Phase II Study of Combined Temozolomide and SGT-53 for Treatment of Recurrent Glioblastoma

February 11, 2021 updated by: SynerGene Therapeutics, Inc.

Phase II Study of Combined Temozolomide and Targeted P53 Gene Therapy (SGT-53) for Treatment of Patients With Recurrent Glioblastoma

This Phase II clinical trial is an open label, single arm, multicenter study of the combination of intravenously administered SGT-53 and oral temozolomide in patients with confirmed glioblastoma who have proven tumor recurrence or progression. The objective of this trial is to assess 6 month progression free survival (PFS), overall survival (OS), anti-tumor activity, safety and possibly to evaluate, nanoparticle delivery to tumor site, and the induction of apoptosis in the tumor..

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The p53 is a vital human tumor suppressor gene. Loss of p53 suppressor function is present in the majority of human cancers. The p53 protein has a diverse range of functions including regulation of cell cycle checkpoints, cell death (apoptosis), senescence, DNA repair, maintenance of genomic integrity, and control of angiogenesis. Abnormalities of the p53 gene may impact the efficacy of standard anticancer treatments such as radiation and chemotherapy. P53 mutation and pathway dysfunction are associated with poor clinical outcomes and the presence of the p53 mutation correlates with resistance to chemotherapy and radiation. The development of somatic gene therapy has created the potential to restore wild type function of p53. SGT-53 is a complex of cationic liposome encapsulating a normal human wild type p53 DNA sequence in a plasmid backbone. This complex has been shown to efficiently and specifically deliver the p53 cDNA to the tumor cells and to cross the blood-brain barrier. Introduction of the p53 cDNA sequence is expected to restore wtp53 function in the apoptotic pathway. P53 restoration has been shown most effective in enhancing cytotoxicity in combination with an agent which results in DNA damage or initiates apoptosis. The primary mechanism of resistance to current standard chemotherapeutic agent Temozolomide (TMZ) is overexpression of O6-methylguanine-DNA-methyl transferase (MGMT), which repairs the TMZ-induced DNA lesion by removing the o6-guanine adducts. Thus, a means to down modulate MGMT activity would enhance the therapeutic effect of TMZ. A number of reports have indicated that increasing wtp53 expression can down-regulate expression of DNA repair genes such as MGMT and increases the sensitivity of tumor cells to alkylating agents. This is a Phase II clinical trial of the tumor-targeted SGT-53 nanocomplex in combination with chemotherapeutic agent, temozolomide which is the standard of care for Glioblastoma Multiforme (GBM) brain tumors. We propose to test the combination of SGT-53 and standard temozolomide to determine efficacy and safety in patients with confirmed glioblastoma who have proven tumor recurrence or progression.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
1

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Taiwan
      • Taichung, Taiwan, 40447
        • China Medical University Hospital
  • United States
    • Texas
      • Houston, Texas, United States, 77030
        • MD Anderson Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Histologically confirmed glioblastoma or gliosarcoma in 1st, 2nd or 3rd relapse.
  • Radiographic demonstration of disease progression following prior therapy
  • Measurable disease on MRI performed within 14 days prior to registration.
  • Male or female patients ≥ 18 years of age.

  • Recurrent disease with an:

    • interval of ≥ 3 months following radiotherapy + TMZ;
    • interval of ≥ 14 days between end of surgery and start of protocol therapy for patients who have undergone surgery for recurrent disease.
  • Patients who tolerated previous administration with TMZ

  • Recovery from the effects of prior therapy:

    • 4 weeks from cytotoxic agents
    • 6 weeks from nitrosoureas
    • 4 weeks from any investigational agent
    • 1 week from non-cytotoxic agents
    • 12 weeks from radiotherapy
  • Karnofsky performance status ≥ 60%.
  • Complete blood count/differential at screening with adequate bone marrow function
  • If patient is receiving steroids, must be on stable or decreasing steroid dose within 5 days prior to treatment initiation with SGT-53.
  • Patients must be willing to forego other cytotoxic and non-cytotoxic drug or radiation therapy against the tumor while enrolled in the study.
  • Women of childbearing potential must have a negative serum beta-HCG pregnancy test documented within 3 days prior to study initiation.
  • Women of childbearing potential must agree to use two reliable methods of contraception from screening and up to 30 days after discontinuation of study treatment
  • Males not naturally or surgically sterile, who have a female partner of childbearing potential, must agree to use two reliable methods of contraception from screening and up to 30 days after discontinuation of study treatment
  • Acceptable liver function
  • Acceptable blood sugar control
  • Urinalysis: No clinically significant abnormalities.
  • PT and PTT ≤ 1.5 X ULN
  • Have recovered from any previous therapy side effects or toxicities
  • Organ function characterized by ≤ Grade 1

Exclusion Criteria:

