Phase I Dose Escalation1.To determine the RP2D in terms of safety and tolerability for:•IV admin of HB-201 in patients with HPV 16+ confirmed HNSCC•IT admin of HB-201 in patients with HPV 16+ confirmed cancers•IV admin of HB-202 in patients with HPV…
ID
Source
Brief title
Condition
- Other condition
- Reproductive and genitourinary neoplasms gender unspecified NEC
Synonym
Health condition
HPV16 positive cancers: head and neck squamous cell carcinoma, anal squamous cell carcinoma, cervical, vulvar, penile, vaginal cancer
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase I Dose Escalation
•Incidence of DLTs from the first study drug administered during the DLT
observation period
Phase II Dose Expansion
Tumor responses will be assessed using RECIST and iRECIST by the Investigator:
•Objective response rate
•Disease control rate
Secondary outcome
Phase I Dose Escalation
•Safety: type, frequency, and severity of AEs and SAEs
•Tolerability: dose interruptions, reductions and dose intensity, and
evaluations of laboratory values
•Tumor responses will be assessed using RECIST and iRECIST by the Investigator:
-Objective response rate
-Disease control rate
Phase II Dose Expansion
Tumor responses will be assessed using RECIST and iRECIST by the Investigator:
•Overall survival
•Progression-free survival
•Duration of response
•Safety: type, frequency, and severity of AEs and SAEs
•Tolerability: dose interruptions, reductions and dose intensity, and
evaluations of laboratory values
Background summary
Human papilloma virus (HPV) infection is linked to several cancer types.
Malignant transformation of cells by HPV necessitates the integration of HPV
viral genome elements into the genome of the host. The generation and
maintenance of the HPV 16+ malignant state of a cell requires the consistent
expression of E7 and E6 proteins from HPV, and therefore, E7 and E6 represent a
potential immunotherapy target. HB-201 and HB-202 therapy targets tumors
induced by HPV 16, by expression of an artificial antigenic E7 and E6 fusion
protein from HPV 16 (E7E6) and is thereby expected to induce a robust CD8+ T
cell response.
Significant preclinical data have been generated demonstrating potent efficacy
in HPV 16 cancer models using HB-201 and HB-202 both intravenous and
intratumoral administration. In animal models, HB-201 and HB-202 were observed
to be highly immunogenic, resulting in a robust CD8+ T cell response. Based on
the levels of antigen-specific CD8+ T cells induced by HB-201 and HB-202 in
preclinical models, notably when compared with the levels induced by other
approaches (including adoptive cell therapies), we believe that HB-201
Monotherapy and/or HB-201 & HB-202 sequential alternating two-vector therapy
have the potential to provide therapeutic benefit to patients with a wide range
of HPV 16+ tumors.
Given the extremely low response rates to existing therapies and limited
overall survival of patients with advanced HPV 16 positive cancers, any therapy
with a chance to prolong life should be developed.
Study objective
Phase I Dose Escalation
1.To determine the RP2D in terms of safety and tolerability for:
•IV admin of HB-201 in patients with HPV 16+ confirmed HNSCC
•IT admin of HB-201 in patients with HPV 16+ confirmed cancers
•IV admin of HB-202 in patients with HPV 16+ confirmed HNSCC
•IV admin of HB-202 in patients with HPV 16+ confirmed cancers
Phase II Dose Expansion
1. To assess the preliminary antitumor activity of:
•IV admin of HB-201 in patients with HPV 16+ confirmed HNSCC
•IT admin of HB-201 followed by IV administration of HB-201 in patients with
HPV 16+ confirmed cancers
•IV administration of HB 201 in combination with pembrolizumab in patients with
HPV 16+ confirmed HNSCC
•Sequential alternating IV admin of HB-201 & HB-202 in patients with HPV 16+
confirmed HNSCC
•IT admin of HB-201 followed by sequential alternating IV admin of HB 201 & HB
202 in patients with HPV 16+ confirmed cancers
•Sequential alternating IV administration of HB-201 & HB-202 in combination
with pembrolizumab in patients with HPV 16+ confirmed HNSCC
Study design
This is a first in human Phase I/II, multinational, multicenter, open-label
study of HB-201 monotherapy and HB-201 & HB-202 alternating two-vector therapy
in patients with HPV 16+ confirmed cancers comprising two parts: Phase I Dose
Escalation and Phase II Dose Expansion. The proposed Phase I Dose Escalation
will evaluate the safe recommended Phase II dose (RP2D) of HB-201 monotherapy
and HB-201 & HB-202 alternating therapy in both intravenous and - for HB-201 -
intratumoral administrations (first dose only).
The Phase II Dose Expansion will evaluate the safety and efficacy of
intravenous administrations of HB-201 monotherapy and HB-201 & HB-202
alternating two-vector therapy alone and in combination with pembrolizumab. It
will also evaluate the safety and efficacy of an initial intratumoral
administration of HB-201 followed either by HB-201 iv monotherapy or HB-201 &
HB-202 iv alternating two-vector therapy alone and in combination with
pembrolizumab.
Patients with HPV 16+ Head and Neck Squamous Cell Carcinoma (HNSCC) will be
enrolled in the intravenous treatment groups. Patients with HPV 16+ HNSCC and
other HPV 16+ confirmed cancers who have an accessible tumor lesion will be
included in the intratumoral treatment groups.
The study will take approximately 5 years to complete including a long-term
follow up, and will be performed as a multicenter, multinational, open label,
safety and efficacy study.
Intervention
Patients with HPV 16+ Head and Neck Squamous Cell Carcinoma (HNSCC) will be
enrolled in the intravenous treatment groups. Patients with HPV 16+ HNSCC and
other HPV 16+ confirmed cancers who have an accessible tumor lesion will be
included in the intratumoral treatment groups.
