Efficacy, Safety and CNS Exposure of G-202 (Mipsagargin) in Patients With Recurrent or Progressive Glioblastoma

Phase 2

Completed

Conditions: Glioblastoma Multiforme

Interventions: Drug: G-202

Registration Number: NCT02067156

Lead Sponsor: GenSpera, Inc.

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)

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 26

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
G-202 (Mipsagargin)	G-202	G-202 (Mipsagargin) administered by intravenous infusion on 3 consecutive days of a 28-day cycle

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.