'DURVIT': Single low-dose DURValumab IntraTumorally injected in cervical cancer: safety, toxicity and effect on the primary tumour- and lymph node microenvironment.

Cervical cancer is the fourth most common cancer in women worldwide and is
caused by a high-risk human papilloma virus (HPV) types persistent infection.
In the Netherlands, the highest cervical cancer incidence lies between 35 and
45 years. The most important prognostic factor in early-stage cervical cancer
is the presence of metastatic tumor cells in the pelvic lymph nodes. After
radical hysterectomy and pelvic lymphadenectomy,
women with negative lymph nodes, staged as FIGO IB or IIA, have a 5-year
survival rate of around 80-85%, compared to 40-75% for patients with lymph node
metastasis. Additional treatments are urgently needed to improve the prognosis
of these patients. In order to achieve this, novel immunotherapeutic strategies
are pursued. A highly promising area of research focuses on lifting of
tumor-induced immune suppression. One of the major recent breakthroughs in
(clinical) oncology has been the unraveling and harnessing of the PD-1/PD-L1
checkpoint pathway for different types of cancer. However, the current systemic
treatment with PD-1 and PD-L1 inhibitors often causes autoimmune-related
inflammatory side-effects. As cervical cancer does not readily metastasize to
distant organs but initially to regional lymph nodes we believe that local,
intratumoral administration of durvalumab (PD-L1 checkpoint inhibitor) at an
early stage (as tested in the DURVIT trial) will deliver these antibodies
exactly where they are needed and most effective, i.e. the primary tumor and
the tumor-draining lymph nodes (TDLN). Consequently, metastatic spread will be
halted at an early stage, resulting in a major clinical benefit for these
patients, while significantly reducing the undesirable systemic side-effects.
Most promisingly, we recently demonstrated in patients with melanoma that such
local immune modulation can also lead to boosting of systemic immunity and
profoundly increased 10-year recurrence-free survival rates(Koster et al.,
submitted). This proposal will demonstrate the biological efficacy of local
PD-L1 blockade in early-stage cervical cancer and will yield informative and
possibly early predictive signatures that may prove useful in patient selection
and the rational design of follow-up clinical trials. The ability to stop
cancer in its tracks at an early stage by local treatment resulting in
loco-regional and systemic tumor control (with minimal side effects), will have
a major impact on patient survival and quality of life. Moreover, it could save
society the towering costs associated with systemic treatments in more advanced
stages of the
disease.

In the proposed project, we will conduct a clinical phase I trial with cervical
cancer patients, scheduled to undergo radical hysterectomy and pelvic
lymphadenectomy, to assess the safety and toxicity as primary endpoints and, as
an explorative outcome, immunological effects of local administration of
durvalumab on the primary tumour- and lymph node microenvironment. Obtained
results may open new ways for pre-operative localized treatment of cervical
cancer with minimal risk of unwanted side effects. The accompanying immune
monitoring program will not only deepen our knowledge of mechanisms underlying
clinical efficacy but may also advance patient stratification, which could aid
personalized treatment.
The ability to stop cancer in its tracks at an early stage by local treatment
resulting in loco-regional and systemic tumor control (with minimal side
effects), will have a major impact on patient survival and quality of life.
Moreover, it could save society the towering costs associated with systemic
treatments in more advanced stages of the disease.

This is a non-randomized, single-arm, open-label, phase I study. Patients with
cervical cancer who are scheduled for radical hysterectomy with lymph node
dissection will be enrolled at the AMC/NKI-AVL (NB: study medication will only
be administered at the AMC). Two weeks before the scheduled surgical treatment
of the patients, durvalumab will be injected locally into the cervix. Three
doses of durvalumab will be tested in a 3+3 dose escalation design: 5, 10 and
20 mg. The Common Terminology Criteria for Adverse Events (CTCAE) v4.3 will be
used for the assessment of adverse events. If no DLTs or treatment related SAEs
are observed in the 3 different dose cohorts (5, 10, 20 mg) and no clear
(systemic) immunological responses are detected, an extra dose cohort of 3
patients treated with 50 mg durvalumab i.t. will be added. The injection
procedure is identical to the i.t. injections already performed in a
standardized fashion for the sentinel lymph node procedure in various centers.
Blood samples will be taken once during the screening period, at day 0 (prior
to durvalumab administration, i.e. baseline), at day +14 (at the time of
surgery), after 4 weeks, and at 3 months after administration of durvalumab.
During surgery, patent blue will be injected intratumorally (in the same manner
as the durvalumab injection), for identification of the sentinel lymph nodes.
Post-surgery biopsies of the removed tumour and draining lymph node samples as
well as pre- and posttreatment peripheral blood samples will be collected for
immunomonitoring.
The proposed correlative immunoassays will shed light on mechanisms underlying
the biological effects of PD-L1 blockade and may demonstrate its biological
efficacy, they will aid in the selection of optimal dose and target population
for subsequent studies, and facilitate a rational approach to the design of
subsequent Phase II trials of this novel immunotherapy.
Since this is a phase I clinical trial, a Data Safety Monitoring Board (DSMB)
does not have to be established.

Two weeks before the scheduled surgical treatment of the patients, durvalumab
will be injected intratumorally. Three escalating dose levels will be tested,
i.e. 5, 10 and 20 mg (three patients per dose level, with an additional three
at the highest tolerated dose). Possibly, an extra dose cohort with 50 mg
durvalumab will be added. The injection procedure is identical to the
injections already performed in a standardized fashion for sentinel lymph node
detection.

Since the patients present with early stage of cervical cancer, we do not
expect or allow any treatment related SAEs exceeding grade 3. In accordance
with this assumption, in the study CD-ON-durvalumab-1108 no treatment-related *
Grade 3 AEs, and no DLTs have been reported in the dose escalation cohorts of
<10 mg/kg.
Immune-related AEs (irAEs) that have been observed with (higher doses of)
intravenously administered durvalumab include colitis, pneumonitis,
hepatitis/hepatotoxicity, neuropathy/neuromuscular toxicity, endocrinopathy,
dermatitis and nephritis. Other inflammatory responses with potential
immune-mediated etiology reported with durvalumab and similar immune checkpoint
inhibitors include, but are not limited to, myocarditis, pericarditis, and
uveitis. These events are manageable by available/established treatment
guidelines as described in the study protocol.
In addition to the AEs described in the IB, which only account for AEs with
intravenous administration, we anticipate that the risks of local
administration of durvalumab may include:
* local inflammation reaction of the vagina, vulva and/or cervix with one or
more of the following symptoms:
o change in the volume, consistency, colour, or odour of vaginal fluor
o vulvar or vaginal irritation or burning sensation
o pruritis
o dysuria
o genital edema
* hemorrhage or fistula due to tumour or tissue necrosis/degeneration

Since this is a phase I study, no benefits for the patients are expected.
Still, our experimental therapy could lead to an increased activation of the
immune system against the tumour and this might even lead to a higher chance of
disease free survival.
Patients will be asked to come to the hospital for follow-up. These visits will
entail blood drawings and clinical examinations. Besides, the patient has to
undergo an extra gynaecological examination for the injection of the
durvalumab.