A phase II study to determine the efficacy and safety of Vvax001, a therapeutic Semliki Forest Virus based cancer vaccine, in patients with HPV-16 induced grade 3 cervical intraepithelial neoplasia.

Human papillomavirus (HPV) infection is an important cause of premalignant
genital and oropharyngeal lesions, cervical cancer, vulvar, anal, and penile
cancer. HPV-induced cancer is the second largest cause of cancer deaths in
women worldwide. Current treatment for premalignant HPV-induced genital lesions
primarily relies on surgery, which can be discomforting and carries a risk of
complications like bleeding, cervical stenosis and/or incompetence which may
lead to infertility and partus prematuris/immaturis. Above all, it does not
necessarily eradicate the underlying HPV infection completely. Therapeutic
immunization is a very attractive alternative to the current treatment options
for precancerous lesions and (invasive) cancer. The immune cells induced by
cancer immunotherapy can target the tumor cells and kill them. When
long-lasting immunity is induced the immunotherapy may prevent recurrence of
the disease. Therefore, the approach taken in this study is to immunize with a
replication-incompetent Semliki Forest Virus (SFV) vector encoding HPV-derived
tumor antigens. Intramuscular immunization with these replication-incompetent
SFV particles (Vvax001) is aimed at eliciting a therapeutic anti-tumor
response.
A phase I study has been conducted in which vaccination with Vvax001 induced
HPV16-E6,7-specific immune responses in women previously treated for cervical
intraepithelial neoplasia (CIN) or cervical cancer (CC). Intramuscular
immunization with Vvax001 was well tolerated, showing only mild to moderate
local adverse reactions. Altogether, the data of this study justify testing of
Vvax001 in CIN grade 3 (CIN3) patients in this phase II study.

The primary objective of this trial is to determine clinical efficacy of
Vvax001 in CIN3 patients.

HPV16-positive CIN3 patients will receive three bilateral intramuscular
immunizations of Vvax001 (total concentration 5x10e7 infectious particles [IP])
with an interval of 3 weeks between vaccinations. Patients will be monitored
for regression of CIN3 lesions by colposcopy and digital imaging at week 9,
week 17 and week 25. When complete regression of the CIN3 lesion is observed, a
biopsy will be taken in week 25 to confirm regression. If complete regression
has not occurred by 25 weeks, a standard-of-care surgical treatment (LLETZ)
will be performed. If progression of the CIN3 lesion is observed during the 25
week interval, a biopsy will be taken to confirm pathological progression. If
pathological progression has occurred, patients will immediately undergo a
LLETZ. If no pathological progression has occurred, patients will continue to
be monitored by colposcopy. Patients with a complete regression will be
followed-up by cytology at 3, 6 and 12 months after exit from the study.
Hereafter, patients will be monitored through regular national screening
programs.

Patients will receive three immunizations, with an interval of 3 weeks between
each immunization. Each vaccination will be given as two injections; 1
injection in each leg. The injections will be administered intramuscularly in
the upper legs, preferably in the m. vastus lateralis. Patient evaluation will
be performed before immunization and during the first follow-up visit (week 7)
including history, physical examination, full blood count, urea, electrolytes
and liver function tests. Besides, a pregnancy test will be taken before each
vaccination. Participants may directly leave the study site after injection of
Vvax001. Participants will be contacted by telephone 4-8 hours after
immunization to obviate any adverse events (AE's). Peripheral blood mononuclear
cells (PBMC) will be collected at baseline, first follow-up visit (week 7),
colposcopy (week 9 and week 17) and at time of biopsy (week 25) to monitor
HPV-specific immune responses. Colposcopy and digital imaging will be performed
after immunization in week 9, in week 17 and in week 25 to monitor regression
of the CIN lesions. If full regression of the lesion does not occur, LLETZ will
be performed 25 weeks after the first immunization. LLETZ will also be
performed if progression occurs (proven by biopsy) during the study. When
complete regression of the CIN3 lesion is observed by colposcopy, a biopsy will
be taken in week 25 to confirm regression. In this case, no LLETZ will be
performed. The biopsies and surgical specimens will be used to determine
vaccine-induced pathological responses.

The study procedures require 8 visits to the hospital. Vaccination by bilateral
intramuscular injection is performed three times. Standard-of-care LLETZ
treatment will be postponed by a maximum of 25 weeks. We consider the risks
associated with this delay very minimal since patients will be closely
monitored during the time of the trial. Standard-of-care colposcopies will be
performed (two in total; one at diagnosis [week 0] and one at time of LLETZ
[week 25]). Patients will undergo an additional 2 colposcopies during the trial
period for monitoring regression of CIN3 lesions (week 9 and week 17). 8
venapunctions will be performed for PBMC and/or biochemistry. Toxicity will be
graded according to the NCI Common Terminology Criteria for Adverse Events
(CTCAE) Version 4.0. Given the results of the Phase I clinical study, and
previous clinical experience with similar viral vector vaccines, only mild to
moderate injection site reactions are anticipated from administration of
Vvax001.

Potential benefit for the patients is vaccine-mediated regression of the CIN3
lesion and HPV16 clearance, due to the induction of a long-lasting protective
HPV16-specific immune response. Hereby, the invasive LLETZ procedure and
recurrence of the disease can be prevented.