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 24, 2013
Last verified: September 2013
  Purpose

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

- To determine the 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 i.v. 1000 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.

In the safety run-in a dose of 2000 mg cilengitide twice weekly was well tolerated for each of the platinum based chemotherapy regimens (cisplatin/vinorelbine or cisplatin/gemcitabine) in combination with cetuximab.

After completion of the safety run-in, the randomized part has been 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
NSCLC
Non Small Cell Lung Cancer
Drug: Cilengitide
Drug: Cilengitide, Cetuximab and platinum-based chemotherapy
Phase 1
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,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

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Safety run-in: Occurrence of any DLT within a subject during the first 3 weeks of treatment (first chemotherapy cycle). [ Time Frame: In the first 3 weeks of treatment ] [ Designated as safety issue: Yes ]
  • Randomized Part: Progression Free Survival Time [ Time Frame: duration of the trial (24 months) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Randomized Part: - Overall survival time - Best overall response - Time to treatment failure [ Time Frame: duration of the trial (24 months) ] [ Designated as safety issue: No ]

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: 1 Drug: Cilengitide

Safety Run-In - only two cohorts of the three will be used:

• Cohort 1: cilengitide 1000 mg twice weekly (Days 1 and 4) in combination with cetuximab and platinum-based chemotherapy.

according to the occurred number of dose limiting toxicities

• Cohort -1 (fall back): cilengitide 500 mg twice weekly (Days 1 and 4) in combination with cetuximab and platinum-based chemotherapy.

or

• Cohort 2: cilengitide 2000 mg twice weekly (Days 1 and 4) in combination with cetuximab and platinum-based chemotherapy will follow.

Experimental: 2 Drug: Cilengitide, Cetuximab and platinum-based chemotherapy

Randomization Part:

A: Cilengitide 2000 mg once weekly in combination with cetuximab and platinum-based chemotherapy that will consist of the following:

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

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

B: Cilengitide 2000 mg 2x 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.

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

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


  Show Detailed Description

  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 ≥ 200 on tumor tissue determined by local testing using the kit and testing procedures described in the study 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 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)/L.
  9. Absolute neutrophil count (ANC) ≥1.5 x 10(9)/L.
  10. Platelets ≥100 x 10(9)/L.
  11. Hemoglobin ≥9 g/dL (without transfusions).
  12. Bilirubin ≤1.5 x upper limit of normality (ULN).
  13. AST ≤5 x ULN and ALT ≤5 x ULN.
  14. Serum creatinine ≤1.25 x ULN and/or creatinine clearance ≥60 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).

1. If female, she must:

  • be neither pregnant nor breast-feeding, nor attempting to conceive and
  • 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 (i.e. less than1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, IUDs (hormonal or copper-based), sexual abstinence or vasectomized partner, or
  • be post-menopausal or surgically sterilized 2. 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 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 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 (see Section 6.8).
  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 (e.g. 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
Last Updated: September 24, 2013
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
Lung Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Cetuximab
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 01, 2014