Primary• To evaluate the safety and tolerability of AMG 910 in adult subjects. • To determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D)Secondary• To characterize the PK of AMG 910• To evaluate preliminary anti-tumor…
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Dose-limiting toxicities (DLT)
• Treatment-emergent adverse events
• Treatment-related adverse events
• Changes in vital signs, electrocardiogram (ECG), and clinical laboratory
tests
Secondary outcome
• PK parameters for AMG 910 following short-term intravenous (IV) and extended
IV (eIV) administration including but not limited to maximum serum
concentration (Cmax), minimum serum concentration (Cmin), area under the
concentration-time curve (AUC) over the dosing interval, accumulation following
multiple dosing, and, if feasible, half-life (t1/2) Objective response (OR) per
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and iRECIST Duration
of response (DOR)
Background summary
AMG 910 is an HLE BiTE antibody construct designed to direct T cells (via CD3
binding) towards Claudin-18 isoform 2 (CLDN18.2)-expressing cells. In AMG 910,
the binding arms for CLDN18.2 and CD3 are genetically fused to the N-terminus
of a single chain IgG Fc (fragment crystallizable; scFc) region. The fusion to
a Fc domain is a well-established strategy to prolong the half-life of protein
therapeutics, such as cytokines, growth factors, and
bispecific antibodies, with several approved for the treatment of cancer
(Kontermann, 2011). The extended half-life of Fc fusion proteins is due to
their interaction with the neonatal Fc receptor, which results in a protected
intracellular protein reservoir that is recycled to the extracellular space
(Rath, et al., 2015).
A detailed description of the chemistry, pharmacology, nonclinical
pharmacokinetics, and toxicology of AMG 910 is provided in the AMG 910
Investigator*s Brochure.
Study objective
Primary
• To evaluate the safety and tolerability of AMG 910 in adult subjects.
• To determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose
(RP2D)
Secondary
• To characterize the PK of AMG 910
• To evaluate preliminary anti-tumor activity of AMG 910
Exploratory
• To evaluate immunogenicity of AMG 910
• To evaluate exploratory biomarkers including pharmacodynamic and potential
patient selection biomarkers
Study design
This is an open-label, ascending, multiple dose, phase 1 study evaluating AMG
910 in subjects with CLDN18.2-positive gastric and GEJ adenocarcinoma. The
study will consist of:
• Dose-exploration phase
• Dose-expansion phase
The dose-exploration phase of the study will estimate the MTD of AMG 910 using
a Bayesian logistic regression model (BLRM). A RP2D may be identified based on
emerging safety, efficacy, and pharmacodynamic data prior to reaching an MTD.
Following the dose-exploration phase, a dose-expansion phase will be conducted
to confirm safety, PK, and pharmacodynamics at the MTD or RP2D and to obtain
further safety and efficacy data and enable correlative biomarker analysis.
Intervention
Extended IV infusion over 96 hours in cycle 1 week 1 and as short-term IV
infusions weekly (or twice weekly) starting cycle 1 day 8 onwards through cycle
6 of 28-day cycles.
Study burden and risks
The key safety risks for AMG 910:
• Cytokine Release Syndrome (CRS) /Infusion-Related Reactions
• Gastrointestinal Toxicity
• Neurologic Events
• Tumor Lysis Syndrome (TLS)
• Sucrose Toxicity:
Minervum 7061
Breda 4817 ZK
NL
Minervum 7061
Breda 4817 ZK
NL
Listed location countries
Age
Inclusion criteria
• Subjects with histologically or cytologically confirmed metastatic or locally
advanced unresectable gastric or GEJ adenocarcinoma positive for CLDN18.2 as
defined by the test described herein (Section 8.2.10.1). Prior treatment with
any CLDN18.2-targeting product requires testing of a tissue sample obtained
after the treatment with the CLDN18.2-targeting product (not applicable for
re-treatment).
• Subjects should not be eligible for curative surgery and should have been
refractory to or have relapsed after 2 or more prior lines of standard systemic
therapy that included a platinum, a fluoropyrimidine, either a taxane or
irinotecan, and an approved vascular endothelial growth factor receptor (VEGFR)
antibody/tyrosine kinase inhibitor (TKI) and depending on country-specific
standards and approvals.
• For subjects eligible for human epidermal growth factor receptor 2 (HER2)
directed therapy, prior therapy should have included an approved HER2 targeting
antibody.
• Subjects may also be included if the aforementioned therapeutic options were
medically not appropriate for them. In these cases, the reason(s) why required
prior therapies for gastric cancer were medically not appropriate should be
documented in the subject*s electronic case report form (eCRF).
• For dose-expansion only: Subjects with at least 1 measurable lesion >= 10mm
which has not undergone biopsy within 3 months of screening scan. This lesion
cannot be biopsied at any time during the study.
For more inclusion criteria, please refer to section 5.1 of the protocol.
Exclusion criteria
• Any anticancer therapy or immunotherapy within 4 weeks of start of first dose
(14 days for palliative radiation).
• Untreated or symptomatic central nervous system (CNS) metastases,
leptomeningeal disease, or spinal cord compression.
• Autoimmune disorders requiring chronic systemic steroid therapy or any other
form of immunosuppressive therapy while on study, eg, ulcerative colitis,
Crohn*s disease, or any other gastrointestinal autoimmune disorder causing
chronic nausea, vomiting, or diarrhea.
Recent or current use of inhaled steroids or physiological substitution in case
of adrenal insufficiency is not exclusionary.
• Evidence or history within last 3 months of gastrointestinal inflammatory
conditions not associated with the underlying cancer disease including
gastrinomas, duodenitis, proven gastric ulcer, duodenal ulcer, pancreatitis, or
subjects with recent gastric bleeding. Subjects may be included if the
symptomatic/immunosuppressive treatment is discontinued more than 4 weeks prior
to the first dose of AMG 910, symptoms have resolved, and gastroscopy does not
indicate signs of active disease.
For more inclusion criteria, please refer to section 5.2 of the protocol.
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 | EUCTR2020-000312-30-NL |
| ClinicalTrials.gov | NCT04260191 |
| CCMO | NL72431.056.20 |