Recurrent Glioblastoma
Conditions
Keywords
Glioblastoma, brain cancer
Brief summary
The objective of this study is to evaluate the response of subjects with recurrent glioblastoma to continuous therapy of PLX3397.
Interventions
DRUGPLX3397
Capsules administered once or twice daily, continuous dosing
Sponsors
Plexxikon
Daiichi Sankyo
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients ≥18 years old with a life expectancy of at least 8 weeks * Radiographically proven recurrent (≥ first relapse), intracranial Glioblastoma (GBM) * For all patients, availability of at least 10 unstained slides (or archival tumor block sufficient to generate at least 10 unstained slides) from any previous GBM surgery * Previous treatment with external beam radiation and temozolomide chemotherapy * Before the first dose of PLX3397,adequate recovery from toxicity of prior therapy as follows: \>28 days for cytotoxic therapy \>42 days for nitrosoureas \>28 days for bevacizumab \>7 days for non cytotoxic therapy such as interferon, tamoxifen, thalidomide, cis-retinoic acid, or erlotinib * Women of child-bearing potential must have a negative pregnancy test within 7 days of initiation of dosing and must agree to use an acceptable method of birth control while on study drug and for 3 months after the last dose. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year. Men of child-bearing potential must also agree to use an acceptable method of birth control while on study drug. * Karnofsky performance status of ≥60 * Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥1.0 x 109/L, Hgb \>9 g/dL, platelet count ≥50 x 109/L, Aspartate aminotransferase/Alanine aminotransferase (AST/ALT) ≤2.5x Upper Limit of Normal (ULN), creatinine ≤1.5x ULN) * Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements
Exclusion criteria
* Investigational drug use within 28 days of the first dose of PLX3397 * GBM progression within 3 months of previous radiation by Response Assessment in Neuro-Oncology (RANO) criteria * History of Grade 2 Common Toxicity Criteria for Adverse Events (CTCAE v4) or greater acute intracranial hemorrhage * Previous failure of bevacizumab or other vascular endothelial growth factor (VEGF) therapy except in a first line setting * History of malignant glioma with co-deletion of 1p/19q * A concurrent active cancer that requires non-surgical therapy (e.g. chemotherapy, radiation, adjuvant therapy). Prior history of other cancer is allowed, as long as there was no active disease within the prior 3 years. * Refractory nausea and vomiting, malabsorption, biliary shunt, or significant bowel resection that would preclude adequate absorption * Patients with serious illnesses, uncontrolled infection, medical conditions, or other medical history including abnormal laboratory results, which in the investigator's opinion would be likely to interfere with a patient's participation in the study, or with the interpretation of the results * Women of child-bearing potential who are pregnant or breast feeding * corrected QT interval (QTc) ≥450 msec at Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Response Rates in Participants on Treatment With PLX3397 | 6 months post dose | Response to treatment was evaluated using the Response Assessment in Neuro-Oncology (RANO) criteria. All participants were evaluated for progression free survival (PFS), and overall survival (OS). The six-month PFS rate was defined as the number of subjects with PFS of at least 6-month duration, with PFS measured from the first day of treatment (Cycle 1, Day 1) to the date of the first documented disease progression or date of death, whichever occurs first, over a 6-month period and evaluated using the Kaplan Meier method. The rate of OS was defined as the number of subjects that survived until study exit. |
| Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15 | Pre-dose and up to 6 post dose during cycle 1, Day 15 | A noncompartmental method of analysis was used to analyze the plasma concentrations of PLX3397. Mean plasma pharmacokinetic parameters, include time to maximum concentration (Tmax) and will be calculated from the Cycle 1, Day 15 values. |
Secondary
| Measure | Time frame |
|---|---|
| Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Up to 1 year post dose |
Countries
United States
Participant flow
Recruitment details
A total of 38 participants who met all inclusion and none of the exclusion criteria were enrolled and received the study drug.
