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Phase I-II Trial of Erlotinib in Higher Risk Myelodysplastic Syndrome

Phase 1/Phase 2
18 Years
Open (Enrolling)
Myelodysplastic Syndrome

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Trial Information

Phase I-II Trial of Erlotinib in Higher Risk Myelodysplastic Syndrome

This is a phase I-II multicenter, open label, sequential cohort dose escalation study of
erlotinib designed to assess the safety and efficacy of a daily administration of erlotinib
in high risk MDS patients.

Five patients per cohort will be enrolled into sequential cohorts receiving increasing
dosages of erlotinib. The first cohort of 5 patients will start with a dosage of 100 mg
erlotinib daily. Response will be determined after 12 weeks of treatment (or earlier upon
major hematologic improvement, whichever event occurs first). At the completion of each
cohort, defined as the fifth subject completing the week 12 visit, the safety review panel
will be responsible for making the decision as to whether the next cohort will begin, an
intermediate dose cohort will be added, or if additional subjects will be enrolled into an
earlier dose cohort.

Upon agreement of the safety review panel, the second cohort of patients will receive 150 mg
of erlotinib daily, and - upon agreement of the safety review panel - the third cohort of
five patients will be enrolled to receive 300 mg of erlotinib daily.

Since it is to be expected that the therapeutically required dosage of erlotinib is higher
than the dosage for which a patient was initially enrolled (i.e. patient enrolled in the
first cohort receiving 100 mg daily), dosage of erlotinib should be increased (for the same
patient) to the next higher level, if no response is documented after 12 weeks of continuous
treatment and no grade III or IV toxicity is documented. In contrast, responders will
continue their treatment with the same dosage of erlotinib until grade III or IV toxicity
arises or treatment loses efficacy (as defined by relapse/progression of the disease).

Consequently, this study plans to enrol 15 patients in 3 cohorts of 5 patients. Once the
dose limiting toxicity has been defined, additional confirmatory subjects (20) will be
enrolled into the appropriate lower dose as recommended by the safety review panel.

Inclusion Criteria:

1. Diagnosis of MDS according to the WHO classification, but also including RAEB in
transformation as defined by the FAB classification (that is patients with up to 30%
of blasts in the bone marrow), with the exception of patients with preceding
myeloproliferative syndrome or LMMC;

2. Higher-risk MDS as defined by a IPSS score >1 (IPSS: Int-2 or High);

3. Life expectancy > 3 months;

4. Percentage of bone marrow blasts >10 and below 30%;

5. Ineligible for or having failed intensive chemotherapy and ineligible for or having
failed previous therapy with a hypomethylating agent;

6. Age ≥ 18 years;

7. Written informed consent;

8. Patient must understand and voluntarily sign consent form;

9. Patient must be able to adhere to the visit schedule as outlined in the study and
follow protocol requirements;

10. ECOG performance status between 0-2 at the time of screening;

11. Females of childbearing potential (defined as a sexually mature woman who has not
undergone a hysterectomy or who is not naturally postmenopausal for at least 24
consecutive months, that is who has had menses at any time during the preceding 24
consecutive months) have to have a negative pregnancy test;

12. Adequate contraceptive methods should be carried out by all patients during therapy
and for at least 2 weeks after completing therapy.

13. No existing contra-indication to treatment with erlotinib.

14. Health insurance.

Exclusion Criteria:

1. Serum creatinine ≥ 1.5 x the upper limit of normal, or creatinine clearance ≤60

2. Concomitant treatment with NSAIDS, warfarin, omeprazole, ranitidine or inducers (i.e.
rifampicin, phenytoin; carbamazepin) or inhibitors (i.e. ketoconazole, ciprofloxacin,
clarithromycin, voriconazole) of CYP3A4;

3. Inadequate liver function as defined by a serum bilirubin ≥ 1.5 x the upper limit of
normal (except in the case of confirmed moderate unconjugated hyperbilirubinemia due
to intramedullary hemolysis, as observed frequently in MDS), and/or ASAT/ALAT/GGT
levels ≥2 x the upper limit of normal;

4. Known HIV-positivity;

5. Any serious medical condition or psychiatric illness that will prevent the subject
from signing the informed consent form or will place the subject at unacceptable risk
if he or she participates in the study;

6. Vitamine B12 or folate deficiency;

7. Pregnant or lactating females;

8. Use of cytotoxic chemotherapeutic agents or experimental agents (agents that are not
commercially available) for the treatment of MDS within the 28 days preceding study

9. Prior history of malignancy other than MDS (except basal cell or squamous cell
carcinoma or carcinoma in situ of the cervix or breast), unless the subject has been
disease-free for ≥3 years;

10. Patients with a history of corneal disorders or another active ophthalmic disorder,
active infections or other concomitant serious and uncontrolled medical conditions.

11. History of interstitial lung disease or any active pulmonary disease.

12. Patients with a history of myeloproliferative syndrome or LMMC

Type of Study:


Study Design:

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

Outcome Measure:

The primary objective is to estimate the overall response rate (CR, PR, mCR The primary objective is to estimate the overall response rate (CR, PR, mCR and HI according to the IWG 2000 and 2006 criteria) in patients treated with erlotinib.

Outcome Time Frame:

After 12 weeks treatment

Safety Issue:


Principal Investigator

Sylvain Thepot, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

GFM/Hôpital Avicenne


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

Study ID:




Start Date:

February 2010

Completion Date:

September 2013

Related Keywords:

  • Myelodysplastic Syndrome
  • Erlotinib
  • myelodysplastic syndrome
  • Myelodysplastic Syndromes
  • Preleukemia