To investigate whether R1507 can induce responses in patients with advanced NSCLC who have developed resistance to to erlotinib therapy and determine if clinical benefit can be obtained by adding R1507 to erlotinib (EGFR TK inhibitor) in this setting. Additionally, the Study will evaluate potential biomarkers that may be predictive of clinical benefit from IGF-1R inhibitor therapy, and explore mechanisms of erlotinib resistance in NSCLC. MedDRA version: 9.1 Level: LLT Classification code 1002
Conditions
Sponsors
F. Hoffmann-La Roche Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male and female patients, age =18 years 2. Able to comply with the protocol 3. Patients must be able to take oral medication. 4. Histologically documented inoperable, locally advanced (stage IIIB and stage IV) NSCLC. (NOTE: Sputum cytology alone is not acceptable). Tumors with mixed histology should be categorized according to the predominant cell type 5. Prior Treatment: Currently receiving monotherapy erlotinib, 150 mg po qd, after failing at least one standard chemotherapy regimen. Patients must have had prior response or stable disease at 12 weeks from start of erlotinib, and have documented progressive disease by RECIST criteria at enrollment 6. No interval chemotherapy between initial course of erlotinib and study entry 7. CT scans documenting 1) baseline tumor assessment prior to start of initial erlotinib therapy, 2) response or stable disease at 12 weeks or longer from start of erlotinib therapy, and 3) subsequent progression of disease on erlotinib, must document both clinical benefit and current progression. These scans must be available to send to Roche. 8. Formalin fixed paraffin embedded (FFPE) and fresh tumor tissue samples, representative of the disease (current progressive disease) obtained no more than 4 weeks prior to first dose of study therapy must be available for shipment to the central laboratory 9. Measurable disease according to RECIST 10. ECOG performance status 0-2 11. Life expectancy > 12 weeks 12. Adequate hematological function : ANC =1.5 x 10 exp9/L; platelets =100 x 10 exp9/L, Hb =9 g/dL 13. INR =1.5 and PTT =1.5 x ULN unless receiving anticoagulant therapy 14. Adequate liver function: Serum bilirubin =1.5 x ULN; transaminases =2.5 x ULN (in case of liver metastases =65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Patients must have a head CT/MRI to evaluate for CNS metastasis within 28 days prior to enrollment. Patients with active CNS lesions are excluded. Patients with radiographically stable, asymptomatic previously irradiated lesions are eligible provided patients is = 4 weeks beyond completing cranial irradiation and = 3 weeks off corticosteroid therapy 2. Prior treatment with an investigational or commercial agent that acts via IGF-1R inhibition 3. Prior treatment with an agent that acts via EGFR targeting, other than current course of erlotinib 4. Prior irradiation: 1) Radiotherapy given within the last 4 weeks prior to first dose of study treatment. 2) Palliative radiotherapy for bone lesions outside the thoracic region within 2 weeks prior to the first dose of study treatment 5. Prior Surgery: Surgery (including open biopsy) or significant traumatic injury within the last 2 weeks prior to first dose of study treatment or anticipation of the need for major surgery during study treatment. 6. Administration of any anti-cancer therapies other than those administered in this study 7. Administration of high doses of systemic corticosteroids. High dose is considered as > 20 mg of dexamethasone a day (or equivalent) for > 7 consecutive days. Dexamethasone may induce CYP3A4 activity. CYP3A4 inhibitors and inducers may influence the plasma level of erlotinib 8. Lactating women 9. Fertile men or women of childbearing potential not using effective methods to prevent pregnancy. 10. Other active cancer requiring treatment. 11. Known hypersensitivity to any of the study drugs or their excipients 12. Any disease (including psychotic disorders, drug abuse, active infection, uncontrolled hypertension, clinically significant cardiovascular disease for example CVA (= 6 months before randomization), myocardial infarction (= 6 months before randomization), unstable angina, NYHA = grade 2 CHF, arrhythmia requiring medication, hepatic, renal or metabolic disease (including uncontrolled diabetes mellitus), metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications 13. History of allogeneic bone marrow transplantation or organ transplantation. 14. Any known significant ophthalmologic abnormalities of the surface of the eye (the use of contact lenses is not recommended) 15. No dysphagia or active gastrointestinal disease or disorder that alters gastrointestinal motility or absorption; no lack of integrity of the gastrointestinal tract (e.g. as significant surgical resection of the stomach or small bowel). Patients unable to swallow intact tablets must be able to swallow tablets dissolved in water 16. Treatment with any other investigational agent, or participation in another clinical trial within 30 days prior to starting study treatment other than a trial of erlotinib alone
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To define PFS rate at 12 weeks in patients with advanced stage IIIB/IV Non-Small Cell Lung Cancer (NSCLC) who have progressive disease after clinical benefit, defined as response or stable disease at 12 weeks from start of second or third line erlotinib monotherapy, treated with combination erlotinib and R1507.;Secondary Objective: - Define the effect of adding R1507 to erlotinib on progression-free survival, overall survival, objective response rate, time to response, time to progressive disease and duration of response. - Define the PET response rate at 4 weeks. - Define population PK of R1507 in combination with erlotinib. - Evaluate the safety profile of the combination of R1507 and erlotinib. - Explore the changes in pharmacodynamic markers in responders and non-responders. - Explore candidate biomarkers related to drug mechanism of action.;Primary end point(s): Progression-free survival at 12 weeks after start of therapy. Tumor response/ progression will be assessed according to the RECIST criteria. Progression-free survival at 12 weeks is a dichotomous endpoint, with a patient categorized as alive and progression-free or in progressive disease or dead at 12 weeks. | — |
Countries
France
Outcome results
None listed