Safety and Efficacy of PF-299804 (Dacomitinib), a Pan-HER Irreversible Inhibitor, in Patients With Recurrent Glioblastoma With EGFR Amplification or Presence of EGFRvIII Mutation. A Phase II CT.

Phase II Pilot, Prospective, Open Label, Multicenter CT, to Evaluate the Safety and Efficacy of PF299804, a Pan-HER Irreversible Inhibitor, in Patients With Recurrent Glioblastoma With EGFR Amplification or Presence of EGFRvIII Mutation

This multicenter, 2-stage, open-label, phase II trial aims to assess the efficacy and safety of dacomitinib in adult patients with recurrent Glioblastoma (GBM) with EGFR gene amplification and/or EGFRvIII mutation.

Inclusion Criteria:

1. Ability to understand and sign the informed consent approved by the Ethic Committee.

2. Men or women aged greater than or equal to 18.

3. Patients with grade IV malignant glioma according to WHO classification (glioblastoma) in first relapse with histologically confirmed diagnosis by the central laboratory. Patients with previous low-grade glioma or anaplastic glioma (anaplastic astrocytoma or anaplastic oligodendroglioma), are not eligible, even if histological assessment demonstrates transformation to GBM.

4. Patients in first relapse (or progression) to chemo-radiotherapy and temozolomide-based chemotherapy (Stupp4 scheme).

5. All patients must have EGFR gene amplification by in situ hybridization fluorescent (FISH) and / or EGFRvIII mutation by PCR in tumor samples made by the central laboratory (Laboratory of Neuropathology. Hospital Universitario 12 de Octubre).

6. For all study cohorts, patients must be at least 15 unstained slides or a block of paraffin-embedded tissue available from a previous biopsy or surgery (archived tumor samples previously).

7. All patients must show progressive disease of the brain MRI is as defined in the Criteria RANO.

8. Interval of at least one week between prior intra-cranial biopsy, healed properly, and inclusion.

9. Interval of at least 12 weeks between prior radiotherapy and inclusion, unless: a) histopathologic confirmation of recurrent tumor, or b) MR recurrence outside the radiation field.

10. Patients must have recovered from previous therapy: 28 days from the completionof any investigational drug and / or the termination of any cytotoxic therapy.

11. ECOG performance status less than or equal to 2.

12. Stable or decreasing doses of corticosteroids during the five days prior to inclusion in the study.

13. Adequate bone marrow reserve, hematocrit greater than or equal to 29%, WBC> 3000 / mcl,ANC greater than or equal to 1,500 cells / ul, platelets greater than or equal a100.000 cells / ul.

14. Adequate hepatic function: bilirubin less than or equal to 1.5 times ULN, AST (SGOT) less than or equal to 2.5 x ULN.

15. Creatinine within the center ULN or creatinine clearance > 60 mL/min/1.73 m2 for subjects with creatinine levels above the center ULN.

16. The patients in whom resection was made in the first tumor recurrence are eligible in the following cases:

    • There is adequate recovery from surgery.
    • There must be measurable or evaluable disease after surgery. For an adequate Radiological evaluation of residual disease, MRI must be completed within 72 hours after surgery or 4 weeks after surgery.

17. The effects of PF-00299804 in human foetal development are unknown. For this reason, women of childbearing potential and men must agree to use effective contraception (hormonal control method, barrier, abstinence or surgical sterilization) before inclusion in the study, during participating in the study and at least 3 months after treatment has ended the trial. The definition of an effective contraceptive method is based on the criterion of the principal investigator or designee. In case of a woman become pregnant or there is suspicion that she is pregnant while participating in this study, the trial physician must inform immediately. All women of childbearing potential must have a negative pregnancy test (serum / urine) in the 2 weeks before the start of treatment. NOTE: Patients who have received treatment based on the scheme Stupp (Chemoradiotherapy with temozolomide followed by temozolomide sequential) are eligible in the trial, even if other drugs have been added to this scheme. It is excluded from this, those patients who have been treated with EGFR inhibitors for obvious reasons. However, those patients who have received Stupp scheme + other drugs like bevacizumab and cilengitide, remain eligible.

Exclusion Criteria:

1. Presence of extra-cranial metastatic disease.

2. Concomitant treatment with other investigational drugs.

3. Prior treatment with an investigational drug/s known or are suspected to be active by the action of any component of the EGFR tyrosine kinase.

4. Surgery of any kind (does not include diagnostic procedures such as minor lymph node biopsy) in the 2 weeks prior to baseline assessments of the disease, or presence of side effects of previous procedures.

5. Presence of any clinically significant gastrointestinal abnormality that can affect oral administration, transit or absorption of study drug, such as the inability to take medication by mouth as tablets.

6. Presence of any psychiatric or cognitive disorder that limits the understanding or the signature of informed consent and / or jeopardize the fulfillment of the requirements of this protocol.

7. Significant or uncontrolled cardiovascular disease, including:

   • Myocardial infarction within the previous 12 months
   • Uncontrolled angina within the previos 6 months
   • Congestive heart failure in the previous 6 months
   • Known or suspected congenital long QT syndrome
   • History of clinically significant ventricular arrhythmias of any type (as ventricular tachycardia, ventricular fibrillation or torsades de pointes)
   • QTc prolongation on electrocardiogram prior to entry (> 470 msec)
   • History of second or third grade heart block (these patients may be eligible if you currently have a pacemaker)
   • Heart rate < 50/minute in the baseline electrocardiogram
   • Uncontrolled hypertension.

8. Any patient with a history of significant cardiovascular disease, even though is currently controlled, or presents signs or symptoms suggestive of impaired left ventricular function at discretion of the investigator,should have an evaluation of LVEF in these circumstances. If the result is under the center lower limit normal or lower than 50%, the patient would not be eligible.

9. History of any cancer, except for the following circumstances:

   • Patients with a history of other malignancies are eligible if they have been free of disease for at least the last 3 years, and at the discretion of the investigator, there is low risk of disease recurrence.
   • Patients with the following cancers are eligible even if they are diagnosed and treated in the last 3 years: carcinoma in situ of the cervix and basal cell or basal cell skin carcinoma. Patients are ineligible if there is evidence of any neoplastic disease that required therapy other than surgery in the past 3 years.

10. Prior stereotactic radiotherapy or brachytherapy.

11. Intratumoral treatment with CCNU in recurrent tumor surgery (second surgery). NOTE: Patients treated with intratumoral CCNU (or what is the same (intratumor carmustine or Gliadel®), in the first intervention can participate in the study.

12. Presence of leptomeningeal dissemination.

13. Pregnant or breastfeeding. Pregnant women are excluded from this study because the potential for teratogenic or abortifacient effects of PF-00299804 is unknown. Because there is an unknown risk of potential adverse effects in infants, secondary to maternal treatment with PF-00299804, breastfeeding should be discontinued if mother is treated with PF-00299804.

14. Patients positive for HIV being treated with antiretroviral combination therapy. These patients are not eligible due to potential pharmacokinetic interactions with PF-00299804. Additionally, these subjects have an increased risk of lethal infections when treated with marrow-suppressive therapy. HIV-positive patients not on antiretroviral combination therapy, are eligible if the disease is controlled at the discretion of the investigator.

15. History of allergic reactions attributed to drugs with similar chemical or biological composition than PF-00299804.

16. Another acute or chronic serious medical condition, uncontrolled intercurrent illness or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of test results and that,investigator's discretion, make the patient inappropriate for entry into this trial. Uncontrolled intercurrent illness including, but are not limited to, ongoing or active infection or psychiatric illness / social situations that limit the compliance of study requirements.