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Safety and Imaging Study of GC1008 in Glioma

Primary Purpose

Primary Brain Tumors

Status

Completed

Phase

Phase 2

Locations

Netherlands

Study Type

Interventional

Intervention

89Zr-GC1008

GC1008

About this trial

This is an interventional treatment trial for Primary Brain Tumors focused on measuring GC1008, PET imaging, primary brain tumors, recurrent high grade glioma's

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Part 1

Inclusion Criteria

> 18 years
WHO 0,1,2
Suspicion of malignant glioma on contrast-enhanced MRI
Able to give written informed consent

Exclusion Criteria

Meningeal carcinomatosis, uncontrolled seizures, or a disease that either causes or threatens neurologic compromise
Pregnant or nursing women
Known allergy to component of 89Zr-GC1008
Significant medical or psychosocial problems

Part 2

Inclusion Criteria

Relapsed malignant glioma
Patient may have undergone surgery for the recurrence. Residual and measurable disease after surgery is not required. Surgery must have confirmed the recurrence. Post-operative MRI must be made within 48 hours following surgery
For non operated patients, recurrent disease must be at least one bidimensionally measurable target lesion (contrast enhancing lesion) with one diameter of at least 2cm, based on MRI scan done within 4 weeks prior to start of treatment
18 years
WHO 0,1,2
Serum albumin ≥3.0 g/dL
Adequate organ function including:
- Hb ≥10.0 g/dL
- ANC ≥1,500/mm3
- platelets ≥100,000/mm3
- Serum total bilirubin ≤1.5 x ULN (Patients with Gilbert's Disease may be included if their total bilirubin is ≤3.0 mg/dL)
- ALT and AST ≤2.5 x ULN.
- Estimated or measured creatinine clearance ≥60 mL/min
- PT and PTT within normal ranges
Negative tests for hepatitis viruses B and C and HIV, unless the result is consistent with prior vaccination or prior infection with full recovery
Enrollment >4 weeks since major surgery, radiotherapy, chemotherapy (≥6 weeks if they were treated with a nitrosourea, mitomycin, or monoclonal antibodies), immunotherapy, or biotherapy/targeted therapies and recovered from the toxicity of prior treatment to ≤ Grade 1, exclusive of alopecia. Concurrent cancer therapy is not permitted (except for corticosteroids) (For long acting agents, a treatment free interval of 2 half lives should be considered)
Able to give written informed consent
Patients of child-producing potential must agree to use effective contraception while enrolled on study and receiving the experimental drug, and for at least 3 months after the last treatment

Exclusion Criteria

History of ascites or pleural effusions , unless successfully treated, completely resolved, and the patient has not been treated for these conditions for >4 months
Active thrombophlebitis, thromboembolism, hypercoagulability states, bleeding, or use of anti-coagulation therapy. Patients with a history of deep venous thrombosis may participate if successfully treated, completely resolved, and no treatment has been given for >4 months
Hypercalcemia: Calcium >11.0 mg/dL (2.75 mmol/L) unresponsive or uncontrolled in response to standard therapy
Pregnant or nursing women
Diagnosis with another malignancy - unless following curative intent therapy, the patient has been disease free for at least 5 years and the probability of recurrence of the prior malignancy is <5%. Patients with curatively treated early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia are eligible for this study
Organ transplant, including allogeneic bone marrow transplant
Investigational agents used within 4 weeks prior to study enrollment (within 6 weeks for long-acting agents such as a monoclonal antibody)
Immunosuppressive therapy including: cyclosporine A, tacrolimus, or sirolimus
Significant or uncontrolled medical illness, such as congestive heart failure, myocardial infarction, symptomatic coronary artery disease, significant ventricular arrhythmias within the last 6 months, or significant pulmonary dysfunction. Patients with a remote history of asthma or active mild asthma may participate
Active infection, including unexplained fever (temperature >38.1 'C), or antibiotic therapy within 1 week prior to enrollment
Systemic autoimmune disease
Known allergy to component of GC1008 or 89Zr-GC1008
Significant medical or psychosocial problems

Sites / Locations

University Medical Center Groningen

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

GC1008 imaging and treatment

Arm Description

Part 1: Feasibility of 89Zr-GC1008 PET imaging in patients with suspicion of a malignant glioma to assess if GC1008 penetrates into the brain tumor and to quantify its uptake. Part 2: 89Zr-GC1008 PET imaging in patients with relapsed malignant glioma and phase II extension study with therapeutic GC1008 in these patients

Outcomes

Primary Outcome Measures

Biomarker imaging

Part 1, Biomarker imaging: 89Zr-GC1008 PET imaging in patients with suspicion of a malignant glioma: Primary endpoint: - Quantification of uptake of 89Zr-GC1008 as determined by PET imaging. The data obtained from the PET-scans will be quantified as standardized uptake value (SUV).

Quantification of uptake

Part 2, In relapsed malignant glioma patients 89Zr-GC1008 PET imaging followed by participation in phase 2 study of GC1008 Primary endpoint: - Quantification of uptake of 89Zr-GC1008 in relapsed malignant glioma patients as determined by PET imaging. The data obtained from the PET-scans will be quantified as standardized uptake value (SUV).

