Glioblastoma
Conditions
Keywords
bosutinib, SKI-606
Brief summary
For many brain tumors, one reason that chemotherapy drugs might not be effective is that the drug may not be able to get into the brain tumor and kill the cancer cells. The brain is protected by a layer called the blood brain barrier. This barrier prevents substances from entering. The purpose of this research study is to determine if bosutinib can get past the blood brain barrier and into the brain tumor, and to see how well bosutinib works in killing cancer cells.
Detailed description
\- Arm A: Participants will receive daily doses of bosutinib orally for 7-9 days prior to surgery. On the day of the scheduled surgery (either craniotomy or surgical resection as planned by the treating doctor), participants will take the bosutinib within 6-12 hours of the surgery. During the surgery, tissue samples of the tumor will be collected to test the levels of bosutinib in the brain. A contrast-enhanced MRI or CT scan will be done within days after the surgery. Daily dosing of bosutinib will resume after a recovery period of 10 days. From then on, the study will be divided into 28-day cycles. The following tests/procedures will be performed regularly during cycles of study treatment: medical history; physical exam; blood tests; contrast-enhanced CT or MRI scans (even numbered cycles only). * Arm B: Participants will receive daily doses of bosutinib. The study is divided int 28-day cycles. There are no breaks from taking bosutinib between treatment cycles. The following tests/procedures will be performed regularly during cycles of study treatment: medical history; physical exam; blood tests; contrast-enhanced CT or MRI scans (even numbered cycles only). * Participants may continue to receive daily bosutinib until their disease worsens, they experience unmanageable side-effects, or they decide to stop treatment.
Interventions
DRUGbosutinib
Taken orally
Sponsors
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Pfizer
Massachusetts General Hospital
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
* 18 years of age or older * Histologically confirmed WHO (World Health Organization) grade IV astrocytoma (glioblastoma). Patients with recurrent disease whose original pathology confirmed glioblastoma will not need re-biopsy. Patients with prior low-grade glioma or anaplastic glioma are eligible if histological assessment demonstrates transformation to GBM. * The first-line regimen must have included, at a minimum, temozolomide and radiation. * First or second episode of progressive disease. * No more than two prior treatment regimens for progressive disease. Concurrent temozolomide and radiation followed by monthly cycles of temozolomide is counted as one regimen. * For all study arms, patients must have at least 15 unstained slides or 1 tissue block available from a prior biopsy or surgery. * All patients must have progressive disease on contrast-enhanced brain CT or MRI as defined by MacDonald Criteria, or have documented recurrent glioblastoma on diagnostic biopsy. Arm A patients may continue treatment in the post-operative period even if there is no residual contrast-enhancing tumor after surgery. * For Arm A, patients must be candidates for surgical partial or gross-total resection. * Interval of at least 2 weeks between prior surgical resection and adequate wound healing. * Interval of at least 12 weeks from prior radiotherapy unless there is either a) histopathologic confirmation of recurrent tumor; b) new enhancement on MRI outside of the XRT (external beam radiation therapy) treatment field. * Patients must have sufficient time for recovery from prior therapy * Karnofsky Performance Status of 60% or greater * Laboratory levels as outlined in the protocol * Women of child-bearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation and for 3 months thereafter.
