| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or metastatic Colorectal Cancer |
|
| MedDRA Classification |
| 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 | 10061451 |
| E.1.2 | Term | Colorectal cancer |
|
| 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 compare Arm A versus Arm B in terms of PFS measured from the time of randomization after completing 6 cycles of first-line therapy for metastatic CRC:
• Arm A: 5-FU/LV plus bevacizumab in combination with enzastaurin
• Arm B: 5-FU/LV plus bevacizumab in combination with placebo. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
• to compare the following between treatment arms:
• OS from the time of randomization
• OS and PFS from the start of first-line therapy.
• to assess the safety and AE profile in both treatment arms using Common Terminology Criteria for Adverse Events (CTCAE Version 3.0, NCI 2006). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1] Histologic diagnosis of locally advanced or metastatic CRC that is not amenable to curative therapy. The histology types to be included are adenocarcinoma, mucinous adenocarcinoma, signet ring, and undifferentiated. Patients with neuroendocrine carcinomas will be excluded.
[2] Performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group scale (Protocol Attachment S064.4; Oken et al. 1982).
[3] Received 6 cycles (3 months [12 weeks]) of first-line therapy with FOLFOX or FOLFIRI, plus bevacizumab for metastatic CRC. Patients who received 6 cycles of first-line therapy with FOLFOX or FOLFIRI, plus bevacizumab for recurrent CRC that has relapsed at least 12 months after completion of adjuvant therapy will also be included. All standard FOLFOX (for example, de Gramont et al. 2000) or FOLFIRI (for example, Tournigand et al. 2004) regimens given on a biweekly schedule will be permitted; however, 21-day regimens will not be allowed.
[4] Prior radiotherapy must be completed 30 days before beginning first-line therapy. Patients must have recovered from the toxic effects of the treatment prior to study enrollment (except for alopecia).
[5] No more than 4 weeks may pass between the end of first-line therapy
(that is, Day 14 of Cycle 6) and randomization.
[6] Documented evidence of tumor response of CR, PR, or SD by computed tomography (CT) scan or magnetic resonance imaging (MRI). Confirmation of response is not required. Baseline tumor assessment must occur between Cycle 6 (Day 1) of first-line therapy and the date of randomization. The first dose of study treatment should be administered within 6 weeks after the baseline scan.
[7] Adequate organ function including the following:
Adequate bone marrow reserve: white blood cell count >3.0 x 109/L, absolute neutrophil count >1.5 x 109/L, platelet count >100 x 109/L, and hemoglobin >9.0 g/dL (>5.6 mmol/L). Hepatic: bilirubin <1.5 times the upper limit of normal (ULN); alkaline phosphatase, aspartate transaminase, and alanine transaminase <2.5 x ULN (<5 x ULN with liver metastases). Renal: serum creatinine <2.0 x ULN.
[8] Estimated life expectancy of at least 12 weeks
[9] Patient compliance and geographic proximity that allow for adequate follow-up.
[10] Patients must sign an informed consent document (ICD).
[11] Patients must be at least 18 years of age.
[12] Male and female patients with reproductive potential must use an approved contraceptive method, if appropriate (for example, intrauterine device, birth control pills, or barrier device) during and for 3 months after discontinuation of study treatment. Women with childbearing potential must have a negative serum pregnancy test <7 days prior to study enrollment.
|
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
[13] Are unable to swallow tablets.
[14] Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.
[15] Are unable to discontinue use of enzyme inducing anti-epileptic drugs (EIAEDs), such as phenytoin, carbamazepine, or phenobarbital (refer to Section 5.7.1).
[16] Have a prior malignancy (other than CRC or adequately treated carcinoma in situ of the cervix or nonmelanoma skin cancer), unless that prior malignancy was diagnosed and definitively treated at least 5 years previously with no subsequent evidence of recurrence.
[17] Are pregnant or lactating.
[18] Are receiving concurrent administration of any other antitumor therapy.
[19] Have known hypersensitivity to any component of enzastaurin.
[20] Have a serious concomitant systemic disorder (for example, active infection including known HIV) that, in the opinion of the investigator, would compromise the patient’s ability to adhere to the protocol.
[21] Have a serious cardiac condition, such as myocardial infarction within the last 6 months, angina, unstable coronary artery disease, known arterial thrombosis, or heart disease, as defined by the New York Heart Association Class II, III or IV (Protocol Attachment S064.5; Bruce 1956).
[22] Have known central nervous system metastases. A screening CT or MRI before enrollment in the absence of a clinical suspicion of brain metastases is not required.
[23] Have inadequately controlled hypertension (defined as systolic blood pressure >140 and/or diastolic >90 mm Hg on antihypertensive medications).
[24] Have any prior history of hypertensive crisis or hypertensive encephalopathy.
[25] Have evidence of bleeding diathesis or coagulopathy.
[26] Have had major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization or have an anticipated need for major surgery during the course of the study.
[27] Have had a core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment.
[28] Have a serious, nonhealing wound, ulcer, or bone fracture.
[29] Have a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study entry.
[30] History of stroke or transient ischemic attack within 6 months prior to randomization.
[31] Have significant vascular disease (such as aortic aneurysm or aortic dissection) or symptomatic peripheral vascular disease.
[32] Have proteinuria at baseline, as demonstrated by either:
• urine dipstick for proteinuria >2+. Patients discovered to have >2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate <1 g of protein in 24 hours to be eligible.
• urine protein:creatinine (UPC) ratio >1.0 at baseline |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is PFS measured from time of randomization. Secondary efficacy endpoints include assessment of OS from randomization, and OS and PFS from start of first-line therapy. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | 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) | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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
| |
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 8 |
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