CERTO: Cilengitide and Cetuximab in Combination With Platinum-based Chemotherapy as First-line Treatment for Subjects With Advanced Non Small Cell Lung Cancer (NSCLC)
Study Details
Study Description
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
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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 or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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.
|
Outcome Measures
Primary Outcome Measures
- 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 [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)]
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 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)]
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 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)]
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 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)]
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 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)]
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).
Eligibility Criteria
Criteria
Inclusion criteria:
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Written informed consent obtained before undergoing any study-related activities.
-
Male or female, at least 18 years of age
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Histologically confirmed NSCLC, Stage IIIb with documented malignant pleural effusion or Stage IV (according to staging system 6th edition)
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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)
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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
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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
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Serum creatinine <=1.25 x ULN and/or creatinine clearance >=60 milliliter per minute (mL/min)
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Prothrombin time (PT), international normalized ratio (INR) within normal limits and partial thromboplastin time (PTT) below upper limit of normal.
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Sodium and potassium within normal limits or <=10% above or below (supplementation permitted).
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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:
-
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
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History of or current brain metastasis and/or leptomeningeal disease (known or suspected)
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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
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Concurrent chronic immunosuppressive or hormone anti-cancer therapy (physiologic hormone replacement or corticosteroid treatment for chronic obstructive pulmonary disease [COPD] is allowed)
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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
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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
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Recent peptic ulcer disease (endoscopically proven gastric, duodenal or esophageal ulcer) within 6 months of study treatment start
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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
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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
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Phenytoin (introduced to prevent the anticonvulsant effect of certain anticancer drugs) (contra-indication for cisplatin)
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Yellow Fever Vaccine, Live Attenuated Vaccines (contra-indications for cisplatin)
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Pregnancy or lactation period
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Concurrent treatment with a non-permitted drug
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Treatment with any other investigational product within the past 30 days
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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
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Medical or psychological conditions that would not permit the subject to complete the study or sign informed consent
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Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such
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Patients with hepatitis, massive liver metastases (>75%), current alcoholism or liver cirrhosis (because of vinorelbine and gemcitabine)
-
Patients who have been therapeutically anticoagulated
-
Legal incapacity or limited legal capacity
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Significant disease (for example, interstitial lung disease) which, in the investigator's opinion, would exclude the subject from the study
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Antwerpen (Edegem) | Belgium | ||
| 2 | Research Site | Brasschaat | Belgium | ||
| 3 | Research Site | Brussel | Belgium | ||
| 4 | Research Site | Gosselies | Belgium | ||
| 5 | Research Site | Leuven | Belgium | ||
| 6 | Research Site | Mons | Belgium | ||
| 7 | Research Site | Liberec | Czech Republic | ||
| 8 | Research Site | Usti nach Labem | Czech Republic | ||
| 9 | Research Site | Bobigny | France | ||
| 10 | Research Site | Bordeaux | France | ||
