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| [ Print-friendly version ] |
| CINATRA: Chromosomal Instability and Anti-Tubulin Response Assessment |
| ISRCTN | ISRCTN58864837 |
| ClinicalTrials.gov identifier | |
| Public title | CINATRA: Chromosomal Instability and Anti-Tubulin Response Assessment |
| Scientific title | A phase 2 study of Epo906/patupilone in metastatic colorectal carcinoma in patients with microsatellite instability or chromosomal instability previously treated with irinotecan, oxaliplatin and fluoropyrimidines |
| Acronym | CINATRA |
| Serial number at source | CCR 2983 |
| Study hypothesis | To determine the anti-tumour activity of Epo906 administered to patients with metastatic colorectal cancer previously treated with irinotecan, oxaliplatin and fluoropyrimidines |
| Ethics approval | Hertfordshire Research Ethics Committee. Approval pending as of 21/04/2008. |
| Study design | Phase II, single-arm, interventional study. |
| Countries of recruitment | United Kingdom |
| Disease/condition/study domain | Metastatic colorectal cancer |
| Participants - inclusion criteria |
1. Male or female
2. 18 years of age or older 3. Histologically confirmed metastatic or locally recurrent carcinoma of the colon or rectum 4. Prior therapy with oxaliplatin, a fluoropyrimidine, and irinotecan for colorectal cancer. If a patient has previously received raltitrexed, this would be considered as equivalent to fluoropyrimidine treatment 5. Availability of paraffin embedded tumour tissue for analysis of microsatellite instability (MSI) status and chromosomal instability (CIN) 6. Life expectancy of 12 weeks or greater 7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 8. Clinically and/or radiographically documented measurable disease according to the Response Evaluation Criteria In Solid Tumours (RECIST), with at least one unidimensionally lesion measuring 10mm or greater by spiral CT or 20mm or greater by conventional (non-spiral) computerised tomography (CT) 9. Adequate liver function: 9.1. Serum aspartate transaminase (AST) <= 5 x upper limit of normal (ULN) 9.2. Serum alanine transaminase (ALT) <= 5 x ULN 9.3. Serum alkaline phosphatase (ALP) <5 x ULN 9.4. Total serum bilirubin <1.5 x ULN 9.5. Prothrombin time (PT) <= 1.5 x ULN 10. Adequate haematological function: 10.1. Absolute neutrophil count (ANC) >= 1.0 x 10^9/L 10.2. Platelets >= 100 x 10^9/L 10.3. Haemoglobin >= 9.0 g/dL 11. Serum creatinine clearance of greater than 50 ml/min according to the Cockcroft-Gault calculation or measured glomerular filtration rate of >50 ml/min 12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures 13. Prior radiotherapy or colostomy are allowed. A marker lesion may not be in a previously irradiated area, unless there has been documented disease progression in that area since radiotherapy 14. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects prior to enrolment 15. For Cohort B, all patients must have tumours which are microsatellite instability (MSI) positive by immunohistochemistry (IHC) 16. Patients must be willing to undertake adequate contraceptive methods or remain sexually abstinent for the duration of study treatment and for at least 28 days after receiving the last dose of study drug |
| Participants - exclusion criteria |
1. Persistent toxicity from previous treatment. Neurotoxicity from prior oxaliplatin must have resolved to at least grade 1
2. Diagnosis of or treatment for any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell carcinoma of the skin, or adequately treated in-situ cervical cancer 3. Any of the following within the 12 months prior to study drug administration: 3.1. Myocardial infarction or severe/unstable angina 3.2. Coronary/peripheral artery bypass graft 3.3. Symptomatic congestive heart failure 3.4. Cerebrovascular accident or transient ischemic attack 3.5. Pulmonary embolism 4. Pregnancy or breastfeeding 5. 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 6. Clinically significant neuropathy that could be worsened by study treatment |
| Anticipated start date | 01/05/2008 |
| Anticipated end date | 01/05/2012 |
| Status of trial | Ongoing |
| Patient information material | Not available in web format, please contact Dr Angela Gillbanks at Angela.Gillbanks@rmh.nhs.uk to request a patient information sheet. |
| Target number of participants | 110 |
| Interventions |
This trial aims to find out whether Epo906 has activity in the two main types of colorectal cancer: cancers with a near normal DNA content (i.e. unselected patients [Cohort A]; microsatellite instability) and cancers with a continuously changing DNA content (Cohort B; chromosomal instability). The first part of the trial will assess the activity of Epo906 in all patients (Cohort A). In the second part of the study, only patients who have tumours with a near normal DNA content will be treated (Cohort B).
