COHORT 1Primary objective: • To assess the safety and tolerability of IV administration of EI 201 as monotherapy in subjects with incurable R/M HPV16+ oropharyngeal and anogenital tumors and to select a starting dose of EI-201 for Cohort 2 Secondary…
ID
Source
Brief title
Condition
- Other condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Health condition
HPV16-positive (HPV16+) tumors (oropharyngeal cancer, cervical, vulvar, vaginal, anal, penile cancer)
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
COHORT 1
Primary endpoint:
• DLT, MTD, RP2D, SAEs, frequency and severity of AEs of escalating doses of
EI-201 as monotherapy per dose level using NCI CTCAE 5.0
COHORT 2
Primary endpoints:
• DLT, MTD, RP2D, SAEs, AEs of EI-201 as add on to pembrolizumab using NCI
CTCAE 5.0
• ORR (based on CR/PR using RECIST v1.1 and iRECIST for highest dose level
only).
Secondary outcome
COHORT 1
Secondary endpoints:
• Number of immune responders to EI-201 per dose level
• ORR (based on CR/PR using RECIST v1.1 and iRECIST)
Exploratory endpoints:
• Changes from baseline in ctHPV16 DNA per dose level
• Dosing confirmation of HPV E6 mRNA and the LNP component Coatsome SS-EC
• Tumor biopsy to assess changes in the tumor microenvironment induced by
EI-201 administration compared to baseline
COHORT 2
Secondary endpoints:
• Immune response to EI-201 as add on to pembrolizumab at each visit
• BOR based on CR, SD, PR, progressive disease (PD) and overall response at
each visit by RECIST 1.1 and iRECIST
• ORR (based on CR/PR using iRECIST and RECIST 1.1 for all other dose levels)
• Overall survival (OS)
Exploratory endpoints:
• Change and percentage change from baseline in ctHPV DNA levels per dose level
and tumor type
• Tumor biopsy to assess changes in the tumor microenvironment induced by
EI-201 administration as add on to pembrolizumab compared to baseline
• Associations between antitumor effect and biomarkers, such as ctHPV16 DNA or
immune response
• Dosing confirmation of HPV E6 mRNA and the LNP component Coatsome SS-EC
Background summary
One main reason for the unsatisfactory efficacy of anti-cancer vaccines is the
activation of immunosuppressive mechanisms within the tumor that counteract the
vaccine-induced T cell immune response. Therefore, the combination of a cancer
vaccine with immune checkpoint inhibition may translate into an additive
clinical benefit (Galon J and Bruni D, 2019).
EI-201, an immunotherapy against HPV16+ cancer, is a novel investigational
medicinal product (IMP) that contains messenger ribonucleic acids (mRNAs)
encoding the HPV16 E6 and HPV16 E7 oncoproteins plus TriMix, a combination of
mRNAs encoding 3 different immune stimulatory proteins. The mRNAs encoding the
E6 and E7 oncoproteins are intended to be translated intracellularly in antigen
presenting cells (APCs) and eventually turned into antigens stimulating an anti
HPV16+ specific T-cell response. TriMix is designed to activate and *educate*
dendritic cells (DCs) towards maturation leading to an optimal stimulation of
the immune system, both locally and systemically. TriMix aims to potentiate the
immune response of the HPV E6 and E7 antigens, and therefore, TriMix is
considered as an adjuvant in the drug product, EI-201.