| 11 | Research Site | Lille | France | ||
| 12 | Research Site | Lyon | France | ||
| 13 | Research Site | Marseille | France | ||
| 14 | Research Site | Nantes - Saint Herblain | France | ||
| 15 | Research Site | Paris | France | ||
| 16 | Research Site | Rennes | France | ||
| 17 | Research Site | Strasbourg | France | ||
| 18 | Research Site | Vandoeuvre | France | ||
| 19 | Research Site | Aachen | Germany | ||
| 20 | Research Site | Berlin | Germany | ||
| 21 | Research Site | Darmstadt | Germany | ||
| 22 | Research Site | Frankfurt | Germany | ||
| 23 | Research Site | Freiburg | Germany | ||
| 24 | Research Site | Goch | Germany | ||
| 25 | Research Site | Halle-Dölau | Germany | ||
| 26 | Research Site | Hamburg | Germany | ||
| 27 | Research Site | Luebeck | Germany | ||
| 28 | Research Site | Mannheim | Germany | ||
| 29 | Research Site | Munic | Germany | ||
| 30 | Research Site | Offenbach | Germany | ||
| 31 | Research Site | Oldenburg | Germany | ||
| 32 | Research Site | Wiesbaden | Germany | ||
| 33 | Research Site | Dublin | Ireland | ||
| 34 | Research Site | Avellino | Italy | ||
| 35 | Research Site | Bologna | Italy | ||
| 36 | Research Site | Meldola | Italy | ||
| 37 | Research Site | Rome | Italy | ||
| 38 | Research Site | Lublin | Poland | ||
| 39 | Research Site | Otwock | Poland | ||
| 40 | Research Site | Poznan | Poland | ||
| 41 | Research Site | Warsaw | Poland | ||
| 42 | Research Site | Wodzislaw Slaski | Poland | ||
| 43 | Research Site | Baracaldo Vizcaya | Spain | ||
| 44 | Research Site | Barcelona | Spain |
Sponsors and Collaborators
- Merck KGaA, Darmstadt, Germany
Investigators
- Study Director: Medical Responsible, Merck KGaA, Darmstadt, Germany
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- EMR200037-014
- EudraCT Number: 2008-004148-35
Study Results
Participant Flow
| Recruitment Details | First/last participant (informed consent): Feb 2009/Jun 2012. Clinical data cut-off: 26 Jun 2013, Study completion date: July 2013. |
|---|---|
| Pre-assignment Detail | In safety run-in part of study, a total of 12 participants were enrolled and treated. In randomized part of study, 220 participants were enrolled and out of these 220 participants, 215 were treated. |
| Arm/Group Title | 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 | Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cetuximab + Chemotherapy |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | Cilengitide (Cil) 1000 milligram (mg) intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 milligram per square meter (mg/m^2) intravenous infusion over 2 hours on Day 1 + Cisplatin (Cis) 75 mg/m^2 intravenous infusion on Day 1 + Gemcitabine (Gem) 1250 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. | Cil 1000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 + Cis 80 mg/m^2 intravenous infusion on Day 1 + Vinorelbine (Vin) 25 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. | Cil 2000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 + Cis 75 mg/m^2 intravenous infusion on Day 1 + Gem 1250 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. | Cil 2000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 + Cis 80 mg/m^2 intravenous infusion on Day 1 + Vin 25 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. | Cil 2000 mg intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cil 2000 mg 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 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. |
| Period Title: Safety Run-in Part | |||||||
| STARTED | 3 | 3 | 3 | 3 | 0 | 0 | 0 |
| COMPLETED | 0 | 1 | 3 | 2 | 0 | 0 | 0 |
| NOT COMPLETED | 3 | 2 | 0 | 1 | 0 | 0 | 0 |
| Period Title: Safety Run-in Part | |||||||
| STARTED | 0 | 0 | 0 | 0 | 85 | 51 | 84 |
| Treated | 0 | 0 | 0 | 0 | 85 | 50 | 80 |
| COMPLETED | 0 | 0 | 0 | 0 | 85 | 50 | 78 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 1 | 6 |
Baseline Characteristics
| Arm/Group Title | 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 | Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cetuximab + Chemotherapy | Total |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Cil 1000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 + Cis 75 mg/m^2 intravenous infusion on Day 1 + Gem 1250 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. | Cil 1000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 + Cis 80 mg/m^2 intravenous infusion on Day 1 + Vin 25 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. | Cil 2000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 + Cis 75 mg/m^2 intravenous infusion on Day 1 + Gem 1250 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. | Cil 2000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 + Cis 80 mg/m^2 intravenous infusion on Day 1 + Vin 25 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. | Cil 2000 mg intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cil 2000 mg 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 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Total of all reporting groups |
| Overall Participants | 3 | 3 | 3 | 3 | 85 | 51 | 84 | 232 |
| Age, Customized (participants) [Number] | ||||||||
| Less than 65 years |
3
100%
|
2
66.7%
|
3
100%
|
3
100%
|
68
80%
|
37
72.5%
|
66
78.6%
|
182
78.4%
|
| Greater than or equal to 65 years |
0
0%
|
1
33.3%
|
0
0%
|
0
0%
|
17
20%
|
14
27.5%
|
18
21.4%
|
50
21.6%
|
| Gender (Count of Participants) | ||||||||
| Female |
1
33.3%
|
0
0%
|
2
66.7%
|
2
66.7%
|
34
40%
|
19
37.3%
|
27
32.1%
|
85
36.6%
|
| Male |
2
66.7%
|
3
100%
|
1
33.3%
|
1
33.3%
|
51
60%
|
32
62.7%
|
57
67.9%
