| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of patients with chemotherapy-naïve, locally advanced or metastatic epithelial cancer of the exocrine pancreas |
|
| 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 | 10033604 |
|
| 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 overall survival of the combination of AG-013736 and gemcitabine is superior to that of gemcitabine alone in patients who have advanced pancreatic cancer that has not been previously treated with systemic therapy. |
|
| E.2.2 | Secondary objectives of the trial |
1) determine the safety profile of treatments based on physical examinations, laboratory tests and assessment of adverse events;
2) evaluate population pharmacokinetics of AG-013736 in the Phase 2 portion of the study;
4) determine the response rate and duration of response (Phase 2 portion) in patients who have measurable disease at baseline;
5) determine progression-free survival and 1-year survival (Phase 2 portion);
6) assess patient-reported outcomes (PROs) of health-related quality of life (HRQoL) and pancreatic cancer-specific symptoms (Phase 2 portion) |
|
| 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 |
Biomarker Substudy (for Patients enrolled at Salpetriere Hospital and Hammersmith Hospital Only):
To investigate whether AG-013736 induces pharmacodynamic changes in soluble proteins that may correlate with clinical benefit or response to therapy, serum and
heparinized plasma samples will be collected from all patients participating in study A4061016 at Salpetriere Hospital. The soluble proteins will be measured by enzyme-linked immunosorbent assay (ELISA) at the immunological laboratory in the Medical Oncology Department of the Salpetriere Hospital. |
|
| E.3 | Principal inclusion criteria |
1. patients with advanced (localized but surgically unresectable or metastatic) histologically/cytologically proven epithelial cancer of the exocrine pancreas
2. no prior therapy for metastatic disease
3. no adjuvant chemotherapy within the 4 weeks before randomization (Phase 2) (patient must have recovered from all treatment-related toxicities and must have evidence of disease progression following adjuvant treatment)
4. no radiotherapy within the 4 weeks before randomization (Phase 2) (patient must have recovered from all treatment-related toxicities and must have evidence of disease progression following treatment. Prior radiotherapy [with or without fluoropyrimidines for radiosensitization] is allowed provided the patient has disease outside the radiation port)
5. adequate bone marrow function as defined by:
- ANC ≥1500 cells/mm3
- platelets ≥100, 000 cells/mm3
- hemoglobin ≥9 g/dL (which may be obtained by transfusion or growth factor support)
6. adequate liver function as defined by:
- bilirubin ≤1.5 times upper limit of normal (x ULN)
- AST and ALT ≤2.5 x ULN
7. adequate renal function as defined by both:
- serum creatinine ≤1.5 x ULN
- ≤500 mg urinary protein/24 hours or dipstick <2+
8. no evidence of preexisting uncontrolled hypertension as documented by 2 baseline blood pressure readings taken at least 1 hour apart on the same day (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)
9. ECOG performance status of 0, 1, or 2 (See Appendix 1)
10. life expectancy ≥ 12 weeks
11. adults ≥18 years of age
12. negative serum or urine pregnancy test for women of child-bearing potential
13. evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the trialpatients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures
|
|
| E.4 | Principal exclusion criteria |
1. prior treatment with gemcitabine, VEGF/VEGFR inhibitors, or anti-angiogenesis treatment of any kind in the adjuvant setting.
2. patients with locally advanced disease who are candidates for radiation therapy.
3. 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
4. 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
5. brain metastases (baseline CT or MRI of brain required only if clinically indicated)
6. inability to take oral medications
7. history of hemorrhagic or thrombotic cerebrovascular event in the past 12 months
8. major surgical procedure within 4 weeks of 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 pancreatic 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
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. other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the patient inappropriate for entry into this trial |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary end point is overall survival (Phase 2 portion). All deaths from any cause will be included in the analysis. |
|
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 | No |
| 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
|
As described in the protocol.
|
|
| 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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