Glioblastoma
Conditions
Keywords
GBM, Malignant Glioma
Brief summary
This is an open label, multi-center, phase 1 safety run-in and phase 2 study of BBI608 in combination with temozolomide in patients with recurrent or progressive glioblastoma who have not received prior bevacizumab therapy.
Detailed description
In arm A, patients who are candidates for surgical resection will receive BBI608 as monotherapy prior to resection, followed by post-operative BBI608 administered in combination with temozolomide. In arm B, patients who are not candidates for surgical resection will receive BBI608 administered orally, daily, in combination with temozolomide. In the phase 1/dose-limiting toxicity (DLT) cohort portion of this study, pharmacokinetics will be evaluated for both arms A and B. Pharmacodynamics will be evaluated in all patients who undergo surgical resection.
Interventions
DRUGBBI608
In arm A, BBI608 will be administered at the recommended Phase 2 dose (RP2D) twice daily for 7(±2) days prior to planned surgical resection or biopsy of recurrent GBM. Upon the clinical recovery of the patient and at a time between 15-28 days after surgery, BBI608 will be administered orally, daily, each day of a 28 day cycle in combination with temozolomide. In arm B, patients who are not candidates for surgical resection will receive BBI608 administered orally, daily, each day of a 28 day cycle at the RP2D in combination with temozolomide.
DRUGTemozolomide
Temozolomide (TMZ) will be administered orally, once daily, at a dose of 150 mg/m\^2 daily on days 1 through 5 of each 28-day study cycle. The dose of temozolomide can be increased to 200 mg/m\^2 as per standard TMZ dosing guidelines for patients who complete at least one cycle at 150 mg/m\^2.
Sponsors
Sumitomo Pharma America, Inc.
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
Major Eligibility Criteria 1. Signed written informed consent must be obtained and documented according to International Conference on Harmonisation (ICH) and local regulatory requirements. 2. A histologically confirmed supratentorial glioblastoma (GBM) at first recurrence/progression (except for transformation from previous low grade glioma) following standard front-line therapy, for which treatment with temozolomide (TMZ) would be acceptable as determined by the Investigator 3. Previously received standard front-line GBM treatment including maximal surgical resection followed by external beam radiation therapy. 4. Patients may or may not be candidates for repeat surgical resection of the recurrent/progressed GBM. 5. Patients must have unequivocal evidence of tumor recurrence/progression by MRI at a minimum of 12 weeks following completion of chemoradiation or radiation therapy. 6. Patients must have measurable or non-measurable disease by response assessment in neuro-oncology Response Assessment in Neuro-oncology (RANO) criteria
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting Toxicities (DLTs) | 28 days after first administration of combination treatment (BBI608+TMZ) | Number of patients who experienced a dose limiting toxicity following a dosing of BBI608 |
| Progression Free Survival (PFS)-6 | From the time of exposure to study drug to first objective documentation of disease progression or death due to any cause, assessed up to 6 months | To assess the effect of BBI608 + temozolomide (TMZ) therapy defined as the percentage of patients who have survived without objective disease progression for at least 6 months after treatment per neuro-oncology (RANO) criteria who had evaluable disease at baseline. PFS-6 is defined as the percentage of patients who survived without objective disease progression per RANO criteria for at least 6 months after treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | 4 weeks | To assess the percentage of patients that had evaluable disease at baseline with a documented complete response, partial response, and stable disease (CR + PR + SD) based on the Response Assessment in Neuro-Oncology (RANO) criteria out of all patients who received at least one dose of any study drug and had evaluable disease at baseline. |
| Overall Response Rate (ORR) | 4 weeks | The proportion of patients with a documented complete response and partial response (CR + PR) based on RANO criteria. |
| Progression Free Survival (PFS)-12 | From the time of exposure to study drug to first objective documentation of disease progression or death due to any cause, up to 12 months | To assess the effect of BBI608 + temozolomide (TMZ) therapy defined as the percentage of patients who have survived without objective disease progression for at least 12 months after treatment per neuro-oncology (RANO) criteria who had evaluable disease at baseline. PFS-12 is defined as the percentage of patients who survived without objective disease progression per RANO criteria for at least 12 months after treatment. |
