This study has been transitioned to CTIS with ID 2024-513770-22-00 check the CTIS register for the current data. Primary objective:• Evaluate the anti-tumor activity of GEN1046 as monotherapy and in combination with pembrolizumab in subjects with…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms benign (excl mesotheliomas)
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
• Objective response rate (ORR) per Response Evaluation Criteria in Solid
Tumors (RECIST) v1.1 as assessed by investigator
Secondary outcome
Secondary Endpoints:
• Duration of response (DOR) per RECIST v1.1
• Time to response (TTR) per RECIST v1.1
• Progression-free survival (PFS) per RECIST v1.1
• Overall survival (OS)
• Incidence and severity of adverse events (AEs)
• Incidence and severity of laboratory abnormalities
Background summary
GEN1046 (DuoBody®-PD-L1×4-1BB) is a PD-L1×4-1BB bispecific antibody that
induces activation of T cells by simultaneously blocking an inhibitory signal
via the programmed cell death protein 1 (PD 1)/ programmed death-ligand 1
(PD-L1) axis and conditionally inducing a stimulatory signal via 4-1BB. The Fc
domain of GEN1046 was engineered to silence interactions with FcγR and the
complement factor C1q. GEN1046 mediated signaling of 4 1BB on activated T cells
is strictly dependent on simultaneous binding of the PD L1 arm. In addition,
the PD L1 specific arm of GEN1046 functions as a classical immune checkpoint
inhibitor (CPI) by blocking the PD-1/PD-L1 axis when 4-1BB binding is absent.
The hypothesis is that by simultaneous binding of PD-L1 on tumor cells or
antigen-presenting cells and 4-1BB on tumor-specific T cells, GEN1046 will
induce efficacious T cell activation in the tumor or in tumor-draining lymph
nodes, thereby enhancing antitumor immunity.
Although anti-PD-1/PD-L1 inhibitors as monotherapy or in combination with other
systemic therapy have been approved for non-small cell lung cancer (NSCLC) as
first line therapy, durable clinical responses are observed only in a minority
of patients and resistance to these therapies remains a major challenge.
Therefore, there is a strong unmet medical need to develop new efficacious
therapies for the patients who no longer respond to standard of care (SOC)
therapy. Thus, the dual-targeted approach by GEN1046 on both 4-1BB and PD-L1
receptors may improve the clinical benefits of anti-PD-1/anti PD-L1 inhibitors
in patients with NSCLC after treatment with anti-PD-1/anti-PD-L1-containing
therapies.
The objectives of the GCT1046-04 trial are to investigate the safety and
efficacy of GEN1046 as monotherapy in a sequential activation regimen and in
combination therapy with pembrolizumab in adult subjects with
relapsed/refractory metastatic NSCLC after treatment with CPI containing
therapy.
Study objective
This study has been transitioned to CTIS with ID 2024-513770-22-00 check the CTIS register for the current data.
Primary objective:
• Evaluate the anti-tumor activity of GEN1046 as monotherapy and in combination
with pembrolizumab in subjects with relapsed/refractory metastatic NSCLC
Secondary objectives:
• Evaluate time to onset and durability of the anti tumor response of GEN1046
as monotherapy and in combination with pembrolizumab in subjects with
relapsed/refractory metastatic NSCLC
• Evaluate the clinical benefit of GEN1046 as monotherapy and in combination
with pembrolizumab
• Assess safety and tolerability of GEN1046 as monotherapy and in combination
with pembrolizumab
Study design
This is a phase 2, multicenter, randomized, open-label trial evaluating the
safety and efficacy of GEN1046 as monotherapy and in combination with
pembrolizumab in adult subjects with relapsed/refractory metastatic NSCLC after
treatment with CPI-containing therapy.
