorelbine
Drug: Chemotherapy
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Safety run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Up to Week 3 ] [ Designated as safety issue: Yes ]
  • Randomized Part: Progression Free Survival (PFS) Time - Independent Read [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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).


Secondary Outcome Measures:
  • Randomized Part: Progression Free Survival (PFS) Time - Investigator Read [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Randomized Part: Overall Survival (OS) Time [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Randomized Part: Best Overall Response (BOR) Rate [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.

  • Randomized Part: Time to Treatment Failure [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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).


Enrollment: 232
Study Start Date: February 2009
Study Completion Date: July 2013
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Safety run-in part: Cil (1000 mg) + Cetuximab + Cis + Gem Drug: Cilengitide
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.
Drug: Cetuximab
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.
Drug: Cisplatin
Cisplatin (Cis) will be administered at a dose of 75 mg/m^2 as intravenous infusion on Day 1.
Drug: Gemcitabine
Gemcitabine (Gem) will be administered at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8.
Experimental: Safety run-in part: Cil (1000 mg) + Cetuximab + Cis + Vin Drug: Cilengitide
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.
Drug: Cetuximab
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.
Drug: Cisplatin
Cis will be administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1.
Drug: Vinorelbine
Vinorelbine (Vin) will be administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8.
Experimental: Safety run-in part: Cil (2000 mg) + Cetuximab + Cis + Gem Drug: Cilengitide
Cil will be administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4.
Drug: Cetuximab
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.
Drug: Cisplatin
Cisplatin (Cis) will be administered at a dose of 75 mg/m^2 as intravenous infusion on Day 1.
Drug: Gemcitabine
Gemcitabine (Gem) will be administered at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8.
Experimental: Safety run-in part: Cil (2000 mg) + Cetuximab + Cis + Vin Drug: Cilengitide
Cil will be administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4.
Drug: Cetuximab
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.
Drug: Cisplatin
Cis will be administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1.
Drug: Vinorelbine
Vinorelbine (Vin) will be administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8.
Experimental: Randomized part: Cil (Once Weekly) + Cetuximab + Chemotherapy Drug: Cilengitide
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.
Drug: Cetuximab
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.
Drug: 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 will be administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.
Experimental: Randomized part: Cil (Twice Weekly) + Cetuximab + Chemotherapy Drug: Cilengitide
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.
Drug: Cetuximab
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.
Drug: 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 will be administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.
Active Comparator: Randomized part: Cetuximab + Chemotherapy Drug: Cetuximab
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.
Drug: 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 will be administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

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  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  1. Written informed consent obtained before undergoing any study-related activities.
  2. Male or female, at least 18 years of age
  3. Histologically confirmed NSCLC, Stage IIIb with documented malignant pleural effusion or Stage IV (according to staging system 6th edition)
  4. 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)
  5. 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)
  6. 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
  7. Eastern Cooperative Oncology Group (ECOG)-performance status 0-1
  8. Leukocyte count >=3.0 x 10^9 per liter (/L)
  9. Absolute neutrophil count (ANC) >=1.5 x 10^9/L
  10. Platelets >=100 x 10^9/L
  11. Hemoglobin >=9 gram per deciliter (g/dL) (without transfusions)
  12. Bilirubin less than or equal to (<=) 1.5 x upper limit of normality (ULN)
  13. Aspartate Aminotransferase (AST) <=5 x ULN and Alanine Aminotransferase (ALT) <=5 x ULN
  14. Serum creatinine <=1.25 x ULN and/or creatinine clearance >=60 milliliter per minute (mL/min)
  15. Prothrombin time (PT), international normalized ratio (INR) within normal limits and partial thromboplastin time (PTT) below upper limit of normal.
  16. Sodium and potassium within normal limits or <=10% above or below (supplementation permitted).
  17. Effective contraception for both male and female subjects (if the risk of conception exists). If female, she must: be neither pregnant nor breast-feeding, nor attempting to conceive, use a highly effective method of contraception for at least 7 days before entry into the trial, throughout the entire duration of the trial and for 6 months following completion of the last dose of trial medication. A highly effective method of contraception is defined as those which result in a low failure rate (that is, <1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, intrauterine devices (IUDs) (hormonal or copper-based), sexual abstinence or vasectomized partner, or be post-menopausal or surgically sterilized. If male, he must be willing to use contraception to avoid pregnancies for at least 7 days before entry into the trial, throughout the entire duration of the trial and for 6 months following the last dose of trial medication. Two negative semen analyses post-vasectomy have to be available in order to be considered infertile

Exclusion criteria:

  1. Prior treatment with an antibody or molecule targeting EGFR- and/or vascular endothelial growth factor receptor (VEGFR)-related signaling pathways
  2. Previous chemotherapy for NSCLC including prior adjuvant therapy
  3. History of or current brain metastasis and/or leptomeningeal disease (known or suspected)
  4. 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
  5. Concurrent chronic immunosuppressive or hormone anti-cancer therapy (physiologic hormone replacement or corticosteroid treatment for chronic obstructive pulmonary disease [COPD] is allowed)
  6. 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
  7. 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
  8. Recent peptic ulcer disease (endoscopically proven gastric, duodenal or esophageal ulcer) within 6 months of study treatment start
  9. 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)
  10. Pregnancy or lactation period
  11. Concurrent treatment with a non-permitted drug
  12. Treatment with any other investigational product within the past 30 days
  13. Previous malignancy other than NSCLC in the last 5 years except for basal cell cancer of the skin or pre-invasive cancer of the cervix
  14. Medical or psychological conditions that would not permit the subject to complete the study or sign informed consent
  15. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such
  16. Patients with hepatitis, massive liver metastases (>75%), current alcoholism or liver cirrhosis (because of vinorelbine and gemcitabine)
  17. Patients who have been therapeutically anticoagulated
  18. Legal incapacity or limited legal capacity
  19. Significant disease (for example, interstitial lung disease) which, in the investigator's opinion, would exclude the subject from the study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00842712

  Show 44 Study Locations
Sponsors and Collaborators
Merck KGaA
Investigators
Study Director: Medical Responsible Merck KGaA
  More Information

No publications provided

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT00842712     History of Changes
Other Study ID Numbers: EMR 200037-014, EudraCT Number: 2008-004148-35
Study First Received: February 10, 2009
Results First Received: July 31, 2014
Last Updated: September 29, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices (BfArM)
Belgium: Federal Agency for Medicines and Health Products (afmps)
Ireland: Irish Medicines Board (IMB)
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Italy: National Monitoring Centre on Clinical Research with Medicines (OsSC)
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Spain: Ministry of Health and Consumption (AEMPS)

Keywords provided by Merck KGaA:
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

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Bronchial Neoplasms
Carcinoma, Bronchogenic
Lung Diseases
Lung Neoplasms
Neoplasms
Neoplasms by Site
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Cetuximab
Cisplatin
Gemcitabine
Vinorelbine
Anti-Infective Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Antiviral Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014