|
147
63.4%
|
Outcome Measures
| Title | Safety run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs) |
|---|---|
| Description | |
| Time Frame | Up to Week 3 |
Outcome Measure Data
| Analysis Population Description |
|---|
| DLT population included all participants who completed first 3 weeks of treatment (first chemotherapy cycle) or who discontinued treatment due to any DLT during the first 3 weeks of treatment in the safety-run-in part. |
| Arm/Group Title | 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 |
|---|---|---|---|---|
| Arm/Group Description | Cil 1000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 milligram per square meter (mg/m^2) intravenous infusion over 2 hours on Day 1 + Cis 75 mg/m^2 intravenous infusion on Day 1 + Gem 1250 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. | Cil 1000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 + Cis 80 mg/m^2 intravenous infusion on Day 1 + Vin 25 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. | Cil 2000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 + Cis 75 mg/m^2 intravenous infusion on Day 1 + Gem 1250 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. | Cil 2000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 + Cis 80 mg/m^2 intravenous infusion on Day 1 + Vin 25 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. |
| Measure Participants | 3 | 3 | 3 | 3 |
| Number [participants] |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Title | Randomized Part: Progression Free Survival (PFS) Time - Independent Read |
|---|---|
| Description | 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 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Intent-to-treat (ITT) population included all participants who were randomized to trial treatment. |
| Arm/Group Title | Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cetuximab + Chemotherapy |
|---|---|---|---|
| Arm/Group Description | Cil 2000 mg intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cil 2000 mg 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 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. |
| Measure Participants | 85 | 51 | 84 |
| Median (95% Confidence Interval) [months] |
6.2
|
5.6
|
5.0
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem, Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem |
|---|---|---|
| Comments | PFS Time: Independent read | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0845 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.718 | |
| Confidence Interval |
(2-Sided) 95% 0.492 to 1.048 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Randomized Part: Progression Free Survival (PFS) Time - Investigator Read |
|---|---|
| Description | 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. |
| 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all participants who were randomized to trial treatment. |
| Arm/Group Title | Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cetuximab + Chemotherapy |
|---|---|---|---|
| Arm/Group Description | Cil 2000 mg intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cil 2000 mg 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 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. |
| Measure Participants | 85 | 51 | 84 |
| Median (95% Confidence Interval) [months] |
5.6
|
5.6
|
5.3
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem, Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.5912 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.909 | |
| Confidence Interval |
(2-Sided) 95% 0.642 to 1.286 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Randomized Part: Overall Survival (OS) Time |
|---|---|
| Description | 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. |
| 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all participants who were randomized to trial treatment. |
| Arm/Group Title | Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cetuximab + Chemotherapy |
|---|---|---|---|
| Arm/Group Description | Cil 2000 mg intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cil 2000 mg 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 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. |
| Measure Participants | 85 | 51 | 84 |
| Median (95% Confidence Interval) [months] |
13.6
|
13.6
|
9.7
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem, Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2648 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.813 | |
| Confidence Interval |
(2-Sided) 95% 0.564 to 1.171 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Randomized Part: Best Overall Response (BOR) Rate |
|---|---|
| Description | 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. |
| 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all participants who were randomized to trial treatment. |
| Arm/Group Title | Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cetuximab + Chemotherapy |
|---|---|---|---|
| Arm/Group Description | Cil 2000 mg intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cil 2000 mg 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 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. |
| Measure Participants | 85 | 51 | 84 |
| Number (95% Confidence Interval) [percentage of participants] |
37.6
1253.3%
|
27.5
916.7%
|
29.8
993.3%
|
| Title | Randomized Part: Time to Treatment Failure |
|---|---|
| Description | 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). |
| 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all participants who were randomized to trial treatment. |
| Arm/Group Title | Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cetuximab + Chemotherapy |