Up to 24 subjects who are PD-L1 positive by local or central testing, are
planned for enrollment in the safety run-in part of the trial. Up to 12
subjects can be enrolled in Arms B and C. Thereafter, enrollment in the
randomized part of the trial will continue until at least 40 subjects, who are
PD-L1 positive by central testing, have been randomized in each arm. It is
expected that in total, approximately 160 subjects will be enrolled in the
trial. Randomization will be stratified by PD-L1 expression (>=50% vs 1% to 49%
PD-L1 positive tumor cells) and histology (squamous vs non-squamous).
a. GEN1046 100 mg Q3W for the first 2 cycles followed by GEN1046 500 mg Q6W for
the subsequent cycles
b. GEN1046 100 mg Q3W in combination with pembrolizumab 200 mg Q3W
c. GEN1046 100 mg Q6W in combination with pembrolizumab 400 mg Q6W
During a preliminary safety run-in to assess tolerability of Arms B and C, an
adapted *3+3* design will be utilized with up to 12 subjects (up to 6 subjects
per arm) to be enrolled in Arms B and C in the following sequence. Three
subjects from Arm C will be treated and closely monitored for 1 treatment
cycle. If no subject experiences a DLT, no more subjects will be evaluated for
DLTs in the safety run-in for Arm C. If at least one subject experiences a DLT,
an additional 3 subjects will be treated in the safety run-in for Arm C.
However, if two or three subjects experience a DLT of a similar nature, no more
subjects will be treated in the safety run-in for Arm C unless endorsed by the
Safety Committee. Upon the completion of 3 DLT-evaluable subjects in the safety
run-in for Arm C, the same process will be followed for Arm B.
To better understand the safety, tolerability, PK, pharmacodynamic, or
anti-tumor activity, up to 6 additional subjects may be allocated to Arms B and
C in the safety run-in if the Safety Committee considers it appropriate. After
completion of the safety run-in for Arms B and C, the collective data
(including, but not limited to, all relevant safety and clinical data) will be
evaluated. After this review, if the combination regimens do not pose
significant safety concerns, randomization for Arms A, B, and C will begin.
Disease status will be evaluated per RECIST v1.1. Contrast-enhanced computed
tomography (CT) or magnetic resonance imaging (MRI) will be obtained at
baseline before the first dose and 6, 12, 18, and 24 weeks (±7 days) after the
first dose of trial medication, and thereafter, every 9 weeks (±7 days). CT or
MRI will continue to be obtained until disease progression (as assessed by the
investigator), start of subsequent anti-cancer therapy, withdrawal of consent,
or death, whichever occurs first. In Germany, the preferred imaging modality
for all radiologic assessments should be MRI, unless the investigator deems
this option is contraindicated for this trial.
Safety, including AEs, physical examinations, Eastern Cooperative Oncology
Group (ECOG) performance status (PS), vital signs, electrocardiograms, and
laboratory values, will be monitored throughout the trial.
Blood samples will be drawn from all subjects to assess PK, pharmacodynamics,
immunogenicity status, and other exploratory biomarkers. Subjects must provide
fresh and/or archival tumor tissue for determination of PD-L1 expression in the
tumors.
Changes in quality of life will be assessed via patient-reported outcomes
questionnaires.
To explore the potential of including decentralized clinical trial (DCT)
components in future studies in order to increase subject participation and
retention, this trial includes an optional DCT part. The DCT part consists of
remote visits conducted in the subject*s home or an agreed upon location by a
dedicated DCT nurse and completion of questionnaires.
Intervention
All components of trial treatment are administered via IV infusion.
• Arm A: GEN1046 100 mg Q3W for the first 2 cycles followed by GEN1046 500 mg
Q6W for the subsequent cycles
• Arm B: GEN1046 100 mg Q3W in combination with pembrolizumab 200 mg Q3W
• Arm C: GEN1046 100 mg Q6W in combination with pembrolizumab 400 mg Q6W
Study burden and risks
A subject will undergo extra examinations and tests which make the visits last
longer than the subject is used to. Additionally, participation in this study
may affect the subject's eligibility for receiving subsequent treatment for
NSCLC.
For the complete study, a subject will need to visit the hospital approximately
53 times over 31 months. One visit will last approximately 4 hours. In total,
approximately 3540 ml of blood will be collected over 31 months. For sites
using CT scans, a subject will receive approximately 85 mSV of radiation in 31
months.
Treatment with GEN1046, whether or not combined with Pembrolizumab, may involve
risks to humans not yet known, including potential life-threatening side
effects. The study doctor will monitor a subject closely and treat side effects
if needed. If needed, extra blood sampling or testing will be performed.
