Glioblastoma Multiforme
Conditions
Keywords
glioblastoma
Brief summary
This study will evaluate if a drug called G-202 can be safely used to treat people with glioblastoma (GBM) that has progressed or recurred. G-202 is given by intravenous infusion on three consecutive days of a 28-day cycle.
Detailed description
Glioblastoma (GBM) comprises about 16% of all malignancies of the nervous system and over 50% of all gliomas. Standard of care for newly-diagnosed GBM is a combination of surgical debulking followed by concurrent radiotherapy and chemotherapy with temozolomide. Efforts to improve second-line therapy in GBM have met with only marginal success and there is a large unmet medical need for new therapies. G-202 (mipsagargin) is an example of prodrug chemotherapy. It is activated by Prostate Specific Membrane Antigen (PSMA), which is expressed by some cancer cells and in the blood vessels of most solid tumors, including GBM, but not by normal cells or blood vessels in normal tissue. It is believed that activation of the prodrug G-202 will allow the drug to kill cancer cells. This study will evaluate the activity, safety and CNS exposure of G-202 in participants with recurrent or progressive GBM receiving G-202 by intravenous infusion on three consecutive days of a 28-day cycle. Funding Source - FDA Office of Orphan Products Development (OOPD)
Interventions
DRUGG-202
G-202 administered by intravenous infusion (IV, in the vein) on Days 1, 2 and 3 of each 28-day cycle until progression or development of unacceptable toxicity
Sponsors
Food and Drug Administration (FDA)
GenSpera, 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
* Written informed consent to participate in this study * Histological or radiological confirmation of glioblastoma * Recurrent or progressive GBM following at least one (1), but no more than two (2) prior regimens; one of the prior regimens must have included surgery and/or radiotherapy * Age \> 18 years * Karnofsky Performance Status (KPS) ≥ 60% * Life expectancy \> 2 months * Adequate hematologic, renal and hepatic function * Adequate coagulation profile * Not pregnant, nursing or planning to become pregnant; willing to use contraception
Exclusion criteria
* Deteriorating neurological symptoms, or need for increasing doses of corticosteroids or new onset of seizures * Surgical resection or major surgery within 4 weeks or stereotactic biopsy within 1 week of first G-202 treatment * Toxicity from prior therapy (excluding alopecia) that has not resolved to ≤ Grade 1 unless otherwise specified * Investigational or cytotoxic therapy within 28 days or nitrosoureas within 42 days of the first treatment with G-202 * Currently requiring any type of full-dose anti-coagulation treatment, systemic administration of antibiotics or chronic administration of anti-viral agents. * History or evidence of cardiac risk, including QTc interval on screening ECG \>470 msec, left ventricular ejection fraction (LVEF) \< 50%, clinically significant uncontrolled arrhythmias or arrhythmia requiring treatment with the exceptions of atrial fibrillation and paroxysmal supraventricular tachycardia, history of acute coronary syndromes within 6 months prior to the first dose of study therapy (including myocardial infarction and unstable angina, coronary artery bypass graft, angioplasty, or stenting) * Uncontrolled cardiac or coronary artery disease * Uncontrolled hypertension (mean systolic BP ≥ 160 mm Hg and/or mean diastolic BP ≥ 100 mm Hg on 3 determinations 5 minutes apart while on 2 anti-hypertensive agents) or hypertension requiring treatment with more than 2 anti-hypertensive agents * Severe or uncontrolled medical disease, including uncontrolled diabetes, congestive heart failure, chronic renal disease or chronic pulmonary disease * Severe GI bleeding within 12 weeks of treatment with G-202 * Known history of HIV, hepatitis B or hepatitis C * Documentation of keratosis follicularis (also known as Darier or Darier-White disease) * Requirement for chronic use of strong inhibitors or inducers of cytochrome (CYP3A4) iso-enzymes * Known hypersensitivity to any study drug component including thapsigargin derivatives, polysorbate 20, or propylene glycol * Any other condition, including concurrent medical condition, social circumstance or drug dependency, which in the opinion of the investigator could compromise patient safety and/or compliance with study requirements * Another primary malignancy that has not been in remission for at least 2 years; non-melanoma skin cancer, intraepithelial carcinoma of the cervix, or prostate cancer with a current PSA ≤ 0.1 ng/mL is allowed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6-month Progression-free Survival (PFS) | 6 months | Percentage of patients who received at least 2 cycles of G-202 and have not progressed or died within 6 months of beginning treatment with G-202. Progression is defined using Response Assessment in Neuro-Oncology Working Group (RANO) for high-grade glioma, as any of the following: by any of the following: 25% or greater increase in sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor, or to decrease in corticosteroid dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity Assessed by CTCAE v 4.03 Criteria | Every 2 weeks for approximately one year | Percentage of all analyzed patients experiencing treatment-emergent adverse events. |
| Objective Tumor Response Rate | approximately one year | Percentage of analyzed participants experiencing a complete response (CR) or partial response (PR) using RANO criteria. CR is defined as complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions; and patient must be off corticosteroids or on physiologic replacement doses only, and stable or improved clinically. PR is defined as at least 50% decrease, compared with baseline, in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no progression of nonmeasurable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and patient must be on a corticosteroid dose not greater than the dose at time of baseline scan and is stable or improved clinically. |
