Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Adult Grade III Meningioma, Adult Grade II Meningioma, Adult Grade I Meningioma, Recurrent Adult Brain Tumor
Conditions
Brief summary
Phase I/II trial to study the effectiveness of erlotinib in treating patients who have recurrent malignant glioma or recurrent or progressive meningioma. Erlotinib may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth.
Detailed description
OBJECTIVES: Phase 1 I. Determine the maximum tolerated dose of erlotinib in patients with recurrent malignant glioma or recurrent or progressive meningioma. II. Determine the safety profile of this drug in these patients. III. Determine the pharmacokinetics of this drug in these patients. Phase 2 I. Determine the 6-month progression-free survival (recurrent malignant glioma) II.12-month survival of patients treated with this drug (stable glioblastoma post radiation therapy) Phase 2 - Secondary Recurrent Malignant Glioma I. Objective Tumor Response rate associated with erlotinib therapy in recurrent or progressive malignant glioma. III. 12-month survival of patients treated with this drug Determine the safety profile of this drug in these patients. IV.. Determine the pharmacokinetics of this drug in these patients OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to study phase (I vs II), concurrent enzyme-inducing antiepileptic drugs (EIAEDs) (yes vs no), histology (recurrent GBM vs recurrent anaplastic glioma vs recurrent meningioma vs stable GBM), preoperative candidacy (yes vs no), and concurrent steroids (yes vs no). Phase I: Patients concurrently receiving EIAEDs receive oral erlotinib once daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of erlotinib until the maximum tolerated dose (MTD) is determined. The MTD is the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase II: Once the MTD is determined, additional patients concurrently receiving EIAEDs are treated with erlotinib as above at the phase II dose. Patients not concurrently receiving EIAEDs are treated with erlotinib as above at a predetermined dose. Patients are followed for survival.
Interventions
DRUGerlotinib hydrochloride
given orally
OTHERlaboratory biomarker analysis
correlative studies
OTHERpharmacological study
correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* One of the following diagnoses: * Histologically confirmed intracranial malignant glioma * Glioblastoma multiforme (GBM), anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligoastrocytoma, or malignant astrocytoma not otherwise specified * Original histology of low-grade glioma allowed provided a subsequent histology of malignant glioma is confirmed * Histologically or radiographically confirmed recurrent or progressive benign or malignant meningioma * Progressive disease or tumor recurrence on MRI or CT scan * Phase I: No more than 3 prior relapses and no more than 2 prior chemotherapy\* or biologic therapy regimens * Phase II: No more than 2 prior relapses and no more than 2 prior chemotherapy\* or biologic therapy regimens * Patients with progressive disease must have failed prior radiotherapy\* that was completed at least 4 weeks ago * Patients with progressive disease between 4 and 12 weeks after completion of external beam radiotherapy must have clear evidence of progression on MRI * Patients with GBM who have completed external beam radiotherapy and do not show progression are eligible * Patients with progressive disease after interstitial brachytherapy or stereotactic radiosurgery must have confirmed true progression rather than radiation necrosis based upon positron-emission tomography, thallium scanning, MRI, or surgical documentation * Measurable or evaluable disease * Performance status - Karnofsky 60-100% * More than 8 weeks * WBC at least 3,000/mm\^3 * Absolute neutrophil count at least 1,500/mm\^3 * Platelet count at least 100,000/mm\^3 * Hemoglobin at least 10 mg/dL (transfusion allowed) * Bilirubin less than 1.5 times upper limit of normal (ULN) * SGOT less than 1.5 times ULN * Creatinine less than 1.5 mg/dL * None of the following ophthalmic abnormalities: * Abnormalities of the cornea (e.g., dry eye syndrome or Sjögren's syndrome) * Congenital abnormality (e.g., Fuch's dystrophy) * Abnormal slit-lamp examination using a vital dye (e.g., fluorescein or Bengal-Rose) * Abnormal corneal sensitivity test (Schirmer test or similar tear production test) * Patients found to have dry eyes on examination but have an otherwise normal examination allowed * No active infection * No other serious concurrent medical illness * No other malignancy within the past 3 years except nonmelanoma skin cancer or carcinoma in situ of the cervix * No other disease that would obscure toxicity or dangerously alter drug metabolism * No significant medical illness that would preclude study participation * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective barrier contraception during and for 12 weeks after study participation * See Disease Characteristics * At least 1 week since prior thalidomide * At least 1 week since prior interferon * At least 4 weeks since prior SU5416 or other experimental biologic agents * See Disease Characteristics * No prior chemotherapy (including polifeprosan 20 with carmustine implant \[Gliadel wafers\]) for patients with stable GBM * At least 2 weeks since prior vincristine * At least 3 weeks since prior procarbazine * At least 6 weeks since prior nitrosoureas * At least 1 week since prior tamoxifen * See Disease Characteristics * Recovered from prior radiotherapy * No more than 6 weeks since prior external beam radiotherapy for patients with GBM without evidence of progression * Recovered from prior surgery * Recovered from prior therapy * At least 1 week since prior noncytotoxic agents (e.g., isotretinoin) except radiosensitizers * At least 4 weeks since prior cytotoxic therapy * At least 4 weeks since prior tipifarnib or imatinib mesylate * No prior erlotinib or other epidermal growth factor receptor inhibitors * No concurrent combination antiretroviral therapy for HIV-positive patients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Dose Limiting Toxicity (DLT) Each Dose Level Phase I | 28 days | DLT Definition: any grade 3 thrombocytopenia and grade 4 anemia and neutropenia; any non-hematologic grade 3 toxicity; failure to recover from toxicities to be eligible for re-treatment with erlotinib within 2 weeks of the last dose of erlotinib. |
