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

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.
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. 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 Common Terminology Criteria for Adverse Events (CTCAE) v4.3 will be used for the assessment of adverse events. 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.

The current systemic treatment with PD-1 and PD-L1 inhibitors can cause autoimmune side effects. As cervical cancer does not readily metastasize to distant organs but initially to regional lymph nodes we believe that local administration of PD-1/PD-L1 checkpoint inhibitors at an early stage will deliver these antibodies exactly where they are needed resulting in a major clinical benefit for these patients while reducing undesirable systemic side effect: this is the central hypothesis of our study. Additional interest in local administration of checkpoint inhibitors is raised by the fact that the locally administered doses are expected to be much lower, leading to a critical and highly desirable decline in the expenses involved, which threaten to cripple the health care system.

For this Phase-I study, we hypothesize that it is safe to locally administer durvalumab in patients with cervical cancer, scheduled to undergo surgery ((radical) hysterectomy with lymphadenectomy). The primary endpoint of this study is safety on the basis of assessment of AEs and serious AEs. This will be measured according to the standard procedures. Common Terminology Criteria for Adverse Events (CTCAE) v4.03 will be used for this.

Day -60 day 0: screening procedures.

Day 0: administration durvalumab

Day 14 (+- 3 days): (radical) hysterectomy with lymph node
dissection

week 4 (+- 3 days): follow-up

month 3 (+- 1 week): follow-up

The Common Terminology Criteria for Adverse Events
(CTCAE) v4.03 will be used for the assessment of adverse
events at timepoints: day 0 (injection durvalumab), day 14
(surgery), week 4 and month 3. Also, blood samples will be
taken on these time points.

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. 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: 5, 10 and 20 mg (three patients per dose
level, with an additional three at the highest tolerated dose).
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. The Common
Terminology Criteria for Adverse Events (CTCAE) v4.3 will be
used for the assessment of adverse events. 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.