Title An open-label, Phase II Trial of Orally Administered PF-00299804 in Adult Patients with Relapsed/Recurrent Glioblastoma (GBM)
IRB DFCI 2312
Hospital Main Campus
Phase Phase 2
Disease Brain, Glioblastoma
- Assess Progression-Free Survival (PFS) at six months (PFS6m) in patients with recurrent GBM and EGFR gene amplification or activating mutation in archival tumor material who are treated with continuous daily dosing of PF-00299804 (Arm B).
- Assess the ability of PF-00299804 to cross the blood-brain-barrier (BBB) in GBM patients who are candidates for surgical re-resection (total, or sub-total) in Arm A.
- Evaluate safety and tolerability of orally administered PF-00299804 on a continuous dosing schedule in patients with recurrent GBM in all Arms.
- Document secondary measures of anti-tumor efficacy of PF-00299804 in patients with recurrent GBM in all Arms.
- Assess anti-tumor response in patients in Arm B using MacDonald criteria .
- Assess Overall Survival (OS) in patients in Arm B.
- Assess the efficacy and safety of PF-00299804 in patients with recurrent GBM who have previously been treated with bevacizumab therapy in Arm C.
- Collect sparse pharmacokinetic (PK) data for population PK in all Arms.
- Assess pharmacodynamic response to PF-00299804 in tumor tissue in patients in Arm A.
- Evaluate potential molecular determinants of response in tumor tissue to PF-00299804 in all Arms.
- Evaluate potential molecular determinants of response in circulation to PF-00299804 using tumor-derived exosome and Diagnostic Magnetic Resonance (DMR) analyses in all Arms.
- Explore patient reported outcomes (PRO) of patients in Arm B.
- Ability to understand and provide signed informed consent approved by the Institutional Review Board prior to any study-related activities and within 30 days of first study dose.
- Male or Female ≥ 18 years old
- Histologically confirmed diagnosis of a recurrent primary WHO grade IV malignant glioma (glioblastoma). Patients with recurrent disease whose diagnostic pathology confirmed glioblastoma will not need re-biopsy. Patients with prior low-grade glioma or anaplastic glioma (anaplastic astrocytoma or anaplastic oligodendroglioma) are eligible if histologic assessment demonstrates transformation to GBM.
- Evidence of either EGFR gene amplification by fluorescence in situ hybridization (FISH) or EGFR activating mutation in the most recent tumor specimen prior to enrollment. Results of EGFR gene amplification will be confirmed by Dr. John Iafrate�s laboratory at MGH post hoc. Gene amplification is defined as EGFR to Cen7 (centromere 7 copy number control) ratio of at least 2 to 1. For EGFR activating mutation, any one of the following EGFR mutations is eligible: Extracellular domain mutation: EGFRvIII, R108K, T263P, A289V, A289D, A289T, G598V; or kinase domain mutation: G719X, T790M, exon19 deletions/insertions (at/near/within codons 744-759), exon 20 insertions/deletions/mutations (insertions/deletions at or near 766-769, S768I, R776C), L858R, L861Q.
- At least 15 unstained slides or 1 tissue block (frozen or paraffin embedded) available from the most recent biopsy or surgery (archival tumor material). Exception: Arm C patients may be allowed to enroll without minimum number of requested unstained slides available, however consultation and approval by Overall PI is required.
- For Arm A, patients must be at first recurrence of GBM, must not have had previous anti-VEGF therapy, and must be candidates for surgical partial or gross-total resection.
- For Arm B, patients must be at first recurrence of GBM and must not have had prior anti-VEGF therapy.
- For Arm C, patients may have had an unlimited number of prior therapies for GBM, however must be at first recurrence from a therapeutic regimen containing bevacizumab.
- Progressive disease on contrast-enhanced brain CT or MRI as defined by MacDonald Criteria , or have documented recurrent glioblastoma on diagnostic biopsy. Patients who have been previously treated with bevacizumab therapy that have T2-weighted or FLAIR MRI sequences considered to be progressive disease by the study investigator but have no contrast-enhancing areas of recurrent disease are eligible for Arm C. Arm A patients may continue treatment in the post-operative period even if there is no residual contrast-enhancing tumor after surgery.
- Interval of at least 2 weeks from any prior neurosurgical resection (1 week for intracranial biopsy) to start of study drug; and patient must have adequate wound healing.
- Interval of at least 12 weeks from prior radiotherapy unless there is either: a) histopathologic confirmation of recurrent tumor, or b) new enhancement on MRI outside of the radiation treatment (RT) field.
