E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic breast cancer not previously treated with chemotherapy. |
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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 | PT |
E.1.2 | Classification code | 10055113 |
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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 |
Determine whether the time to progression of the combination of AG-013736 and docetaxel is superior to that of docetaxel plus placebo in patients who have not received prior chemotherapy for metastatic breast cancer. |
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E.2.2 | Secondary objectives of the trial |
1) Determine the dose of AG-013736 that can be given with docetaxel administered on an every 3-week schedule; 2) determine the adverse drug event profile and dose-limiting toxicities for the combination; 3) evaluate population pharmacokinetics of AG-013736 in the Phase 2 and single-agent portions of the study and assess docetaxel and AG-013736 pharmacokinetic parameters in the Phase 1 portion of the study; 4) determine the response rate and duration of response for the combination; 5) assess the response rate and duration of response of single-agent AG-013736 in patients who progress on the docetaxel plus placebo arm. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1. female patients with histologically/cytologically proven metastatic breast carcinoma (Stage IV, or recurrent with local or regional spread or distant metastatic disease) 2. no prior chemotherapy for metastatic disease. (If chemotherapy given in the adjuvant setting, then the patient must have completed chemotherapy at least 12 months before the first documentation of metastatic disease. Patients who received adjuvant therapy with a taxane [paclitaxel or docetaxel] are eligible.) 3. at least 1 target lesion, as defined by RECIST (see Protocol Appendix C) 4. adequate bone marrow function as defined by: - ANC ≥1500 cells/mm3 - platelets ≥100, 000 cells/mm3 - Hgb ≥10 g/dL 5. adequate liver function as defined by: - bilirubin ≤upper limit of normal (ULN) - AST and ALT ≤2.5 x ULN if alkaline phosphatase is ≤ULN, or alkaline phosphatase may be up to 4 x ULN if aminotransferases are ≤ULN. (Patients with aminotransferase elevation >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN should not be entered due to the decreased clearance of docetaxel and increased risk of toxicity.) 6. adequate renal function as defined by both: - serum creatinine ≤1.5 mg/dL - ≤500 mg urinary protein/24 hours or dipstick <1+ 7. 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 less than or equal to 140 mm Hg, and the baseline diastolic blood pressure readings must be less than or equal to 90 mm Hg. Patients whose hypertension is controlled by antihypertensive therapies are eligible) 8. ECOG performance status of 0, 1, or 2 (See Protocol Appendix D) 9. life expectancy ≥12 weeks 10. adults ≥18 years of age 11. negative serum or urine pregnancy test for patients of child-bearing potential 12. written informed consent |
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E.4 | Principal exclusion criteria |
1. adjuvant chemotherapy given within the past 12 months or prior chemotherapy for metastatic disease 2. current use or anticipated need for drugs that are known CYP3A4 inhibitors (ie, grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, clarithromycin, ergot derivatives, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, and delavirdine) during the course of study 3. current use or anticipated need for drugs that are known CYP3A4 or CYP1A2 inducers (ie, carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin, primidone, rifabutin, rifampin, and St John’s wort) during the course of study. (Note: the use of dexamethasone as part of the docetaxel dosing regimen is not an exclusion criterion) 4. requirement of anticoagulant therapy except for low-dose anticoagulants for maintenance of patency of central venous access or prevention of deep vein thrombosis (DVT) 5. uncontrolled brain metastases (a controlled brain metastasis must be previously treated, asymptomatic, and without growth for 4 months) 6. clinically significant gastrointestinal abnormalities including the following: - inability to take oral medication - requiring intravenous alimentation - malabsorption syndrome - requiring treatment of active ulcer disease in the past 6 months - prior gastric resection - active gastrointestinal bleeding, unrelated to cancer, as evidenced by either hematemesis, hematochezia, or melena in the past 3 months 7. history of hemorrhagic or thrombotic cerebrovascular event in the past 12 months 8. major surgical procedure within 4 weeks of treatment for Phase 1 or randomization for Phase 2 9. unstable or severe intercurrent medical condition that, in the opinion of the investigator, might interfere with achievement of study objectives 10. psychological or sociological conditions, addictive disorders, or family problems, which would preclude compliance with the protocol 11. history of a malignancy (other than breast cancer) except those patients treated with curative intent for skin cancer (other than melanoma) or in situ cervical cancer or those treated with curative intent for any other cancer with no evidence of disease for 5 years 12. patients having procreative potential who are not using adequate contraception or practicing abstinence 13. women who are pregnant or breast-feeding 14. patients with proteinuria. (Patients with ≥1+ protein on urine dipstick at baseline should undergo a 24-hour urine collection. Results must demonstrate ≤500 mg of protein in 24 hours to allow participation in the study.) 15. known prior severe hypersensitivity reactions to agents containing polysorbate 80 16. patients with Her-2/Neu over-expression |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary end point(s): Time to Progression (Phase 2 portion of the study)
Secondary end point(s): 1) Confirm the dose of each drug in the combination 2) Safety profile of treatments based on physical examinations, laboratory tests, and assessment of adverse events 3) Pharmacokinetic parameters of AG-013736 and docetaxel when given in combination during the Phase 1 portion and population pharmacokinetics of AG-013736 when given in combination in the Phase 2 portion or as a single agent in the single-agent portion of the study 4) Response rate according to RECIST criteria and duration of response of the combination 5) Response rate and duration of response of single-agent AG-013736 in patients who progressed on docetaxel plus placebo |
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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 | Yes |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
There will be no Czech patients participating in Ph 1 portion of the trial |
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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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
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 | Yes |
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
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The entire trial will be stopped when: - The drug combination is considered too toxic to continue treatment prior to the required number of patients being recruited. - The study is terminated prematurely on the basis of the interim futility analysis. - The stated number of patients to be recruited is reached and all patients have been followed for at least 9 months unless they have discontinued therapy sooner. - The stated objectives of the trial are achieved. |
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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 | |
E.8.9.1 | In the Member State concerned months | 13 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 25 |