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Pre-emptive Cycline Treatment on Cetuximab-induced Skin Toxicity in Patients With Metastatic Colorectal Cancer Treated With an Intensified FOLFIRI.

Phase 3
18 Years
80 Years
Open (Enrolling)
Colorectal Cancer Metastatic, Skin Toxicity

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Trial Information

Pre-emptive Cycline Treatment on Cetuximab-induced Skin Toxicity in Patients With Metastatic Colorectal Cancer Treated With an Intensified FOLFIRI.

Cetuximab, an Epidermal Growth Factor Receptor (EGFR) inhibitor, has shown to improve
FOLFIRI efficacy up to 59.3% OR, in wild KRAS patients with advanced colorectal cancer.
Skin toxicity occurs in 81.6% of patients as an acne-like skin rash developed on the face
and the trunk inducing pain, decreasing quality of life and drug compliance. Over 104
patients enrolled in a phase II clinical trial sponsored by Center Paul Papin (NCT 00
559741), a grade > or = 2 cetuximab-acneiform rash occured in 51 patients (49%). In this
trial Cetuximab was combined with a FOLFIRI intensified (5-FU intensification based on
pharmacokinetics and pharmacogenetic studies of UGT1A1 status and DPD). Until now, no
pre-emptive skin toxicity treatment with cycline has been demonstrated. Because of cycline's
anti inflammatory properties and their use in inflammatory acne, cycline could prevent
cetuximab-induced skin rash. In a randomized double-blind placebo-controlled phase III
trial, Jatoi et al., failed to highlight any cycline effect on 61 patients. On the other
hand, the STEPP study (95 pts) showed the impact of cycline to prevent panitumumab related
skin toxicities. Our primary objective is to reduce the incidence of grade > or = 2
acne-like skin rash by 30% with a 6 weeks pre-emptive cycline treatment in patients with
metastatic colorectal cancer undergoing cetuximab therapy.

Inclusion Criteria:

- Advanced or metastatic colorectal cancer, histologically confirmed, first or second
metastatic line

- K-RAS wild-type

- Adjuvant prior chemotherapy allowed provided that all toxicities are grade < or = 1
(excepted alopecia and neuropathy)

- Age between 18 and 80 years

- WHO Performance Status < or = 2

- Complete initial assessment before first treatment administration for imaging and
pharmacogenetic, within 15 days for biology, and within 7 days for clinical

- Haematologic and hepatic parameters : neutrophils > or = 1500 /mm3, platelets > or =
100000/mm3, Total bilirubin < or 2 x ULN, AST and ALT < or = 3 x ULN, APL < or = 5 x

- Absence of total dihydropyrimidine dehydrogenase deficiency

- Patient able to comply with study requirements

- Signed written informed consent

Exclusion Criteria:

- History or presence of an other cancer, excepted cutaneous cancer (basocellular
carcinoma), in situ cancer of the cervix or breast cancer curatively treated

- Any other concomitant anti-cancer therapy

- Prior anti EGFR therapy, anti angiogenic therapy is allowed

- Prior cyclines hypersensitivity

- Treatment with cyclines within 7 days before randomization

- Presence of a rash at randomization time

- Symptomatic or uncontrolled ventral nervous system metastases

- Total dihydropyrimidine dehydrogenase deficiency

- No recovery of any toxicity Grade < or = 1 related to a past anticancerous treatment
excepted for alopecia and neuropathy

- Active inflammatory bowel disease or other bowel

- Significant serious pathology or any unstable medical condition (cardiac pathology
uncontrolled, myocardial infarction within 6 months before enrollment, systemic
active uncontrolled infection)

- atropine contra-indication

- any investigational agent without marketing authorization within 4 weeks before

- Patient who is pregnant or breast feeding

- Woman or man of childbearing potential not consenting to use adequate contraceptive
precautions during the study

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

reduction of Grade > or = 2 acne-like skin rash by 30%

Outcome Description:

Skin tolerance will be assessed by a dermatologist at each cycle and NCI CTCAE v4.0 will be use for grading. Skin standardized photographs will be done at every cycle and a central double blind review wil be planned. Time to first occurence of grade > or =2 skin toxicity will be assessed, and specificity.

Outcome Time Frame:

6 weeks of pre-emptive cycline treatment

Safety Issue:


Principal Investigator

Olivier Capitain, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

ICO Paul Papin


France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Study ID:




Start Date:

December 2010

Completion Date:

November 2015

Related Keywords:

  • Colorectal Cancer Metastatic
  • Skin Toxicity
  • Metastatic Colorectal Cancer
  • K-RAS wild-type
  • Cetuximab
  • Colorectal Neoplasms
  • Neoplasms
  • Neoplasms, Second Primary