Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Mesothelioma

Mesothelioma, Malignant

Adenoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Mesothelial

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Pleural Neoplasms

Lung Diseases

Respiratory Tract Diseases

Malignant Mesothelioma

All Drugs and Chemicals

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Phase II, Single-Arm, Multi-Site study. All subjects will receive the investigational agent, GC1008 in 3 week cycles of treatment

GC1008 is a human IgG4 kappa monoclonal antibody capable of neutralizing all mammalian isoforms of TGFbeta (i.e., beta1, beta 2 and beta 3). GC1008 is a high affinity antibody with dissociation constants (Kds) of 1.8 nM, 2.8 nM and 1.4 nM for TGF1,2,and 3, respectively.

GC1008

James Stevenson, MD

This study is being conducted to evaluate the overall safety and effectiveness of an investigational drug, GC1008, in patients with mesothelioma. An investigational drug is one that has not been approved by the FDA. Approximately 40 people will be enrolled on this study at the University of Pennsylvania (Main Institution/Coordinating Site) and the University of Chicago (Participating Institution). We expect about 20 subjects to be enrolled at each institution.

Primary: - To assess progression-free survival rate at three months.

Secondary: - To determine the toxicity and safety of systemic infusion of anti-TGF beta antibody at three-week dosing intervals. - To assess time to progression and overall survival - to assess response rate using Modified RECIST Criteria for Mesothelioma Additional Objectives: - To assess efficacy using serial measurements of serum \[and intrapleural, if indwelling catheter in place\] biomarkers, including serum-mesothelin related peptide (SMRP/Mesomark®) and osteopontin. - To assess systemic \[and intrapleural if indwelling catheter in place\] humoral anti-tumor immune responses after repeated anti-TGF beta antibody instillation. - To assess systemic \[and intrapleural, if indwelling catheter in place\] TGF beta, and other cytokine levels after repeated anti-TGF beta antibody instillation. - To assess biologic response measurements of TGF beta blockade from serum tests and from pleural fluid or biopsy tissue if this is available.

Anti-TGF Monoclonal Antibody (GC1008) in Relapsed Malignant Pleural Mesothelioma

A Phase II Trial of Anti-TGF Monoclonal Antibody (GC1008) in Relapsed Malignant Pleural Mesothelioma (MPM))

Assessment of time to disease progression and overall survival

Response and progression will be evaluated in this study using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in RECIST. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.

Evaluation of changes after treatment therapy to a number of potential blood biomarkers of TGF-β effect (serum osteopontin, serum hyaluronan, serum MMP-1, serum MMP-7, serum IL-6, plasma CCL18, plasma VEGF, and plasma PAI-1). Animal models predict acute changes in TGF-β levels in blood associated with changes in serum biomarkers.

Comparing antibody bands in pre-treatment versus post-treatment serum

The number of participants with significant change in percentage of circulating CD4+ T regulatory cells, marked by expression of FOXP3 after treatment. TGFβ has been implicated in the formation of T regulatory cells, and the blockade of TGFβ in animal models can inhibit the formation of T regulatory cells.

Number of participants who demonstrated upregulation of NK cell receptors 3 weeks after treatment. There are data that show anti-TGFβ antibodies can upregulate NK cell receptors in patients with chronic viral infections. TGFβ blockade was measured in samples of serum tests and from pleural fluid or biopsy if available.

The fraction of subjects surviving 3 months without disease progression.

The toxicity and safety of systemic infusion of anti-TGF antibody at three-week dosing intervals. Number subjects with Grade 2 and Grade 3/4 treatment related toxicities.

Abramson Cancer Center at Penn Medicine

Phase II, Single-Arm, Multi-Site study. All subjects will receive the investigational agent, GC1008 in 3 week cycles of treatment.

GC1008: GC1008 is a human IgG4 kappa monoclonal antibody capable of neutralizing all mammalian isoforms of TGFbeta (i.e., beta1, beta 2 and beta 3). GC1008 is a high affinity antibody with dissociation constants (Kds) of 1.8 nM, 2.8 nM and 1.4 nM for TGF1,2,and 3, respectively.