The type of treatment the patient receives will depend on which phase of the
study they joined.
At Phase I, the patient will be receiving either all doses of the study drug
intravenously (into a vein) or the first dose of the study drug regimen
intratumorally (into the tumor) and all later doses of the study drug will be
given intravenously.
Four different doses of the study drugs are planned to be studied.
At Phase II, the *recommended doses* of the study drugs as determined in Phase
I will be used. Depending on the group that the patients will be assigned they
will be receiving either the study drugs alone, or together with Pembrolizumab
intravenously. Patients who have an accessible tumor lesion will receive the
first dose of the study drugs intratumorally.
Pembrolizumab will be administered on a 200 mg once every 3 weeks or 400 mg
once every 6 weeks schedule, overlapping with study visits.
Study burden and risks
Based on the levels of antigen-specific CD8 cytotoxic T cells induced by HB-201
and HB-201 & HB-202 in nonclinical models, notably when compared with the
levels induced by other approaches (including adoptive cell therapies), HB-201
monotherapy as well as HB-201 & HB-202 alternating two-vector therapy have the
potential to provide therapeutic benefit to patients with a wide range of HPV
16+ tumors.
Given the extremely low response rates to existing therapies and limited OS of
patients with advanced HPV 16+ cancers, any therapy with a chance to prolong
life should be developed.
Thus, it is expected that the benefits of HB-201 monotherapy and HB-201 &
HB-202 alternating two-vector therapy significantly outweigh the negligible
risk of developing any AEs.
Subject*s participation in this study will last years and consists of a
screening period, treatment period and a follow-up period.
During the treatment period, subjects will need to visit the study site to
receive their treatment and take their safety/efficacy assessments as well as
sample collection for biomarker analyses.
During the follow-up period, subjects will be contacted every 6-8 weeks for
progression-free survival follow-up and every 12 weeks for long term FU. Aside
from the intervention described above, participation in this study involves
blood draws at multiple visits, and might involve tumor biopsy at screening and
on the day of their first study drug administration and involve exposure
through CT or MRI. Also samples from saliva, feces (e.g., fecal swab) and urine
will be collected.
Helmut-Qualtinger-Gasse 2
Vienna 1030
AT
Helmut-Qualtinger-Gasse 2
Vienna 1030
AT
Listed location countries
Age
Inclusion criteria
All Patients:
- 18 years of age or older
- >= 1 measurable lesion by imaging for tumor response following RECIST and
iRECIST
- ECOG performance status of 0 to 1.
- Prior curative radiation therapy must have been completed >= 4 weeks prior to
study treatment administration. Prior focal palliative radiotherapy must have
been completed >= 2 weeks prior to study treatment administration.
- Screening laboratory values must meet protocol-specified criteria
- Female patients who are of childbearing potential must have a negative serum
β-human chorionic gonadotropin (β-hCG) pregnancy test prior to the first
administration of study treatment or be surgically/biologically sterile
(hysterectomy or bilateral oophorectomy) or postmenopausal.
- Male patients with sexual partners of childbearing potential can participate
in the study if they agree to use barrier contraception from signing of the ICF
through 5 months after the last study treatment administration.
Treatment Group 1, Group 3, Group 4, Group 5 Group A, or Group D:
- Documentation of confirmed HPV 16+ HNSCC via genotype testing
- Tumor progression or recurrence on standard of care therapy, including >= 1
systemic therapy or be a patient for whom standard of care therapy is
contraindicated.
Treatment Group 2, Group 4, Group C, or Group F:
- Documentation of confirmed HPV 16+ cancer via genotype testing
- Tumor progression or recurrence on standard of care therapy, including >= 1
systemic therapy
- Safe and accessible tumor site amenable for biopsy and IT administration
- Apart from the tumor site(s) amenable for biopsy and IT administration
>= 1 measurable lesion for RECIST assessment
Treatment Group B or Group E:
- Documentation of confirmed HPV 16+ HNSCC via genotype testing
- Must be eligible, as per standard of care, to receive pembrolizumab
Exclusion criteria
- Untreated and/or symptomatic metastatic central nervous system (CNS) disease,
and/or carcinomatous meningitis. With some exceptions for treated and stable
brain/CNS metastases
- Any serious or uncontrolled medical disorder that, in the opinion of the
Investigator, may increase the risk associated with study participation /
treatment administration
- Concurrent malignancy that is clinically significant or requires active
intervention
- Active, known or suspected, autoimmune or inflammatory disorders requiring
immunosuppressive therapy
- Toxicity attributed to systemic prior anticancer therapy, including radiation
and surgery, other than alopecia and fatigue that has not resolved to Grade 1
or Baseline prior to the first administration of study
- Not meeting the protocol-specified washout periods for prohibited medications
per the protocol
- Treatment with any chemotherapy, biological, or investigational therapy for
cancer within 28 days of the first administration of study treatment., unless
agreed otherwise between the Sponsor and the Investigator on a case-by-case
basis based on the half-life of the anticancer therapy.
Exception: Ongoing treatment with pembrolizumab is permitted if the subject is
enrolling in a backfill cohort continuing pembrolizumab and adding either
HB-201 monotherapy or HB-201 & HB-202 alternating two vector therapy.
- Prior anaphylactic or other severe reaction to human immunoglobulin or
antibody formulation administration
- Positive hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV)
antibody, indicating acute or chronic infection
- Known history of AIDS.
For patients receiving pembrolizumab:
- History of severe hypersensitivity reaction to pembrolizumab
- Any contraindication to receiving pembrolizumab per package insert or SmPC
- Allogeneic tissue/solid organ transplant.
- History of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
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 | EUCTR2019-000907-34-NL |
| ClinicalTrials.gov | NCT04180215 |
| CCMO | NL78667.000.21 |