|---|---|---|---|
| Arm/Group Description | Cil 2000 mg intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cil 2000 mg 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 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. |
| Measure Participants | 85 | 51 | 84 |
| Median (95% Confidence Interval) [months] |
4.4
|
2.8
|
4.2
|
Adverse Events
| Time Frame | Time from first dose up to 28 days after last dose of study treatment, reported between day of first participant randomized, that is, Feb 2009 until cut-off date (26 Jun 2013) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | The analysis was performed on safety population, defined as all participants who received any dose of the trial treatment (cilengitide, cetuximab, or chemotherapy), whereby participants were analyzed according to the actual treatment they received. | |||||||||||||
| Arm/Group Title | 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 | Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cetuximab + Chemotherapy | |||||||
| Arm/Group Description | Cilengitide (Cil) 1000 milligram (mg) intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 milligram per square meter (mg/m^2) intravenous infusion over 2 hours on Day 1 + Cisplatin (Cis) 75 mg/m^2 intravenous infusion on Day 1 + Gemcitabine (Gem) 1250 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. | Cil 1000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 + Cis 80 mg/m^2 intravenous infusion on Day 1 + Vinorelbine (Vin) 25 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. | Cil 2000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 + Cis 75 mg/m^2 intravenous infusion on Day 1 + Gem 1250 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. | Cil 2000 mg intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 + Cis 80 mg/m^2 intravenous infusion on Day 1 + Vin 25 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks. | Cil 2000 mg intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cil 2000 mg 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 + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 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. 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) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles. | |||||||
All Cause Mortality |
||||||||||||||
| 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 | Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cetuximab + Chemotherapy | ||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | |||||||
Serious Adverse Events |
||||||||||||||
| 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 | Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cetuximab + Chemotherapy | ||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/3 (0%) | 2/3 (66.7%) | 1/3 (33.3%) | 0/3 (0%) | 42/85 (49.4%) | 29/50 (58%) | 45/80 (56.3%) | |||||||
| Blood and lymphatic system disorders | ||||||||||||||
| NEUTROPENIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 4/85 (4.7%) | 1/50 (2%) | 3/80 (3.8%) | |||||||
| THROMBOCYTOPENIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 1/50 (2%) | 4/80 (5%) | |||||||
| ANAEMIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 1/50 (2%) | 2/80 (2.5%) | |||||||
| FEBRILE NEUTROPENIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 3/85 (3.5%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| FEBRILE BONE MARROW APLASIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| LEUKOPENIA | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| PANCYTOPENIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| Cardiac disorders | ||||||||||||||
| ACUTE MYOCARDIAL INFARCTION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| ARRHYTHMIA SUPRAVENTRICULAR | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| ATRIAL FIBRILLATION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| PERICARDIAL EFFUSION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 0/80 (0%) | |||||||
| STRESS CARDIOMYOPATHY | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| VENTRICULAR TACHYCARDIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 0/80 (0%) | |||||||
| Ear and labyrinth disorders | ||||||||||||||
| HYPOACUSIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| Eye disorders | ||||||||||||||
| PERIORBITAL OEDEMA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| Gastrointestinal disorders | ||||||||||||||
| VOMITING | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/85 (2.4%) | 1/50 (2%) | 4/80 (5%) | |||||||
| ABDOMINAL PAIN | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 1/50 (2%) | 2/80 (2.5%) | |||||||
| NAUSEA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 2/50 (4%) | 1/80 (1.3%) | |||||||
| DIARRHOEA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 1/50 (2%) | 1/80 (1.3%) | |||||||
| ABDOMINAL PAIN UPPER | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| CONSTIPATION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| DIVERTICULAR PERFORATION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| DUODENAL ULCER HAEMORRHAGE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| LARGE INTESTINE PERFORATION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| PROCTITIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| HAEMATOCHEZIA | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| General disorders | ||||||||||||||
| GENERAL PHYSICAL HEALTH DETERIORATION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 4/85 (4.7%) | 1/50 (2%) | 3/80 (3.8%) | |||||||
| PYREXIA | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 1/50 (2%) | 1/80 (1.3%) | |||||||
| ASTHENIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 1/80 (1.3%) | |||||||
| DISEASE PROGRESSION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| FATIGUE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 1/80 (1.3%) | |||||||
| MALAISE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| CHEST PAIN | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| IMPAIRED HEALING | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| MEDICAL DEVICE COMPLICATION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| Hepatobiliary disorders | ||||||||||||||
| CHOLECYSTITIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| Immune system disorders | ||||||||||||||
| ANAPHYLACTIC REACTION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| DRUG HYPERSENSITIVITY | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| Infections and infestations | ||||||||||||||
| PNEUMONIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 1/50 (2%) | 4/80 (5%) | |||||||
| SEPSIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 2/50 (4%) | 0/80 (0%) | |||||||
| STAPHYLOCOCCAL INFECTION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 1/50 (2%) | 0/80 (0%) | |||||||
| BRONCHITIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 0/80 (0%) | |||||||
| BRONCHOPNEUMONIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 0/80 (0%) | |||||||
| BRONCHOPULMONARY ASPERGILLOSIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| CYSTITIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 0/80 (0%) | |||||||
| DEVICE RELATED INFECTION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| DIVERTICULITIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| GASTROINTESTINAL INFECTION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 0/80 (0%) | |||||||
| LUNG INFECTION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| NAIL BED INFECTION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| PNEUMONIA BACTERIAL | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| PROTEUS INFECTION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| STAPHYLOCOCCAL SKIN INFECTION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| URINARY TRACT INFECTION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| Injury, poisoning and procedural complications | ||||||||||||||
| HIP FRACTURE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/85 (2.4%) | 0/50 (0%) | 0/80 (0%) | |||||||
| LIMB INJURY | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| FAILURE TO ANASTOMOSE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| INCISIONAL HERNIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 0/80 (0%) | |||||||
| SPINAL COMPRESSION FRACTURE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| SPLENIC RUPTURE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| Investigations | ||||||||||||||
| HAEMOGLOBIN DECREASED | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| PLATELET COUNT DECREASED | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| Metabolism and nutrition disorders | ||||||||||||||
| DECREASED APPETITE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 0/80 (0%) | |||||||
| DEHYDRATION | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| HYPERCALCAEMIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 0/80 (0%) | |||||||
| HYPOKALAEMIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| HYPOMAGNESAEMIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 0/80 (0%) | |||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||||
| BACK PAIN | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||
| MALIGNANT PLEURAL EFFUSION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| METASTASES TO MENINGES | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| TUMOUR EMBOLISM | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| Nervous system disorders | ||||||||||||||
| CEREBROVASCULAR ACCIDENT | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 2/50 (4%) | 1/80 (1.3%) | |||||||
| CONVULSION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/85 (2.4%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| SYNCOPE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| CENTRAL NERVOUS SYSTEM LESION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| COMA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| SOMNOLENCE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| STATUS EPILEPTICUS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| Psychiatric disorders | ||||||||||||||
| ANXIETY | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| CONFUSIONAL STATE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| Renal and urinary disorders | ||||||||||||||
| RENAL FAILURE ACUTE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| RENAL FAILURE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 0/80 (0%) | |||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||
| PULMONARY EMBOLISM | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 4/85 (4.7%) | 5/50 (10%) | 8/80 (10%) | |||||||
| PLEURAL EFFUSION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 1/50 (2%) | 0/80 (0%) | |||||||
| EPISTAXIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 1/80 (1.3%) | |||||||
| HAEMOPTYSIS | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/85 (1.2%) | 1/50 (2%) | 0/80 (0%) | |||||||
| PULMONARY THROMBOSIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 1/50 (2%) | 0/80 (0%) | |||||||
| RESPIRATORY FAILURE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 2/50 (4%) | 0/80 (0%) | |||||||
