The primary objective of the study is to estimate the clinical benefit of cemiplimab + ISA101b after progression on first line chemotherapy, as assessed by objective response rate (ORR).The secondary objectives of the study are:• To characterize the…
ID
Source
Brief title
Condition
- Reproductive neoplasms female malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Objective response rate (ORR) [Time Frame: Until disease progression, up to 36
months]
Secondary outcome
Secondary Outcome Measures :
1. Incidence and severity of treatment emergent adverse events (TEAEs) [Time
Frame: Up to 90 days after the last dose of study treatment]
2. Incidence and severity of adverse events of special interest (AESIs) [Time
Frame: Up to 90 days after the last dose of study treatment]
3. Incidence and severity of serious adverse events (SAEs) [Time Frame: Up to
90 days after the last dose of study treatment]
4. Incidence and severity of >= grade 3 laboratory abnormalities [Time Frame: Up
to 90 days after the last dose of study treatment]
5. Duration of response (DOR) [Time Frame: Until disease progression, up to 36
months]
6. Progression free survival (PFS) [Time Frame: Until disease progression, up
to 36 months]
Overall survival (OS) [Time Frame: Up to 60 months]
Background summary
Background on Cervical Cancer
The global annual incidence of cervical cancer is approximately 527,000 cases
per year, and there are approximately 265,000 deaths (Torre, 2015). The highest
incidence rates are in the Caribbean, Africa, Eastern Europe, and South America
(Forman, 2012). In the United States (US), there are approximately 13,170 new
cases and 4,250 deaths annually (Siegel, 2019). In most cases, causation is due
to infection with human papillomavirus (HPV). Although vaccination against high
risk strains of HPV is projected to gradually decrease the global incidence of
cervical cancer in the next 15 years, the burden of this disease remains
profound (Bray, 2012).
Internationally, the etiologic fraction of HPV-associated malignancy, based on
HPV detection, varies by geography and anatomic site, but overall suggests that
70% of cervical cancers are caused by HPV16/18, and HPV16 is the primary
oncogenic virus in other anogenital and oropharyngeal cancers. In a study of
777 cervical cancer tissue samples, the HPV16 genotype was detected in 50.1%
while the HPV18 genotype was detected in 16.1%, comprising 66.2% of
HPV-associated cervical cancers. Widespread uptake of HPV16/18 vaccines has
already been shown to decrease high-grade cervical lesions and is anticipated
to substantially reduce the burden of HPV-associated cancers (Saraiya, 2015).
For patients with locally advanced disease, the curative intent therapy is
definitive radiation with concurrent cisplatin. However, recurrent or
metastatic disease occurs in approximately one third of cervical cancer
patients in the US. For women with recurrent or metastatic disease, the GOG240
study established that standard first line therapy is platinum plus taxane
doublet with the addition of bevacizumab, if clinically appropriate. Median
survival with the triplet regimen is 17 months (Tewari, 2014).
After progression on first line platinum-taxane based chemotherapy for
recurrent or metastatic disease, conventional cytotoxic chemotherapy has
limited efficacy. Non-randomized phase 2 trials have demonstrated survival
times of 7.4 to 8.1 months (N = 29 and N = 43 patients, respectively) with
single agent pemetrexed, gemcitabine, topotecan, vinorelbine, or irinotecan
monotherapy (Lorusso, 2010), (Miller, 2008), (Schilder, 2005), (Bookman, 2000),
(Muggia, 2004), (Muggia, 2005), (Look, 1998), (Takeuchi, 1991).
Immunotherapy for advanced cervical cancer is a burgeoning field. Almost all
cervical cancer is associated with high risk strains of HPV (Cancer Genome
Atlas Research, 2017), and the presence of viral antigen may support anti-tumor
immune responses. An example of a virally-associated tumor for which
immunotherapy has demonstrated efficacy is Merkel Cell carcinoma (Gillison,
2016), (Nghiem, 2016). Cervical squamous cell carcinoma (SCC) may evade immune
response by expression of PD-L1 (programmed-death ligand 1), the ligand for the
immune-checkpoint receptor PD-1 (programmed death-1) on T cells (Heeren, 2016).
