GBM, Glioblastoma, Glioma
Conditions
Keywords
Primary brain tumor, Glioblastoma, Glioma, GBM, Radiation therapy
Brief summary
This open-label study evaluated the safety and efficacy of TSC when dosed concomitantly with the standard of care (radiation therapy and temozolomide) for newly diagnosed glioblastoma in adults. All patients received TSC in the study. The objective of the study was to evaluate the effect of TSC on survival and tumor response in patients with GBM while establishing an acceptable patient risk profile.
Detailed description
The overall objectives of this Phase 1/2 clinical study in newly diagnosed GBM patients was to evaluate the safety and tolerability, efficacy, PK profile, PFS/time to disease progression, QoL, and overall survival in adults when TSC is added to the standard of care regimen of radiation therapy and temozolomide. All patients received TSC in this study. The primary objective of the Phase 1 portion of the study was to evaluate the safety (DLT rate) and to define the dosing regimen of TSC for the larger Phase 2 study. The primary clinical endpoint was overall survival at 24 months and patients will be followed for up to 3 years.
Interventions
TSC administered intravenously as a bolus injection prior to radiation therapy sessions during 6 weeks of radiotherapy.
Sponsors
Diffusion Pharmaceuticals Inc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Aged at least 18 years of age; male or female. A patient who is 70 years of age or older may be considered for enrollment after review of patient clinical and laboratory data by the Protocol Medical Monitor. * Histologically confirmed diagnosis of GBM. * Contrast enhancing disease on MRI within 21 days prior to screening. * Karnofsky score (KPS) of ≥ 60 at Screening. * No prior RT, chemotherapy (including Gliadel wafer), immunotherapy or therapy with a biologic agent, or hormonal therapy. Glucocorticoid therapy is allowed. * Within 2 weeks of baseline visit, hematologic and renal functions as specified: Absolute neutrophil count ≥ 1500/mm3, platelets ≥ 100,000/mm3, Hgb ≥ 9.0g/dL, creatinine ≤ 1.7mg/dl, total bilirubin ≤ 1.5mg/dL, blood urea nitrogen (BUN) within 2 times the upper limit of normal, transaminases ≤ 4 times above the upper limits of the institutional norm. * Sexually active patients must use an acceptable method of contraception while receiving doses of study medication. * Females of childbearing potential must have a negative serum or urine pregnancy test at screening and have additional pregnancy tests during study.
Exclusion criteria
* Patient who cannot undergo MRI. * Pregnant or lactating. * Serious concurrent infection or medical illness that would jeopardize the ability of the patient to receive study treatment with reasonable safety. * Patient receiving concurrent chemotherapeutics or investigational agents within 30 days of baseline assessments, including gliadel wafers or gliasite application.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicities (DLTs) | During phase 1 | Number of Participants in Phase 1 with Dose Limiting Toxicities (DLTs) |
| Overall Survival | 6, 12, 18, 24 months | Participants in phase 2 (18 dose group, 6 weeks treatment with TSC) were monitored for up to 3 years (last follow-up - February 16, 2016). Overall Survival (OS) was defined as the length of time from the date of tumor resection surgery or definitive biopsy to the date of death. The OS analyses were performed using the Kaplan-Meier estimate method. The OS rates at 6, 12, 18 and 24 months were estimated. Median OS values were calculated; a corresponding 95% confidence interval for each median value was determined using a log rank analysis. The length of OS (in months) was calculated as follows: date of death or censored - date of surgery or definitive biopsy / 30.4375. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | 6,12,18, 24 months | The PFS analyses were performed using the Kaplan-Meier estimate method. The PFS rates at 6, 12, 18 and 24 months were estimated. Median PFS values were calculated; a corresponding 95% confidence interval for each median value was determined using a log rank analysis. Time to disease progression (in months) was calculated as follows: date of event\* or censoring - date of surgery or definitive biopsy / 30.4375; \*event = first tumor progression or death. |
| Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction | From Baseline to Week 110 | The sum of the product of the diameters of the tumor (using recorded tumor diameter measurements made from brain MRI images) was used to express tumor size. Results were summarized for actual and percentage change from baseline. Individual subjects results were listed, including tumor volume and tumor response from independent reviewers. Investigator data were listed but not used in the analysis. Percent response (according to independent reviewer assessments) by percentage tumor reduction from tumor resection or definitive biopsy to the last MRI were summarized. |
Countries
United States
Participant flow
Recruitment details
Treatment naive patients with a histologically confirmed diagnosis of GBM who were scheduled to receive standard-of-care radiation and temozolomide treatment per Stupp et al (2005) were enrolled in the study at 18 academic clinical sites in the U.S.
Pre-assignment details
Open-label, historical control (Stupp et al; N Engl J Med 2005; 352: 987-996, March 10, 2005, DOI: 10.1056/NEJMoa043330); patients received standard-of-care radiation/temozolomide treatment plus Trans Sodium Crocetinate (TSC); three (3) patients completed 9 doses (phase 1) as a safety run-in followed by 56 patients who received 18 doses (phase 2).