| Pharmacodynamic Activity of BBI608 When Administered in Combination With Temozolomide as Assessed by Tumor Biopsy and Cancer Stem Cell Assays as Well as the Concentration of Study Drug in Tumors | At the time of surgical resection | Tumor samples to provide information of the biomarkers by histopathology and Cancer Stem Cell assays as well as the concentration of study drug in tumors. |
| Pharmacokinetic Profile of BBI608 and Temozolomide When Administered in Combination With Temozolomide as Assessed by the Area Under the Curve | On Day 1 and Day 5 after the first dosing, prior to dosing and 1, 2, 3, 5, 5h40m (day 1 only), 6, 7, 8 and 24 hours after first dose of BBI608 | The area under the curve of BBI608, from time 0 to the last quantifiable concentration, calculated by a combination of linear and logarithmic trapezoidal methods (linear up/log down method) |
| Overall Survival (OS) | From the time of exposure to study drug to death from any cause. If patient discontinued study drug, they were assessed the first 3 months after discontinuation, then every 3 months up to 1 year, then every 6 months thereafter until death. | To assess the effect of BBI608 + temozolomide (TMZ) on the overall survival of patients with recurrent or progressive glioblastoma multiforme (GBM) who had not received prior treatment with bevacizumab or other anti-vascular endothelial growth factor agents who either were eligible or not eligible for surgical resection. |
Countries
Canada, United States
Participant flow
Pre-assignment details
There are no pre-assignment details, study arm was determined at patient enrollment to the study
Participants by arm
| Arm | Count |
|---|---|
| Candidates Whom Surgery is Recommended. Candidates who were candidates for repeat surgical resection | 4 |
| Candidates Whom Surgery is Not Recommended Candidates who were not candidates for repeat surgical resection | 30 |
| Total | 34 |
Baseline characteristics
| Characteristic | Candidates Whom Surgery is Recommended. | Candidates Whom Surgery is Not Recommended | Total |
|---|---|---|---|
| Age, Continuous | 58.8 years STANDARD_DEVIATION 10.14 | 54.6 years STANDARD_DEVIATION 15.54 | 55.1 years STANDARD_DEVIATION 14.95 |
| Height | 177.25 centimeters STANDARD_DEVIATION 7.411 | 173.91 centimeters STANDARD_DEVIATION 9.896 | 174.30 centimeters STANDARD_DEVIATION 9.605 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 26 Participants | 26 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 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 | 4 Participants | 0 Participants | 4 Participants |
| Sex: Female, Male Female | 2 Participants | 12 Participants | 14 Participants |
| Sex: Female, Male Male | 2 Participants | 18 Participants | 20 Participants |
| Smoking Current smoker | 0 Participants | 2 Participants | 2 Participants |
| Smoking Former smoker | 1 Participants | 7 Participants | 8 Participants |
| Smoking Lifetime nonsmoker | 3 Participants | 21 Participants | 24 Participants |
| Weight | 100.55 kilograms STANDARD_DEVIATION 26.345 | 78.21 kilograms STANDARD_DEVIATION 16.17 | 80.84 kilograms STANDARD_DEVIATION 13.608 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 4 | 22 / 30 |
| other Total, other adverse events | 4 / 4 | 30 / 30 |
| serious Total, serious adverse events | 3 / 4 | 5 / 30 |
Outcome results
Primary
Dose-limiting Toxicities (DLTs)
Number of patients who experienced a dose limiting toxicity following a dosing of BBI608
Time frame: 28 days after first administration of combination treatment (BBI608+TMZ)
Population: Up to the first 6 patients whom surgery was and wasn't recommended that received 28 days of continuous daily administration of BBI608 in combination with TMZ. Patients also had to be≥ 80% compliant to assigned dose to qualify for DLT analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Candidates Whom Surgery is Recommended. | Dose-limiting Toxicities (DLTs) | 0 Participants |
| Candidates Whom Surgery is Not Recommended | Dose-limiting Toxicities (DLTs) | 0 Participants |
Primary
Progression Free Survival (PFS)-6
To assess the effect of BBI608 + temozolomide (TMZ) therapy defined as the percentage of patients who have survived without objective disease progression for at least 6 months after treatment per neuro-oncology (RANO) criteria who had evaluable disease at baseline. PFS-6 is defined as the percentage of patients who survived without objective disease progression per RANO criteria for at least 6 months after treatment.
Time frame: From the time of exposure to study drug to first objective documentation of disease progression or death due to any cause, assessed up to 6 months
Population: Data was only collected and analyzed for arms that enrolled at least 10 evaluable patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Candidates Whom Surgery is Recommended. | Progression Free Survival (PFS)-6 | 28.07 percentage of participants |
Secondary
Disease Control Rate (DCR)
To assess the percentage of patients that had evaluable disease at baseline with a documented complete response, partial response, and stable disease (CR + PR + SD) based on the Response Assessment in Neuro-Oncology (RANO) criteria out of all patients who received at least one dose of any study drug and had evaluable disease at baseline.
