| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Second-or Later Line treatment in patients with advanced Non-Small Cell lung Cancer |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 5.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10061873 |
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| 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 |
| The primary objective of this study is to determine the activity of AG-013736 in advanced non-small cell lung cancer as measured by the overall response rate, complete response (CR) and partial response (PR) by RECIST. |
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| E.2.2 | Secondary objectives of the trial |
Secondary are objectives are to:
• determine the safety profile of AG-013736
• determine the progression free survival (PFS)
• determine the duration of response (DR)
• determine overall survival (OS)
• obtain blood samples for population pharmacokinetic analyses
• explore relationships between clinical response and plasma soluble proteins
• explore the value of dceMRI imaging (for tumour blood flow and permeability) to predict response |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
To be eligible for the study, subjects must satisfy all the following criteria:
1. Histologically documented non-small cell lung cancer with metastases (Stage IV or recurrent disease) or locally advanced (Stage IIIB) with malignant pleural effusion.
2. At least 1 prior systemic platinum-based therapy, or alternative appropriate therapy in case of contraindication against platinum-based therapy for metastatic disease (Prior adjuvant therapy for localized disease does not count as a prior therapy for metastatic disease).
3. No expectation of further effects of prior anticancer therapy.
4. At least 1 target lesion, as defined by RECIST, that has not been irradiated. New lesions that have developed in a previously irradiated field may be used as sites of measurable disease assuming all other criteria are met. All target lesions must have a unidimensional diameter of at least 2 cm. (1 cm is acceptable for spiral CT scans if the reconstruction algorithm is 0.5 cm). Baseline measurements/evaluations must be completed within 4 weeks prior to treatment and performed at the participating investigational site.
5. Adequate bone marrow, hepatic, and renal function documented within 14 days prior to treatment as documented by:
• absolute neutrophil count (ANC, calculated as the absolute number of neutrophils and bands) >=1.5 x 1 000 000 000 cells/L
• platelets >=100 x 1 000 000 000 cells /L
• AST and ALT =<2.5 x upper limit of normal (ULN), unless there are liver metastases in which case AST and ALT =<5.0 x ULN
• total bilirubin =<1.5 x ULN
• serum creatinine =<1.5 x ULN or calculated creatinine clearance >=60 mL/min
• urinary protein <2+ by urine dipstick. If dipstick is >=2+ then a 24-hour urine collection can be done and the patient may enter only if urinary protein is <2 g per 24 hours
6. Age >=18 years.
7. ECOG performance status of 0 or 1
8. No evidence of 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, and the baseline diastolic blood pressure readings must be =<90. Patients whose hypertension is controlled by antihypertensive therapies are eligible.
9. Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to treatment.
10. Written and voluntary informed consent.
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| E.4 | Principal exclusion criteria |
Subjects with one or more of the following criteria are ineligible for this study:
1. Central lung lesions involving major blood vessels (arteries or veins). (Central lesions that maintain the structural integrity of vessels have the potential to bleed if the tumor lesion undergoes necrosis. MRI or CT angiography should be used in any case where there is any question as to whether blood vessels are involved.)
2. Patients with a history of Grade 2 or worse hemoptysis are not eligible. Patients with a history of Grade 1 hemoptysis within 30 days of entry are not eligible.
3. Patients who are poor candidates for functional imaging studies (poor candidates include patients who cannot suspend breathing for at least 30 seconds, patients whose only lesions are near the vein that will be used for intravenous contrast injection such as the superior vena cava and subclavian vein [this includes lesions near the hilum of both upper lobes and in the superior mediastinum], patients with lesions that are too small or that could be subjected to cardiac motion or major breathing motion, patients with lesions near metallic clips or hardware, and patients who are allergic to the contrast material) (Note: lesions near either the subclavian or axillary veins may be used for imaging provided that the intravenous catheter for contrast injection is placed in the other site, eg, the axillary vein should be used for contrast injection when a lesion near the subclavian vein is imaged).
4. 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.
5. Previous treatment with an anti-angiogenesis agent such as bevacizumab, SU-11248, sorafenib (however, previous treatment with inhibitors of EGFR, such as cetuximab, erlotinib or gefitinib is allowed).
6. Current use or anticipated inability to avoid use of drugs that are known potent CYP3A4 inhibitors (ie, grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, clarithromycin, ergot derivatives, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, and delavirdine).
7. Current use or anticipated inability to avoid use of drugs that are known CYP3A4 or CYP1A2 inducers (ie, carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin, primidone, rifabutin, rifampin, and St. John’s wort).
8. Active seizure disorder or uncontrolled brain metastases (to be eligible, brain metastasis must be previously treated, asymptomatic, without growth for at least 1 month, and must not require steroids)
9. A serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment.
10. History of a malignancy (other than non-small cell lung cancer) except those treated with curative intent for skin cancer (other than melanoma) or in situ breast or cervical cancer or those treated with curative intent for any other cancer with no evidence of disease for 5 years
11. Major surgical procedure or any radiation therapy within 4 weeks of treatment.
12. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol.
13. Patients (male and female) having procreative potential who are not using adequate contraception or practicing abstinence. Fertile patients must use effective double contraception (1 hormonal method plus 1 barrier method OR 2 simultaneous barrier methods) for female patients or barrier contraception for male patients for more than 4 weeks prior to, during, and for at least 6 months after study participation.
14. Women who are pregnant or breast-feeding.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy parameter is the overall response rate. All patients who receive at least 1 dose of AG 013736 and have a baseline assessment of disease will be included in the analysis. Patients who were inadvertently enrolled (eg, patients who are determined to have the incorrect histological cancer type after receiving a dose of medication, based on their screening disease assessment) will be excluded from analyses and will be replaced.
The overall response rate is defined to be the percentage of patients with a confirmed CR or PR. Patients who die, progress, or drop out for any reason after receiving a dose of AG 013736 prior to reaching a CR or PR will be included in the analysis as non-responders.
For response rate, duration of response, and progression-free survival, assessments from the independent third party will be considered the primary data. Additionally, the primary analyses for these endpoints will be based on the data collected from the disease assessment method(s) used starting at baseline to follow a patient’s lesions. If PET scans or ultrasound is used on some patients during study who are believed to have central tumor necrosis or intratumor bleeding, these data and any subsequently collected lesion assessment data will not be used in the primary analyses but may be used in exploratory analyses of response rate, duration of response and progression-free survival.
The secondary efficacy parameters are:
• progression-free survival
• duration of overall objective response (CR or PR)
• survival
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Explore relationship between clinical response and plasma soluble proteins |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| 2-stage Minimax Phase 2 trial |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| 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.8.5 | The trial involves multiple Member States | No |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
|
The study will be complete after 8 cycles (each cycle of four weeks). If the treatment is discontinued before the patient will be followed up to disease progression and up to one year after randomization.
Premature termination of this clinical trial may occur because of a regulatory authority decision, change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer. |
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| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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