Ignite Creation Date:
2024-05-06 @ 12:45 PM
Last Modification Date:
2024-10-26 @ 1:04 PM
Study NCT ID:
NCT03844763
Status:
UNKNOWN
Last Update Posted:
2020-03-03
First Post:
2019-02-11
Brief Title:
Targeting the Tumor Microenvironment in RM SCCHN
Sponsor:
Gruppo Oncologico del Nord-Ovest
Organization:
Gruppo Oncologico del Nord-Ovest
Study Overview
Official Title:
The CONFRONT Phase I - II Trial ACtivatiON oF Immune RespONse in paTients With R-M Head and Neck Cancer Multimodality Immunotherapy With Avelumab Short Course Radiotherapy and Cyclophosphamide in Head and Neck Cancer
Status:
UNKNOWN
Status Verified Date:
2020-03
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
CONFRONT
Brief Summary:
Phase I - II trial of the combination of cyclophosphamide RT and Avelumab in relapsedmetastatic HNSCC RM-HNC Patients pretreated with at least one line therapy containing platinum fluorouracil and Cetuximab Treatment consists of metronomic cyclophosphamide 50 mg daily without drug free break avelumab 10 mgkg d1 and 15 q 29 and radiotherapy in one or three daily fractions up to 8 Gy maximum dose starting at day 8 The aim of the study is to reverse tumor immune-escape by
1 Provide a self-vaccination with radiotherapy
2 Inhibit the immunosuppressive CD4 CD25 FoxP3 Treg cells with metronomic cyclophosphamide
3 Reactivate the effector T cell by the inhibition of PD-1 - PD-L1 axis with avelumab
Due to the supposed biological effects of the present trial an ancillary translational study is needed and will be extended to all the patients population enrolled
1 Provide a self-vaccination with radiotherapy
2 Inhibit the immunosuppressive CD4 CD25 FoxP3 Treg cells with metronomic cyclophosphamide
3 Reactivate the effector T cell by the inhibition of PD-1 - PD-L1 axis with avelumab
Due to the supposed biological effects of the present trial an ancillary translational study is needed and will be extended to all the patients population enrolled
Detailed Description:
Rational of the trial
A phase I - II trial in RM-HNC based on pharmacologic and physic interventions related to each other facing immunology as a system rather than a single pathway theoretically able to restore immune competence toward the tumor The immune suppressive mechanisms that could be affected by this study and how the experimental approach could inhibit them are listed below
PD-1 - PD-L1 axis is widespread among immune cell family including CTL Treg NK NKT APC and others showing for example opposite effect in CD8 CTL inhibitory signal or in CD4 CD25 Foxp3 activating signal
Depletion of Treg results in tumor regression in experimental models The effect seems to be dependent on the extent of Treg suppression
Avelumab is a fully human anti-PD-L1 IgG1 monoclonal antibody It enables the activation of T-cells and the adaptive immune system by inhibiting PD-1 - PD-L1 axis induces antibody-dependent cell-mediated cytotoxicity ADCC and engages the innate immune system
Low dose cyclophosphamide metronomic cyclophosphamide selectively reduce Treg population both in experimental models and in humans but it does not affect effector T cells
PD-1 - PD-L1 axis enhances and sustains Foxp3 expression and the suppressive function of inducible Tregs iTrge7 The blockade of the PD1 - PDL1 axis by Avelumab may have an opposite effect
The contemporary use of two independent mechanisms of Treg control Avelumab inhibiting Treg clonal expansion and functions and cyclophosphamide reducing Treg population may result in a profound inhibition of Treg population
If the suppressive mechanisms of the immune system are weakened the release of high quantity of tumor specific antigens or stress related antigens epcam HSPs HMBG-1 Calreticulin ATP obtained by the induction of immunogenic cell death may induce a sort of self vaccination resulting into an effective immune response
Radiation may induce immunogenic cell death even in heavily pretreated patients in whom the use of cytotoxic chemotherapy may not due to the previous exposure to drugs and the development of resistance mechanisms More precisely this effect is considered the basis of the Abscopal effect ie the regression of tumor deposits outside the irradiated field This effect is more frequently observed with low-dose non ablative hypofractionated radiation therapy described at point 232 and represent a proof of concept that in particular situations radiotherapy act as an inducer of self vaccination
IgG1 mAbs such as Avelumab triggers ADCC PD-L1 is widely express in many tumors and so ADCC may represent an additional mechanism of tumor control
A phase I - II trial in RM-HNC based on pharmacologic and physic interventions related to each other facing immunology as a system rather than a single pathway theoretically able to restore immune competence toward the tumor The immune suppressive mechanisms that could be affected by this study and how the experimental approach could inhibit them are listed below
PD-1 - PD-L1 axis is widespread among immune cell family including CTL Treg NK NKT APC and others showing for example opposite effect in CD8 CTL inhibitory signal or in CD4 CD25 Foxp3 activating signal
Depletion of Treg results in tumor regression in experimental models The effect seems to be dependent on the extent of Treg suppression
Avelumab is a fully human anti-PD-L1 IgG1 monoclonal antibody It enables the activation of T-cells and the adaptive immune system by inhibiting PD-1 - PD-L1 axis induces antibody-dependent cell-mediated cytotoxicity ADCC and engages the innate immune system
Low dose cyclophosphamide metronomic cyclophosphamide selectively reduce Treg population both in experimental models and in humans but it does not affect effector T cells
PD-1 - PD-L1 axis enhances and sustains Foxp3 expression and the suppressive function of inducible Tregs iTrge7 The blockade of the PD1 - PDL1 axis by Avelumab may have an opposite effect
The contemporary use of two independent mechanisms of Treg control Avelumab inhibiting Treg clonal expansion and functions and cyclophosphamide reducing Treg population may result in a profound inhibition of Treg population
If the suppressive mechanisms of the immune system are weakened the release of high quantity of tumor specific antigens or stress related antigens epcam HSPs HMBG-1 Calreticulin ATP obtained by the induction of immunogenic cell death may induce a sort of self vaccination resulting into an effective immune response
Radiation may induce immunogenic cell death even in heavily pretreated patients in whom the use of cytotoxic chemotherapy may not due to the previous exposure to drugs and the development of resistance mechanisms More precisely this effect is considered the basis of the Abscopal effect ie the regression of tumor deposits outside the irradiated field This effect is more frequently observed with low-dose non ablative hypofractionated radiation therapy described at point 232 and represent a proof of concept that in particular situations radiotherapy act as an inducer of self vaccination
IgG1 mAbs such as Avelumab triggers ADCC PD-L1 is widely express in many tumors and so ADCC may represent an additional mechanism of tumor control
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None