This study has been transitioned to CTIS with ID 2024-510722-10-00 check the CTIS register for the current data. • Evaluate antitumor activity based on response assessment criteria (RECIST v1.1)• Determine RP2D (unless determined in the Escalation…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
breast, uterine, ovarian and squamous non-small cell lung cancer (NSCLC-SCC)
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Dose Expansion Part:
• Objective response rate (ORR) based on RECIST v1.1 as assessed by the
independent review committee (IRC)
Secondary outcome
Dose Expansion Part:
• Antitumor activity, based on RECIST v1.1 as assessed by the IRC: DOR, TTR, DCR
• Progression-free survival (PFS) based on RECIST v1.1 as assessed by the IRC;
Overall Survival (OS)
• AEs and safety laboratory parameters
• PK parameters (clearance; volume of distribution; AUClast; AUCinf; Cmax;
Tmax; Ctrough; t1/2)
• ADA response
Background summary
There is a strong unmet medical need to develop new efficacious therapies for
patients with advanced solid cancers whose disease no longer responds to
currently available therapies. GEN1047 (DuoBody®-CD3×B7H4) is a bispecific
antibody (bsAb) that induces T-cell mediated cytotoxicity of B7H4-positive
cells by crosslinking cluster of differentiation (CD)3 on T cells with B7H4
expressed on target cells. The immune regulatory molecule B7H4 is expressed on
various solid cancers. This is a first-in-human (FIH), open-label,
multinational, phase 1/2a trial to evaluate the safety, preliminary efficacy,
pharmacokinetics (PK), and pharmacodynamics of GEN1047. GEN1047 will be
administered as an intravenous (IV) infusion to a population of patients with
various malignant solid tumors known to express B7H4.
Study objective
This study has been transitioned to CTIS with ID 2024-510722-10-00 check the CTIS register for the current data.
• Evaluate antitumor activity based on response assessment criteria (RECIST
v1.1)
• Determine RP2D (unless determined in the Escalation part)
Study design
This is an FIH, open-label, multinational, multicenter phase 1/2a trial to
evaluate the safety, PK, pharmacodynamics, and preliminary efficacy of GEN1047.
The trial consists of 2 consecutive parts: a Dose Escalation (phase 1) and an
Expansion (phase 2a). In the Dose Escalation, subjects will receive escalating
doses of GEN1047. The incidence of dose-limiting toxicities (DLTs) will be
monitored to determine the maximum tolerated dose (MTD) and/or recommended
phase 2 dose(s) (RP2D). In the Expansion, preliminary efficacy of GEN1047 at
the RP2D will be assessed together with safety, tolerability, PK,
pharmacodynamics, and biomarkers.
Netherlands participation is for the Expansion (phase 2a) only.
Intervention
GEN1047 will be administered as an IV infusion to a mixed population of
subjects with solid tumors.
Study burden and risks
Potential Benefit: The tumor-associated antigen B7H4 is expressed in a variety
of solid cancers with unmet medical need, while expression on normal cells is
limited. GEN1047 (DuoBody-CD3×B7H4) is a bsAb that induces T-cell mediated
cytotoxicity of B7H4-positive tumor cells, associated with CD4+ and CD8+ T-cell
activation and cytokine production, by crosslinking CD3* on T cells and B7H4 on
tumor cells. Crosslinking of CD3* and B7H4 by GEN1047 may have therapeutic
benefits in patients with selected solid tumors in advanced stages who have
very limited treatment options beyond palliative intent.
Potential Risks: GEN1047 is an investigational drug with safety data only
available from nonclinical studies; no information is available regarding the
adverse effects of GEN1047 in humans. Based upon the information to date,
potential safety risks are based on the known MOA of GEN1047 in addition to
nonclinical findings. Available clinical safety data from other compounds that
engage with T cells suggest that cytokine release syndrome (CRS) is a frequent
(>50%) adverse event (AE). CRS results in a defined constellation of symptoms
including but not limited to chills, fever, hypoxia, and hypotension.
