Metastatic colorectal cancer Cancer Colorectal cancer
Conditions
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
microsatellite instability): Epo906/patupilone is given intravenously (iv) at a dose of 8 mg/m^2 over 20 minutes on day 1 of a 21-day cycle, after pre-medication with iv dexamethasone and metocloprami
Sponsors
The Royal Marsden Hospital NHS Foundation Trust (UK)
Eligibility
Sex/Gender
All
Inclusion criteria
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 aminotransferase (AST) less than or equal to 5 x upper limit of normal (ULN) 9.2. Serum alanine aminotransferase (ALT) less than or equal to 5 x ULN 9.3. Serum alkaline phosphatase (ALP) less than 5 x ULN 9.4. Total serum bilirubin less than 1.5 x ULN 9.5. Prothrombin time (PT) less than or equal to 1.5 x ULN 10. Adequate haematological function: 10.1. Absolute neutrophil count (ANC) greater than or equal to 1.0 x 10^9/L 10.2. Platelets greater than or equal to 100 x 10^9/L 10.3. Haemoglobin greater than or equal to 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 greater than 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
Exclusion criteria
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 ischaemic 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 versus MSI APCmutant versus 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 tr | — |
Countries
England, United Kingdom
Outcome results
None listed