  • Histology other than astrocytoma grade IV
  • Tumor foci detected below the tentorium or beyond the cranial vault.
  • Glioblastoma or gliosarcoma disease with leptomeningeal spread.
  • Patients with a history of any other cancer, unless in complete remission, and off all therapy for that disease for a minimum of 5 years
  • Patients with serum aspartate aminotransferase, alanine aminotransferase > 2.5 X the upper limit of normal (ULN) and bilirubin >1.5 ULN
  • Moderate to severe hepatic impairment.
  • Positive results from HIV serology testing, if any available.
  • Supine systolic blood pressure < 100 mmHg or supine diastolic blood pressure < 50 mmHg at screening and baseline
  • Renal insufficiency or serum creatinine >1.5 X ULN at screening.
  • Females who are pregnant or lactating or plan to become pregnant during the course of this study.
  • Substance or alcohol abuse or dependence, within 12 months prior to screening.
  • Prior chemotherapy for recurrent GBM with nitrosourea compounds including Gliadel® wafers or bevacizumab.
  • Prior focal radiotherapy within 3 months of screening.
  • Planned treatment, or treatment with any investigational drug within 4 weeks prior to screening.
  • Severe, active co-morbidity
  • Patients who are currently taking Coumadin or Coumadin derivatives other than to maintain patency of venous access lines.
  • Requiring renal dialysis
  • Receiving hematopoietic growth factors
  • Have significant baseline neuropathies
  • Had prior exposure to gene vector delivery products within 6 months
  • Any condition that prevents compliance with the protocol or adherence to therapy.
  • Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy.
  • Treated with antibiotics for infection within one week prior to study entry.
  • Fever (> 38.1°C)
  • Have diastolic blood pressure of > 90 mm Hg resting at baseline despite medication.
  • Serious nonmalignant disease
  • Enrollment in a concomitant clinical study
  • Have a history of hypersensitivity reaction to any of the components of Temozolomide
  • Have a history of hypersensitivity to dacarbazine (DTIC)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: SGT-53 with Temozolomide
SGT-53, at 3.6 mg DNA/infusion, will be administered twice weekly in a 28 day cycle starting on Day 1 (cycle 1), Day 29 (cycle 2) and Day 57 (cycle 3). Temozolomide (TMZ) will be administered by mouth daily on days 9-13 of each cycle. Patients who are responding to treatment may receive three additional cycles of SGT-53/TMZ therapy or continue on TMZ alone at investigator's discretion. Surgical resection of recurrent or progressive tumor for tumor analysis is an optional procedure. In these individuals SGT-53, at 3.6 mg DNA/infusion, will be administered twice (on days -1 and -3) in the week prior to surgery. Surgical resection is Day 0. 14-21 days post operatively and having recovered from the effects of surgery, the patients will then start cyclical TMZ with SGT-53 as described above.
Genetic: SGT-53
SGT-53, at 3.6 mg DNA per infusion, will be administered twice per week for 3 weeks (on Day 1, 4, 8, 11, 15 and 18 of each cycle) for 3 cycles. If SGT-53-related toxicity occurs, the dose of SGT-53 will be de-escalated to 2.4 or 1.2 mg DNA/infusion when appropriate.
Drug: Temozolomide
TMZ will be administered orally on days 9-13 of each cycle. In cycle 1, the dose of TMZ will be 150 mg/m². If the TMZ-related toxicities are tolerated in cycle 1, the dose of TMZ will be escalated to 200 mg/m² for cycle 2 and beyond. If TMZ-related toxicity occurs, the dose if TMZ will be de-escalated to 125 mg/m² (dose level -1), 100 mg/m² (dose level -2) or 75 mg/m² (dose level -3) when appropriate.
Other Names:
  • Temodar

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Tumor Response
Time Frame: 6 months
The 6 month progression-free survival (PFS) was evaluated using RANO Response Criteria.
6 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Incidence of Treatment-Emergent Adverse Events
Time Frame: Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later, approximately 90 days.
The safety of the combination of SGT-53 and Temozolomide was assessed by analysis of adverse experiences, clinical laboratory tests and physical examinations.
Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later, approximately 90 days.
Progression-free Survival (PFS)
Time Frame: From date of registration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months.
Progression-free survival is defined as the time from the date of enrollment to the date of disease progression, or death (any cause) on or prior to the clinical cutoff date, whichever occurs earlier. Subjects who do not have disease progression or have not died will be censored at the date of the last tumor assessment on or prior to the clinical cutoff.
From date of registration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months.
Overall Survival (OS)
Time Frame: From date of registration until the date of death from any cause, assessed up to 180 months.
Overall survival is defined as the time from the date of enrollment to the date of death from all causes.
From date of registration until the date of death from any cause, assessed up to 180 months.
Anti-tumor Activity
Time Frame: From date of registration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months.
The anti-tumor activity of the combination of SGT-53 and Temozolomide was determined based upon the RANO criteria.
From date of registration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months.
Induction of Apoptosis
Time Frame: 3 days
Flow cytometry or histological examination was used to determine the level of apoptosis induced by SGT-53 in tumors resected 3 days after the first SGT-53 infusion (optional procedure)
3 days
Nanoparticle Tumor Delivery
Time Frame: 3 days
As an indicator of nanoparticle delivery to the tumors, DNA PCR was used to determine the presence of SGT-53 delivered exogenous wt p53 in the tumors. This analysis will be performed on any tumors resected 3 days after the first SGT-53 infusion (optional procedure)
3 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
SynerGene Therapeutics, Inc.

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: John DeGroot, MD, M.D. Anderson Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 1, 2014

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 1, 2018

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 1, 2018

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 18, 2014

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 15, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 16, 2015

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 3, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 11, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • SGT53-02-2

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