| Define Maximum Tolerated Dose (MTD) of Erlotinib by Phase 1 Cohorts | cycle 1 - 28 days | standard 3+3 dose escalation design 3 patients in each dose level, observed for 28 days before enrollment to next level. if none of the patients experienced DLT dose escalated, if 1 of 3 experienced DLT 3 more enrolled at that level, if none of the 3 additional pts had DLT escalate to next level, if one or more of the additional pts experienced DLT, the MTD was exceeded and 3 more patients were treated at the next lower dose (if only 3 pts treated at the lower dose). The MTD is the dose at which 0/3 or 1/6 patients have experienced a DLT with the next higher dose having at least 2/3 or 2/6 patients encountering DLT. |
| 6 Months Progression-free Survival in Recurrent Malignant Gliomas (Phase II) | 6 months | Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over BL if no decrease), OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time of Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. | plasma concentrations relative to erlotiniab administration and sample time and dose level |
| Response Rate (Complete or Partial Response) Graded Using Modified RECIST Criteria Phase II | At 1 year | Measurable: Bidimensionally measurable lesions w/ clearly defined margins by MRI Evaluable: Unidimensionally measurable lesions, masses w/margins not clearly defined. Complete Response (CR): Complete disappearance of all measurable/evaluable disease. No new lesions. No evidence of non-evaluable disease. Patients on minimal/no steroids. Partial Response (PR): \>/= to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. Responders must be on same/decreasing doses of dexamethasone. Stable/No Response: Does not qualify for CR, PR, or progression. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over BL if no decrease), OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). |
| Percent of Patients With One or More Grade 3-5 Toxicity Described Based on the CTC Severity Grading Phase II | Up to 1 year | Summarized by descriptive statistics. |
| Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. One sample on day 8 cycle 1 and day 1 of cycle 2,3 and 5 | plasma concentrations relative to erlotiniab administration and sample time and dose level |
| Estimation of the Area Under the Curve Per Dose Level Phase I (on Anticonvulsants) - | baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. One sample on day 8 cycle 1 and day 1 of cycle 2,3 and 5 | plasma concentrations relative to erlotiniab administration and sample time and dose level |
| Trough Level Per Dose Level Phase I (on Anticonvulsants) - | cycle 1 day eight | plasma concentrations relative to erlotiniab administration and sample time and dose level |
| Percent of Participants With a Grade 3 or 4 Adverse Events Phase 1 | 1 year | CTCAE |
| Time to Peak Plasma Concentration for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg - | baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. One sample on day 8 cycle 1 and day 1 of cycle 2,3 and 5 | plasma concentrations relative to erlotiniab administration and sample time and dose level |
| Estimation of Area Under the Curve for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg- | baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. One sample on day 8 cycle 1 and day 1 of cycle 2,3 and 5 | plasma concentrations relative to erlotiniab administration and sample time and dose level |
| Trough Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg - | One sample on day 8 cycle 1 | plasma concentrations relative to erlotiniab administration and sample time and dose level |
| Pharmacokinetics (Plasma) Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs | Pre-surgery and time of resection | Drug administered 6 days prior to surgery |
| Pharmacokinetics (Tissue) Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs | Pre-surgery and time of resection | Drug administered 6 days prior to surgery |
| Peak Plasma Concentration Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg - | baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. One sample on day 8 cycle 1 and day 1 of cycle 2,3 and 5 | plasma concentrations relative to erlotiniab administration and sample time and dose level |
| 1 Year Survival - Phase II Newly Diagnosed GBM Post RT | At 1 year | 12 month survival for newly diagnosed stable GBM post RT treated with erlotinib post RT |
| Overall Survival Newly Diagnosed GBM Post RT | 2 years | Overall Survival defined as Time from Start of treatment to time of death due to any cause |
Countries
United States
Participant flow
Recruitment details
Subjects enrolled between August 15, 2002 and August 18, 2005. Patient recruited from outpatient oncology centers.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 Dose Escalation Phase I: Patients concurrently receiving EIAEDs receive oral erlotinib once daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of erlotinib until the maximum tolerated dose (MTD) is determined. The MTD is the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
erlotinib hydrochloride given orally
Other: pharmacological study, laboratory biomarker analysis. | 32 |
| Phase 2 w/ Recurrent Malignant Glioma Phase II: Patients not concurrently receiving EIAEDs are treated with erlotinib at a predetermined dose (150mg/day).