Time frame: 4 weeks
Population: Data was only collected and analyzed for arms that enrolled at least 10 evaluable patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Candidates Whom Surgery is Recommended. | Disease Control Rate (DCR) | 30 percentage of patients |
Secondary
Overall Response Rate (ORR)
The proportion of patients with a documented complete response and partial response (CR + PR) based on RANO criteria.
Time frame: 4 weeks
Population: Data was only collected and analyzed for arms that enrolled at least 10 evaluable patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Candidates Whom Surgery is Recommended. | Overall Response Rate (ORR) | 3 percentage |
Secondary
Overall Survival (OS)
To assess the effect of BBI608 + temozolomide (TMZ) on the overall survival of patients with recurrent or progressive glioblastoma multiforme (GBM) who had not received prior treatment with bevacizumab or other anti-vascular endothelial growth factor agents who either were eligible or not eligible for surgical resection.
Time frame: From the time of exposure to study drug to death from any cause. If patient discontinued study drug, they were assessed the first 3 months after discontinuation, then every 3 months up to 1 year, then every 6 months thereafter until death.
Population: Data was only collected and analyzed for arms that enrolled at least 10 evaluable patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Candidates Whom Surgery is Recommended. | Overall Survival (OS) | 8.05 months |
Secondary
Pharmacodynamic Activity of BBI608 When Administered in Combination With Temozolomide as Assessed by Tumor Biopsy and Cancer Stem Cell Assays as Well as the Concentration of Study Drug in Tumors
Tumor samples to provide information of the biomarkers by histopathology and Cancer Stem Cell assays as well as the concentration of study drug in tumors.
Time frame: At the time of surgical resection
Population: Candidates whom surgery is either recommended or nor recommended that received 28 days of study drug and provided tissue samples.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Candidates Whom Surgery is Recommended. | Pharmacodynamic Activity of BBI608 When Administered in Combination With Temozolomide as Assessed by Tumor Biopsy and Cancer Stem Cell Assays as Well as the Concentration of Study Drug in Tumors | pSTAT3+ | 19 Participants |
| Candidates Whom Surgery is Recommended. | Pharmacodynamic Activity of BBI608 When Administered in Combination With Temozolomide as Assessed by Tumor Biopsy and Cancer Stem Cell Assays as Well as the Concentration of Study Drug in Tumors | pSTAT3- | 2 Participants |
| Candidates Whom Surgery is Recommended. | Pharmacodynamic Activity of BBI608 When Administered in Combination With Temozolomide as Assessed by Tumor Biopsy and Cancer Stem Cell Assays as Well as the Concentration of Study Drug in Tumors | Not Applicable | 2 Participants |
Secondary
Pharmacokinetic Profile of BBI608 and Temozolomide When Administered in Combination With Temozolomide as Assessed by the Area Under the Curve
The area under the curve of BBI608, from time 0 to the last quantifiable concentration, calculated by a combination of linear and logarithmic trapezoidal methods (linear up/log down method)
Time frame: On Day 1 and Day 5 after the first dosing, prior to dosing and 1, 2, 3, 5, 5h40m (day 1 only), 6, 7, 8 and 24 hours after first dose of BBI608
Population: Candidates for who surgery was and was not recommended that received at least one dose of study drug and had at least one quantifiable concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Candidates Whom Surgery is Recommended. | Pharmacokinetic Profile of BBI608 and Temozolomide When Administered in Combination With Temozolomide as Assessed by the Area Under the Curve | 4820 h*ng/ml | Geometric Coefficient of Variation 19 |
| Candidates Whom Surgery is Not Recommended | Pharmacokinetic Profile of BBI608 and Temozolomide When Administered in Combination With Temozolomide as Assessed by the Area Under the Curve | 4200 h*ng/ml | Geometric Coefficient of Variation 37.4 |
Secondary
Progression Free Survival (PFS)-12
To assess the effect of BBI608 + temozolomide (TMZ) therapy defined as the percentage of patients who have survived without objective disease progression for at least 12 months after treatment per neuro-oncology (RANO) criteria who had evaluable disease at baseline. PFS-12 is defined as the percentage of patients who survived without objective disease progression per RANO criteria for at least 12 months after treatment.
Time frame: From the time of exposure to study drug to first objective documentation of disease progression or death due to any cause, up to 12 months
Population: Data was only collected and analyzed for arms that enrolled at least 10 evaluable patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Candidates Whom Surgery is Recommended. | Progression Free Survival (PFS)-12 | 16.84 percentage of participants |