A multicentre, open-label, randomized, phase III study to evaluate the efficacy of Tarceva™ or comparator Alimta® (pemetrexed) or Taxotere® (docetaxel) in patients with histologically documented, advanced or recurrent (stage IIIB and not amenable for combined modality treatment) or metastatic (Stage IV) non-small cell lung cancer who have experienced disease progression during platinum-based chemotherapy. - TITAN

• Register: EUCTR
• Last refreshed on: 10 December 2012
• Main ID: EUCTR2005-003220-19-DK
• Date of registration: 03/01/2006
• Prospective Registration: No
• Primary sponsor: F. Hoffmann-La Roche Ltd
• Public title: A multicentre, open-label, randomized, phase III study to evaluate the efficacy of Tarceva™ or comparator Alimta® (pemetrexed) or Taxotere® (docetaxel) in patients with histologically documented, advanced or recurrent (stage IIIB and not amenable for combined modality treatment) or metastatic (Stage IV) non-small cell lung cancer who have experienced disease progression during platinum-based chemotherapy. - TITAN
• Scientific title: A multicentre, open-label, randomized, phase III study to evaluate the efficacy of Tarceva™ or comparator Alimta® (pemetrexed) or Taxotere® (docetaxel) in patients with histologically documented, advanced or recurrent (stage IIIB and not amenable for combined modality treatment) or metastatic (Stage IV) non-small cell lung cancer who have experienced disease progression during platinum-based chemotherapy. - TITAN
• Date of first enrolment: 13/12/2005
• Target sample size: 648
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2005-003220-19
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no

Countries of recruitment

Denmark, Germany, Greece, Hungary, Italy, Lithuania, Portugal, Spain, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:

1. Patients with histologically documented, locally advanced or recurrent (stage IIIB and not amenable for combined modality treatment) or metastatic (Stage IV) non-small cell lung cancer. Formalin-fixed, paraffin-embedded tumour tissue samples representative of the tumour will be provided to the sponsor within 3 weeks of the patient starting platinum-based chemotherapy. This Is A Mandatory Requirement For Study Entry.
2. Patients must have measurable disease according to the RECIST criteria.
3. Previous adjuvant or neo-adjuvant treatment is permitted if completed >= 6 months before start of chemotherapy.
4. ECOG performance status of 0 – 1
5. Written (signed) Informed Consent for use of tumour samples.


1. Failure (disease progression) during 1 to 4 cycles of an acceptable, standard, platinum based chemotherapy doublet. This Is A Mandatory Requirement For Study Entry.
2. Patients should have recovered from any toxic effects of platinum-based chemotherapy treatment
3. ECOG performance status of 0 - 2.
4. Patients must be able to take oral medication.
5. At least 4 weeks must have elapsed since any prior surgery or radiotherapy. Patients who, in the opinion of the investigator, have fully recovered from surgery in less than 4 weeks may also be considered for the study
6. Granulocyte count >= 1,500/mm3 and platelet count > 100,000/mm3. Haemoglobin >= 9.0g/dl.
7. SGOT (AST) and SGPT (ALT) < 2.5 x ULN in the absence of liver metastases or up to 5 x ULN in case of liver metastases.
8. Alkaline phosphatase (ALP) < 2.5 x ULN. If alkaline phosphatase is > 2.5 x ULN, SGOT (AST) and SGPT (ALT) must be < 1.5 x ULN.
9. Serum bilirubin must be =< 1.5 upper limit of normal (ULN).
10. Creatinine clearance >= 60 ml/min based on the standard Cockcroft and Gault formula.
11. Normal serum calcium.
12. For all females of childbearing potential a negative pregnancy test must be obtained within 48 hours before entry into the study (starting Tarceva™ /chemotherapy).
13. Patients with reproductive potential must use 2 effective methods of contraception.
14. Age 18 (or legal age of consent if greater than 18) or greater.
15. Able to comply with study and follow-up procedures.
16. Able to provide written (signed) Informed Consent to participate in the TITAN study.
17. Patients must be able to effectively read and understand the local language(s) in which the FACT-L (Quality of Life) questionnaires are written.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Prior exposure to agents directed at the HER axis (e.g. gefitinib, cetuximab, trastuzamab).
2. Prior agents directed at Alimta® molecular targets (i.e., TS or DHFR inhibitors)
3. Prior chemotherapy or therapy with systemic anti-neoplastic therapy (e.g., monoclonal antibody therapy or any experimental therapy) for advanced disease other than the permitted platinum-based chemotherapies. Prior surgery and/or localised irradiation is permitted.
4. Any unstable systemic disease (including active infections, significant cardiovascular disease, [including myocardial infarction within the previous year], any significant hepatic, renal or metabolic disease) metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of study medication(s) or that might affect the interpretation of the results or render the patient at high risk from treatment complications.
5. Any other malignancies within 5 years (except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer).
6. Patients are excluded if they have brain metastasis or spinal cord compression that has not yet been definitively treated with surgery and/or radiation; previously diagnosed and treated CNS metastases or spinal cord compression without evidence of stable disease (clinically stable imaging) for at least 2 months will also cause patients to be excluded.
7. Patients who are at risk (in the investigator’s opinion) of transmitting human immunodeficiency virus (HIV) through blood or other body fluids are excluded.
8. Any inflammatory changes of the surface of the eye.
9. Patients who cannot take oral medication, who require intravenous alimentation, have had prior surgical procedures affecting absorption, or have active peptic ulcer disease.
10. Patients who are unable to interrupt acetylic salicylic acid therapy (where aspirin dose is >= 1.3 g/day).
11. Nursing mothers.
12. Severe hypersensitivity to Tarceva™ or to any of the excipients. (see the Tarceva™ SPC) or to the excipients in Alimta® or Taxotere® (see respective SPCs).
13. History of severe hypersensitivity reactions to Taxotere® or to other drugs formulated with polysorbate 80.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Advanced (stage IIIB or IV) non-small cell lung cancer (NSCLC) previously treated with a platinum-based chemotherapy.

Intervention(s)

Product Name: Tarceva
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: erlotinib
CAS Number: 183319-69-9
Current Sponsor code: Ro 50-8231/OSI-774
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25, 100, 150-

Product Name: ALIMTA
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: pemetrexed
CAS Number: 137281-23-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-

Product Name: TAXOTERE
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: docetaxel
CAS Number: 114977-28-5
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-

Product Name: TAXOTERE
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: docetaxel
CAS Number: 114977-28-5
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 80-

Primary Outcome(s)

Primary end point(s): The primary efficacy variable is duration of survival. Overall survival will be determined from the date of randomisation to the date of death irrespective of the cause of death. Patients who have not died at the time of the final analysis will be censored at the date of last contact.

Secondary Objective: 1. To compare overall survival between the treatment arms in patients with:
• EGFR protein expression (IHC) positive
• EGFR protein expression (IHC) negative
2. To compare progression free survival (PFS) between the treatment arms for all patients and in patients with:
• EGFR protein expression (IHC) positive
• EGFR protein expression (IHC) negative
3. To compare the response rate between the treatment arms.
4. To perform exploratory evaluations of available tumourtissue for biological or genomic determinants of outcome, including but not limited to EGFR and K-ras mutational status and EGFR and HER2 expression status and other downstream targets.
5. To compare time to symptom progression between the treatment arms.
6. To evaluate the safety profile of administering Tarceva™ after disease progression on a standard platinum based chemotherapy in the treatment of NSCLC and compared with Alimta® and Taxotere®. and etc.

Main Objective: To determine if the administration of Tarceva™ after disease progression on standard platinum-based chemotherapy in the treatment of NSCLC results in improved overall survival when compared to Alimta® (pemetrexed) or Taxotere® (docetaxel).

Secondary ID(s)

BO18602

2005-003220-19-ES