The safety run-in will be of a single arm de-escalating design which will recruit up to 16 patients with a variety of recurrent and/or metastatic squamous cell carcinomas. The modified Continual Reassessment Method (mCRM) will be used to determine dose de-escalation. The purpose is to establish the safety of the combination of cetuximab and avelumab in the planned schedule.

Up to 16 patients with squamous cell carcinomas of any origin will be registered to the safety run in. Patients will receive avelumab + cetuximab treatment in 4-week cycles and treatment may continue for up to one year.. The dose of cetuximab will be either 500, 400 or 300 mg/m2 depending on the dose level being studied at the time of registration.

Trial rationale: Platinum resistant HNSCC has limited therapeutic options and represents an area of unmet clinical need. It does, however, possess an immune landscape that is poised to respond to immunotherapeutic approaches. Whilst nivolumab and pembrolizumab have both shown encouraging results in HNSCC, further improvements are required. These human or humanised monoclonal antibodies targeting the PD1/PDL1 axis are either IgG4 isotypes, which do not mediate ADCC responses, or IgG1 isotypes which have been specifically engineered to eliminate ADCC activity.

Avelumab is a fully human IgG1 anti-PDL1 monoclonal antibody which also has potential ADCC properties.

We hypothesise that avelumab’s anti-tumour activity will not only be by interruption of the PD1/PDL1 axis but also enhanced by activation of the ADCC pathway and augmentation of the NK response. The latter of these mechanisms will also be assisted by the secondary actions of cetuximab, alongside its direct effect on the frequently overexpressed EGFR and its potential to influence T cell architecture through tumour glycolysis regulation.

This study aims to examine the impact of the synergistic mechanisms of actions of cetuximab and avelumab.

Justification of the doses: We are aiming to give both drugs at their standard single agent doses in the EACH trial, but the phase II dose of cetuximab will be guided by the safety run-in.

Overall Aim: Safety run-in: To establish the safety of the combination of avelumab + cetuximab and to determine the optimum dose of cetuximab to use in this combination in patients with squamous cell carcinomas; 

Target accrual: Safety run-in: up to 16 patients with squamous cell carcinomas (SCC)

Definition of end of trial: The end of the trial will be 24 months after registration of the final patient, or once all patients have progressed or died, whichever is sooner.

Safety run-in

Patients will receive avelumab + cetuximab. The dose of cetuximab will be either 500, 400 or 300 mg/m² depending on the dose level being studied at the time of registration. All IMPs are administered intravenously (IV). Patients on both arms will receive treatment in 4-week cycles and treatment may continue for up to one year.

Avelumab + cetuximab will be given as follows:

·    Cycle 1

o   Day 1: Cetuximab 500* mg/m² given IV over approximately 3 hours

o   Day 15: Cetuximab 500* mg/ m² given IV over approximately 2 hours, followed by avelumab 10 mg/kg given IV over approximately 1 hour

·    All other cycles:

o   Days 1 and 15: Cetuximab 500* mg/m² given IV over approximately 2 hours, followed by avelumab 10 mg/kg given IV over approximately 1 hour

*Cetuximab dose will be according to current cohort.

There must be a 60 minute break between the administration of cetuximab and avelumab.

Inclusion criteria

1.       Histologically or cytologically confirmed recurrent or metastatic squamous cell carcinoma of any site that is considered incurable by local therapies.

2.       No previous treatment with cetuximab for metastatic/recurrent disease.

3.      Age ≥ 18 years.

4.      World Health Organisation Performance Status of 0 or 1.

5.      Measurable disease according to RECIST v1.1.

6.      Adequate major organ function.

8.      Agreement to use adequate contraception.

9.     Able to give informed consent.

Exclusion criteria

1.        Patients with sino-nasal cancers.

2.        Disease suitable for treatment with curative intent.

3.        Prior therapy with an anti-PD-1, anti-PD-L1 or anti-PD-L2 agent.

4.        Treatment with any investigational agents within 4 weeks prior to the first dose of trial treatment.

5.        Anti-cancer monoclonal antibody therapy within 4 weeks prior to registration

6.        Chemotherapy, targeted small molecule therapy, or radiotherapy within 2 weeks prior to registration

7.        Persisting grade ≥ 2 toxicity related to prior therapy, except the following:

o   Alopecia

o   Sensory neuropathy grade 2

o   Other grade 2 toxicity as long as it does not constitute a safety risk based on the investigator’s judgement.

8.        Concurrent or previous malignancy that could compromise assessment of the primary or secondary endpoints of the trial.

9.       Women who are pregnant or breast feeding.

10.     Grade 3 or 4 peripheral neuropathy.

11.     Hepatitis infection at screening.

12.     Known history of testing positive for HIV or known acquired immunodeficiency syndrome. Testing for HIV is not mandatory, however if this test has been done the result should be known prior to registration.

13.     Prior organ transplantation including allogeneic stem-cell transplantation.

14.     Has a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.

15.     Has received a live vaccine within 28 days prior to first dose of trial treatment (seasonal flu vaccines that do not contain live virus are permitted).

16.   Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment (NB: the use of physiologic doses of corticosteroids may be approved after consultation with UCL CTC).

17.     Active autoimmune disease that might deteriorate when receiving an immune-checkpoint inhibitor. Patients with the following are eligible:

o   autoimmune-related hyperthyroidism or autoimmune-related hypothyroidism who are in remission or on a stable dose of thyroid-replacement hormone

o   vitiligo

o   psoriasis.

18.     Current use of immunosuppressive medication, except for the following:

o   intranasal, inhaled, topical steroids, or local steroid injection

o   Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisolone or equivalent

o   Steroids as premedication for hypersensitivity reactions.

19.     History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organising pneumonia, or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field is permitted).

20.     Significant cardiovascular disease.

21. Patients with a history of keratitis, ulcerative keratitis or severe dry eye.

5 months