Furthermore, the onset of this syndrome is acute (when administered IV). Immune
effector cell-associated neurotoxicity syndrome (ICANS) is distinct
manifestation of the same pathophysiology associated with activated T cell
mediated cytokine release. It usually occurs concurrently with or after CRS
onset and may temporarily affect cognitive function, speech, and level of
consciousness (Lee et al., 2019). CRS and ICANS can be mitigated by 1)
premedications including antipyretics, corticosteroids, and antihistamines and
2) a priming dose, defined as a dose of the compound of interest less than the
*full* or subsequent doses. Mandatory short-term hospitalizations will further
allow close observation of subjects treated with GEN1047 during the time period
during which CRS may arise. Management of CRS and ICANS includes IV hydration,
oxygen, corticosteroids, and interleukin (IL)-6 signaling pathway antagonist
tocilizumab. Identification of potential risks and the risk mitigation
strategies are detailed for GEN1047 in Table 2-2 of the protocol.
In addition to the above mitigation strategies against the potential risk of
CRS and ICANS, multiple independent safety groups ie, the Dose Escalation
Committee (DEC), and the sponsor Safety Committee will be reviewing data from
this trial. The potential for enhanced benefit with manageable toxicity
indicates that GEN1047 should be administered in patients of high unmet need
including patients with solid malignancies who have progressed on all available
SOC therapies and are therefore ineligible to receive these. All patients
enrolled in this trial will be monitored by qualified health care
professional(s) who will provide care and evaluate the patient's response to
GEN1047, in terms of its safety and efficacy.
Carl Jacobsens Vej 30
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Listed location countries
Age
Inclusion criteria
Criteria - Escalation Part:
• Subject must have histologically or cytologically confirmed solid tumor(s) in
any of the following selected indications for which there is no further
available standard therapy likely to confer clinical benefit (or subject is not
a candidate or has previously refused such earlier available therapy), and for
whom, in the opinion of the investigator, experimental therapy with GEN1047 may
be beneficial (breast cancer, endometrial cancer, ovarian cancer, squamous
non-small-cell lung cancer [NSCLC-SCC]).
• Subjects with ovarian cancer must have documented progressive disease (PD) on
or after last prior treatment and within 60 days of Screening.
• Must be at least 18 years of age (or the legal age of consent in the
jurisdiction in which the trial is taking place) on the day of signing informed
consent.
• Must have either recurrence after, or progression on or lack of response to
available relevant standard of care (SoC) anticancer therapies; or are deemed
intolerant to or ineligible for, standard curative therapy in the recurrent
setting.
• Must have at least 1 measurable lesion per RECIST v1.1. The measurable
lesion(s) must be outside the field of radiation therapy (RT) if there was
prior treatment with RT.
• Must have an Eastern Cooperative Oncology Group performance status (ECOGPS)
score of 0 to 1 at Screening and on C1D1 pretreatment.
• Should provide a tumor tissue sample during the Screening period and prior to
C1D1.
• Provide all tumor-assessing pre-trial CT scans since failure of last prior
therapy.
Criteria - Expansion Part:
• Subjects must have documented PD according to RECIST v1.1 on or after last
prior treatment with latest scan performed a maximum of 28 days prior to the
first dose.
• Subject must have advanced (unresectable) or metastatic, histologically
confirmed diagnosis (breast cancer, endometrial cancer, ovarian cancer,
squamous non-small cell lung cancer [NSCLC-SCC]).
• Must be a female and at least 18 years of age (or the legal age of consent in
the jurisdiction in which the trial is taking place) at the time of consent.
• Must have at least 1 measurable lesion per RECIST v1.1 as assessed by local
investigator.
• Must have an ECOG- PS score of 0 to 1 at Screening and on Cycle 1 Day 1
(C1D1) pretreatment.
• Should provide a tumor tissue sample during the Screening period and prior to
C1D1.
• Provide all tumor-assessing pre-trial CT scans since failure of last prior
therapy.
Exclusion criteria
• Significant cardiovascular impairment within 6 months of the first dose of
trial drug.
• Subject with new or progressive brain metastases or spinal cord compression.
• Subject has a history of bowel obstruction related to underlying disease.
• Subject has been exposed to any prior therapy with a compound targeting CD3
and/or B7H4 or cell based therapies.
• Current pneumonitis (any grade) including any radiological change of ongoing
pneumonitis at baseline or history of non-infectious drug-, immune-, or
radiation-related pneumonitis that required steroid.
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 | CTIS2024-510722-10-00 |
| EudraCT | EUCTR2021-001790-23-NL |
| ClinicalTrials.gov | NCT05180474 |
| CCMO | NL82658.056.23 |