Patients requiring surgery were treated 7 days prior to tumor removal PK analysis and effects of erlotinib on epidermal growth factor receptor (EGFR) erlotinib hydrochloride given orally
Other: pharmacological study, laboratory biomarker analysis | 59 |
| Phase 2 Newly Diagnosed GBM Post RT Phase II: Patients not concurrently receiving EIAEDs are treated with erlotinib as above at a predetermined dose. (150mg/day)
erlotinib hydrochloride given orally
Other: pharmacological study, laboratory biomarker analysis | 45 |
| Total | 136 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 100mg Phase 1 Dose Escalalation | did not initiate treatment | 0 | 2 | 1 |
| 100mg Phase 1 Dose Escalalation | ineligible histology | 0 | 0 | 1 |
| 100mg Phase 1 Dose Escalalation | prior treatment history | 0 | 4 | 0 |
Baseline characteristics
| Characteristic | Phase 1 Dose Escalation | Phase 2 w/ Recurrent Malignant Glioma | Phase 2 Newly Diagnosed GBM Post RT | Total |
|---|---|---|---|---|
| Age, Continuous | 45 years | 54 years | 52 years | 52 years |
| Histology Anaplastic Astrocytoma | 8 participants | 14 participants | 1 participants | 23 participants |
| Histology Anaplastic oligodendroglioma | 2 participants | 1 participants | 0 participants | 3 participants |
| Histology Atypical meningioma | 1 participants | 0 participants | 0 participants | 1 participants |
| Histology Glioblastoma | 21 participants | 42 participants | 44 participants | 107 participants |
| Histology Oligodendroglioma | 0 participants | 1 participants | 0 participants | 1 participants |
| Histology Pleomorphic Xanthoastrocytoma | 0 participants | 1 participants | 0 participants | 1 participants |
| Karnofsky Performance Status Scale | 90 units on a scale | 80 units on a scale | 90 units on a scale | 80 units on a scale |
| Prior Number of Chemotherapy Regimens 0 treatments | 3 participants | 4 participants | 0 participants | 7 participants |
| Prior Number of Chemotherapy Regimens 1 treatment | 13 participants | 31 participants | 45 participants | 89 participants |
| Prior Number of Chemotherapy Regimens 2 treatments | 14 participants | 21 participants | 0 participants | 35 participants |
| Prior Number of Chemotherapy Regimens 3 treatments | 2 participants | 3 participants | 0 participants | 5 participants |
| Prior Radiation Treatment No | 0 participants | 4 participants | 0 participants | 4 participants |
| Prior Radiation Treatment Yes | 32 participants | 55 participants | 45 participants | 132 participants |
| Sex: Female, Male Female | 12 Participants | 25 Participants | 10 Participants | 47 Participants |
| Sex: Female, Male Male | 20 Participants | 34 Participants | 35 Participants | 89 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 32 | 11 / 99 |
| serious Total, serious adverse events | 0 / 32 | 2 / 99 |
Outcome results
Primary
6 Months Progression-free Survival in Recurrent Malignant Gliomas (Phase II)
Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over BL if no decrease), OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time frame: 6 months
Population: 38 Glioblastoma, 15 anaplastic gliomas not receiving Enzyme-inducing Antiepileptic Drugs
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1 Dose Escalation | 6 Months Progression-free Survival in Recurrent Malignant Gliomas (Phase II) | Recurrent GBM | 2 Participants |
| Phase 1 Dose Escalation | 6 Months Progression-free Survival in Recurrent Malignant Gliomas (Phase II) | Recurrent Anaplastic Glioma | 14 Participants |
Primary
Define Maximum Tolerated Dose (MTD) of Erlotinib by Phase 1 Cohorts
standard 3+3 dose escalation design 3 patients in each dose level, observed for 28 days before enrollment to next level. if none of the patients experienced DLT dose escalated, if 1 of 3 experienced DLT 3 more enrolled at that level, if none of the 3 additional pts had DLT escalate to next level, if one or more of the additional pts experienced DLT, the MTD was exceeded and 3 more patients were treated at the next lower dose (if only 3 pts treated at the lower dose). The MTD is the dose at which 0/3 or 1/6 patients have experienced a DLT with the next higher dose having at least 2/3 or 2/6 patients encountering DLT.