| ACUTE RESPIRATORY DISTRESS SYNDROME | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| DYSPNOEA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| DYSPNOEA EXERTIONAL | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| PNEUMOTHORAX | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| RESPIRATORY DISTRESS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| Vascular disorders | ||||||||||||||
| DEEP VEIN THROMBOSIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 2/80 (2.5%) | |||||||
| AORTIC THROMBOSIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| PERIPHERAL ARTERIAL OCCLUSIVE DISEASE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 2/80 (2.5%) | |||||||
| ARTERIAL DISORDER | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| ARTERIAL THROMBOSIS LIMB | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| AXILLARY VEIN THROMBOSIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| HYPOTENSION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| HYPOVOLAEMIC SHOCK | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 0/80 (0%) | |||||||
| JUGULAR VEIN THROMBOSIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| PERIPHERAL EMBOLISM | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| SHOCK | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| SUBCLAVIAN VEIN THROMBOSIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| SUPERIOR VENA CAVA SYNDROME | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 0/80 (0%) | |||||||
| THROMBOSIS | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| VENA CAVA THROMBOSIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
Other (Not Including Serious) Adverse Events |
||||||||||||||
| 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 | Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy | Randomized Part: Cetuximab + Chemotherapy | ||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/3 (100%) | 3/3 (100%) | 3/3 (100%) | 3/3 (100%) | 84/85 (98.8%) | 48/50 (96%) | 78/80 (97.5%) | |||||||
| Blood and lymphatic system disorders | ||||||||||||||
| NEUTROPENIA | 2/3 (66.7%) | 0/3 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 42/85 (49.4%) | 21/50 (42%) | 34/80 (42.5%) | |||||||
| ANAEMIA | 1/3 (33.3%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 33/85 (38.8%) | 21/50 (42%) | 22/80 (27.5%) | |||||||
| THROMBOCYTOPENIA | 1/3 (33.3%) | 0/3 (0%) | 2/3 (66.7%) | 0/3 (0%) | 28/85 (32.9%) | 16/50 (32%) | 21/80 (26.3%) | |||||||
| LEUKOPENIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/3 (66.7%) | 20/85 (23.5%) | 7/50 (14%) | 9/80 (11.3%) | |||||||
| LYMPHOPENIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 4/85 (4.7%) | 3/50 (6%) | 4/80 (5%) | |||||||
| THROMBOCYTOSIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 3/85 (3.5%) | 4/50 (8%) | 1/80 (1.3%) | |||||||
| FEBRILE NEUTROPENIA | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| Cardiac disorders | ||||||||||||||
| TACHYCARDIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 3/50 (6%) | 1/80 (1.3%) | |||||||
| BRADYCARDIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/85 (0%) | 1/50 (2%) | 1/80 (1.3%) | |||||||
| PALPITATIONS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 3/85 (3.5%) | 2/50 (4%) | 1/80 (1.3%) | |||||||
| Ear and labyrinth disorders | ||||||||||||||
| TINNITUS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 3/50 (6%) | 6/80 (7.5%) | |||||||
| Eye disorders | ||||||||||||||
| CONJUNCTIVITIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 10/85 (11.8%) | 7/50 (14%) | 5/80 (6.3%) | |||||||
| VISION BLURRED | 0/3 (0%) | 0/3 (0%) | 2/3 (66.7%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| BLEPHARITIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| EYE IRRITATION | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| EYE PAIN | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| Gastrointestinal disorders | ||||||||||||||
| NAUSEA | 2/3 (66.7%) | 2/3 (66.7%) | 2/3 (66.7%) | 1/3 (33.3%) | 49/85 (57.6%) | 26/50 (52%) | 42/80 (52.5%) | |||||||
| DIARRHOEA | 2/3 (66.7%) | 2/3 (66.7%) | 2/3 (66.7%) | 1/3 (33.3%) | 21/85 (24.7%) | 13/50 (26%) | 22/80 (27.5%) | |||||||
| VOMITING | 1/3 (33.3%) | 0/3 (0%) | 2/3 (66.7%) | 1/3 (33.3%) | 17/85 (20%) | 13/50 (26%) | 22/80 (27.5%) | |||||||
| CONSTIPATION | 2/3 (66.7%) | 2/3 (66.7%) | 0/3 (0%) | 0/3 (0%) | 17/85 (20%) | 14/50 (28%) | 19/80 (23.8%) | |||||||
| STOMATITIS | 2/3 (66.7%) | 2/3 (66.7%) | 0/3 (0%) | 0/3 (0%) | 15/85 (17.6%) | 10/50 (20%) | 11/80 (13.8%) | |||||||
| ABDOMINAL PAIN UPPER | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 7/85 (8.2%) | 5/50 (10%) | 6/80 (7.5%) | |||||||
| ABDOMINAL PAIN | 0/3 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 0/3 (0%) | 7/85 (8.2%) | 1/50 (2%) | 6/80 (7.5%) | |||||||
| DYSPEPSIA | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 4/85 (4.7%) | 5/50 (10%) | 2/80 (2.5%) | |||||||
| HAEMORRHOIDS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/85 (2.4%) | 4/50 (8%) | 1/80 (1.3%) | |||||||
| GASTROOESOPHAGEAL REFLUX DISEASE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 3/50 (6%) | 1/80 (1.3%) | |||||||
| ABDOMINAL DISCOMFORT | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/85 (2.4%) | 1/50 (2%) | 0/80 (0%) | |||||||
| ABDOMINAL PAIN LOWER | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| DYSPHAGIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 4/85 (4.7%) | 1/50 (2%) | 0/80 (0%) | |||||||
| ERUCTATION | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| GASTRIC ULCER | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| ORAL PAIN | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/85 (0%) | 0/50 (0%) | 2/80 (2.5%) | |||||||
| General disorders | ||||||||||||||