- Patients must have sufficient time for recovery from prior therapy: 28 days from any investigational agent, 28 days from prior cytotoxic therapy (except 23 days from prior temozolomide, 14 days from vincristine, 42 days from nitrosoureas, 21 days from procarbazine administration), and 7 days for patients who received metronomic chemotherapy or non-cytotoxic agents, e.g., bevacizumab, interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count).
- Karnofsky Performance Score (KPS) ≥ 70%
- Adequate hematologic function: Hematocrit ≥ 29%, Leukocytes ≥ 3,000/mcL, ANC ≥ 1,500 cells/ml, platelets ≥ 100,000 cells/ml.
- Adequate liver function: Bilirubin ≤ 2 X ULN; AST (SGOT) ≤ 2.5 X ULN
- Creatinine below or within the upper institutional limit of normal or creatinine clearance ≥ 60 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal.
- The effects of PF-00299804 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence; surgical sterilization) prior to registration, through the last study dose and for at least 3 months thereafter. The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. All female patients with reproductive potential must have a negative pregnancy test (serum/urine) within 2 weeks prior to starting treatment.
- Presence of extra-cranial metastatic disease.
- Receiving any other investigational agents.
- Prior investigational therapy with an agent that is known or proposed to be active by action on any component of the EGFR tyrosine kinase, IGF1R, mTOR, or c-MET pathways.
- Patients who have been previously treated with an anti-VEGF agent will be excluded from Arm A and Arm B.
- Patients must not have received prior Gliadel wafers.
- For patients in Arm A, if the diagnostic pathology of the biopsy specimen is not consistent with recurrent glioblastoma (for example, only reactive gliosis or necrosis is detected), then the subject will be taken off study and be replaced with another subject that meets the inclusion criteria and is eligible for surgical resection.
- Major surgery (not including minor diagnostic procedures such as lymph node biopsy) within 2 weeks of start of study drug; or not fully recovered from any side effects of previous procedures.
- Any clinically significant gastrointestinal abnormalities, which may impair intake, transit or absorption of the study drug, such as the inability to take oral medication in tablet form.
- Any psychiatric or cognitive disorder that would limit the understanding or rendering of informed consent and/or compromise compliance with the requirements of this protocol.
- Known interstitial lung disease.
- Uncontrolled or significant cardiovascular disease, including:
- A myocardial infarction within 12 months of registration;
- Uncontrolled angina within 6 months of registration;
- Congestive heart failure within 6 months of registration;
- Diagnosed or suspected congenital long QT syndrome;
- Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes);
- Prolonged QTc interval on pre-entry electrocardiogram ( > 470 msec);
- Any history of second or third degree heart block (may be eligible if currently have a pacemaker);
- Heart rate < 50/minute on pre-entry electrocardiogram;
- Uncontrolled hypertension.
- History of significant cardiovascular disease, even if currently controlled, or who has signs or symptoms suggesting impaired left ventricular function in the judgment of the investigator must have a screening left ventricular ejection fraction (LVEF) evaluation by ECHO or MUGA. Patients with LVEF measurements below local institutional lower limit of normal or less than 50% will not be eligible.
- Patients with a history of a different malignancy are ineligible except for the following circumstances: if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; patients with treated cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin. Patients will not be eligible if they have evidence of other malignancy requiring therapy other than surgery within the last 3 years.
- Patients who have had prior stereotactic radiotherapy, convection enhanced delivery or brachytherapy as gliosis/scarring from these modalities may limit delivery. However, if a patient has a resection or biopsy at the site of prior stereotactic radiotherapy, convection enhanced delivery, or brachytherapy and the biopsy specimen shows recurrent GBM and EGFR amplification by FISH, the patient will be eligible. Patients with recurrence outside the radiosurgery field will be considered for eligibility if the recurrence is clearly documented to be outside the field and more than 3 months have lapsed since the last dose of radiosurgery.
- 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 but potential risk of adverse events in nursing infants secondary to treatment of the mother with PF-00299804, breastfeeding should be discontinued at least two weeks prior to the start of PF-00299804 dosing.
- HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with PF-00299804. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to PF-00299804.
- Other severe acute or chronic 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 trial results and, in the judgment of the investigator, would make the patient inappropriate for entry into this trial. Uncontrolled intercurrent illness includes, but is not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
- Prohibited Therapies and/or Medications or Diet: Medications and/or diet are prohibited if they affect oral absorption of PF-00299804 or if primarily metabolized by CYP2D6 as described below (Section 3.3). Patients must have been off treatment with these drugs for 2 weeks prior to enrollment as stated in section 3.3. Patients who otherwise are eligible can be enrolled only if drug substitution is performed with acceptable clinical outcome prior to enrollment.
- Proton pump inhibitors, such as rabeprazole, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, and pantoprazole are prohibited as these agents decrease plasma dacomitinib exposure. Short acting antacids such as Maalox Maximum Strength are allowed.