| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| First line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer (NSCLC) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029515 |
| E.1.2 | Term | Non-small cell lung cancer recurrent |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029521 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIB |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess progression free survival (PFS) of AG-013736 in combination with paclitaxel and carboplatin (Arm A) versus bevacizumab in combination with paclitaxel and carboplatin (Arm B). |
|
| E.2.2 | Secondary objectives of the trial |
- Assess the Overall Survival (OS) in each arm;
- To assess the overall response rate (ORR) in each arm;
- Estimate the duration of response (DR) in each arm;
- Evaluate the safety and tolerability of AG-013736 in combination with paclitaxel and carboplatin;
- Conduct population PK analysis using AG-013736 plasma concentrations;
- Evaluate the HRQoL and lung cancer/treatment related symptoms of patients in each arm according to European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30) and Quality of Life Questionnaire Lung Cancer 13 (QLQ LC 13).
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Molecular Profiling Supplement, Version and Date: 1.0, Final, 2 October 2007.
The primary objective of this additional research component is to collect, store, and use samples to investigate possible associations between genomic and metabonomic variation:
- in relation to response to the study drugs, and
- in relation to characteristics of the disease/condition under study in the associated clinical trial, and related conditions.
In addition, samples may be used as controls in genomic and metabonomic investigations of the causes, natural history, and other aspects of important diseases and conditions for which Pfizer is researching new or improved drug therapies.
Scientific information about these differences among groups of subjects can help researchers to better understand the response of subjects to investigational drugs and to learn more about diseases/conditions for which we are developing treatments.
Samples collected will be stored in Pfizer’s Exploratory Research Biobank in the USA.
|
|
| E.3 | Principal inclusion criteria |
1. Histologically- or cytologically-confirmed diagnosis of advanced non-squamous cell,
NSCLC with documented Stage IIIB with pleural effusion, or Stage IV or recurrent
disease.
2. At least one site of measurable disease (per RECIST). Measurable disease that has been previously irradiated will not be considered a target lesion unless the lesion diameter has grown by ≥20 % since completion of the prior radiation therapy or if the lesion is a new lesion, assuming all other criteria are met.
3. No prior systemic treatment for NSCLC except prior adjuvant/neo-adjuvant therapy if last dose was >12 months prior to enrollment.
4. Adequate organ function as determined by the following criteria:
• Absolute neutrophil count (ANC) ≥1500 cells/mm3;
• Platelet count ≥100,000 cells/mm3;
• Hemoglobin ≥9 g/dL;
• Serum creatinine ≤1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥60 mL/min;
• AST and ALT <2.5 x ULN, or AST and ALT <5 x ULN if liver function abnormalities are due to underlying malignancy;
• Total bilirubin ≤1.5 x ULN;
• Urine protein:creatinine ratio <0.5.
5. Age ≥18 years.
6. ECOG performance status of 0 or 1.
7. Life expectancy >12 weeks.
8. Prior surgery or radiation therapy is permitted. Radiation therapy must have completed
≥21 days or major surgery ≥28 days prior to start of treatment. All acute toxicities must have resolved to baseline or to CTC Grade 1 (NCI CTCAE v3.0). Fine needle aspiration procedures (if necessary) must have been completed ≥7 days prior to treatment.
9. Female patients may not be pregnant or breastfeeding. Female patients or their partners must be surgically sterile or be postmenopausal, or must agree to use effective contraception while receiving study treatment and for at least 6 months thereafter.
10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including completion of patient reported outcome measures.
11. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial before enrollment |
|
| E.4 | Principal exclusion criteria |
1. Histologic evidence of predominantly squamous-cell NSCLC.
2. Prior treatment with systemic therapy for advanced disease.
3. Prior treatment with a VEGF or VEGFR inhibitor.
4. Preexisting uncontrolled hypertension as documented by 2 baseline blood pressure readings taken at least 1 hour apart. The baseline systolic blood pressure readings must be ≤140 mm Hg, and the baseline diastolic blood pressure readings must be ≤90 mm Hg. Patients whose hypertension is controlled by antihypertensive therapies are eligible.
5. Known central nervous system (CNS) metastasis. CNS imaging at baseline is required.
6. Current or recent (within 1 month) use of a thrombolytic agent.
7. History of a hematologic diathesis or coagulopathy within 6 months of study entry
8. Need for therapeutic anticoagulation (at time of screening).
9. Ongoing or recent (within 10 days prior to treatment start) need for full therapeutic dose of oral or parenteral anticoagulant or chronic daily treatment with aspirin (>325 mg/day)
or clopidogrel (>75 mg/day).
10. History of hemoptysis ≥½ tsp of bright red blood per day within 4 weeks of enrollment.
11. Any of the following within the 12 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, deep vein thrombosis or pulmonary embolism.
12. Gastrointestinal abnormalities including:
• Inability to take oral medication;
• Requirement for intravenous alimentation;
• Prior surgical procedures affecting absorption including gastric resection;
• Treatment for active peptic ulcer disease in the past 6 months;
• Active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis,
hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy;
• Malabsorption syndromes.
13. Active, invasive malignancies other than NSCLC:
• The patient may not have radiographic or clinical signs of another cancer, and must
not be getting any form of treatment for cancer.
14. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors (ie, grapefruit juice, verapamil, ketoconazole, itraconazole, erythromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, and delavirdine) is not permitted.
15. Current use or anticipated need for treatment with drugs that are known CYP3A4 or CYP1A2 inducers (ie, carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin, primidone, rifabutin, rifampin, and St. John’s wort) is not permitted. (Note: The short-term use of dexamethasone as a premedication for chemotherapy is not an exclusion criterion).
16. Acute or chronic medical or psychiatric condition or laboratory abnormality that could increase the risk associated with study participation or study drug administration or could interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint:
- Progression Free Survival (PFS) defined as the time from randomization to the date of progression or death due to any cause, whichever occurs first.
Secondary Endpoints:
- Overall Survival (OS) defined as the time from randomization to the date of death due to any cause.
- Overall confirmed objective response rate (ORR) defined as the proportion of randomized patients with a confirmed best response characterized as either a complete response (CR) or partial response (PR) (target lesions and tumor response defined according to RECIST guidelines). Confirmed responses are those that persist on a follow up imaging assessment ≥4 weeks after the initial objective documentation of response.
- Duration of response (DR) defined as the time from first documentation of response to the date of progression or death due to any cause, whichever occurs first.
- Overall safety profile characterized by type, frequency, severity (as graded using NCI (National Cancer Institute) Common Terminology Criteria for Adverse Events (CTCAE), v3.0 and relationship to study therapy of adverse events and laboratory abnormalities.
- Population pharmacokinetic analysis using AG-013736 plasma concentrations.
- Patient Reported Outcome (PRO) changes in scores for HRQoL and lung cancer/treatment related symptoms according to European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30) and Quality of Life Questionnaire Lung Cancer 13 (QLQ LC 13)
- Molecular Profiling and Biomarkers of AG-013736 mechanism of action and clinical benefit will be explored with optional pharmacogenomic and gene expression profiling in whole blood. VEGF receptor and associated signaling pathways will be explored using circulating endothelial cells and soluble proteins in blood.
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|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of Trial in all participating countries is defined as the time at which one of more of following has occurred:
- Drug combination is considered too toxic to continue treatment (Tx) prior to the required number (#) of patients (pts) being recruited
- # of pts to be recruited is reached and all pts have been followed for ≥12 months after randomization of the last patient unless they have discontinued Tx sooner
- Stated objectives of the trial are achieved.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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