Primary objectives: • To assess the safety and tolerability of different doses of the ISA101 vaccine with or without pegylated IFNα as combination therapy with carboplatin and paclitaxel.• To qualitatively assess the safety profile of ISA101b…
ID
Source
Brief title
Condition
- Reproductive neoplasms female malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoints of the study are:
• Safety:
o Safety will be determined by the incidence rate at each dose level based on
the following safety parameters: adverse events (AEs) and serious adverse
events (SAEs), changes in haematology and chemistry values, including those
associated with hepatic and renal function, and assessment of physical
examinations, vital signs and performance status. NCI-CTCAE version 4.0 will be
used.
The safety profile of ISA101b in the bridging cohort(s) will be
qualitatively compared to the safety profile observed at the same dose level(s)
of ISA101.
• HPV-specific immune responses:
o HPV-specific immune responses to the ISA101 vaccine with or without pegylated
IFNα in combination with carboplatin and paclitaxel will be determined by the
quality, breadth and magnitude of the HPV16 E6/E7-specific T-cell responses as
measured by a validated assay (IFNγ-ELISPOT) following injection of the
different doses of the ISA101 vaccine.
o The HPV-specific immune responses to ISA101b in the bridging cohort(s) will
be qualitatively compared to the responses observed at the same dose level(s)
of ISA101.
Secondary outcome
Secondary endpoint:
• Antitumor efficacy according to RECIST 1.1:
o Objective Response Rate (ORR) will be calculated as the proportion of
patients with a best overall response of confirmed Complete Response (CR) or
Partial Response (PR).
o Disease Control Rate (DCR) will be calculated as the proportion of patients
with a best overall response of confirmed CR, PR or Stable Disease (SD).
o Progression Free Survival (PFS) is defined as the time from start of
carboplatin and paclitaxel (with or without bevacizumab) treatment to the
documented progression or death from any cause.
Exploratory endpoint:
• General responsiveness of the immune system as measured by exploratory assays
, in particular 1) lymphocyte proliferation as measured by 3H-thymidine
incorporation in PBMCs in response to HPV E6/E7 peptides in vitro, 2)
antigen-presenting cell (APC) function tests, 3) assay of myeloid and lymphoid
cell composition as assessed by flow cytometry and 4) recall proliferative
responses of PBMC in response to common microbial antigens as measured by
3H-thymidine incorporation.
.
Background summary
Cervical cancer is the second most frequent cancer in women worldwide. Cervical
cancer is divided into early-stage cervical cancer (FIGO stages IA1-IIA) with a
low risk of recurrence (15%) after treatment and advanced cervical cancer (FIGO
stages IIB/III/IV) with a high risk of recurrence (up to 70%) and a poor
prognosis.
The causal role of HPV infections in the development of cervical
intraepithelial neoplasia and subsequent cervical carcinoma has been
unambiguously established. Genital infections with high-risk HPV are mainly
acquired through sexual activity and are highly prevalent in young sexually
active individuals. In the majority of infected subjects the infection is
cleared within one year. However, infection with the high-risk HPV type 16
(HPV16) is associated with a greater risk for progression and is most common in
patients with invasive cervical cancer. HPV16 encodes the two tumour-specific
oncoproteins E6 and E7 that can elicit a favourable immune response in which
specific T-cells play a critical role in the control and elimination of the HPV
infection. The virus-specific interferon-γ (IFNγ)-producing CD4+ cells (Th1
cells) and CD8+ cytotoxic T-lymphocytes (CTL) are able to recognise peptides
processed from the oncoproteins E6 and E7 and contribute to the virus
elimination.
However, in case of an uncontrolled persistent infection with a high-risk HPV
type, the expression of the viral oncoproteins E6 and E7 contributes to the
development of cervical (pre)malignancies. Apparently, the spontaneous
HPV-specific T-cell response fails in these patients and there is no or a
negligible activation and expansion of the proper HPV16-specific CD4+ and CD8+
T cells.
The standard treatment for advanced cervical cancer consists of platinum-based
chemotherapy, often in combination with a taxane such as paclitaxel. However,
with a response rate of 20% to 50%, this therapy is rarely curative and should
be considered as palliative treatment. . The simultaneous use of several
chemotherapeutic agents has been shown to marginally increase survival times,
and was sporadically associated with higher response rates. Treatment with
chemotherapy combinations in the setting of stage IVB, recurrent, or persistent
cervical carcinoma leads to median overall survival (OS) of approximately 1
year (range 10-14 months). Importantly, if women with these disease stages are
offered the option to receive combination chemotherapy it also seems as if a
proportion of them, approximately 10-20%, can survive 3 years and beyond.
