ImmunoModulation by the Combination of Ipilimumab and nivolumab neoadjuvant to Surgery In advanced Or recurrent Head and Neck Carcinoma, (IMCISION), a phase-Ib/II trial. Subtitle: Hypoxia as a determinant for the effect of nivolumab with or without ipilimumab on intra-tumoral T cell capacity

Head and neck squamous cell carcinoma (HNSCC) is the 7th most common cancer in
men and the 9th most common cancer in women. In 2011, 3000 patients were
diagnosed with head and neck cancer in the Netherlands. In advanced stage oral
cavity carcinoma and salvage surgery after failed (chemo)radiation, patients
generally suffer extensive mutilating surgery, and nevertheless have a very
poor prognosis of 37% 5-year overall survival in stage IV oral HNSCC and 20-40%
2-year overall survival after salvage surgery. Although multiple (neo)adjuvant
chemotherapeutic regimens have been evaluated, clinical benefit fails to appear.

T cell checkpoint blockade by anti-CTLA and/or anti-PD1 is currently the most
promising in immunomodulation anticancer therapies. In HNSCC, pembrolizumab
(anti-PD1 monoclonal antibody) given at a fixed dose of 200 mg every 3 weeks
was well tolerated and demonstrated a clinically meaningful overall response
rate of 24.8% in patients with recurrent/metastatic disease, irrespective of
HPV status. In addition, biweekly Nivolumab 3 mg/kg in recurrent or metastatic
setting of HNSCC has doubled the 1 year survival rate from 16% to 36%.

The rationale behind combining aPD1 and aCTLA4 is that nivolumab and ipilimumab
enhance T-cell antitumor activity through distinct but complementary mechanisms
resulting in both enhanced T-cell priming and enhanced local T-cell-mediated
tumor destruction. The complementary effect of both checkpoint inhibitors was
first proven in a phase III trial treating metastatic melanoma with response
rates of 58%. Shortly after, a study involving thirty-nine stage IIIB/IV
Non-Small Cell Lung Carcinoma patients treated with nivolumab 3 mg/kg and
ipilimumab 1 mg/kg, 8 and 2 infusions respectively, and an overall treatment
period of 15-18 weeks, resulted in 31% durable response rates.

Moreover, very recently, it was postulated that offering the combination of
nivolumab and ipilimumab in neo-adjuvant setting would exert even stronger
immunomodulation and increased tumor responses to treatment, when compared to
adjuvant immunotherapy. One hypothesis is that the presence of tumor load
before surgery offers increased neo-antigen presentation with consequently more
efficient T-cell receptor triggering. In addition, reduced tumor heterogeneity,
as compared to treatment in the metastatic setting, and improved immune status
during earlier disease status are factors that are likely to positively
influence the efficacy of immunomodulation in this setting. Indeed, recent,
early clinical data evaluating the activity of neo-adjuvant nivolumab and
ipilimumab in stage III melanoma provide support for this hypothesis.

Although immunotherapy has proven to be effective in various tumor types, a
reliable predictive biomarker for treatment response does not exist. Hypoxia is
a well-known biomarker for treatment response (RT, chemotherapy and surgery) in
various solid tumors (e.g. lung, kidney, HNSCC) and a vast amount of
preclinical data indicates a key role for hypoxia on T cell (both CD4 and CD8)
metabolism, fate and function. Therefore, hypoxia may be a clinical biomarker
for tumor response to immunotherapy in solid cancers in general.

Reported by others, repeated hypoxia PET scans with [18F]HX4 provide
reproducible and spatially stable results in patients with head and neck cancer
and patients with lung cancer. [18F]HX4 PET imaging can be used to assess the
hypoxic status of tumors and has the potential to aid hypoxia-targeted
treatments. Furthermore, robust RNA expression hypoxia signatures have been
developed over the years. Such signatures are used to identify patients for
selective treatment to overcome hypoxia. Recently, a 15-gene hypoxia classifier
was validated in 323 patients with HNSCC randomized for hypoxic modification or
placebo in combination with radiotherapy. Tumors categorized as hypoxic on the
basis of the classifier were associated with a significantly poorer clinical
outcome than non-hypoxic tumors. In addition, technical validation of the
15-gene hypoxia classifier demonstrated that it is suitable for implementation
in prospective clinical trials as well.

Herewith, we present a research protocol that allows us to examine feasibility
and safety of checkpoint blockade neoadjuvant to standard of care (SOC) in a
patient population in need for improved clinical outcome and in tumors likely
to respond to neoadjuvant aPD1 and aCTLA4. Participation in this trial, may
offer our patients the chance for a significant improved clinical outcome in
terms of loco-regional control and survival.

In addition, with this research protocol we can assess the potential impact of
intratumoral hypoxia on tumor infiltrating lymphocyte (TIL) abundance,
differentiation and effector function, and the potentially divergent effects of
T cell checkpoint blockade in areas of hypoxia and normoxia. As such, the
results of our study may have large implications for the development of
combination treatments that aim to further enhance tumor-specific T cell
activity in solid tumors characterized by intra-tumoral hypoxia (as ao HNSCC
and lung cancer) during checkpoint blockade therapy.