Study objective
COHORT 1
Primary objective:
• To assess the safety and tolerability of IV administration of EI 201 as
monotherapy in subjects with incurable R/M HPV16+ oropharyngeal and anogenital
tumors and to select a starting dose of EI-201 for Cohort 2
Secondary objectives:
• To assess the immune response following EI-201 administration in subjects
with incurable R/M HPV16+ oropharyngeal and anogenital tumors
• To assess the preliminary anti tumor activity of IV administration of EI-201
as monotherapy in subjects with incurable R/M HPV16+ oropharyngeal and
anogenital tumors
Exploratory objectives:
• To evaluate circulating tumor HPV16 DNA (ctHPV16 DNA) levels in subjects with
incurable R/M HPV16+ oropharyngeal and anogenital tumors
• To confirm the dose of HPV E6 mRNA and the LNP component Coatsome SS-EC in
subjects with incurable R/M HPV16+ oropharyngeal and anogenital tumors
• To assess changes in the tumor microenvironment induced by EI-201
administration in subjects with incurable R/M HPV16+ oropharyngeal and
anogenital tumors
COHORT 2
Primary objectives
• To assess the safety and tolerability of IV administration of EI-201 as add
on to pembrolizumab in subjects with incurable R/M HPV16+ oropharyngeal and
anogenital tumors
• To assess the anti-tumor activity of IV administration of EI-201 as add on to
pembrolizumab in subjects with incurable R/M HPV16+ oropharyngeal and
anogenital tumors
Secondary objectives:
• To assess the immunogenicity of EI-201 as add on to pembrolizumab in subjects
with incurable R/M HPV16+ oropharyngeal and anogenital tumors
• To assess additional anti-cancer activity of EI-201 as add on to
pembrolizumab in subjects with incurable R/M HPV16+ oropharyngeal and
anogenital tumors
Exploratory objectives:
• To monitor ctHPV16 DNA levels in subjects with incurable R/M HPV16+
oropharyngeal and anogenital tumors
• To assess changes in the tumor microenvironment induced by EI-201
administration as add on to pembrolizumab compared to baseline in subjects with
incurable R/M HPV16+ oropharyngeal and anogenital tumors
• To assess the relationship between anti-tumor effect and biomarkers, such as
ctHPV16 DNA or immune response in subjects with incurable R/M HPV16+
oropharyngeal and anogenital tumors
• To confirm the dose of HPV E6 mRNA and the LNP component Coatsome SS-EC in
subjects with incurable R/M HPV16+oropharyngeal and anogenital tumors
Study design
This phase I/IIa study plans to investigate the safety and tolerability as well
as the anti tumor activity of intravenous (IV) EI-201 as monotherapy (Cohort 1)
and in combination with the immune checkpoint inhibitor pembrolizumab (Cohort
2) in subjects with R/M HPV16+ carcinoma. In Cohort 1, safety and tolerability
of EI-201 as monotherapy will be investigated in subjects with incurable R/M
HPV16+ carcinoma. Also, Cohort 1 aims at defining a dose which is safe and
tolerable for further investigation in Cohort 2. In Cohort 2, safety and
tolerability and anti-tumor activity of EI-201 in combination with
pembrolizumab will be investigated in subjects with incurable R/M HPV16+
oropharyngeal or anogenital cancer. Cohort 2 consists of a dose escalation part
and a dose expansion part.
In Cohort 1, subjects are planned to be dosed IV with up to 4 administrations
of EI 201 as monotherapy: at the start of treatment (Day 1, first infusion)
plus 3 weekly infusions (Day 8, 15 and 22). Dose finding will follow a Bayesian
Optimal Interval (BOIN) design and is planned to investigate 5 dose levels of
EI-201: 20µg, 60µg, 180µg, 360µg, and 540µg.
At dose level I (20µg), an initial 3 subjects will be enrolled. Enrollment will
be staggered with at least 1 week between the first dose of the first subject
and the second subject. All subjects remain in the hospital for 24 hours after
their first infusion. The dose limiting toxicity (DLT) observation period of
each subject consists of a period of 4 weeks (Day 29) after start of the
treatment, i.e., until one week after the last administration of EI 201. All
available safety data at Day 29 will be assessed by the safety review committee
(SRC). Decisions to escalate, de-escalate, or stay for each dose level will be
guided by a BOIN dose escalation design, dependent on the number of evaluable
subjects and the number of DLTs observed at a dose level. Based on simulations
with the BOIN design, it is planned to enroll up to 21 evaluable subjects in
Cohort 1.
The Sponsor may decide to add intermediate dose levels while the study remains
ongoing. In this case, 9 additional subjects may be added to Cohort 1 to a
maximum of 30 evaluable subjects, depending on the number of dose levels used
and subjects on study at that point.
For all dose levels, assessment of anti-tumor response using RECIST and iRECIST
is planned at the end of Week 6 after the start of EI-201 infusions. If a
partial response (PR) per RECIST and iRECIST is present at 6 weeks after
baseline, a third imaging assessment will be performed 4 weeks later.
Cohort 2 will investigate the safety, tolerability, and anti-tumor effect of
escalating doses of EI-201 in combination with pembrolizumab using a BOIN
design for dose finding followed by a dose expansion part. Based on simulations
with the BOIN design, it is planned to enroll up to 18 subjects in the dose
finding part of Cohort 2. In total, 4 dose levels of EI-201 plus pembrolizumab
will be evaluated: 60µg, 180µg, 360µg, and 540µg. Enrollment will be staggered
with at least 1 week between the first dose of the first subject and the second
subject.