Investigational Drug infusion-for Safety and Effectiveness

Phase II, Single-Arm, Multi-Site study. All subjects will receive the investigational agent, GC1008 in 3 week cycles of treatment

GC1008: GC1008 is a human IgG4 kappa monoclonal antibody capable of neutralizing all mammalian isoforms of TGFbeta (i.e., beta1, beta 2 and beta 3). GC1008 is a high affinity antibody with dissociation constants (Kds) of 1.8 nM, 2.8 nM and 1.4 nM for TGF1,2,and 3, respectively.

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

Limitations of the trial include small sample size and lack of post-tumor treatment samples.

James Robinson

Outcome analysis presented in manuscript of results of trial based on 13 participants.

3-month Progression Free Survival Rate

Grade 2 Treatment Related Toxicities

Grade 3/4 Treatment Related Toxicities

Toxicity and Safety of Systemic Infusion of Anti-TGF Antibody

Time to Progression

Overall Survival

Time to Progression and Overall Survival

Response Rate Using Modified RECIST Criteria for Mesothelioma

Change in serum osteopontin after treatment

Change in serum hyaluronan after treatment

Change in serum MMP-1 after treatment

Change in serum MMP-7 after treatment

Change in serum IL-6 V after treatment

Change in plasma CCL18 v after treatment

Change in plasma VEGF after treatment

Change in plasma PAI-1 after treatment

Number of Participants With a Change of Serum Biomarkers After Therapy

Number of Participants With Systemic Humoral Anti-tumor Immune Response After Repeated Anti-TGFβ Antibody Instillation

Assessment of Systemic TGFβ After Repeated Anti-TGFβ Antibody Installation

Biologic Response Measurements of TGFβ Blockade

Overall Study

Symptoms and General Pathology

Nervous System Diseases

Recurrence

Glioma

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Immunologic Factors

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

radioactive labeled GC1008, intravenous use, 37 MBq total

89Zr-GC1008

Annemiek ME Walenkamp, MD, PhD

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.

Drugs affecting transforming growth factor-β (TGF-β) might be of great interest for malignant glioma treatment. TGF-β is 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 and its TGF-β receptors, TβRI and TβRII, are overexpressed in GBMs. TGF-β signaling is involved in multiple steps of GBM development. GC1008 is an antibody that is capable of neutralizing TGF-β and may therefore offer a new treatment option for patients with malignant glioma.

For therapeutic success, it may be essential for GC1008 to reach the target site, in this case located in the brain. We will be able to prove this with 89Zr-GC1008 PET imaging. This imaging method also allows quantification of the amount of GC1008 reaching the tumor.

This study consists of 2 parts. In part 1, patients with a suspicion of a malignant glioma undergo an 89Zr-GC1008 PET scan before standard (surgical)treatment. In part 2, patients with relapsed malignant glioma will undergo an 89Zr-GC1008 PET scan and will be treated with GC1008 in a phase II study as there is no standard treatment for these patients.

We hypothesize that GC1008 uptake in brain tumors can be visualized and quantified using the 89Zr-GC1008 PET scan and GC1008 might offer a new treatment option for patients with relapsed malignant gliomas.

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.

Safety and Imaging Study of GC1008 in Glioma

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

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).

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.

Part 1, Biomarker imaging: 89Zr-GC1008 PET imaging in patients with suspicion of a malignant glioma:

Secondary endpoint:

- 89Zr-GC1008 biodistribution in humans.

* 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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Anti-TGF Monoclonal Antibody (GC1008) in Relapsed Malignant Pleural Mesothelioma	NCT01112293	Pleural Maligna...	GC1008	18 Years -	Abramson Cancer Center at Penn Medicine
Safety and Imaging Study of GC1008 in Glioma	NCT01472731	Primary Brain T...	89Zr-GC1008 GC1008	18 Years - 75 Years	University Medical Center Groningen
Anti-TGF Monoclonal Antibody (GC1008) in Relapsed Malignant Pleural Mesothelioma	NCT01112293	Pleural Maligna...	GC1008	18 Years -	Abramson Cancer Center at Penn Medicine

Spots Global Cancer Trial Database for gc1008

Every month we try and update this database with for gc1008 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for gc1008

Every month we try and update this database with for gc1008 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for gc1008 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.