Temsirolimus and Irinotecan for Treatment Resistant Patients With Metastatic Colorectal Cancer and KRAS Mutations (TIRASMUS)
Primary Purpose
Metastatic Colorectal Cancer
Status
Completed
Phase
Phase 2
Locations
Denmark
Study Type
Interventional
Intervention
Irinotecan
Temsirolimus
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Colorectal Cancer focused on measuring KRAS mutation
Eligibility Criteria
Inclusion Criteria:
- Histologically verified colorectal adenocarcinomas
- Age > 18 years and < 70
- Metastatic colorectal cancer refractory 5-FU, oxaliplatin and irinotecan containing treatment regimes
- KRAS mutation detected by DxS kit in primary tumor or metastatic lesion.
- Measurable disease according to RECIST
- ECOG performance status 0, 1 or 2
- Adequate renal, hepatic and haematological function
- Normal serum cholesterol and triglycerides
- Blood samples and available paraffin embedded tumor material for translational research studies
- Fertile males and females (< 2 years after last period for women) must use effective birth control
- Signed Informed consent
Exclusion Criteria:
- Clinically significant heart disease, active severe infections or other concurrent disease
- Other malignant diseases within 5 years of inclusion in the study, except basal cell squamous cell carcinoma of the skin and cervical carcinoma-in-situ
- Prior radiotherapy within 30 days of treatment start
- Other experimental therapy within 30 days of treatment initiation
- Patients who are breast feeding, childbearing or of childbearing potential without using dual effective contraception
- Clinical or radiological evidence of CNS metastasis
Completed any major surgery, excision biopsy or significant traumatic lesion ≥ 4 weeks from start of treatment and completed any minor surgery ≥ 1 week prior to start of treatment
- Insertion of a vascular access device is not considered major or minor surgery from the viewpoint of protocol eligibility
- Patients must have fully recovered from the procedure and have a fully healed incision
- Planned radiation therapy against target-lesions
- Patients with significant non-healing wounds or ulcers
History or evidence of thrombotic or hemorrhagic disorders
- Significant haemorrhage (> 30 ml/bleeding episode in previous 3 months)
- Haemoptysis (> 5 ml fresh blood in previous 4 weeks)
Patients on full-dose anticoagulation (e.g., warfarin) are eligible provided that both of the following criteria are met:
- The patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or is on a stable dose of low molecular weight heparin
- The patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
- Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub-Arachnoid Hemorrhage (SAH) within 12 months prior to randomization
- No known or history of HIV seropositivity
- The use of ACE inhibitors is not permitted during the study
- Known allergy to temsirolimus, sirolimus, polysorbate 80 or included agents.
- Agents with strong CYP3A4-inhibitory potential
Sites / Locations
- Rigshospitalet, Department of Oncology
- Vejle Hospital, Dept. of Oncology
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Experimental
Arm Label
Response or stable disease
Progression
Arm Description
will receive Temsirolimus
Will receive a combination of Temsirolimus and Irinotecan
Outcomes
Primary Outcome Measures
Objective response rates
Secondary Outcome Measures
Progression free survival
Overall survival
Translational Research
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00827684
Brief Title
Temsirolimus and Irinotecan for Treatment Resistant Patients With Metastatic Colorectal Cancer and KRAS Mutations
Acronym
TIRASMUS
Official Title
Phase II Study of Temsirolimus and Irinotecan in Chemotherapy Refractory Patients With KRAS Mutated Metastatic Colorectal Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
June 2011
Overall Recruitment Status
Completed
Study Start Date
March 2009 (undefined)
Primary Completion Date
January 2011 (Actual)
Study Completion Date
June 2011 (Actual)
3. Sponsor/Collaborators
Name of the Sponsor
Vejle Hospital
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this study is to investigate the safety and efficacy of temsirolimus as a single drug, and of temsirolimus in combination with irinotecan in chemotherapy resistant patients with KRAS mutated colorectal cancer.
Detailed Description
Chemotherapy resistance is a major challenge in metastatic colorectal cancer (mCRC), and EGFR inhibitors have been introduced as 3rd line treatment to chemotherapy refractory patients. However, it has recently been established that response to treatment with irinotecan and cetuximab is confined to patients with wtKRAS tumors. Therefore, downstream targets are being proposed as potential inhibitors of the EGFR signalling in tumours with KRAS mutations. mTOR is a central intracellular signalling molecule and a rational approach for potential reversion of chemotherapy resistance in these patients.