After the third dose level in Cohort 1 has been shown to be safe based on SRC
recommendation and DLT observation, enrollment of the first 3 subjects in
Cohort 2 can start with EI-201 dose level 2 from Cohort 1.
Subjects will receive 4 weekly infusions of EI-201 followed 4 weeks later by 5
booster infusions (interval of 3 weeks for the first 4 booster injections [5th
to 8th infusions] on Day 50, 71, 92, and 113 followed by an interval of 6 weeks
between the 8th and the 9th infusion, Day 155). All subjects will remain in the
hospital for 24 hours after their first infusion of EI-201. Pembrolizumab is
planned to be administered Q3W according to SmPC, with the first infusion of
EI-201 to start one week before the first infusion of pembrolizumab (Day 8, 29,
50, 71, 92, 113, 134, and 155).
The BOIN dose finding algorithm will be the same as for Cohort 1.
The dose-finding part for Cohort 2 will be followed by a dose expansion, to
ensure a total of 30 subjects are treated at the identified RP2D for the
combination with pembrolizumab.
For all dose levels and the dose expansion in Cohort 2, assessment of
anti-tumor response using RECIST and iRECIST is planned at Week 9, Week 17 and
Week 25 after the start of EI-201 infusions. If a PR is present, an additional
imaging assessment will be performed 4 weeks later.
Intervention
Not applicable
Study burden and risks
Please be referred to Section 1.4 of Protocol V2.0, 03Nov2021 - Risk-benefit
assessment
Galileilaan 19
Niel B-2845
BE
Galileilaan 19
Niel B-2845
BE
Listed location countries
Age
Inclusion criteria
Inclusion criteria to be assessed at Screening:
1. Age greater than or equal to 18 years.
2. Cohort 1: Confirmed recurrent and/or metastatic (R/M) HPV16+ cancer
(including oropharyngeal, cervical, vulvar, vaginal, anal, penile cancer) based
on expression analysis of HPV type 16 in tumor tissue by HPV 16 ISH or HPV E1
PCR. Cancer must have progressed after at least 1 available standard therapy
for incurable disease, or the subject is intolerant to or refuses standard
therapy(ies) or has a tumor for which no standard therapy(ies) exists.
Cohort 2: Confirmed R/M HPV16+ oropharyngeal cancer (based on expression of HPV
type 16 in tumor tissue by HPV 16 ISH or HPV E1 PCR), and eligible for 1st line
monotherapy pembrolizumab treatment OR
subjects with confirmed incurable R/M anogenital HPV16+ cancer (cervical, anal,
penile, vulvar, or vaginal cancer) confirmed by HPV 16 ISH or HPV E1 PCR.
Maximum 2 previous systemic therapies with chemotherapy and/or targeted
therapies for recurrent and/or metastatic disease, no prior aPD(L)-1, and a
CPS>1.
3. Life expectancy of at least 12 weeks.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
5. At least one measurable lesion, as defined by Response Evaluation Criteria
in Solid Tumors version 1.1 (RECIST 1.1; Eisenhauer et al, 2009).
6. Willing and able to give written informed consent.
7. Willing and able to attend the scheduled study visits and to comply with the
study procedures, treatment schedule, laboratory test and other requirements of
the study.
8. Subjects entering the study will need to consent to provide a tumor tissue
sample (formalin fixed paraffin embedded blocks/slides less than 2 months old
or older only upon approval by Sponsor) or a fresh biopsy before the first dose
of the study treatment and a mandatory biopsy at Week 6 (Cohort 1) or Week 9
(Cohort 2) post start of treatment. Biopsy should be excisional, incisional or
core needle. Fine needle aspiration is insufficient.
9. Adequate hematologic function with:
a) white blood cell (WBC) count >= 3,000 mm³
b) hemoglobin >= 9 g/dL
c) platelets >= 75,000/mm³
d) lymphocyte count >=500 cells/mm3
10. Adequate renal and hepatic function with:
a) serum creatinine <= 1.5 x upper limit of normal (ULN) or creatinine-clearance
>= 40 mL/minute using the Cockcroft-Gault formula
b) alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino
transferase (AST) <= 1.5 x ULN (subjects with liver metastasis can have up to 5
x ULN
c) bilirubin < 2.0 mg/dL (except for subjects with Gilbert*s disease)
11. Adequate coagulation parameters with:
a) Prothrombin international normalized ratio (INR) < 1.5
b) Partial thromboplastin time < 1.5 x ULN
12. Men who are sexually active with WOCBP must agree to use any contraceptive
method with a failure rate of less than 1% per year. The Investigator shall
review contraception methods and the time period that contraception must be
followed.