| FATIGUE | 3/3 (100%) | 3/3 (100%) | 1/3 (33.3%) | 1/3 (33.3%) | 29/85 (34.1%) | 13/50 (26%) | 19/80 (23.8%) | |||||||
| ASTHENIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 20/85 (23.5%) | 14/50 (28%) | 22/80 (27.5%) | |||||||
| PYREXIA | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 7/85 (8.2%) | 13/50 (26%) | 14/80 (17.5%) | |||||||
| OEDEMA PERIPHERAL | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 5/85 (5.9%) | 5/50 (10%) | 5/80 (6.3%) | |||||||
| CHEST PAIN | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 5/85 (5.9%) | 5/50 (10%) | 2/80 (2.5%) | |||||||
| NON-CARDIAC CHEST PAIN | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 5/85 (5.9%) | 2/50 (4%) | 2/80 (2.5%) | |||||||
| CHILLS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/85 (2.4%) | 3/50 (6%) | 2/80 (2.5%) | |||||||
| XEROSIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 4/80 (5%) | |||||||
| Infections and infestations | ||||||||||||||
| PARONYCHIA | 1/3 (33.3%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 14/85 (16.5%) | 1/50 (2%) | 8/80 (10%) | |||||||
| NASOPHARYNGITIS | 0/3 (0%) | 1/3 (33.3%) | 2/3 (66.7%) | 0/3 (0%) | 5/85 (5.9%) | 5/50 (10%) | 7/80 (8.8%) | |||||||
| FOLLICULITIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/85 (2.4%) | 5/50 (10%) | 5/80 (6.3%) | |||||||
| BRONCHITIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 3/85 (3.5%) | 2/50 (4%) | 5/80 (6.3%) | |||||||
| CATHETER SITE INFECTION | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| NAIL INFECTION | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 4/85 (4.7%) | 0/50 (0%) | 0/80 (0%) | |||||||
| RHINITIS | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 2/85 (2.4%) | 0/50 (0%) | 2/80 (2.5%) | |||||||
| TRACHEOBRONCHITIS | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| VAGINAL INFECTION | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| Injury, poisoning and procedural complications | ||||||||||||||
| FALL | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| Investigations | ||||||||||||||
| WEIGHT DECREASED | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 9/85 (10.6%) | 3/50 (6%) | 15/80 (18.8%) | |||||||
| HAEMOGLOBIN DECREASED | 0/3 (0%) | 3/3 (100%) | 0/3 (0%) | 1/3 (33.3%) | 8/85 (9.4%) | 7/50 (14%) | 7/80 (8.8%) | |||||||
| BLOOD CREATININE INCREASED | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 3/85 (3.5%) | 5/50 (10%) | 5/80 (6.3%) | |||||||
| WHITE BLOOD CELL COUNT DECREASED | 0/3 (0%) | 3/3 (100%) | 0/3 (0%) | 0/3 (0%) | 6/85 (7.1%) | 1/50 (2%) | 3/80 (3.8%) | |||||||
| GAMMA-GLUTAMYLTRANSFERASE INCREASED | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 5/85 (5.9%) | 0/50 (0%) | 4/80 (5%) | |||||||
| ALANINE AMINOTRANSFERASE INCREASED | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 6/85 (7.1%) | 1/50 (2%) | 1/80 (1.3%) | |||||||
| NEUTROPHIL COUNT DECREASED | 0/3 (0%) | 2/3 (66.7%) | 0/3 (0%) | 0/3 (0%) | 2/85 (2.4%) | 0/50 (0%) | 2/80 (2.5%) | |||||||
| PLATELET COUNT DECREASED | 0/3 (0%) | 2/3 (66.7%) | 0/3 (0%) | 0/3 (0%) | 5/85 (5.9%) | 1/50 (2%) | 3/80 (3.8%) | |||||||
| BLOOD ALKALINE PHOSPHATASE INCREASED | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 1/85 (1.2%) | 0/50 (0%) | 3/80 (3.8%) | |||||||
| BLOOD CREATINE INCREASED | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| BLOOD SODIUM DECREASED | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| C-REACTIVE PROTEIN INCREASED | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/85 (0%) | 2/50 (4%) | 2/80 (2.5%) | |||||||
| Metabolism and nutrition disorders | ||||||||||||||
| DECREASED APPETITE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 30/85 (35.3%) | 13/50 (26%) | 21/80 (26.3%) | |||||||
| HYPOMAGNESAEMIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 18/85 (21.2%) | 9/50 (18%) | 7/80 (8.8%) | |||||||
| HYPOKALAEMIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 10/85 (11.8%) | 5/50 (10%) | 7/80 (8.8%) | |||||||
| HYPOCALCAEMIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 6/85 (7.1%) | 3/50 (6%) | 6/80 (7.5%) | |||||||
| HYPONATRAEMIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 6/85 (7.1%) | 1/50 (2%) | 2/80 (2.5%) | |||||||
| HYPERKALAEMIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/85 (2.4%) | 3/50 (6%) | 3/80 (3.8%) | |||||||
| ANOREXIA | 2/3 (66.7%) | 3/3 (100%) | 1/3 (33.3%) | 1/3 (33.3%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| IRON DEFICIENCY | 0/3 (0%) | 2/3 (66.7%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| IRON OVERLOAD | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||||
| BACK PAIN | 1/3 (33.3%) | 2/3 (66.7%) | 0/3 (0%) | 0/3 (0%) | 13/85 (15.3%) | 8/50 (16%) | 7/80 (8.8%) | |||||||
| PAIN IN EXTREMITY | 0/3 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 0/3 (0%) | 10/85 (11.8%) | 3/50 (6%) | 6/80 (7.5%) | |||||||
| MUSCULOSKELETAL PAIN | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 4/85 (4.7%) | 3/50 (6%) | 4/80 (5%) | |||||||
| ARTHRALGIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/85 (2.4%) | 1/50 (2%) | 5/80 (6.3%) | |||||||
| MUSCLE SPASMS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/85 (2.4%) | 4/50 (8%) | 2/80 (2.5%) | |||||||
| MUSCULOSKELETAL CHEST PAIN | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/85 (2.4%) | 1/50 (2%) | 4/80 (5%) | |||||||
| MYALGIA | 0/3 (0%) | 2/3 (66.7%) | 0/3 (0%) | 0/3 (0%) | 3/85 (3.5%) | 0/50 (0%) | 3/80 (3.8%) | |||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||
| TUMOUR PAIN | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 2/50 (4%) | 0/80 (0%) | |||||||
| Nervous system disorders | ||||||||||||||
