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

Glioblastoma Multiforme Clinical Trial

Official title:

An Open-Label, Single-Arm, Phase II Study to Evaluate the Efficacy, Safety and CNS Exposure of G-202 (Mipsagargin) in Patients With Recurrent or Progressive Glioblastoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02067156
• Other study ID #: G-202-004
• Secondary ID: R01FD005077
• Status: Completed
• Phase: Phase 2
• Start date: February 2014
• Est. completion date: February 2017

Study information

• Verified date: May 2024
• Source: GenSpera, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 26
• Est. completion date: February 2017
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Glioblastoma
• Glioblastoma Multiforme

Intervention

Drug:
• 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

Locations

Country	Name	City	State
United States	University of California, San Diego Moores Cancer Center	La Jolla	California

Sponsors (2)

Lead Sponsor	Collaborator
GenSpera, Inc.	Food and Drug Administration (FDA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	6 months
Secondary	Toxicity Assessed by CTCAE v 4.03 Criteria	Percentage of all analyzed patients experiencing treatment-emergent adverse events.	Every 2 weeks for approximately one year
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.	approximately one year
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.	Every 4 weeks for approximately one year
Secondary	Overall Survival	Duration of time from the first administration of G-202 until the date of death, assessed up to 12 months	Every 4 weeks for approximately one year
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.	Within 4 weeks of receiving G-202