13. A female subject is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
a) Not a woman of childbearing potential (WOCBP)
b) A WOCBP (defined as < 2 years after last menstruation or not surgically
sterile) must have a negative highly sensitive pregnancy test at screening
(serum) and must follow contraceptive guidance (highly effective method for
contraception according to the EU Clinical Trial Facilitation Group guidance)
from time of signing the ICF until at least 120 days after the last
administration of study medication. The partners of subjects of childbearing
potential must also apply contraceptive methods and are recommended not to
donate sperm
Exclusion criteria
Exclusion criteria to be assessed at Screening:
1. Subjects treated with any investigational agent within the past 4 weeks
before the start of therapy are excluded.
2. Grade 3 or 4 peripheral neuropathy at time of screening.
3. Subjects with active or history of autoimmune disease or immune deficiency
such as, but not restricted to, myasthenia gravis, antiphospholipid antibody
syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome,
inflammatory bowel disease, systemic lupus erythematosus, ankylosing
spondylitis, scleroderma, rheumatoid arthritis or multiple sclerosis, with the
following exceptions:
- endocrine autoimmune disorders (i.e., autoimmune hypothyroidism who are on
thyroid replacement hormone, type 1 diabetes, Addison*s disease, etc.)
- controlled eczema, psoriasis, lichen simples or vitiligo with dermatological
manifestations only
- rash < 10% of body surface area.
4. Subjects with serious intercurrent chronic or acute illness such as
pulmonary [severe asthma or chronic obstructive pulmonary disease (COPD)],
cardiac (New York Heart Association [NYHA] class III or IV), hepatic disease,
renal insufficiency or other illness considered by the Investigator to
constitute an unwarranted high risk for investigational drug treatment.
5. Subjects with known history of allergic reactions to contrast.
6. Subjects with significant psychiatric disabilities or seizure disorders.
7. Legal incapacity or limited legal capacity.
8. Subjects who have had a splenectomy.
9. Subjects with known hypersensitivity to any component of the Investigational
Medicinal Product and/or pembrolizumab (Cohort 2).
10. Prior treatment with therapeutic HPV vaccines. Subjects may have received a
preventive HPV vaccine.
11. Subjects who received an mRNA LNP based vaccine less than 30 days prior to
start of the therapy.
12. Concurrent second malignancy other than non-melanoma skin cancer or
controlled superficial bladder cancer. In the event of prior malignancies
treated surgically, the subject must be considered NED (no evidence of disease)
for a minimum of 3 years prior to enrollment.
13. Subjects on corticosteroid therapy > 10 mg prednisone (or equivalent) or
other immunosuppressive agents such as azathioprine or cyclosporine A (but not
limited to these) are excluded on the basis of potential immune suppression.
14. Presence of an active acute or chronic infection, including symptomatic
urinary tract infection, human immunodeficiency virus (as determined by enzyme
linked immunosorbent assay and confirmed by Western Blot) or viral hepatitis
(as determined by hepatitis B antigen and hepatitis C serology).
15. Subject is pregnant, intending to become pregnant or is currently
breast-feeding.
16. Subject testing positive for SARS-CoV-2 infection as detected by nasal real
time polymerase chain reaction (RT-PCR) or subjects who have been in contact
with SARS-CoV-2 infected individuals in the 2 weeks prior to first dosing of
IMP. Subjects presenting any signs or symptoms of SARS-CoV-2 infection as
detected at screening and/or baseline following careful physical examination
(e.g., cough, fever, headaches, fatigue, dyspnea, myalgia, anosmia, dysgeusia,
anorexia, sore throat, etc.) will also be excluded. In addition, any other
locally applicable standard diagnostic criteria may also apply to diagnose
SARS-CoV-2 infection.
Additional Criteria for Cohort 2:
17. Subjects with undifferentiated nasopharyngeal or sino-nasal cancers.
18. Subjects with symptomatic central nervous system (CNS) metastases must have
been treated and metastases should be asymptomatic.
19. Chemotherapy, targeted small molecule therapy, or radiotherapy within 4
weeks prior to start of treatment with EI-201 for subjects with anogenital
cancers.
20. Subjects who have received prior systemic therapy and/or active
immunotherapy for HNSCC, such as antigen loaded dendritic cells, chimeric
antigen receptor (CAR) T cells that target HPV antigens, or checkpoint
inhibitors are excluded.
Design
Recruitment
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 | EUCTR2021-004277-31-NL |
| CCMO | NL81414.000.22 |