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

• Register: EUCTR
• Last refreshed on: 29 May 2012
• Main ID: EUCTR2007-001568-66-SE
• Date of registration: 02/07/2007
• Prospective Registration: Yes
• Primary sponsor: Pfizer Inc, 235 East 42nd Street, New York, NY 10017, USA
• Public title: 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
• Scientific title: 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
• Date of first enrolment: 25/10/2007
• Target sample size: 596
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-001568-66
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: yes Other: no

Countries of recruitment

Austria, Belgium, Czech Republic, France, Germany, Hungary, Ireland, Italy, Portugal, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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 yea

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Unresectable or metastatic pancreatic cancer
MedDRA version: 9.1 Level: LLT Classification code 10033605 Term: Pancreatic cancer metastatic
MedDRA version: 9.1 Level: LLT Classification code 10033606 Term: Pancreatic cancer non-resectable

Intervention(s)

Product Code: AG-013736
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Axitinib
CAS Number: 319460-85-0
Current Sponsor code: AG-013736
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Code: AG-013736
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Axitinib
CAS Number: 319460-85-0
Current Sponsor code: AG-013736
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Gemzar
Product Name: gemcitabine
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: gemcitabine
CAS Number: 95058-81-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Trade Name: Gemzar
Product Name: gemcitabine
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: gemcitabine
CAS Number: 95058-81-4
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 1-

Primary Outcome(s)

Secondary Objective: - 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

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

Main Objective: - Compare the Overall Survival (OS) of patients receiving gemcitabine plus AG-013736 versus gemcitabine plus placebo

Secondary ID(s)

A4061028

2007-001568-66-IE