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Phase II Study of Temsirolimus and Irinotecan in Chemotherapy Refractory Patients With KRAS Mutated Metastatic Colorectal Cancer

Phase 2
18 Years
70 Years
Not Enrolling
Metastatic Colorectal Cancer

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Trial Information

Phase II Study of Temsirolimus and Irinotecan in Chemotherapy Refractory Patients With KRAS Mutated Metastatic Colorectal Cancer

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.

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

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Primary Purpose: Treatment

Outcome Measure:

Objective response rates

Principal Investigator

Anders Jakobsen, MD, DMSc

Investigator Role:

Study Chair

Investigator Affiliation:

Vejle Hospital


Denmark: Ethics Committee

Study ID:




Start Date:

March 2009

Completion Date:

June 2011

Related Keywords:

  • Metastatic Colorectal Cancer
  • KRAS mutation
  • Colorectal Neoplasms