Time frame: cycle 1 - 28 days
Population: Cohorts/dose levels: 150mg; 200mg; 275mg; 400mg; 525mg; 650mg; 775mg patients on Enzyme-inducing Antiepileptic Drugs
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Dose Escalation | Define Maximum Tolerated Dose (MTD) of Erlotinib by Phase 1 Cohorts | 650 mg |
Primary
Number of Dose Limiting Toxicity (DLT) Each Dose Level Phase I
DLT Definition: any grade 3 thrombocytopenia and grade 4 anemia and neutropenia; any non-hematologic grade 3 toxicity; failure to recover from toxicities to be eligible for re-treatment with erlotinib within 2 weeks of the last dose of erlotinib.
Time frame: 28 days
Population: Patients were eligible if they had recurrent disease or if they were newly diagnosed post RT and did NOT have tumor progression (nonprogression glioblastoma) on Enzyme-inducing Antiepileptic Drugs
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 Dose Escalation | Number of Dose Limiting Toxicity (DLT) Each Dose Level Phase I | Dose 150mg (Rash) | 1 dose limiting toxicities |
| Phase 1 Dose Escalation | Number of Dose Limiting Toxicity (DLT) Each Dose Level Phase I | Dose 200mg | 0 dose limiting toxicities |
| Phase 1 Dose Escalation | Number of Dose Limiting Toxicity (DLT) Each Dose Level Phase I | Dose 275mg | 0 dose limiting toxicities |
| Phase 1 Dose Escalation | Number of Dose Limiting Toxicity (DLT) Each Dose Level Phase I | Dose 400mg | 0 dose limiting toxicities |
| Phase 1 Dose Escalation | Number of Dose Limiting Toxicity (DLT) Each Dose Level Phase I | Dose 525mg | 0 dose limiting toxicities |
| Phase 1 Dose Escalation | Number of Dose Limiting Toxicity (DLT) Each Dose Level Phase I | Dose 650mg (DVT/PE) | 1 dose limiting toxicities |
| Phase 1 Dose Escalation | Number of Dose Limiting Toxicity (DLT) Each Dose Level Phase I | Dose 775mg (Rash [2]) | 2 dose limiting toxicities |
Secondary
1 Year Survival - Phase II Newly Diagnosed GBM Post RT
12 month survival for newly diagnosed stable GBM post RT treated with erlotinib post RT
Time frame: At 1 year
Population: not receiving Enzyme-inducing Antiepileptic Drugs; stable glioblastoma after RT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Dose Escalation | 1 Year Survival - Phase II Newly Diagnosed GBM Post RT | 57 % of participants |
Secondary
Estimation of Area Under the Curve for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg-
plasma concentrations relative to erlotiniab administration and sample time and dose level
Time frame: baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. One sample on day 8 cycle 1 and day 1 of cycle 2,3 and 5
Population: AUC=area under the curve;
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Dose Escalation | Estimation of Area Under the Curve for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg- | 11.86 ug * h/mL | Standard Deviation 5.01 |
Secondary
Estimation of the Area Under the Curve Per Dose Level Phase I (on Anticonvulsants) -
plasma concentrations relative to erlotiniab administration and sample time and dose level
Time frame: baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. One sample on day 8 cycle 1 and day 1 of cycle 2,3 and 5
Population: AUC=area under the curve
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Dose Escalation | Estimation of the Area Under the Curve Per Dose Level Phase I (on Anticonvulsants) - | 5.33 ug* h/mL | Standard Deviation 2.04 |
| Phase 1 Dose Escalation - 200 mg | Estimation of the Area Under the Curve Per Dose Level Phase I (on Anticonvulsants) - | 7.28 ug* h/mL | Standard Deviation 2.54 |