| HEADACHE | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 9/85 (10.6%) | 6/50 (12%) | 6/80 (7.5%) | |||||||
| DYSGEUSIA | 1/3 (33.3%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 7/85 (8.2%) | 4/50 (8%) | 5/80 (6.3%) | |||||||
| DIZZINESS | 2/3 (66.7%) | 0/3 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 8/85 (9.4%) | 4/50 (8%) | 2/80 (2.5%) | |||||||
| PARAESTHESIA | 0/3 (0%) | 3/3 (100%) | 0/3 (0%) | 0/3 (0%) | 3/85 (3.5%) | 1/50 (2%) | 8/80 (10%) | |||||||
| NEUROPATHY PERIPHERAL | 1/3 (33.3%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/85 (1.2%) | 3/50 (6%) | 1/80 (1.3%) | |||||||
| MIGRAINE | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| Psychiatric disorders | ||||||||||||||
| ANXIETY | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 4/85 (4.7%) | 4/50 (8%) | 8/80 (10%) | |||||||
| INSOMNIA | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 4/85 (4.7%) | 3/50 (6%) | 9/80 (11.3%) | |||||||
| DEPRESSION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 3/85 (3.5%) | 2/50 (4%) | 4/80 (5%) | |||||||
| Renal and urinary disorders | ||||||||||||||
| DYSURIA | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 4/85 (4.7%) | 4/50 (8%) | 1/80 (1.3%) | |||||||
| HAEMATURIA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 3/50 (6%) | 1/80 (1.3%) | |||||||
| LEUKOCYTURIA | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| POLLAKIURIA | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/85 (1.2%) | 1/50 (2%) | 0/80 (0%) | |||||||
| POLYURIA | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| Reproductive system and breast disorders | ||||||||||||||
| DYSPAREUNIA | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| ERECTILE DYSFUNCTION | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 1/50 (2%) | 1/80 (1.3%) | |||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||
| COUGH | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 13/85 (15.3%) | 11/50 (22%) | 12/80 (15%) | |||||||
| EPISTAXIS | 3/3 (100%) | 2/3 (66.7%) | 2/3 (66.7%) | 0/3 (0%) | 10/85 (11.8%) | 9/50 (18%) | 13/80 (16.3%) | |||||||
| DYSPNOEA EXERTIONAL | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 9/85 (10.6%) | 10/50 (20%) | 7/80 (8.8%) | |||||||
| DYSPNOEA | 1/3 (33.3%) | 2/3 (66.7%) | 0/3 (0%) | 0/3 (0%) | 11/85 (12.9%) | 6/50 (12%) | 5/80 (6.3%) | |||||||
| HAEMOPTYSIS | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/85 (2.4%) | 3/50 (6%) | 7/80 (8.8%) | |||||||
| DYSPHONIA | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 2/85 (2.4%) | 2/50 (4%) | 5/80 (6.3%) | |||||||
| PRODUCTIVE COUGH | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 1/50 (2%) | 5/80 (6.3%) | |||||||
| OROPHARYNGEALPAIN | 1/3 (33.3%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 3/85 (3.5%) | 1/50 (2%) | 1/80 (1.3%) | |||||||
| Skin and subcutaneous tissue disorders | ||||||||||||||
| RASH | 3/3 (100%) | 3/3 (100%) | 3/3 (100%) | 3/3 (100%) | 35/85 (41.2%) | 17/50 (34%) | 29/80 (36.3%) | |||||||
| ACNE | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 19/85 (22.4%) | 11/50 (22%) | 17/80 (21.3%) | |||||||
| DERMATITIS ACNEIFORM | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 17/85 (20%) | 7/50 (14%) | 16/80 (20%) | |||||||
| ALOPECIA | 1/3 (33.3%) | 1/3 (33.3%) | 2/3 (66.7%) | 0/3 (0%) | 13/85 (15.3%) | 7/50 (14%) | 9/80 (11.3%) | |||||||
| DRY SKIN | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 13/85 (15.3%) | 5/50 (10%) | 9/80 (11.3%) | |||||||
| SKIN TOXICITY | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 10/85 (11.8%) | 8/50 (16%) | 7/80 (8.8%) | |||||||
| PRURITUS | 0/3 (0%) | 2/3 (66.7%) | 0/3 (0%) | 0/3 (0%) | 7/85 (8.2%) | 6/50 (12%) | 3/80 (3.8%) | |||||||
| SKIN FISSURES | 1/3 (33.3%) | 0/3 (0%) | 2/3 (66.7%) | 0/3 (0%) | 6/85 (7.1%) | 2/50 (4%) | 6/80 (7.5%) | |||||||
| ERYTHEMA | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/85 (1.2%) | 5/50 (10%) | 4/80 (5%) | |||||||
| NAIL TOXICITY | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 4/85 (4.7%) | 3/50 (6%) | 1/80 (1.3%) | |||||||
| HIRSUTISM | 0/3 (0%) | 0/3 (0%) | 2/3 (66.7%) | 0/3 (0%) | 2/85 (2.4%) | 0/50 (0%) | 1/80 (1.3%) | |||||||
| ECCHYMOSIS | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| HYPERHIDROSIS | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 3/85 (3.5%) | 0/50 (0%) | 0/80 (0%) | |||||||
| INTERTRIGO | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| PETECHIAE | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 2/80 (2.5%) | |||||||
| PHOTOSENSITIVITY REACTION | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| Vascular disorders | ||||||||||||||
| HYPERTENSION | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 9/85 (10.6%) | 6/50 (12%) | 5/80 (6.3%) | |||||||
| HYPOTENSION | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/3 (33.3%) | 1/85 (1.2%) | 4/50 (8%) | 4/80 (5%) | |||||||
| ORTHOSTATIC HYPOTENSION | 1/3 (33.3%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/85 (1.2%) | 0/50 (0%) | 0/80 (0%) | |||||||
| DEEP VEIN THROMBOSIS | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 4/85 (4.7%) | 1/50 (2%) | 0/80 (0%) | |||||||
| PERIPHERAL COLDNESS | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/85 (0%) | 0/50 (0%) | 0/80 (0%) | |||||||
| THROMBOPHLEBITIS | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/85 (2.4%) | 2/50 (4%) | 1/80 (1.3%) | |||||||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Merck KGaA Communication Center |
|---|---|
| Organization | Merck Serono, a division of Merck KGaA |
| Phone | +49-6151-72-5200 |
| service@merckgroup.com |
- EMR200037-014
- EudraCT Number: 2008-004148-35