Pre-assignment details
Enrollment planned to include approximately 40 participants (10 in Cohort 1 and 30 in Cohort 2) recruited from approximately 6 clinic sites.
Participants by arm
| Arm | Count |
|---|---|
| PLX3397 - Cohort 1 (Surgical) Participants with recurrent glioblastoma who required reoperation were treated with PLX3397 for 7 days prior to surgery. | 14 |
| PLX3397 - Cohort 2 (Non-surgical) Participants with recurrent glioblastoma who received PLX3397 continuously on 28 day cycles. | 24 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Disease progression | 13 | 22 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | PLX3397 - Cohort 1 (Surgical) | Total | PLX3397 - Cohort 2 (Non-surgical) |
|---|---|---|---|
| Age, Continuous | 56.1 years STANDARD_DEVIATION 8.6 | 54.8 years STANDARD_DEVIATION 10.6 | 54.1 years STANDARD_DEVIATION 11.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 35 Participants | 21 Participants |
| Region of Enrollment United States | 14 participants | 38 participants | 24 participants |
| Sex: Female, Male Female | 6 Participants | 13 Participants | 7 Participants |
| Sex: Female, Male Male | 8 Participants | 25 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 1 / 24 |
| other Total, other adverse events | 14 / 14 | 22 / 24 |
| serious Total, serious adverse events | 8 / 14 | 11 / 24 |
Outcome results
Primary
Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15
A noncompartmental method of analysis was used to analyze the plasma concentrations of PLX3397. Mean plasma pharmacokinetic parameters, include time to maximum concentration (Tmax) and will be calculated from the Cycle 1, Day 15 values.
Time frame: Pre-dose and up to 6 post dose during cycle 1, Day 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Surgical Cohort 1 (N=14) | Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15 | 2.09 hours | Standard Deviation 1.04 |
| Non-Surgical Cohort 2 (N=24) | Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15 | 1.71 hours | Standard Deviation 0.9 |
Primary
Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15
A noncompartmental method of analysis was used to analyze the plasma concentrations of PLX3397. Mean plasma pharmacokinetic parameters include maximum concentration (Cmax) and will be calculated from the Cycle 1, Day 15 values.
Time frame: Pre-dose and up to 6 post dose during cycle 1, Day 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Surgical Cohort 1 (N=14) | Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15 | 7760 ng/mL | Standard Deviation 2330 |
| Non-Surgical Cohort 2 (N=24) | Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15 | 8030 ng/mL | Standard Deviation 2790 |
Primary
Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15
A noncompartmental method of analysis was used to analyze the plasma concentrations of PLX3397. Mean plasma pharmacokinetic parameters include an assessment of area under the curve over 0-4 hours (AUC0-4), and will be calculated from the Cycle 1, Day 15 values.
Time frame: Pre-dose and up to 6 post dose during cycle 1, Day 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Surgical Cohort 1 (N=14) | Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15 | 24900 hr*ng/mL | Standard Deviation 6700 |
| Non-Surgical Cohort 2 (N=24) | Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15 | 26100 hr*ng/mL | Standard Deviation 9260 |
Primary
Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15
A noncompartmental method of analysis was used to analyze the plasma concentrations of PLX3397. Mean plasma pharmacokinetic parameters include an assessment of area under the curve over 0-6 hours (AUC0-6), and will be calculated from the Cycle 1, Day 15 values.
Time frame: Pre-dose and up to 6 post dose during cycle 1, Day 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Surgical Cohort 1 (N=14) | Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15 | 36100 hr*ng/mL | Standard Deviation 10000 |
| Non-Surgical Cohort 2 (N=24) | Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15 | 36900 hr*ng/mL | Standard Deviation 12200 |
Primary
Summary of Response Rates in Participants on Treatment With PLX3397
Response to treatment was evaluated using the Response Assessment in Neuro-Oncology (RANO) criteria. All participants were evaluated for progression free survival (PFS), and overall survival (OS). The six-month PFS rate was defined as the number of subjects with PFS of at least 6-month duration, with PFS measured from the first day of treatment (Cycle 1, Day 1) to the date of the first documented disease progression or date of death, whichever occurs first, over a 6-month period and evaluated using the Kaplan Meier method. The rate of OS was defined as the number of subjects that survived until study exit.
