| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable or metastatic pancreatic cancer |
|
| MedDRA Classification |
| 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 | 10033605 |
| E.1.2 | Term | Pancreatic 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 | 10033606 |
| E.1.2 | Term | Pancreatic cancer non-resectable |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| - Compare the Overall Survival (OS) of patients receiving gemcitabine plus AG-013736 versus gemcitabine plus placebo |
|
| E.2.2 | Secondary objectives of the trial |
- Compare the Progression Free Sursvival (PFS) of patients in each arm
- Compare the Objective Response Rate (ORR) of patients in each arm
- Estimate the Duration of Objective Response (DR) of patients in each arm
- Evaluate the safety and tolerability of AG-013736 plus gemcitabine
- Compare the health related quality of life (HRQOL), pain ratings, and health status of patients in each arm as measured by the European Organization for the Research and Treatment of Cancer, EORTC QLQ-C30, PAN26, BPI-sf, and EQ-5D
- Conduct population pharmacokinetic analysis using AG-013736 plasma concentrations |
|
| 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 |
Clinical Pharmacogenomics Supplement.
A randomized, double blind phase 3 study of gemcitabine plus AG-013736 versus gemcitabine plus placebo for the first line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.
Version and date: Final; Februrary 28, 2007;
The primary objective of this additional research component is to allow for the collection, storage, and use of samples to investigate possible associations between genomic variation in relation to response to AG-013736 and in relation to characteristics of pancreatic cancer and related conditions. Scientific information about these differences among groups of subjects can help researchers to better understand the reponse of subjects to investigational drugs such as AG-013736 and to learn more about conditions such as pancreatic cancer.
|
|
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed, metastatic or locally-advanced pancreatic adenocarcinoma not amenable to curative resection. Radiologically measurable disease is not required. Patients with documented invasion of adjacent hollow organs (colon, duodenum, stomach) by MRI/CT scan are not eligible. Patients with no endoscopic findings of cancer invasion are eligible, even if they are suspected of having invasion by MRI/CT scan.
2. Adequate coagulation, hepatic and renal function documented within 14 days prior
to treatment as documented by:
• INR ≤ 1.5 x ULN (except for patients on full-dose anticoagulation);
• 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 ≤1.0 x ULN;
• Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min;
• Urinary protein <1+ by urine dipstick. If dipstick is ≥1+ then a 24-hour urine collection should be done and the patient may enter only if urinary protein is <2 grams per 24 hours.
3. Adequate bone marrow function as defined by:
• ANC ≥1500 cells/mm3;
• platelets ≥100,000 cells/mm3;
• hemoglobin ≥9 g/dL;
4. Male or female, age ≥18 years (20 years in Japan only).
5. ECOG performance status of 0 or 1 (See Appendix 4).
6. Life expectancy of ≥12 weeks.
7. At least 4 weeks since the last dose of prior adjuvant therapy, if any. Adjuvant therapy is defined as systemic therapy without evidence of disease following surgical removal of the primary tumor. To be eligible, evidence of disease must be present at the time of enrollment. Prior radiation therapy, with or without a radio-sensitizing dose of fluoropyrimidines, is allowed provided the patient has either measurable or non-measurable disease outside the radiation port.
8. Resolution of all acute toxic effects of prior therapies or surgical procedures to NCI CTCAE Grade ≤1. For patients having received prior elective surgery, study treatment should not be administered until surgical incision is fully healed.
9. 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 mm Hg, and the baseline diastolic blood pressure readings must be ≤90 mm Hg. Patients whose hypertension is controlled by antihypertensive therapies are eligible.
10. Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to treatment.
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 prior to enrollment.
12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including completion of patient-reported outcome (PRO) measures. |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment with any systemic chemotherapy for locally advanced or metastatic disease.
2. Other concurrent anticancer therapy.
3. Prior treatment with gemcitabine, AG 013736, or other VEGF inhibitors (eg, bevacizumab). Prior use of these agents as adjuvant therapy or with radiation therapy also excludes the patient.
4. Current or recent (within 1 month) use of a thrombolytic agent (eg, streptokinase [SK], alteplase [rt-PA], reteplase [r-PA], tenecteplase [TNK-tPA], etc).
5. 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.
6. History of hemoptysis > ½ tsp (2.5 mL) of bright red blood per day within past 1 week.
7. Gastrointestinal abnormalities including:
• inability to take oral medication;
• requirement for intravenous alimentation;
• prior surgical procedures affecting absorption including gastric resection;
• active peptic ulcer disease requiring treatment 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;
• esophageal varices or acute, symptomatic portal vein thromboses.
8. Current use or anticipated need for treatment with 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).
9. 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). Intermittent use of dexamethasone, as an antiemetic before gemcitabine infusion, is allowed. Patients who need to be on anticoagulant therapy during treatment should be treated with low molecular weight heparin as the preferred therapy. The administration of coumadin may be allowed; however, due to possibility of inhibition of CYP1A2 mediated metabolism of coumadin by AG 013736, appropriate monitoring of prothrombin time/international normalized ratio (PT/INR) should be performed for any potential increased coumadin effect.
10. Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis.
11. A serious uncontrolled medical disorder (eg, bleeding disorder) or active infection that would impair their ability to receive study treatment.
12. 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.
13. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness.
14. History of a malignancy (other than pancreatic 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.
15. Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks of treatment. (Also excluded are patient with fine needle aspirations within 7 days of treatment).
16. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol.
17. Patients (male and female) having procreative potential who, or their partners, are not using adequate contraception (See Section 4.4 of the protocol) or practicing abstinence.
18. Pregnancy or breastfeeding. (see section 4.2 of the protocol for full definition)
19. Other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint:
Overall Survival
Seondary endpoints:
1. Progression Free Survival
2. Objective Response Rate
3. Duration of Objective Response
4. Type, incidence, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] Version 3.0), timing, seriousness, and relatedness of adverse events, and laboratory abnormalities
5. Patient Reported Ooutcomes: EORTC QLQ C30, QLQ PAN26, BPI sf, EQ 5D
6. AG-013736 population pharmacokinetic 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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
|
Based on the predefined interim analysis, the DMC found no evidence of improvement in the primary endpoint, overall survival, and concluded that it was futile to continue the study. Protocol Amendment 5 (Appendix 7) contains a revised Schedule of Activities, instructions regarding unblinding, patient access to AG013736 following unblinding, and patient follow-up (incl. adverse event reporting).The study will be ended as soon as LPLV occurs on the study.
|
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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