Secondary Outcome Measures

Correlation of 89Zr-GC1008 tumor uptake

Part 1, Biomarker imaging: 89Zr-GC1008 PET imaging in patients with suspicion of a malignant glioma: Secondary endpoint: - Correlation of 89Zr-GC1008 tumor uptake with tumor histology, immunohistochemistry for TGF-β, VEGF expression, TGF-β tumor levels as determined by ELISA.

Correlation of 89Zr-GC1008 tumor uptake

Part 1, Biomarker imaging: 89Zr-GC1008 PET imaging in patients with suspicion of a malignant glioma: Secondary endpoint: - 89Zr-GC1008 biodistribution in humans.

Secondary endpoints Part 2

Radiological Response Rate; measured by conventional MRI Overall survival (OS); assessed by clinical follow up 6-month progression-free survival (PFS) rate; assessed by clinical follow up Correlation of 89Zr-GC1008 tumor uptake pre-surgery and at relapse in the subgroup that underwent a 89Zr-GC1008 PET scan before primary surgery Number of patients with a positive PET scan as determined by quantification of uptake of 89Zr-GC1008 in relapsed malignant glioma patients. Correlation of 89Zr-GC1008 tumor uptake with treatment outcome.

Full Information

NCT ID

NCT01472731

First Posted

July 18, 2011

Last Updated

November 13, 2012

Sponsor

University Medical Center Groningen

Collaborators

Genzyme, a Sanofi Company

1. Study Identification

Unique Protocol Identification Number

NCT01472731

Brief Title

Safety and Imaging Study of GC1008 in Glioma

Official Title

Guiding GC1008 Treatment of Primary Brain Tumors by 89Zr-GC1008 PET Imaging.

Study Type

Interventional

2. Study Status

Record Verification Date

November 2012

Overall Recruitment Status

Completed

Study Start Date

December 2011 (undefined)

Primary Completion Date

November 2012 (Actual)

Study Completion Date

November 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University Medical Center Groningen

Collaborators

Genzyme, a Sanofi Company

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Detailed Description

Brain tumors account for only 2% of all cancers but result in a disproportionate share of cancer morbidity and mortality. The five-year survival rates for the most common histologic subtypes, anaplastic astrocytoma and glioblastoma (glioblastoma multiforme, GBM), are 30% and 10%, respectively. After surgery, the standard treatment of malignant glioma is focused on cell death induction by DNA damage, neglecting the fact that invasion into surrounding brain tissue is a fundamental feature of and the major reason for treatment failure. Drugs affecting transforming growth factor-β (TGF-β) might be of great interest for malignant glioma treatment. The reason for this is the fact that TGF-β acts as a tumor suppressor in normal epithelial cells and early-stage tumors but transforms in an oncogenic factor in advanced tumors where it induces proliferation, angiogenesis, invasion, and metastasis as well as suppresses the antitumoral immune response. In addition TGF-β expression and its TGF-β receptors, TβRI and TβRII, are overexpressed in GBMs. TGF-β signaling is involved in multiple steps of GBM development (Golestaneh, Mishra, 2005) and invasion (Wesolowska et al, 2008). Plasma TGF-β levels are elevated in GBM patients and decrease after surgical tumor resection (Schneider et al, 2006). Progression-free survival and overall survival are worse for malignant glioma patients with high TGF-β signaling compared with glioma patients with low TGF-β signaling activity (Bruna et al, 2007). All these features make TGF-β a promising target molecule for biological treatment approaches for GBM (Wick et al, 2006). Phase I/II-studies with the TGF-β2-specific antisense oligodeoxynucleotide AP12009 in malignant glioma showed promising results (Hau et al, 2007). Another approach to target TGF-β is with monoclonal antibodies, such as GC1008. GC1008 is a fully human IgG4 kappa monoclonal antibody capable of neutralizing all mammalian isoforms of TGF-β (i.e., 1, 2, and 3). For therapeutic success, it may be essential for GC1008 to reach the target site, in this case located in the brain. Our own data with 89Zr-bevacizumab, which is also an IgG, showed that the VEGF directed antibody bevacizumab penetrates the brain and is localized in brain metastases. We therefore expect GC1008 to reach the malignant glioma as well. In order to initiate clinical trials with TGF-β antibody in these patients it would clearly be of great help to prove that the drug arrives at the tumor site. 89Zr-GC1008 PET imaging will allow us to prove this. In addition, PET imaging allows quantification of the amount of GC1008 reaching the malignant glioma. A phase II study with GC1008 in patients with relapsed malignant gliomas will be initiated as currently, there is no standard treatment available for these patients. Study objectives: Part 1: Feasibility of 89Zr-GC1008 PET imaging in patients with suspicion of a malignant glioma to assess if GC1008 penetrates into the brain tumor and to quantify its uptake. Part 2: 89Zr-GC1008 PET imaging in patients with relapsed malignant glioma and phase II extension study with therapeutic GC1008 in these patients. For part 1, 12 patients will be included. For part 2, 12-20 patients will be included.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Primary Brain Tumors