Recently, a phase III trial of four cisplatin-containing doublet combinations
was performed in patients with stage IVB, recurrent or persistent cervical
carcinoma. The median OS varied between 10 and 13 months. There was a trend
towards a slightly improved response rate, progression-free survival (PFS) and
OS with the combination of paclitaxel plus cisplatin. In a retrospective
evaluation, carboplatin/paclitaxel compared favourably with
cisplatin/paclitaxel and demonstrated a superior overall response rate (53% vs.
29%) and similar survival (median survival of 14 and 11 months, respectively).
In addition, the authors considered the ease of administration and improved
toxicity profile of carboplatin/paclitaxel as important factors using this
treatment for advanced, recurrent or progressive cervical cancer18. The
utilization of chemotherapy, including the specific combination of carboplatin
and paclitaxel for women with metastatic, persistent and recurrent cervical
cancer is included in global and local guidelines. A recent study showed that
addition of bevacizumab to standard of care chemotherapy of patients with
recurrent or metastatic cervical cancer further improves the therapeutic
results, improving overall survival with 3.7 months (17 months versus 13.3
months with chemotherapy alone
Combining current treatment strategies such as radiotherapy, chemotherapy, in
addition to bevacizumab and combinations thereof with immunotherapy could offer
a novel approach in which traditional chemotherapy and radiation treatment are
expected to synergize with immunotherapy. The rationale for exploring this is
that several chemotherapeutic agents have shown a positive influence on the
immune system, in particular on the immunosuppressive micro-environment, both
in preclinical animal models and in clinical trials. In addition, pre-clinical
data have shown promising results of the combination of traditional
chemotherapy with therapeutic vaccines. Indeed, application of therapeutic
vaccines for malignancies has been generally disappointing in the clinic when
applied as monotherapy, sometimes due to suboptimal vaccine design, but more
importantly as a result of the tumour-associated immunosuppressive
micro-environment discussed above. However, combination treatment of powerful
therapeutic cancer vaccines, such as synthetic long peptides (SLPs), in
combination with chemotherapy that alleviates the cancer-associated
immunosuppression, creates a novel treatment paradigm of considerable promise.
Study objective
Primary objectives:
• To assess the safety and tolerability of different doses of the ISA101
vaccine with or without pegylated IFNα as combination therapy with carboplatin
and paclitaxel.
• To qualitatively assess the safety profile of ISA101b vaccine compared to
ISA101 at the same dose level(s).
• To assess the safety of ISA101b vaccine with carboplatin, paclitaxel with or
without bevacizumab.
• To assess the HPV-specific immune responses to different doses of the ISA101
vaccine with or without pegylated IFNα as combination therapy with carboplatin
and paclitaxel.
• To qualitatively assess the HPV-specific immune responses of ISA101b vaccine
relative to the same dose level(s) of ISA101.
• To qualitatively assess the HPV-specific immune responses of ISA101b vaccine
with carboplatin, paclitaxel with or without bevacizumab.
Secondary objective:
• To evaluate the clinical efficacy of immunotherapy with ISA101/ISA101b in
combination with standard therapy i.e. carboplatin and paclitaxel with or
without bevacizumab.
Exploratory objective:
• To evaluate the general responsiveness of the immune system of the patient in
correlation with the HPV-specific immune responses and/or clinical efficacy.
Study design
This is a multicenter, open label, non-randomized Phase I/II study. Patients
with advanced or recurrent HPV16 positive cervical cancer for whom no curative
treatment options exist will be enrolled in eight cohorts of six patients each
to include in total 48 patients. The maximum total treatment duration for a
patient is six cycles (1 cycle is 21 days) of carboplatin and paclitaxel (18
weeks, if there are no dose interruptions/delays). On Day 15 (±3 days) of Cycle
2 the vaccination scheme of ISA101 with or without pegylated IFNα will start.
The patients will be vaccinated with a fixed dose of ISA101 every three weeks
for a total of three rounds of vaccination. Four dose levels of ISA101 will be
tested. The first 6 patients will be enrolled in cohort 1, the next 6 patients
in cohort 2, and so on until completion of all 8 cohorts (i.e. there are 2
cohorts at each ISA101 dose-level, an initial cohort at a given dose level in
which patients do not receive IFNα (cohorts 1, 3, 5, and 7) followed by an
additional cohort at the same dose of ISA101 that does receive IFNα [cohorts 2,
4, 6 and 8]). The decision to start enrollment at the next dose level (i.e
cohort 3, 5 or 7) will be made by assessing the safety after at least 3 out of
6 patients at the previous dose level (i.e. cohort 1, 3 or 5) have completed
chemotherapy Cycle 1 to 3 and received at least 2 of the possible 3
vaccinations with ISA101. The Data Monitoring Committee (DMC) will receive
listings of individual patient data from the Sponsor related to baseline
characteristics, safety, and study medication administration for the patients
necessary to assess per above before enrolment is started at the next dose
level. Based on review of the available data, the DMC will make a
recommendation to the Sponsor whether or not to start of enrolment at the next
dose level.