A non-randomized phase 2 trial of the anti-PD1 antibody pembrolizumab showed a
durable response rate for patients with PD-L1 positive metastatic or recurrent
cervical cancer treated with pembrolizumab monotherapy. Response rate for these
patients was 14.6% (12/82 patients) with a median follow up time of 10.2 months
(0.6 to 22.7 months) (Chung, 2019). These data led to an accelerated approval
by the US FDA for patients with PD L1 positive tumors in the United States. A
non-randomized phase 1/2 trial showed a durable response rate for patients with
metastatic or recurrent cervical cancer treated with nivolumab monotherapy.
Response rate for these patients was 26.3% (5/19 patients) with a median follow
up of 19.2 months (1.4 to 31.4 months) (Naumann, 2019). An ongoing multicohort
phase 1/2 trial showed early signals of durable responses in both first and
second line metastatic cervical cancer with combination therapy with nivolumab
and ipilimumab, an antibody directed against the CTLA-4 immune checkpoint.
Responses ranged from 23.1% (6/26 patients) to 45.8% (11/24 patients) in
varying dose levels. Median follow-up time ranged from 10.7 to 13.9 months
(Naumann, 2019). The anti-PD1 monoclonal antibody cemiplimab (also known as
REGN2810) has also demonstrated preliminary efficacy against cervical cancer,
as described in Section 1.2.
These data are reassuring that immunotherapy has a role in recurrent/metastatic
cervical cancer. While PD-1/PD-L1 blockade alone has a modest response rate,
the consistent durability of these responses make it into a reasonable backbone
for future combination therapies.
Taken together, these data support a single arm study of the anti-PD1 antibody
cemiplimab in combination with other agents such that may enhance anti-tumor
immune responses, such as ISA101b in patients with recurrent or metastatic
HPV16+ cervical cancer with SCC and AC histology who have experienced disease
progression after first line chemotherapy (Section 1.3).
Background on Cemiplimab
LIBTAYO® (cemiplimab) is approved for the treatment of patients with metastatic
cutaneous squamous cell carcinoma or patients with locally advanced cutaneous
squamous cell carcinoma who are not candidates for curative surgery or curative
radiation. It is also approved for the treatment of patients with locally
advanced basal cell carcinoma, and as a first-line treatment option in advanced
non-small cell lung cancer. In the United States, it is approved with a suffix
as cemiplimab-rwlc.
Cemiplimab is a high-affinity, recombinant human immunoglobulin G (IgG4P)
monoclonal antibody that binds to PD-1 and blocks its interaction with
programmed death ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2),
countering PD-1-mediated inhibition of the anti-tumor immune response.
Cemiplimab is being evaluated in more than 20 phase 1 through phase 3 clinical
studies in a variety of tumor types. The safety profile of cemiplimab
demonstrated in these clinical trials is consistent with the expected safety
profile of an anti-PD-1 antibody.
In the cemiplimab phase 1 study (R2810-ONC-1423), patients with cervical cancer
were enrolled in the dose escalation phase and in 2 expansion cohorts.
Cumulatively, there were 4/23 (17%) responses. All responses were in SCC
patients. Duration of response ranged from 6.4 to 14.7 months (NCT03257267).
