NCT03844763

Targeting the Tumor Microenvironment in R/M SCCHN

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
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 71 (estimated)
• Sponsor: Gruppo Oncologico del Nord-Ovest · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Phase I - II trial of the combination of cyclophosphamide, RT, and Avelumab in relapsed/metastatic HNSCC (R/M-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 mg/kg 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.

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 (iTrge)7. 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, i.e. 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 2.3.2) 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.

Conditions

• Head and Neck Cancer

Interventions

Type	Name	Description
DRUG	Avelumab	Avelumab: 10 mg/kg every 2 weeks, untill PD or major toxicity
DRUG	CTX	CTX: 50 mg Daily untill PD or major toxicity
RADIATION	RT	RT: 8 Gy single shot day 8

Timeline

• Start date: 2019-01-07
• Primary completion: 2024-06-30
• Completion: 2024-06-30
• First posted: 2019-02-18
• Last updated: 2020-03-03

Locations

2 sites across 1 country: Italy