Time frame: 6 months post dose
Population: Response rates were assessed in the modified intent-to-treat population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Surgical Cohort 1 (N=14) | Summary of Response Rates in Participants on Treatment With PLX3397 | Six-month PFS rate | 1 Participants |
| Surgical Cohort 1 (N=14) | Summary of Response Rates in Participants on Treatment With PLX3397 | Overall survival | 10 Participants |
| Surgical Cohort 1 (N=14) | Summary of Response Rates in Participants on Treatment With PLX3397 | Complete response rate | 0 Participants |
| Surgical Cohort 1 (N=14) | Summary of Response Rates in Participants on Treatment With PLX3397 | Stable disease rate | 3 Participants |
| Surgical Cohort 1 (N=14) | Summary of Response Rates in Participants on Treatment With PLX3397 | Partial response rate | 0 Participants |
| Surgical Cohort 1 (N=14) | Summary of Response Rates in Participants on Treatment With PLX3397 | Progressive disease rate | 10 Participants |
| Surgical Cohort 1 (N=14) | Summary of Response Rates in Participants on Treatment With PLX3397 | Not Evaluable | 1 Participants |
| Non-Surgical Cohort 2 (N=24) | Summary of Response Rates in Participants on Treatment With PLX3397 | Progressive disease rate | 18 Participants |
| Non-Surgical Cohort 2 (N=24) | Summary of Response Rates in Participants on Treatment With PLX3397 | Six-month PFS rate | 2 Participants |
| Non-Surgical Cohort 2 (N=24) | Summary of Response Rates in Participants on Treatment With PLX3397 | Partial response rate | 0 Participants |
| Non-Surgical Cohort 2 (N=24) | Summary of Response Rates in Participants on Treatment With PLX3397 | Overall survival | 21 Participants |
| Non-Surgical Cohort 2 (N=24) | Summary of Response Rates in Participants on Treatment With PLX3397 | Stable disease rate | 4 Participants |
| Non-Surgical Cohort 2 (N=24) | Summary of Response Rates in Participants on Treatment With PLX3397 | Complete response rate | 0 Participants |
| Non-Surgical Cohort 2 (N=24) | Summary of Response Rates in Participants on Treatment With PLX3397 | Not Evaluable | 2 Participants |
Secondary
Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population)
Time frame: Up to 1 year post dose
Population: Safety events were assessed in the Safety Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Any Event | 12 Participants |
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Headache | 1 Participants |
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Hair color changes | 2 Participants |
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Pyrexia | 2 Participants |
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Dry Mouth | 2 Participants |
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Constipation | 3 Participants |
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Rash | 2 Participants |
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Aspartate aminotransferase increased | 3 Participants |
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Neutropenia | 0 Participants |
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Fatigue | 6 Participants |
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Lymphopenia | 2 Participants |
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Alanine aminotransferase increased | 2 Participants |
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Blood Lactate Dehydrogenase Increased | 2 Participants |
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Nausea | 1 Participants |
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Hypertension | 2 Participants |
| Surgical Cohort 1 (N=14) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Decreased appetite | 3 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Hypertension | 0 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Any Event | 22 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Fatigue | 14 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Constipation | 1 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Nausea | 3 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Hair color changes | 4 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Aspartate aminotransferase increased | 3 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Alanine aminotransferase increased | 3 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Decreased appetite | 3 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Headache | 3 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Dry Mouth | 0 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Rash | 1 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Neutropenia | 3 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Lymphopenia | 0 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Blood Lactate Dehydrogenase Increased | 1 Participants |
| Non-Surgical Cohort 2 (N=24) | Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) | Pyrexia | 1 Participants |