| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Second line treatment of patients with metastatic carcinoma of colon and rectum |
|
| 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 | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052358 |
| E.1.2 | Term | Colorectal cancer metastatic |
|
| 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 |
| To demonstrate that the combination of AG-013736 with either FOLFIRI or FOLFOX is superior to FOLFIRI or FOLFOX in combination with bevacizumab in prolonging the PFS in the second-line treatment of patients with metastatic CRC after failure of an irinotecan or oxaliplatin-containing first-line regimen. |
|
| E.2.2 | Secondary objectives of the trial |
- To compare the OS in patients randomized to AG-013736 with either FOLFIRI or FOLFOX versus that in patients randomized to FOLFIRI or FOLFOX in combination with bevacizumab.
- To compare the ORR and duration of response (DR) in patients randomized to AG-013736 with either FOLFIRI or FOLFOX versus that in patients randomized to FOLFIRI or FOLFOX in combination with bevacizumab.
- To evaluate the safety and tolerability of AG-013736 in combination with either FOLFIRI or FOLFOX.
-To evaluate patient reported symptom severity and interference using the M D Anderson Symptom Inventory –Diarrhea (MDASI-D).
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically-documented metastatic CRC plus any one of the following:
- Failure of one prior irinotecan- or oxaliplatin-containing regimen documented with radiographic evidence of disease progression as defined by RECIST criteria and documented with 2 sets of CT/MRI scans during irinotecan or oxaliplatin therapy or within 6 months after the last dose of the irinotecan- or oxaliplatin-containing regimen (patients with prior adjuvant chemotherapy or radiation therapy are eligible); or
- Intolerance to prior oxaliplatin therapy, defined as occurrence of Grade 3 or 4 neurotoxicity that is persistent between cycles.
2. Adequate organ function, as defined by the following criteria:
- Absolute neutrophil count (ANC) ≥1500 cells/mm3
- Platelets ≥100,000 cells/mm3
- Hemoglobin ≥9.0 g/dL
- Total serum bilirubin ≤1.5 times upper limit of normal (x ULN)
- AST and ALT ≤2.5 x ULN, or AST and ALT ≤5 x ULN if liver function abnormalities are due to underlying malignancy
- Serum creatinine ≤1.5 x ULN
- 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. Measurable disease by RECIST. Measurable diseases that have been previously radiated will not be considered target lesions unless an increase in size has been observed following completion of radiation therapy.
4. Male or female, ≥18 years of age
5. Life expectancy ≥12 weeks
6. ECOG performance status 0 or 1
7. Resolution of all acute toxic effects of prior radiotherapy (except for alopecia), 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
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 mm Hg, and the baseline diastolic blood pressure readings must be ≤90 mm Hg. 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 3 days prior to treatment.
10. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial before enrollment.
11. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including completion of PRO measures.
12. Eligible to receive FOLFIRI or FOLFOX in combination with bevacizumab |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment of metastatic CRC with more than 1 systemic chemotherapy regimen for metastatic disease. Patients who participated in study A4061020 are not eligible to participate in this study.
2. Prior irradiation to ≥25% of the bone marrow (whole pelvis =25%; a patient with prior whole pelvis irradiation is ineligible).
3. Pleural effusion or ascites that causes ≥ Grade 2 dyspnea.
4. Current use or anticipated need for food or drugs that are known cytochrome P450 (CYP) 3A4 inhibitors (i.e., grapefruit juice, verapamil, ketoconazole, itraconazole, erythromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, and delavirdine) during the course of the study
5. Current use or anticipated need for drugs that are known CYP3A4 or CYP1A2 inducers (i.e., carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin, primidone, rifabutin, rifampin, and St John's wort) during the course of study (Note: the short-term use of dexamethasone as a premedication for chemotherapy is not an exclusion criterion)
6. History of hemoptysis > ½ tsp of bright red blood in one day within past 1 week.
7. Patients with active seizure disorder or brain metastases
8. Gastrointestinal abnormalities including:
- inability to take oral medication
- requirement for intravenous alimentation
- prior surgical procedures affecting absorption including total 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
9. History of any second malignancy except those patients 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.
10. 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) Note: Insertion of a vascular access device is not considered major or minor surgery.
11. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol.
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 dihydropyridine dehydrogenase deficiency.
14. History of hypersensitivity to 5-FU or LV.
15. Known human immunodeficiency virus (HIV) seropositivity or acquired immunodeficiency syndrome (AIDS) related illness.
16. Serious active infection (viral, fungal, bacterial). Infection requiring parenteral antibiotics at time of enrollment will disqualify the patient.
17. Female patients who are pregnant or lactating, or men and women of reproductive potential not willing or not able to employ an effective method of birth control/contraception to prevent pregnancy during treatment and for 6 months after discontinuing study treatment.
18. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality 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
- PFS defined as the time from randomization to the date of progression or death due any cause, whichever occurs first.
Secondary Endpoints
- OS defined as the time from randomization to the date of death due to any cause.
- ORR defined as the proportion of randomized patients with baseline measurable disease and a best response characterized as either a complete response (CR) or partial response (PR) (CR or PR defined according to RECIST).
- DR defined as the time from first documentation of response to the date of progression or death due to any cause, whichever occurs first.
- Overall safety profile characterized by type, frequency, severity as graded using NCI (National Cancer Institute) Common Terminology Criteria for Adverse Events (CTCAE), v3.0 and relationship to study therapy of adverse events and laboratory abnormalities.
- Patient Reported Outcome (PRO) changes in scores for symptom severity and interference according to the MDASI–D. |
|
| 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) | 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) | Yes |
| 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.8.4.1 | 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 | 12 |
| 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
|
| End of Trial in all participating countries is defined as the time at which all patients enrolled in the study have completed treatment on 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
Print