Participants by arm
| Arm | Count |
|---|---|
| TSC 0.25 mg/kg for 9 or 18 Doses Trans Sodium Crocetinate (TSC): TSC administered intravenously as a bolus injection prior to radiation therapy sessions during 6 weeks of radiotherapy. | 56 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Admitted to hospice | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | TSC 0.25 mg/kg for 9 or 18 Doses |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 15 Participants |
| Age, Categorical Between 18 and 65 years | 41 Participants |
| Age, Continuous | 57.2 years STANDARD_DEVIATION 10.79 |
| Count of participants | 56 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 52 Participants |
| Region of Enrollment United States | 56 participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 56 / 56 |
| serious Total, serious adverse events | 1 / 3 | 10 / 56 |
Outcome results
Primary
Dose Limiting Toxicities (DLTs)
Number of Participants in Phase 1 with Dose Limiting Toxicities (DLTs)
Time frame: During phase 1
Population: Dose limiting toxicities were only assessed for Phase 1 participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TSC 0.25 mg/kg - 9 Dose Group | Dose Limiting Toxicities (DLTs) | 0 Participants |
Primary
Overall Survival
Participants in phase 2 (18 dose group, 6 weeks treatment with TSC) were monitored for up to 3 years (last follow-up - February 16, 2016). Overall Survival (OS) was defined as the length of time from the date of tumor resection surgery or definitive biopsy to the date of death. The OS analyses were performed using the Kaplan-Meier estimate method. The OS rates at 6, 12, 18 and 24 months were estimated. Median OS values were calculated; a corresponding 95% confidence interval for each median value was determined using a log rank analysis. The length of OS (in months) was calculated as follows: date of death or censored - date of surgery or definitive biopsy / 30.4375.
Time frame: 6, 12, 18, 24 months
Population: All participants who received any amount of TSC and at least 1 session of RT (modified ITT)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TSC 0.25 mg/kg - 9 Dose Group | Overall Survival | 6 month OS | 89.3 participants |
| TSC 0.25 mg/kg - 9 Dose Group | Overall Survival | 12 month OS | 71.2 participants |
| TSC 0.25 mg/kg - 9 Dose Group | Overall Survival | 18 month OS | 43.8 participants |
| TSC 0.25 mg/kg - 9 Dose Group | Overall Survival | 24 month OS | 36.3 participants |
Secondary
Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction
The sum of the product of the diameters of the tumor (using recorded tumor diameter measurements made from brain MRI images) was used to express tumor size. Results were summarized for actual and percentage change from baseline. Individual subjects results were listed, including tumor volume and tumor response from independent reviewers. Investigator data were listed but not used in the analysis. Percent response (according to independent reviewer assessments) by percentage tumor reduction from tumor resection or definitive biopsy to the last MRI were summarized.
Time frame: From Baseline to Week 110
Population: Of the 56 modified ITT population (subjects in the TSC 18 dose group) tumor size data exist for 37 subjects. Four (4) tumor-bearing subjects at baseline MRI did not have any post-baseline MRIs. Fourteen (14) subjects had a complete resection before baseline.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TSC 0.25 mg/kg - 9 Dose Group | Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction | tumor not reduced | 1 Participants |
| TSC 0.25 mg/kg - 9 Dose Group | Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction | 0 to 39% tumor reduction | 0 Participants |
| TSC 0.25 mg/kg - 9 Dose Group | Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction | 40 to 63% tumor reduction | 0 Participants |
| TSC 0.25 mg/kg - 9 Dose Group | Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction | 64 to 93% tumor reduction | 0 Participants |
| TSC 0.25 mg/kg - 9 Dose Group | Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction | 94 to 99% tumor reduction | 0 Participants |
| TSC 0.25 mg/kg - 9 Dose Group | Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction | 100% tumor reduction | 2 Participants |
| TSC 0.25 mg/kg - 18 Dose Group | Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction | 94 to 99% tumor reduction | 2 Participants |
| TSC 0.25 mg/kg - 18 Dose Group | Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction | tumor not reduced | 10 Participants |
| TSC 0.25 mg/kg - 18 Dose Group | Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction | 64 to 93% tumor reduction | 6 Participants |
| TSC 0.25 mg/kg - 18 Dose Group | Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction | 0 to 39% tumor reduction | 6 Participants |
| TSC 0.25 mg/kg - 18 Dose Group | Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction | 100% tumor reduction | 11 Participants |
| TSC 0.25 mg/kg - 18 Dose Group | Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction | 40 to 63% tumor reduction | 2 Participants |
Secondary
Progression-Free Survival (PFS)
The PFS analyses were performed using the Kaplan-Meier estimate method. The PFS rates at 6, 12, 18 and 24 months were estimated. Median PFS values were calculated; a corresponding 95% confidence interval for each median value was determined using a log rank analysis. Time to disease progression (in months) was calculated as follows: date of event\* or censoring - date of surgery or definitive biopsy / 30.4375; \*event = first tumor progression or death.
Time frame: 6,12,18, 24 months
Population: The analysis of PFS was performed in phase 2 only and included the modified ITT population which included 54 of the 56 subjects (98.2%) at the 2-year time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TSC 0.25 mg/kg - 9 Dose Group | Progression-Free Survival (PFS) | 6 months | 30.9 percentage of participants |
| TSC 0.25 mg/kg - 9 Dose Group | Progression-Free Survival (PFS) | 12 months | 9.9 percentage of participants |
| TSC 0.25 mg/kg - 9 Dose Group | Progression-Free Survival (PFS) | 18 months | 4.0 percentage of participants |
| TSC 0.25 mg/kg - 9 Dose Group | Progression-Free Survival (PFS) | 24 months | 0.0 percentage of participants |