Exclusion criteria
* Participants may not be receiving any other investigational agents * Previously treated with an anti-VEGF (anti-vascular endothelial growth factor) agent * For subjects in Arm A: if the diagnostic pathology of the biopsy specimen is not consistent with recurrent glioblastoma 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 * Any surgery within 2 weeks of baseline disease assessments, 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 medications 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 * Concomitant use of CYP3A4/5 inhibitors during the treatment phase of the study and within 72 hours prior to starting study drug administration * Concomitant use of CYP3A4/5 inducers, which include enzyme inducing antiepileptic drugs during treatment phase of the study and within 2 weeks prior to starting treatment. * Uncontrolled or significant cardiovascular disease * Prior stereotactic radiotherapy, convection enhanced delivery or brachytherapy as gliosis/scarring from these modalities may limit delivery * Pregnant or breast feeding women * HIV-positive individuals on combination antiretroviral therapy * Other severe acute or chronic medical condition or laboratory abnormality
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival | 2 years | Assess progression-free survival at six months in patients with recurrent glioblastoma at first or second recurrence who are treated with continuous daily dosing of bosutinib (Arm B). Progression-free survival is measured from initiation of study treatment to date of progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intratumoral Concentration | 2 years | Assess the intratumoral concentration of bosutinib in recurrent glioblastoma patients who are candidates for surgical re-resection (ARM A). |
| Safety Profile | 2 years | Overall safety profile will be characterized by type, frequency, severity (as graded by NCI CTCAE), timing and relationship of study therapy of adverse events and laboratory abnormalities. Safety and tolerability will be measured by the proportion of patients who experience Grade 3 or higher Adverse Events that are possibly, probably or definitely related to bosutinib and the number of same Adverse Events per patient. Adverse Events will be summarized by treatment for each arm by the frequency of patients experiencing treatment emergent adverse events. |
| Anti-tumor Response | 2 years | Assess anti-tumor response in patients in Arm B using MacDonald criteria. There are four possible responses: complete response, partial response, stable disease, or progressive disease. Criteria are based on measurements of tumor dimension as visualized with a contrast-enhanced MRI. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A Patients who are surgical candidates
bosutinib: Taken orally | 2 |
| Arm B Patients that are not surgical candidates
bosutinib: Taken orally | 9 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Lack of Efficacy | 2 | 8 |
Baseline characteristics
| Characteristic | Arm B | Total | Arm A |
|---|---|---|---|
| Age, Continuous | 44 years | 52 years | 60 years |
| Karnofsky Performance Status (KPS) | 90 units on a scale | 90 units on a scale | 80 units on a scale |
| Prior chemoradiation | 9 participants | 11 participants | 2 participants |
| Prior Surgery Gross Total Resection | 6 participants | 7 participants | 1 participants |
| Prior Surgery No prior surgery | 0 participants | 1 participants | 1 participants |
| Prior Surgery Sub total Resection | 3 participants | 3 participants | 0 participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 11 / 11 |
| serious Total, serious adverse events | 6 / 11 |
Outcome results
Primary
Progression-Free Survival
Assess progression-free survival at six months in patients with recurrent glioblastoma at first or second recurrence who are treated with continuous daily dosing of bosutinib (Arm B). Progression-free survival is measured from initiation of study treatment to date of progression.
Time frame: 2 years
Population: This outcome was only applicable to participants enrolled on Arm B.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm B | Progression-Free Survival | 7.71 weeks |
Secondary
Anti-tumor Response
Assess anti-tumor response in patients in Arm B using MacDonald criteria. There are four possible responses: complete response, partial response, stable disease, or progressive disease. Criteria are based on measurements of tumor dimension as visualized with a contrast-enhanced MRI.
Time frame: 2 years
Population: Only Arm B participants were evaluable for this outcome measure
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm B | Anti-tumor Response | Complete response | 0 participants |
| Arm B | Anti-tumor Response | Partial response | 0 participants |
| Arm B | Anti-tumor Response | Stable Disease | 1 participants |
| Arm B | Anti-tumor Response | Progressive disease | 8 participants |
Secondary
Intratumoral Concentration
Assess the intratumoral concentration of bosutinib in recurrent glioblastoma patients who are candidates for surgical re-resection (ARM A).
Time frame: 2 years
Population: Participants in Arm B were never eligible for this outcome measure. Because only two participants were enrolled to Arm A, this analysis was not done as there were not sufficient tumor samples to generate meaningful results.
Secondary
Safety Profile
Overall safety profile will be characterized by type, frequency, severity (as graded by NCI CTCAE), timing and relationship of study therapy of adverse events and laboratory abnormalities. Safety and tolerability will be measured by the proportion of patients who experience Grade 3 or higher Adverse Events that are possibly, probably or definitely related to bosutinib and the number of same Adverse Events per patient. Adverse Events will be summarized by treatment for each arm by the frequency of patients experiencing treatment emergent adverse events.
Time frame: 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A | Safety Profile | Grade 3 treatment-emergent lymphopenia | 0 participants |
| Arm A | Safety Profile | Grade 3 treatment-emergent hypophosphatemia | 0 participants |
| Arm B | Safety Profile | Grade 3 treatment-emergent lymphopenia | 1 participants |
| Arm B | Safety Profile | Grade 3 treatment-emergent hypophosphatemia | 1 participants |