Keywords

GC1008, PET imaging, primary brain tumors, recurrent high grade glioma's

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

12 (Actual)

8. Arms, Groups, and Interventions

Arm Title

GC1008 imaging and treatment

Arm Type

Experimental

Arm Description

Intervention Type

Other

Intervention Name(s)

89Zr-GC1008

Other Intervention Name(s)

89Zr-fresolimumab

Intervention Description

radioactive labeled GC1008, intravenous use, 37 MBq total

Intervention Type

Drug

Intervention Name(s)

GC1008

Other Intervention Name(s)

fresolimumab

Intervention Description

5 mg/kg intravenous use

Primary Outcome Measure Information:

Title

Biomarker imaging

Description

Time Frame

2 years

Title

Quantification of uptake

Description

Time Frame

2 years

Secondary Outcome Measure Information:

Title

Correlation of 89Zr-GC1008 tumor uptake

Description

Time Frame

2 years

Title

Correlation of 89Zr-GC1008 tumor uptake

Description

Part 1, Biomarker imaging: 89Zr-GC1008 PET imaging in patients with suspicion of a malignant glioma: Secondary endpoint: - 89Zr-GC1008 biodistribution in humans.

Time Frame

2 years

Title

Secondary endpoints Part 2

Description

Time Frame

2 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Part 1 Inclusion Criteria > 18 years WHO 0,1,2 Suspicion of malignant glioma on contrast-enhanced MRI Able to give written informed consent Exclusion Criteria Meningeal carcinomatosis, uncontrolled seizures, or a disease that either causes or threatens neurologic compromise Pregnant or nursing women Known allergy to component of 89Zr-GC1008 Significant medical or psychosocial problems Part 2 Inclusion Criteria Relapsed malignant glioma Patient may have undergone surgery for the recurrence. Residual and measurable disease after surgery is not required. Surgery must have confirmed the recurrence. Post-operative MRI must be made within 48 hours following surgery For non operated patients, recurrent disease must be at least one bidimensionally measurable target lesion (contrast enhancing lesion) with one diameter of at least 2cm, based on MRI scan done within 4 weeks prior to start of treatment 18 years WHO 0,1,2 Serum albumin ≥3.0 g/dL Adequate organ function including: Hb ≥10.0 g/dL ANC ≥1,500/mm3 platelets ≥100,000/mm3 Serum total bilirubin ≤1.5 x ULN (Patients with Gilbert's Disease may be included if their total bilirubin is ≤3.0 mg/dL) ALT and AST ≤2.5 x ULN. Estimated or measured creatinine clearance ≥60 mL/min PT and PTT within normal ranges Negative tests for hepatitis viruses B and C and HIV, unless the result is consistent with prior vaccination or prior infection with full recovery Enrollment >4 weeks since major surgery, radiotherapy, chemotherapy (≥6 weeks if they were treated with a nitrosourea, mitomycin, or monoclonal antibodies), immunotherapy, or biotherapy/targeted therapies and recovered from the toxicity of prior treatment to ≤ Grade 1, exclusive of alopecia. Concurrent cancer therapy is not permitted (except for corticosteroids) (For long acting agents, a treatment free interval of 2 half lives should be considered) Able to give written informed consent Patients of child-producing potential must agree to use effective contraception while enrolled on study and receiving the experimental drug, and for at least 3 months after the last treatment Exclusion Criteria History of ascites or pleural effusions , unless successfully treated, completely resolved, and the patient has not been treated for these conditions for >4 months Active thrombophlebitis, thromboembolism, hypercoagulability states, bleeding, or use of anti-coagulation therapy. Patients with a history of deep venous thrombosis may participate if successfully treated, completely resolved, and no treatment has been given for >4 months Hypercalcemia: Calcium >11.0 mg/dL (2.75 mmol/L) unresponsive or uncontrolled in response to standard therapy Pregnant or nursing women Diagnosis with another malignancy - unless following curative intent therapy, the patient has been disease free for at least 5 years and the probability of recurrence of the prior malignancy is <5%. Patients with curatively treated early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia are eligible for this study Organ transplant, including allogeneic bone marrow transplant Investigational agents used within 4 weeks prior to study enrollment (within 6 weeks for long-acting agents such as a monoclonal antibody) Immunosuppressive therapy including: cyclosporine A, tacrolimus, or sirolimus Significant or uncontrolled medical illness, such as congestive heart failure, myocardial infarction, symptomatic coronary artery disease, significant ventricular arrhythmias within the last 6 months, or significant pulmonary dysfunction. Patients with a remote history of asthma or active mild asthma may participate Active infection, including unexplained fever (temperature >38.1 'C), or antibiotic therapy within 1 week prior to enrollment Systemic autoimmune disease Known allergy to component of GC1008 or 89Zr-GC1008 Significant medical or psychosocial problems

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Annemiek ME Walenkamp, MD, PhD

Organizational Affiliation

University Medical Center Groningen

Official's Role

Principal Investigator

Facility Information:

Facility Name

University Medical Center Groningen

City

Groningen

ZIP/Postal Code

9713 GZ

Country

Netherlands

12. IPD Sharing Statement

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Safety and Imaging Study of GC1008 in Glioma

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