The purpose of this study is to evaluate, in patients with tumors known to express the protein mesothelin, the following properties of BAY2287411 injection: - safety (to identify, assess, minimize, and appropriately manage the risks associated to…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
mesotheline expressie solide tumoren. (epithelioid mesothelioma, sereuze ovarium carcinoma, pancreas adenocarcinoma).
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study variable is the incidence of DLTs during the first 6 weeks of
treatment (Cycle 1) following administration of BAY 2287411 Injection.
Secondary outcome
- Cmax of Thorium-227 after single dose of Cycle 1
- Cmax of Radium-223 after single dose of Cycle 1
- Cmax of Total antibody after single dose of Cycle 1
- AUC(0-42 days) of Radium-223 after single dose of Cycle 1
- AUC(0-42 days) of Total antibody after single dose of Cycle 1
- AUC(0-42 days) of Thorium-227 after single dose of Cycle 1
Background summary
BAY 2287411 Injection is a radiolabeled tumor targeting biopharmaceutical,
which belongs to the Targeted Thorium Conjugates (TTC). TTCs are a novel class
of compounds, which provides a unique approach to deliver directly to tumor
cells a localized lethal dose of α- radiation by decay of the α particle
emitter thorium 227, using targeting molecules such as monoclonal antibodies
(mAb).
BAY 2287411 Injection comprises the mesothelin (MSLN) targeted, fully human
mAb anetumab, which is conjugated with the octadentate 3, 2 HOPO chelator and
an α particle emitting radionuclide. The antibody chelator conjugate is
radiolabeled with the tetravalent ion of the α particle emitting nuclide
thorium 227, resulting in the formation of a stable complex of thorium-227 with
the antibody-chelator conjugate. The mode of action of BAY 2287411 consists in
the specific binding of the mAb to tumor cells expressing MSLN, which enables
the targeted delivery of thorium 227 to the tumor and the release of a
localized lethal dose of α radiation.
MSLN is physiologically expressed on mesothelial cells lining the pleura,
peritoneum and pericardium. MSLN is pathologically expressed on a number of
solid tumors, including mesothelioma, ovarian and pancreatic cancers, and
certain subsets of triple negative breast cancer, cholangiocarcinoma and non
small cell lung cancer.
Despite an impressive increase in treatment options, clinical benefit in
patients with MSLN positive tumors has remained limited and there is still a
high unmet medical need for treatments that offer durable clinical benefit and
further improve overall survival. BAY 2287411 Injection is being developed for
patients with tumors known to express MSLN, which have exhausted available
therapeutic options.
The purpose of the sub study is to learn how the Zr-89-MSLN imaging agent (BAY
2616506) administered in combination with different doses of the cold antibody
(BAY 2287409) is distributed through the body and how much enters the tumor.
This will help in selecting the antibody dose for the development of the
thorium-227 labeled study drug.
Study objective
The purpose of this study is to evaluate, in patients with tumors known to
express the protein mesothelin, the following properties of BAY2287411
injection:
- safety (to identify, assess, minimize, and appropriately manage the risks
associated to the study drug)
- tolerability (the degree to which side effects can be tolerated by your body)
- maximum tolerated dose
- pharmacokinetics (the effect of your body on the study drug)
- anti-tumor activity
- recommended dose (to determine the recommended dose for further clinical
development)
Study design
This is an open-label, multi-center, Phase 1 study, comprising 2 parts:
- a dose escalation part, with the objective to define the MTD of BAY 2287411
Injection
- a dose expansion part, with the objectives to investigate the PK and
determine the recommended dose for further clinical development of BAY 2287411
Injection.
There is a sub study available for the 18795 participants with the purpose to
learn how the Zr-89-MSLN imaging agent (BAY 2616506) administered in
combination with different doses of the cold antibody (BAY 2287409) is
distributed through the body and how much enters the tumor.
Intervention
BAY 2287411 Injection will be administered intravenously on Day 1 of each cycle
lasting 6 weeks (42 days). Subjects will receive a starting dose of thorium-227
of 1.5 MBq with antibody doses within the range of 10 to 400 mg. The
thorium-227 dose will be escalated in a stepwise fashion up to the MTD or to
the maximum feasible dose
After the MTD has been determined, the dose-expansion phase starts to define
the recommended dose for further clinical development.
Also in the expansion part, subjects receive an intravenous BAY2287411
Injection on day 1 of each cycle.