| Duration of PFS | Every 4 weeks for approximately one year | Duration of time from the first administration of G-202 until the first documented progression or date of death, assessed up to 12 months. Progression is defined using Response Assessment in Neuro-Oncology Working Group (RANO) for high-grade glioma, as any of the following: by any of the following: 25% or greater increase in sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor, or to decrease in corticosteroid dose. |
| Overall Survival | Every 4 weeks for approximately one year | Duration of time from the first administration of G-202 until the date of death, assessed up to 12 months |
| Biomarkers in Tumor | Within 4 weeks of receiving G-202 | PSMA immunohistochemistry staining score on tumor tissue collected prior to start of G-202 study treatment. Intensity of staining was ranked on a scale of 0, 1, 2, or 3 (with 0 representing no staining and 3 representing maximum intensity): absence of staining (0), weak staining (1), medium staining (2), or strong staining (3) relative to a staining calibration curve and normalized to the image mean background intensity. The scoring scale does not have a title nor does it have a subscale. It is not known whether PSMA staining intensity is associated with tumor molecular phenotypes or response outcome to G-202; therefore, this was an exploratory analysis. However, the lack of objective tumor response in the trial precluded comparative analysis. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| G-202 (Mipsagargin) G-202 (Mipsagargin) administered by intravenous infusion on 3 consecutive days of a 28-day cycle
G-202: G-202 administered by intravenous infusion (IV, in the vein) on Days 1, 2 and 3 of each 28-day cycle until progression or development of unacceptable toxicity | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 4 |
Baseline characteristics
| Characteristic | G-202 (Mipsagargin) |
|---|---|
| Age, Continuous | 55 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 4 Participants |
| Race (NIH/OMB) White | 21 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 22 / 26 |
| other Total, other adverse events | 24 / 26 |
| serious Total, serious adverse events | 6 / 26 |
Outcome results
Primary
6-month Progression-free Survival (PFS)
Percentage of patients who received at least 2 cycles of G-202 and have not progressed or died within 6 months of beginning treatment with G-202. Progression is defined using Response Assessment in Neuro-Oncology Working Group (RANO) for high-grade glioma, as any of the following: by any of the following: 25% or greater increase in sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor, or to decrease in corticosteroid dose.
Time frame: 6 months
Population: response-evaluable participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| G-202 (Mipsagargin) | 6-month Progression-free Survival (PFS) | 1 Participants |
Secondary
Biomarkers in Tumor
PSMA immunohistochemistry staining score on tumor tissue collected prior to start of G-202 study treatment. Intensity of staining was ranked on a scale of 0, 1, 2, or 3 (with 0 representing no staining and 3 representing maximum intensity): absence of staining (0), weak staining (1), medium staining (2), or strong staining (3) relative to a staining calibration curve and normalized to the image mean background intensity. The scoring scale does not have a title nor does it have a subscale. It is not known whether PSMA staining intensity is associated with tumor molecular phenotypes or response outcome to G-202; therefore, this was an exploratory analysis. However, the lack of objective tumor response in the trial precluded comparative analysis.
Time frame: Within 4 weeks of receiving G-202
Population: Only 11 samples of tumor tissue collected prior to the start of study treatment (G-202) were available for immunohistochemistry. PSMA staining was not an eligibility criterion.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| G-202 (Mipsagargin) | Biomarkers in Tumor | 2 score on a scale | Standard Deviation 1.1 |
Secondary
Duration of PFS
Duration of time from the first administration of G-202 until the first documented progression or date of death, assessed up to 12 months. Progression is defined using Response Assessment in Neuro-Oncology Working Group (RANO) for high-grade glioma, as any of the following: by any of the following: 25% or greater increase in sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; the appearance of any new lesions; clear progression of nonmeasurable lesions; or definite clinical deterioration not attributable to other causes apart from the tumor, or to decrease in corticosteroid dose.
Time frame: Every 4 weeks for approximately one year
Population: response-evaluable participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| G-202 (Mipsagargin) | Duration of PFS | 1.64 months |
Secondary
Objective Tumor Response Rate
Percentage of analyzed participants experiencing a complete response (CR) or partial response (PR) using RANO criteria. CR is defined as complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions; and patient must be off corticosteroids or on physiologic replacement doses only, and stable or improved clinically. PR is defined as at least 50% decrease, compared with baseline, in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no progression of nonmeasurable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and patient must be on a corticosteroid dose not greater than the dose at time of baseline scan and is stable or improved clinically.
Time frame: approximately one year
Population: response-evaluable participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| G-202 (Mipsagargin) | Objective Tumor Response Rate | 0 Participants |
Secondary
Overall Survival
Duration of time from the first administration of G-202 until the date of death, assessed up to 12 months
Time frame: Every 4 weeks for approximately one year
Population: response-evaluable participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| G-202 (Mipsagargin) | Overall Survival | 7.23 months |
Secondary
Toxicity Assessed by CTCAE v 4.03 Criteria
Percentage of all analyzed patients experiencing treatment-emergent adverse events.
Time frame: Every 2 weeks for approximately one year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| G-202 (Mipsagargin) | Toxicity Assessed by CTCAE v 4.03 Criteria | 26 Participants |