Erlotinib in Higher Risk Myelodysplastic Syndrome

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

The aim of this study is to evaluate the toxicity and therapeutic efficacy of erlotinib in high-risk myelodysplastic syndrome (MDS) patients (with at least 10% of bone marrow blasts) ineligible for or having failed intensive chemotherapy and ineligible or after failure of treatment with a hypomethylating agent.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndrome
• Intervention / Treatment: Drug: Erlotinib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Angers, France, 49033
    • CHU d'Angers
  • Bobigny, France, 93009
    • hopital Avicenne
  • Le Mans cedex, France, 72037
    • Centre Hospitalier du Mans
  • Lille, France, 59037
    • CHRU Huriez
  • Limoges, France, 87046
    • CHRU de Limoges
  • Lyon, France, 69495
    • Centre Hospitalier Lyon Sud
  • Marseille, France, 13273
    • Institut Paoli-Calmettes
  • Nantes, France, 44093
    • CHU Nantes
  • Nimes, France, 30029
    • CHU Carémeau
  • Paris, France, 75679
    • Hopital Cochin
  • Paris, France, 75475
    • Hopital St Louis
  • Toulouse, France
    • Hopital Purpan
  • Toulouse, France, 31059
    • Hopital Purpan-Medecine interne
  • Villejuif, France, 94805
    • Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 mL/min.
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 entry;
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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; The first cohort of 5 patients will start with a dosage of 100 mg erlotinib daily	Drug: Erlotinib; Erlotinib oral capsule, 100, 150, or 300 mg/day during 12 weeks at study start; Other Names: OSI-774
Experimental: Cohort 2; The second cohort of patients will receive 150 mg of erlotinib daily	Drug: Erlotinib; Erlotinib oral capsule, 100, 150, or 300 mg/day during 12 weeks at study start; Other Names: OSI-774
Experimental: Cohort 3; The third cohort of five patients will be enrolled to receive 300 mg of erlotinib daily	Drug: Erlotinib; Erlotinib oral capsule, 100, 150, or 300 mg/day during 12 weeks at study start; Other Names: OSI-774

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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.	After 12 weeks treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
·assessment of response duration	While patient is on study/during follow-up.
· survival	While patient is on study/during follow-up.
· treatment-related toxicity;	While patient is on study/during follow-up.
· correlation of prognostic parameters, response and survival, with the assessed biological parameters;	While patient is on study/during follow-up.

Collaborators and Investigators

• Sponsor: Groupe Francophone des Myelodysplasies
• Collaborators: Roche Pharma AG
• Investigators: Principal Investigator: Sylvain Thepot, MD, GFM/Hôpital Angers; Principal Investigator: Lionel Ades, MD, GFM/Hôpital Saint Louis

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: March 11, 2010
• First Submitted That Met QC Criteria: March 11, 2010
• First Posted (Estimate): March 12, 2010

Study Record Updates

• Last Update Posted (Estimate): November 8, 2016
• Last Update Submitted That Met QC Criteria: November 7, 2016
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: Erlotinib; myelodysplastic syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride
• Other Study ID Numbers: GFM-ERLOTINIB-08

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO