Cilengitide and Cetuximab in Combination With Platinum-based Chemotherapy as First-line Treatment for Subjects With Advanced Non Small Cell Lung Cancer (NSCLC)
Condition: Carcinoma, Non-Small-Cell Lung
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Cilengitide; Cilengitide; Cetuximab; Cisplatin; Cisplatin; Gemcitabine; Vinorelbine; Cilengitide; Cilengitide; Cetuximab; Chemotherapy
Intervention description: 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.; 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.
Intervention MeSH terms: Cisplatin; Gemcitabine; Cetuximab; Vinorelbine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 232.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
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

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.
    

Eligibility 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