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))

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01112293

Enrollment

Registered

2010-04-28

Start date

2010-04-30

Completion date

2014-12-31

Last updated

2020-04-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pleural Malignant Mesothelioma

Keywords

Subjects who have pleural malignant mesothelioma

Brief summary

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.

Detailed description

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.

Interventions

DRUGGC1008

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.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Pathologically \[histologically or cytologically\] documented pleural malignant mesothelioma. Patients must have had at least one, but no more than two prior systemic therapies, at least one of which contained pemetrexed. * Documented progressive disease evaluable by Modified RECIST criteria. \[Progressive symptoms after 1st line therapy in the absence of objective progression are acceptable as a criterion for enrollment\]. Patients who have had previous extrapleural pneumonectomy and disease recurrence will be eligible if they have no other

Exclusion criteria

. * ECOG Performance status of 0 or 1. * Greater or equal to 18 years of age. * Male and female 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. * Women of childbearing potential must have a negative serum or urine pregnancy test within 1 week prior to beginning treatment on this trial. * Must be able and willing to give written informed consent. Patients may not be consented by a durable power of attorney. * Serum albumin greater or equal to 2.5 * Adequate organ function * Patients must have negative tests for human immunodeficiency virus (HIV) and for hepatitis viruses B and C (antibody and/or antigen) unless the result is consistent with prior vaccination or prior infection with full recovery. * At the time of enrollment, patients must be greater than 3 weeks since major surgery, radiotherapy, chemotherapy (greater or equal to 6 weeks if they were treated with a nitrosourea, mitomycin or monoclonal antibody), immunotherapy, or biotherapy/targeted therapies and recovered from the toxicity of prior treatment to less than or equal to Grade 1, exclusive of alopecia. Concurrent non-protocol cancer therapy is not permitted. (In patients who received long acting agents, a treatment free interval of 2 half lives should be considered.) Note: Although a patient can be entered by these criteria, if a patient is less than 3-6 months from radiotherapy or talc pleurodesis, FDG-PET scanning will not be useful. 12).

Design outcomes

Primary

Measure	Time frame	Description
3-month Progression Free Survival Rate	3 months	The fraction of subjects surviving 3 months without disease progression.

Secondary

Measure	Time frame	Description
Toxicity and Safety of Systemic Infusion of Anti-TGF Antibody	18 months	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.

Other

Measure	Time frame	Description
Number of Participants With a Change of Serum Biomarkers After Therapy	18 months	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.
Number of Participants With Systemic Humoral Anti-tumor Immune Response After Repeated Anti-TGFβ Antibody Instillation	18 months	Comparing antibody bands in pre-treatment versus post-treatment serum
Time to Progression and Overall Survival	18 months	Assessment of time to disease progression and overall survival
Biologic Response Measurements of TGFβ Blockade	3 weeks	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.
Assessment of Systemic TGFβ After Repeated Anti-TGFβ Antibody Installation	18 months	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.
Response Rate Using Modified RECIST Criteria for Mesothelioma	18 months	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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
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.	14
Total	14

Arm

Count

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.

Total

Baseline characteristics

Characteristic	Investigational Drug infusion-for Safety and Effectiveness
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	11 Participants
Age, Categorical Between 18 and 65 years	3 Participants
Region of Enrollment United States	14 participants
Sex: Female, Male Female	2 Participants
Sex: Female, Male Male	12 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	12 / 14
other Total, other adverse events	12 / 14
serious Total, serious adverse events	6 / 14

Outcome results

Primary