This is a Phase 1b/II trial. For the design see figure 1.

The phase Ib is designed as 3 + 3, with primary objective feasibility and
toxicity.
The phase II is designed as a single arm design with primary endpoint efficacy.
Of Note: we wish to see endpoints reached in all 6 patients of cohort 1 and 2,
before we will continue to the next cohort.

In phase Ib, two cohorts will be used (cohort 1: nivolumab only and cohort 2:
nivolumab and ipilimumab neoadjuvant to surgery) to define which neoadjuvant
immunotherapy regimen will be taken towards the expansion cohort 3. Of Note: we
wish to see endpoints reached in all 6 patients of cohort 1 and 2, before we
will continue to the next cohort.

Thirty-two patients will be treated with : nivolumab (240 mg flat dose, week 1
and week 3, twice in total) as a single agent or: the combination of ipilimumab
(1 mg/kg) + nivolumab (240 mg flat dose) in week 1, and nivolumab 240 mg flat
dose in week 3, neoadjuvant to SOC (surgery with or without adjuvant (C)RT).

Patients will be treated with
- 2x nivolumab 240 mg flat dose, weeks 1 and 3, OR
- the combination of 1x ipilimumab 1 mg/kg + nivolumab 240 mg flat dose in week
1 and nivolumab mono-therapy 240 mg flat dose in week 3.

Immunotherapy (IT) is given neoadjuvant to standard of care (SOC: surgery with
or without adjuvant (C)RT). Surgery will be planned in week 5. Adjuvant (C)RT
will start 4-6 weeks after surgery.

Benefit
Advanced primary or recurrent HNSCC is treated with major surgery
(commando-procedure) with or without (C)RT. Despite the use of surgical free
vascular reconstruction flaps *allowing for the reconstruction of large defects
and proper resection margins- and despite adding high-dose cisplatin
concurrently to adjuvant RT, the overall survival of these patients remained
20-40% 5-year. In addition, no improvement of clinical outcome was established
by applying neo-adjuvant chemotherapy regimens.

In 2015, with Pembrolizumab a new and promising treatment modality for this
type of patients was introduced, as Seiwert found 25% tumor response rate in
metastatic HNSCC, in both HPV- and non-HPV related disease. In addition, in
recurrent and metastatic disease, Nivolumab has shown to double the one-year
survival rates of HNSCC form 17% to 39%.
Meanwhile, it was shown that combining aPD1 and aCTLA4 checkpoint inhibitors
leads to superior immunomodulation, resulting in increased durable tumor
response rates of 58% and 31% in other carcinomas with a high-mutational load
as melanoma and lung carcinoma, respectively.

Therefore, participation in this trial may offer these patients the chance for
significant improved clinical outcome in terms of loco-regional control and
survival, based on the above observations.

Risk
In palliative HNSCC setting, Nivolumab monotherapy 3 mg/kg every 2 weeks for a
treatment time of 1.9 months has resulted in 13% grade 3-4 side effects. In a
previous trial involving lung carcinoma and the combination treatment of
(neoadjuvant) nivolumab 3 mg/kg (median 8 doses, every 2 weeks) and ipilimumab
1 mg/kg (median 2 doses, every 6 weeks) was accompanied by 28% grade 3-4 AEs.
As lung carcinoma patients may be relatively comparable to head and neck SCC
patients concerning age and smoking status, it could be that the toxicity data
of this lung carcinoma trial may reflect the toxicity to be expected in our
patient population. Of Note: Our IMCISION trial involves less infusions (two
dosages) of immunotherapy and consequently a shorter immunotherapy treatment
time (3 weeks), when compared to the above described trial.

Preliminary data of our institute show that our hospital has gained the
expertise to manage a nivo/ipi combination scheme in a neoadjuvant setting
without delaying the time of surgery. Nevertheless, of caution, the proposed
IMCISION treatment cohort 2 will offer the combination of nivo/ipi (nivo 240 mg
flat dose and ipi 1mg/kg) once in the first week, and it will offer nivo
monotherapy (240 mg flat dose) in week 3, whereas the OPACIN trial offered
combined nivo/ipi (3 and 3 mg/kg) in both weeks 1 and 4. As in our proposed
study the combination of nivolumab and ipilimumab (cohort 2) will be given 4
weeks prior to surgery, and as the last infusion of nivolumab will be given two
weeks prior to surgery, patients will be enabled to recover from acute side
effects.

In summary, we believe that the expected grade 3-4 toxicity in the proposed
IMCISION trial will be manageable and will not delay the time of surgery.

For this trial, patients will undergo 2-3 extra tumor biopsies for research
purposes twice: the first time during routine investigation under general
anesthesia, and the second time during routine surgery. The first time, it is
our experience that patients may endure slight temporarily discomfort due
taking extra biopsies and a very small enlarged risk (< 1%) for bleeding and
infection afterwards. The second time, patients will obviously not experience
any side-effects from harvesting these biopsies, as the whole tumor will be
dissected during surgery.