Cemiplimab is currently under investigation in R2810-ONC-1676, an open-label,
randomized, multi-center, phase 3 trial comparing cemiplimab versus
investigator*s choice chemotherapy in patients with recurrent or metastatic
cervical cancer after platinum-based therapy. The primary objective is to
compare overall survival (OS) between the arms. The trial showed a clinically
and statistically significant survival benefit in patients with squamous cell
carcinoma (SCC) and adenosquamous/adenocarcinoma (AC) histology. A total of 608
patients, including 477 patients with SCC histology and 131 patients with AC
histology, were randomized in a 1:1 ratio to receive either monotherapy with
cemiplimab or IC chemotherapy. Patients on the cemiplimab arm had a median
survival of 12.0 months (95% CI 10.3 months to 13.5 months). Patients on the
chemotherapy arm had a median survival of 8.5 months (95% CI 7.5 months to 9.6
months). In addition to a survival benefit, patients had a clinically and
statistically significant improvement in progression free survival (PFS) and
overall response rate (ORR) (Tewari, 2021). Patients on the cemiplimab arm had
an ORR of 16.4% (95% CI 12.5% to 21.1%). Patients on the chemotherapy arm had
an ORR of 6.3% (95% CI 3.8 to 9.6%) (Press Release: Phase 3 Trial of Libtayo®
(cemiplimab) Monotherapy in Advanced Cervical Cancer Stopped Early for Positive
Result on Overall Survival, 2021).
Additional information, including preclinical and clinical safety data, is
available in the Investigator*s Brochure.
Background on ISA101b
ISA101/ISA101b is a therapeutic vaccine targeting the HPV type 16 E6/E7
proteins. The HPV16 long peptides in ISA101b act as a therapeutic vaccine that
stimulates the actions of both CD4+ T-helper cells and CD8+ cytotoxic T cells
against the known oncogenic sequences of the HPV16 virus. These long peptides,
containing multiple cytotoxic T-lymphocyte (CTL) and T-helper epitopes, are
predominantly processed by professional antigen presenting cells (APCs), the
dendritic cells (Bijker, 2007), (Bijker, 2008), (Rosalia, 2013). This leads to
presentation of the exact amino acid sequences (epitopes) by human leukocyte
antigen (HLA) class I and II molecules on dendritic cells.
ISA101b consists of 9 overlapping long E6 peptides (five 32-mer and four 25-mer
E6 peptides) and three 35-mer E7 peptides. These peptides overlap by 10 to 18
residues and cover the complete sequence of HPV16 E6. The E7 oncoprotein
sequence is almost completely represented by the peptide sequences (only amino
acids 57 to 63 are not covered), due to the omission of 1 poorly manufacturable
peptide (G-3980-R).
The peptide sequences are synthetically produced and individually released and
stored as bulk drug substances according to current good manufacturing
processes.
A dose of 100 µg/peptide has been selected for further study based on both the
strength of the induced HPV16 immune response and safety data in clinical
trials.
Study objective
The primary objective of the study is to estimate the clinical benefit of
cemiplimab + ISA101b after progression on first line chemotherapy, as assessed
by objective response rate (ORR).
The secondary objectives of the study are:
• To characterize the safety profile of cemiplimab + ISA101b
To assess preliminary efficacy of cemiplimab + ISA101b as measured by duration
of response (DOR), progression-free survival (PFS), and overall survival (OS)
Study design
This will be a single-arm, phase 2, global study of treatment with cemiplimab +
ISA101b in HPV16 positive cervical cancer patients with disease progression on
first line chemotherapy in the recurrent or metastatic setting. Study treatment
and duration include cemiplimab every 3 weeks (Q3W) (with 3 doses of ISA101b on
days 1, 29, and 50) until progression or any reason for early discontinuation.
The primary endpoint is ORR.
Patients will undergo screening evaluations to determine eligibility within 28
days prior to first treatment. All patients will receive the following regimen:
• ISA101b 100 µg/peptide by subcutaneous (SC) injection on day 1, day 29, and
day 50 (total of 3 doses).
• Cemiplimab 350 mg given by intravenous (IV) infusion over 30 minutes Q3W on
days 8 and 29 in cycle 1, on days 1 and 22 in cycle 2 through 4, and on days 1,
22, and 43 in all subsequent cycles or until disease progression or
discontinuation of study drug for any other reason.
Note: On days 29 and 50, cemiplimab will be administered first, and ISA101b
will be administered approximately 1 hour after the end of the cemiplimab
infusion. Patients must be observed for 4 hours after each ISA101b
administration.