Preclinical data suggest that different solid tumors could respond to mTOR inhibitors and report on enhanced antitumor activity in combination with different traditional cytostatic drugs. Furthermore recent preclinical data suggest that mTOR inhibition may induce tumor reduction in colon cancer xenographs. Temsirolimus (CCI-779) has been widely investigated in different clinical settings and is presently registered for treatment of renal cell carcinomas. Furthermore, is has recently shown response in metastatic breast cancer patients, but at present there are no clinical data on efficacy or safety in metastatic colorectal cancer patients.
The present study aims at investigating the safety and efficacy of monotherapy temsirolimus and a combination of temsirolimus and irinotecan in chemotherapy resistant, KRAS mutated colorectal adenocarcinomas.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Colorectal Cancer
Keywords
KRAS mutation
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Enrollment
50 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Response or stable disease
Arm Type
Active Comparator
Arm Description
will receive Temsirolimus
Arm Title
Progression
Arm Type
Experimental
Arm Description
Will receive a combination of Temsirolimus and Irinotecan
Intervention Type
Drug
Intervention Name(s)
Irinotecan
Intervention Type
Drug
Intervention Name(s)
Temsirolimus
Primary Outcome Measure Information:
Title
Objective response rates
Secondary Outcome Measure Information:
Title
Progression free survival
Title
Overall survival
Title
Translational Research
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Histologically verified colorectal adenocarcinomas
Age > 18 years and < 70
Metastatic colorectal cancer refractory 5-FU, oxaliplatin and irinotecan containing treatment regimes
KRAS mutation detected by DxS kit in primary tumor or metastatic lesion.
Measurable disease according to RECIST
ECOG performance status 0, 1 or 2
Adequate renal, hepatic and haematological function
Normal serum cholesterol and triglycerides
Blood samples and available paraffin embedded tumor material for translational research studies
Fertile males and females (< 2 years after last period for women) must use effective birth control
Signed Informed consent
Exclusion Criteria:
Clinically significant heart disease, active severe infections or other concurrent disease
Other malignant diseases within 5 years of inclusion in the study, except basal cell squamous cell carcinoma of the skin and cervical carcinoma-in-situ
Prior radiotherapy within 30 days of treatment start
Other experimental therapy within 30 days of treatment initiation
Patients who are breast feeding, childbearing or of childbearing potential without using dual effective contraception
Clinical or radiological evidence of CNS metastasis
Completed any major surgery, excision biopsy or significant traumatic lesion ≥ 4 weeks from start of treatment and completed any minor surgery ≥ 1 week prior to start of treatment
Insertion of a vascular access device is not considered major or minor surgery from the viewpoint of protocol eligibility
Patients must have fully recovered from the procedure and have a fully healed incision
Planned radiation therapy against target-lesions
Patients with significant non-healing wounds or ulcers
History or evidence of thrombotic or hemorrhagic disorders
Significant haemorrhage (> 30 ml/bleeding episode in previous 3 months)
Haemoptysis (> 5 ml fresh blood in previous 4 weeks)
Patients on full-dose anticoagulation (e.g., warfarin) are eligible provided that both of the following criteria are met:
The patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or is on a stable dose of low molecular weight heparin
The patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub-Arachnoid Hemorrhage (SAH) within 12 months prior to randomization
No known or history of HIV seropositivity
The use of ACE inhibitors is not permitted during the study
Known allergy to temsirolimus, sirolimus, polysorbate 80 or included agents.
Agents with strong CYP3A4-inhibitory potential
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anders Jakobsen, MD, DMSc
Organizational Affiliation
Vejle Hospital
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Karen-Lise G Spindler, MD, PhD
Organizational Affiliation
Vejle Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Rigshospitalet, Department of Oncology
City
Copenhagen
ZIP/Postal Code
DK-2100
Country
Denmark
Facility Name
Vejle Hospital, Dept. of Oncology
City
Vejle
Country
Denmark
12. IPD Sharing Statement
Learn more about this trial
Temsirolimus and Irinotecan for Treatment Resistant Patients With Metastatic Colorectal Cancer and KRAS Mutations
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