Once the screening period for the main study is completed the subject will
receive the first dose of the Zr-89-MSLN imaging agent in addition to a dose of
the cold antibody which is not labeled with thorium-227. This is administered
by an intravenous injection. The second dose will be given about 6 weeks later,
after completion of the first cycle of treatment with the thorium-227 labeled
antibody.
Study burden and risks
This first-in-human study of BAY 2287411 Injection is to be performed in
patients with advanced malignant epithelioid mesothelioma, advanced recurrent
serous ovarian cancer or metastatic pancreatic adeno carcinoma, who have
exhausted available therapeutic options. In the escalation part it is aimed to
evaluate the safety, tolerability and MTD or maximum feasible dose of BAY
2287411 Injection. After establishment of the maximum feasible dose BAY2287411
the sponsor will define the recommended dose in conjunction with the
investigator for further development in the expansion part of the study.
A therapeutic benefit in monotherapy in MSLN-expressing tumors is anticipated
based on preclinical observations in vitro and in in vivo xenograft models.
All subjects enrolled in this study will be closely monitored for safety and
tolerability with visits planned for 3 times during the first week after each
dosing followed by weekly visits up to the end of treatment visit. Risks for
the patients will be minimized by intensive safety monitoring and patients will
only be enrolled in the study if they have already exhausted available
therapeutic options.
Close monitoring of patients will be performed, especially for bone marrow
toxicity (blood count), liver toxicity, as well as cardiac toxicity (QT
prolongation and LVEF) and any ophthalmologic side effects.
Men and women of childbearing potential must use adequate barrier birth control
measures, starting from before the study and continuing during the entire
course of the study and for at least 6 months after the last administration of
MSLN-TTC.
Safety calls and dose escalation safety calls will be performed, in which the
decision to escalate the dose of thorium-227 will be based on the collective
analysis of all available safety and PK data and benefit-risk assessment.
Due to the small amount of radioactivity administered with the Zr-89-MSLN
imaging agent, there should be no exposure problems for others. However, as
soon as the patient participates in the main study and receives the thorium
227-labeled antibody, it is important to follow the hygiene guidelines that the
patient has received from the research team.
Energieweg 1
Mijdrecht 3641 RT
NL
Energieweg 1
Mijdrecht 3641 RT
NL
Listed location countries
Age
Inclusion criteria
Inclusion Criteria:
- Signed informed consent
- Male or female subjects >= 18 years of age
- ECOG (Eastern Cooperative Oncology Group) PS of 0 or 1
- Patients with advanced malignant epithelioid mesothelioma or advanced
recurrent serous ovarian cancer, who have exhausted available therapeutic
options; in addition, in the dose expansion part of the study, patients with
metastatic pancreatic adenocarcinoma, who have exhausted available therapeutic
options
- Availability of fresh or archival tumor samples
- Adequate bone marrow, liver, and renal function, as assessed by the following
laboratory requirements (within 28 days before start of study drug treatment)
- Negative serum pregnancy test in women of childbearing potential (WOCBP)
performed within 7 days before the start of study drug administration. Women
and men of reproductive potential must agree to use highly effective methods of
contraception, when sexually active.
Exclusion criteria
Exclusion Criteria:
- Impaired cardiac function or clinically significant cardiac disease
- Pericarditis (any CTCAE grade) or pericardial effusion (CTCAE Grade >= 2)
- Left Ventricular Ejection Fraction (LVEF) < 50% (as measured at screening by
echocardiogram).
- History of anaphylactic reactions to monoclonal antibody therapy
- History of Myelodysplastic syndrome (MDS)/treatment-related acute myeloid
leukemia (t-AML) or with features suggestive of MDS/AML
- Infections of CTCAE (Common Terminology Criteria for Adverse Events) version
5.0 Grade 2 not responding to therapy or active clinically serious infections
of CTCAE Grade >2; known human immunodeficiency virus (HIV) infection; active
hepatitis B virus (HBV) or hepatitis C virus (HCV)infection requiring
treatment. Patients with chronic HBV or HCV infection are eligible at the
investigator*s discretion provided that the disease is stable and sufficiently
controlled under treatment
- Known brain, spinal or meningeal metastases
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 | EUCTR2017-004052-29-NL |
| ClinicalTrials.gov | NCT03507452 |
| CCMO | NL64302.042.17 |