Frequent dose limiting toxicities are not anticipated based on previous
clinical experience in approximately 180 women with premalignant vulvar,
cervical intraepithelial neoplasia or cervical cancer who received vaccination
HPV-16-SLP in Montanide. Patients will be evaluable for immunogenicity if they
have received at least two vaccinations with ISA101 and have pre-vaccination
blood sample and two post-second vaccination blood samples (all with sufficient
peripheral blood mononuclear cells (PBMCs)). Patients who are not evaluable
for the HPV16 E6/E7-specific T-cell response assays (Interferon
gamma-Enzyme-linked immunosorbent spot (IFNγ-ELISPOT)) and will be replaced
unless treatment was stopped prematurely due to toxicity of ISA101.
In the extension study a total of approximately 12 evaluable patients will be
enrolled, 6 subjects in each of two cohorts (03B and 05B) with an ISA101 dose
regimen previously determined to have an acceptable safety profile.
After completion of enrolment of the extension cohorts at 40 and 100 µg per
peptide, the study will continue to enroll additional patients in bridging
cohort(s) using the modified ISA101b vaccine at a dose of 100 µg per peptide
plus carboplatin and paclitaxel to determine if the safety profile of the new
drug product is qualitatively similar to those induced by the original ISA101
used in previous cohorts. In addition, data on the immune response to ISA101b
will be collected. These data on the safety and immune response to ISA101b
will inform the dose selection for further clinical studies of ISA101b. After
evaluation of the initial safety data of 3 patients who have received at least
two ISA101b doses of 100 µg per peptide, the safety data will be reviewed by
the sponsor and the DMC to determine if 3 additional patients will be treated
at the 100 µg/peptide dose level. Based on review of the data and
recommendations of the DMC, another cohort is planned to assess patients who
would otherwise receive standard first line therapy (paclitaxel, carboplatin
and bevacizumab) for recurrent cervical cancer. This cohort will include 6
additional patients to be treated with carboplatin, paclitaxel, and bevacizumab
with ISA101b (100 µg per peptide pending DMC safety review). If deemed
appropriate, based on recommendation of the DMC, an additional 12 patients may
receive a dose of ISA101b at <=100 µg per peptide without or with bevacizumab.
In the bridging cohorts a total of 24 patients will be enrolled, 6 subjects in
each of four cohorts:
- Cohort 9 (ISA101b 100µg per peptide)
- Cohort 10 (ISA101b µg per peptide, with bevacizumab 15mg/kg)
- Cohort 11 (ISA101b <= 100µg per peptide)
- Cohort 12 (ISA101b <= 100µg per peptide, with bevacizumab 15mg/kg)
Intervention
Subjects eligible for the study will be assigned to a dose level cohort. All
patients will be treated with AUC 6 Carboplatin and 175 mg/m2 paclitaxel.
Patients will be treated at one of 4 different dose levels of ISA101 vaccine
(namely 20, 40, 100 or 300 µg per peptide). Half of the patients will
additionally receive 1 µg/kg pegylated IFNα during dose escalation. In the
extension cohorts, patients will not receive IFNα.
In the bridging cohorts, patients will be treated with AUC 6 Carboplatin and
175 mg/m2 paclitaxel and ISA101b (maximum dose 100 µg per peptide), with or
without bevacizumab 15mg/kg.
Study burden and risks
In summary, the patient population to be included in the current study
constitutes a population of women with cervical cancer who according to global
and local consensus should be offered standard chemotherapy as used in this
study. These women may benefit by tumor load reduction leading to symptom
improvement and prolonged time to disease progression. In addition to the
standard chemotherapy, the women participating in the trial will receive
well-timed (in relation to the chemotherapy , see Section 1.5) vaccinations
with ISA101/ISA101b formulated in Montanide for the induction of a strong and
broad cytotoxic T cell response against HPV16 E6 and E7, which in turn might
lead to a prolonged control of the tumor compared with chemotherapy only (as
has been documented in preclinical models, see above). Half of the women will
also receive concurrent injections with Pegintron at the time points of
vaccinations to further potentiate the HPV16 immunity which may further enhance
the possibility of achieving a strong enough immune response to synergize with
chemotherapy and improve outcomes.