Cohort A (75 unselected patients; microsatellite instability): Epo906/patupilone is given intravenously (iv) at a dose of 8 mg/m2 over 20 minutes on day 1 of a 21-day cycle, after pre-medication with iv dexamethasone and metoclopramide. Patients will receive 8 cycles (8 doses) unless there is evidence of disease progression or unacceptable toxicity. Cohort B (35 patients selected for microsatellite instability): As above |
| Primary outcome measure(s) | Twelve-week progression free survival (PFS). This will be measured by comparing a CT scan of the thorax/abdomen and pelvis at baseline (Within 28 days of starting treatment) to a second CT scan performed after 12 weeks from trial registration, evaluated by RECIST criteria. |
| Secondary outcome measure(s) |
1. To determine the effect of CIN and MSI on the efficacy (Response rate and progression-free survival [PFS]) of Epo906 as an anticancer agent, assuming that MSI+ colorectal cancer patients will benefit more than CIN+ colorectal cancer patients.
2. To describe the safety of Epo906 and quality of life benefits associated with treatment 3. To correlate specific genetic variation with outcome following EPO906 therapy, in particular with reference to adenomatous polyposis coli (APC) gene status (MSI+ APCwt vs MSI APCmutant vs CIN). Other genetic analysis will include but not be limited to, b-catenin, Kras, or Braf mutations; copy number polymorphisms; loss of heterozygosity (LOH) 4. To retrospectively assess the response to prior treatment in relation to MSI and CIN status, particularly with reference to response to irinotecan and oxaliplatin containing regimens The following assessments will be carried out: a. Overall survival (Time from trial registration to death from any cause), response rate (Proportion of patients with complete or partial response as their best response as measured by RECIST criteria), tumour control rate (Total number of patients with best response measured by RECIST criteria as complete response, partial response or stable disease) b. Twelve-week PFS stratified by MSI and CIN status, tested by flow immunohistochemistry, flow cytometry and DNA analysis of tumour sample c. Response rate stratified by MSI and CIN status, tested by flow immunohistochemistry, flow cytometry and DNA analysis of tumour sample d. Incidence of serious toxicity with Epo906 therapy, measured by CTCAE version 3.0 e. Quality of life parameters, measured by EORTC QLQ-C30 and QLQ-CR38 questionnaires at baseline, prior to cycles 2 and 5 and at the end of treatment f. To retrospectively assess response to prior treatments according to MSI and CIN status, tested by flow immunohistochemistry, flow cytometry and DNA analysis of tumour sample |
| Sources of funding |
1. The Royal Marsden Hospital NHS Foundation Trust (UK)
2. This study is supported by Novartis Pharmaceuticals, in conjunction with Professor Cunningham's Charitable Research Fund (UK) |
| Trial website | |
| Publications | |
| Contact name | Dr Ian Chau |
| Address |
Department of Medicine
Royal Marsden Hospital Downs Road |
| City/town | Sutton |
| Zip/Postcode | SM2 5PT |
| Country | United Kingdom |
| Sponsor | The Royal Marsden Hospital NHS Foundation Trust (UK) |
| Address | Downs Road |
| City/town | Sutton |
| Zip/Postcode | SM2 5PT |
| Country | United Kingdom |
| Tel | +44 (0)208 6613279 |
| Fax | +44 (0)208 6613750 |
| angela.gillbanks@rmh.nhs.uk | |
| Date applied | 05/03/2008 |
| Last edited | 22/04/2008 |
| Date ISRCTN assigned | 21/04/2008 |
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