| Phase 1 Dose Escalation - 275 mg | Estimation of the Area Under the Curve Per Dose Level Phase I (on Anticonvulsants) - | 13.58 ug* h/mL | Standard Deviation 2.99 |
| Phase 1 Dose Escalation - 400 mg | Estimation of the Area Under the Curve Per Dose Level Phase I (on Anticonvulsants) - | 21.09 ug* h/mL | Standard Deviation 0 |
| Phase 1 Dose Escalation - 525 mg | Estimation of the Area Under the Curve Per Dose Level Phase I (on Anticonvulsants) - | 25.94 ug* h/mL | Standard Deviation 21.6 |
| Phase 1 Dose Escalation - 650 mg | Estimation of the Area Under the Curve Per Dose Level Phase I (on Anticonvulsants) - | 15.77 ug* h/mL | Standard Deviation 7.43 |
| Phase 1 Dose Escalation - 775 mg | Estimation of the Area Under the Curve Per Dose Level Phase I (on Anticonvulsants) - | 18.83 ug* h/mL | Standard Deviation 11.9 |
Secondary
Overall Survival Newly Diagnosed GBM Post RT
Overall Survival defined as Time from Start of treatment to time of death due to any cause
Time frame: 2 years
Population: not receiving Enzyme-inducing Antiepileptic Drugs, glioblastoma stable after RT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Dose Escalation | Overall Survival Newly Diagnosed GBM Post RT | 14 months |
Secondary
Peak Plasma Concentration Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg -
plasma concentrations relative to erlotiniab administration and sample time and dose level
Time frame: baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. One sample on day 8 cycle 1 and day 1 of cycle 2,3 and 5
Population: Cpmax =peak plasma concentration;
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Dose Escalation | Peak Plasma Concentration Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg - | 872 ng/mL | Standard Deviation 399 |
Secondary
Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) -
plasma concentrations relative to erlotiniab administration and sample time and dose level
Time frame: baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. One sample on day 8 cycle 1 and day 1 of cycle 2,3 and 5
Population: Cp=peak plasma concentration;
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Dose Escalation | Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | 603 ng/mL | Standard Deviation 160 |
| Phase 1 Dose Escalation - 200 mg | Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | 722 ng/mL | Standard Deviation 186 |
| Phase 1 Dose Escalation - 275 mg | Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | 1075 ng/mL | Standard Deviation 308 |
| Phase 1 Dose Escalation - 400 mg | Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | 487 ng/mL | Standard Deviation 0 |
| Phase 1 Dose Escalation - 525 mg | Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | 2327 ng/mL | Standard Deviation 1609 |
| Phase 1 Dose Escalation - 650 mg | Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | 1351 ng/mL | Standard Deviation 441 |
| Phase 1 Dose Escalation - 775 mg | Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | 2009 ng/mL | Standard Deviation 1133 |
Secondary
Percent of Participants With a Grade 3 or 4 Adverse Events Phase 1
CTCAE
Time frame: 1 year
Population: During Cycle 1 only grade 3 severity; patients on Enzyme-inducing Antiepileptic Drugs
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Dose Escalation | Percent of Participants With a Grade 3 or 4 Adverse Events Phase 1 | 4 Participants |
Secondary
Percent of Patients With One or More Grade 3-5 Toxicity Described Based on the CTC Severity Grading Phase II
Summarized by descriptive statistics.