Furthermore, study procedures like blood draws, biopsies, MRI/CT and ECGs also
carry potential risks.
Carl Jacobsens Vej 30
Valby 2500
DK
Carl Jacobsens Vej 30
Valby 2500
DK
Listed location countries
Age
Inclusion criteria
• Subject must be at least 18 years of age.
• Subject has histologically or cytologically confirmed diagnosis of stage 4
NSCLC with at least 1 prior line of systemic therapy containing an
anti-PD-1/PD-L1 monoclonal antibody (mAb). Subjects must have demonstrated
disease progression (PD) as defined by RECIST v1.1. For the subjects whose most
recent anti-cancer therapy contained an anti-PD-1/PD-L1 mAb, their recent
evidence of PD must be confirmed by a second assessment no less than 4 weeks
from the date of the initial documented PD.
Note: Subject must have received at least 2 doses of an approved anti
PD-1/PD-L1 mAb approved in NSCLC.
o Subject has progressed during or after treatment with 1 anti-PD-1/PD-L1 mAb
administered either as monotherapy, or as SOC combination (subjects who have
received only anti-PD-1/PD-L1 mAb monotherapy as first-line therapy, are
eligible for this study if the investigator determines treatment with
platinum-containing chemotherapy is not appropriate, in line with local
treatment guidelines) or;
o Subject has progressed during or after platinum doublet chemotherapy
following an anti-PD-1/PD-L1 mAb or;
o Subject has progressed during or after an anti-PD-1/PD-L1 following platinum
doublet chemotherapy.
• Subject must have a tumor PD-L1 expression result available prior to C1D1
demonstrating PD-L1 expression in >=1% of tumor cells as assessed by a sponsor
designated central laboratory using the Dako PD-L1 IHC 22C3 pharmDx assay
(TPS>=1%), or per site local assessment with the Dako PD-L1 IHC 22C3 pharmDx
assay (TPS>=1%) or the VENTANA PD-L1 (SP263) assay (TC >=1%) adhering to the
manufacturer*s instructions.
Note: Local PD-L1 result needs to be performed on fresh tumor tissue (obtained
within 3 months prior to enrollment and after failure/stop of last prior
treatment) or, if not feasible, archival tissue (obtained within 12 months
prior to enrollment).
• Subject must have measurable disease per RECIST v1.1 as assessed by the
investigator.
• Subject must have ECOG PS <=1.
• Subject must have life expectancy of at least 3 months.
• Subject must have adequate organ and bone marrow function as described in the
protocol.
Exclusion criteria
• Documentation of known EGFR sensitizing mutations, KRAS, RET, ROS1, BRAF
mutations, NTRK gene infusions, RET rearrangement, ALK gene rearrangements,
high level
MET amplification, or METex 14 skipping. If documentation of mutation status is
not available, for subjects with non-squamous histology or a mixed histology of
non-squamous and squamous, a formalin-fixed, paraffin-embedded tumor tissue
should be tested for biomarker panel analysis (which may include, but is not
limited to, EGFR, ALK, ROS1, BRAF, KRAS mutations, RET rearrangement, or NTRK
gene infusions, etc.). Subjects must not be randomized until biomarker status
is available in source
documentation at the site.
Note: Subjects with tumors harboring such targetable mutations, gene
rearrangements, or gene amplifications as described above may enroll in the
trial, if such subjects have also received an approved targeted therapy for
this indication assuming satisfactory fulfilment of all other eligibility
criteria (especially, at least 1 prior line of systemic therapy
containing an anti-PD-1/PD-L1 mAb for metastatic NSCLC disease).
• Subject has been exposed to any of the following prior therapies:
o Prior treatment with docetaxel for NSCLC.
o Prior treatment with a 4-1BB (CD137) targeted agent, any type of antitumor
vaccine, or autologous cell immunotherapy.
o Treatment with an anti-cancer agent within 28 days prior to GEN1046
administration.
• Subject discontinued treatment due to disease progression within the first 6
weeks of a CPI-containing treatment.
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 |
|---|---|
| EU-CTR | CTIS2024-513770-22-00 |
| EudraCT | EUCTR2021-001928-17-NL |
| ClinicalTrials.gov | NCT05117242 |
| CCMO | NL79351.056.21 |