There will be a 90-day safety follow-up after the last dose of cemiplimab.
Patients who discontinue study drug for reasons other than progression will be
followed approximately every 4 months by scans (eg, CT scan and/or MRI) until
disease progression or until the patient commences another anticancer systemic
therapy, whichever comes first. After progression, survival follow-up should
occur approximately every 4 months.
Intervention
Study Drug: Cemiplimab
Dose/Route/Schedule: Cemiplimab will be administered IV at a dose of 350 mg
over 30 minutes (±10 minutes) Q3W.
Study Drug: ISA101b
Dose/Route/Schedule: ISA101b 100 µg/peptide will be administered by 2 separate
SC injections per dose on day 1, day 29, and day 50 (total of 3 doses).
Study burden and risks
The combination of ISA101b and cemiplimab in this study is expected to have a
positive benefit risk profile for the treatment of patients with HPV16 positive
cervical cancer. Anti-PD1 inhibitors given as monotherapy have shown activity
and a well-established acceptable toxicity profile in recurrent/metastatic
cervical cancer patients. ISA101b has been demonstrated to induce a robust and
persistent T-cell response in patients with HPV16 driven malignancies,
including cervical cancer and OPC. The combination of ISA101b with the anti-PD1
nivolumab achieved higher response rates compared to a historical control of
nivolumab alone in the treatment of HPV16 positive OPC, albeit in a small
number of patients with heterogeneous prior therapy. Finally, the combination
of ISA101 with nivolumab has shown no unexpected toxicities in patients with
OPC (Massarelli, 2019).
For patients with HPV-16 positive cervical cancer who failed prior platinum
containing therapy, the use of cemiplimab in combination with ISA101b is
therefore acceptable in order to objectively test the hypothesis of improved
efficacy.
Old Saw Mill River Road 777
Tarrytown NY 10591
US
Old Saw Mill River Road 777
Tarrytown NY 10591
US
Listed location countries
Age
Inclusion criteria
1. Adult patients >=18 years of age (or the legal age of adults to consent to
participate in a clinical study per country specific regulations).
2. Has histologically confirmed recurrent or metastatic HPV16 positive cervical
cancer as determined by an investigational HPV16 PCR assay by Qiagen, who have
experienced disease progression after treatment with platinum containing
therapy as defined in the protocol.
3. Patient must be determined to be positive for HPV16 genotype, as determined
by a specified central reference laboratory.
4. Patient must have measurable disease as defined by RECIST 1.1.
5. ECOG performance status of 0 or 1.
6. Has adequate organ and bone marrow function as defined in the protocol.
7. Anticipated life expectancy >=20 weeks.
Other protocol-defined Inclusion criteria apply.
Exclusion criteria
1. Prior treatment with an agent that blocks the PD-1/PD-L1 pathway.
2. Prior treatment with other systemic immune-modulating agents as defined in
the protocol.
3. Major surgery or radiation therapy within 14 days of first administration of
study drug.
4. Has received treatment with an approved systemic therapy within 4 weeks of
first dose of study drug, or has not yet recovered (ie, grade <=1 or baseline)
from any acute toxicities except for laboratory changes as described in the
protocol.
5. Has another malignancy that is progressing or requires active treatment
and/or history of malignancy other than cervical cancer within 3 years of date
of first planned dose of study drug as defined in the protocol.
6. Has any condition that requires ongoing/continuous corticosteroid therapy
(>10 mg prednisone/day or anti-inflammatory equivalent) within 4 weeks prior to
the first dose of study drug.
7. Has ongoing or recent (within 5 years) evidence of significant autoimmune
disease that required treatment with systemic immunosuppressive treatments as
defined in the protocol.
Other protocol-defined Exclusion criteria apply.
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 | EUCTR2020-001239-29-NL |
| ClinicalTrials.gov | NCT04646005 |
| CCMO | NL75765.000.21 |