Time frame: Up to 1 year
Population: drug related events grade 3-5 CTCAE. 5 patients were not evaluable for response/toxicity.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Dose Escalation | Percent of Patients With One or More Grade 3-5 Toxicity Described Based on the CTC Severity Grading Phase II | 29 percent of participants |
Secondary
Pharmacokinetics (Plasma) Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs
Drug administered 6 days prior to surgery
Time frame: Pre-surgery and time of resection
Population: sample 5 and 6 suspected of contamination with blood clot
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Dose Escalation | Pharmacokinetics (Plasma) Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs | 761 plasma concentration ng/mL | Standard Deviation 499 |
Secondary
Pharmacokinetics (Tissue) Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs
Drug administered 6 days prior to surgery
Time frame: Pre-surgery and time of resection
Population: sample 5 and 6 suspected of contamination with blood clot tumor/tissue concentration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Dose Escalation | Pharmacokinetics (Tissue) Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs | 497 tumor/tissue concentration ng/g dry weig | Standard Deviation 353 |
Secondary
Response Rate (Complete or Partial Response) Graded Using Modified RECIST Criteria Phase II
Measurable: Bidimensionally measurable lesions w/ clearly defined margins by MRI Evaluable: Unidimensionally measurable lesions, masses w/margins not clearly defined. Complete Response (CR): Complete disappearance of all measurable/evaluable disease. No new lesions. No evidence of non-evaluable disease. Patients on minimal/no steroids. Partial Response (PR): \>/= to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. Responders must be on same/decreasing doses of dexamethasone. Stable/No Response: Does not qualify for CR, PR, or progression. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over BL if no decrease), OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time frame: At 1 year
Population: recurrent malignant gliomas - anaplastic and glioblastoma
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 Dose Escalation | Response Rate (Complete or Partial Response) Graded Using Modified RECIST Criteria Phase II | complete response | 1 participants |
| Phase 1 Dose Escalation | Response Rate (Complete or Partial Response) Graded Using Modified RECIST Criteria Phase II | Partial response | 1 participants |
| Phase 1 Dose Escalation | Response Rate (Complete or Partial Response) Graded Using Modified RECIST Criteria Phase II | stable disease | 5 participants |
| Phase 1 Dose Escalation | Response Rate (Complete or Partial Response) Graded Using Modified RECIST Criteria Phase II | Progression | 41 participants |
Secondary
Time of Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) -
plasma concentrations relative to erlotiniab administration and sample time and dose level
Time frame: baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1.
Population: tmax=time of peak plasma concentration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Dose Escalation | Time of Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | 2.3 h | Standard Deviation 1.37 |
| Phase 1 Dose Escalation - 200 mg | Time of Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | 2.8 h | Standard Deviation 2.2 |
| Phase 1 Dose Escalation - 275 mg | Time of Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | 3.3 h | Standard Deviation 1.2 |
| Phase 1 Dose Escalation - 400 mg | Time of Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | 6 h | Standard Deviation 0 |
| Phase 1 Dose Escalation - 525 mg | Time of Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | 3.5 h | Standard Deviation 3.54 |
| Phase 1 Dose Escalation - 650 mg | Time of Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | 2.2 h | Standard Deviation 0.98 |
| Phase 1 Dose Escalation - 775 mg | Time of Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | 2.4 h | Standard Deviation 2.07 |
Secondary
Time to Peak Plasma Concentration for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg -
plasma concentrations relative to erlotiniab administration and sample time and dose level
Time frame: baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. One sample on day 8 cycle 1 and day 1 of cycle 2,3 and 5
Population: tmax=time to peak plasma concentration;
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Dose Escalation | Time to Peak Plasma Concentration for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg - | 3.0 h | Standard Deviation 1.91 |
Secondary
Trough Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg -
plasma concentrations relative to erlotiniab administration and sample time and dose level
Time frame: One sample on day 8 cycle 1
Population: Cp=peak plasma concentration; tmax=time to Cp; AUC=area under the curve;
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Dose Escalation | Trough Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg - | 975 ng/mL | Standard Deviation 535 |
Secondary
Trough Level Per Dose Level Phase I (on Anticonvulsants) -
plasma concentrations relative to erlotiniab administration and sample time and dose level
Time frame: cycle 1 day eight
Population: trough level
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Dose Escalation | Trough Level Per Dose Level Phase I (on Anticonvulsants) - | 412 ng/mL | Standard Deviation 430 |
| Phase 1 Dose Escalation - 200 mg | Trough Level Per Dose Level Phase I (on Anticonvulsants) - | 227 ng/mL | Standard Deviation 82 |
| Phase 1 Dose Escalation - 275 mg | Trough Level Per Dose Level Phase I (on Anticonvulsants) - | 821 ng/mL | Standard Deviation 154 |
| Phase 1 Dose Escalation - 400 mg | Trough Level Per Dose Level Phase I (on Anticonvulsants) - | 634 ng/mL | Standard Deviation 0 |
| Phase 1 Dose Escalation - 525 mg | Trough Level Per Dose Level Phase I (on Anticonvulsants) - | 1356 ng/mL | Standard Deviation 132 |
| Phase 1 Dose Escalation - 650 mg | Trough Level Per Dose Level Phase I (on Anticonvulsants) - | 591 ng/mL | Standard Deviation 574 |
| Phase 1 Dose Escalation - 775 mg | Trough Level Per Dose Level Phase I (on Anticonvulsants) - | 942 ng/mL | Standard Deviation 775 |