The toxicity burden and risks associated with delivering the standard of care
carboplatin and paclitaxel and bevacizumab chemotherapy combination far
outweigh the burden and risks associated with vaccination against HPV16. Based
on the already available data from the CervISA trial, the combination treatment
with chemotherapy and ISA101/ISA101b including Montanide (with or without
Pegintron) does not appear to be associated with substantially greater toxicity
than the individual components by themselves. In contrast, the immunological
and therefore potential clinical benefits might be considerable as judged from
the preclinical and clinical experiments data outlined above. Thus, it is
judged that the possible benefits outweigh the risks and thereby the
benefit/risk assessment performing the study is favorable.
J.H.Oortweg 19
Leiden 2333CH
NL
J.H.Oortweg 19
Leiden 2333CH
NL
Listed location countries
Age
Inclusion criteria
1) Women >= 18 years of age.
2) Cervical cancer confirmed by histology.
3) Advanced (Stage IIIb/IVa with para-aortic lymph nodes involvement beyond the renal vein) or, metastatic (Stage IVb ) or recurrent cervical cancer confirmed by clinical and/or radiological proof with no curative treatment options.
4) For cohort 10 (and 12) patients should be eligible to receive bevacizumab at each site per standard of care, patients may be primary stage IVB (including persistent) or first recurrent carcinoma of the uterine cervix (squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma). Prior treatment with chemotherapy for recurrent disease is not permitted. However, one prior line of chemotherapy with platinum during primary radio-chemotherapy or platinum-base chemotherapy as neoadjuvant chemotherapy prior to surgery is permitted.
5) Tumour must be HPV16 positive (to be determined on archival tumour tissue (<=10 years old); if that is not available a pre-treatment biopsy will be required).
6) Patients should be eligible for chemotherapy with carboplatin and paclitaxel, and have consented with chemotherapy with carboplatin and paclitaxel, before the start of the informed consent procedure for the study.
7) Performance status (WHO scale/ECOG) <= 1.
8) Written informed consent according to local guidelines.
9) Written approval by the treating physician / investigator of his/her clinical judgment that the patient has a reasonable life expectancy and is sufficiently fit and motivated to complete the study treatment and comply to all study procedures specified by the protocol.
Exclusion criteria
1) Prior treatment with anti-HPV agents.
2) Chronic systemic steroid use. Local application (i.e. stable doses of topical or inhaled corticosteroids) is allowed.
3) Less than 4 weeks since the last treatment with other cancer therapies less than 8 weeks for cranial radiotherapy, and less than 6 weeks for nitrosoureas and mitomycin C.
4) Toxicities resulting from previous anti-cancer therapy
5) Recent treatment (within 30 days of first study treatment) with another investigational drug.
6) Patients with known hypersensitivity to any component of the Investigational Medicinal Product (e.g. ISA101/ISA101b,, Montanide, dimethylsulfoxide pegylated, cremophor also known as Macrogolglycerol Ricinoleate, or IFNα for those subjects assigned to pegylated IFNα cohorts).
7) Any contraindication to the use of authorized applied products (i.e. paclitaxel, carboplatin or bevacizumab).
8) Inadequate bone marrow function
9) Inadequate liver function
10) Clinical suspicion or radiological evidence of brain or leptomeningeal metastases.
11) Previous or current malignancies at other sites
12) Active HIV, chronic hepatitis B or C infection.
13) Patients of childbearing potential (defined as < 2 years after last menstruation and
having an intact reproductive system), not willing to consistently and correctly use a
contraceptive method according to ICH (M3) resulting in low failure rate, i.e. less
than 1% per year such as oral contraceptives or use of effective means of contraception.
14) Pregnancy or lactation.
15) Major surgical procedure within 28 days prior to the first study treatment.
16) Uncontrolled sustained hypertension
17) Clinically significant (i.e. active) cardiovascular disease
18) History of severe bronchial asthma and/or severe allergy.
19) Evidence of any other medical conditions (such as psychiatric illness, infectious diseases, auto-immune diseases) that may interfere with the planned treatment (i.e. the possibility to receive all six cycles of planned chemotherapy including the concomitant vaccinations), affect patient compliance or place the patient at high risk from treatment-related complications
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-001804-12-NL |
| ClinicalTrials.gov | NCT02128126 |
| CCMO | NL44981.000.13 |