To demontrate improvement of progression-free survival (PFS) and/or overall survival (OS) with M7824 compared with pembrolizumab in first-line participants with advanced NSCLC with high PD-L1 tumor expression.
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1) Progression-free survival (PFS) according to RECIST 1.1 assessed by the
independent review committee (IRC)
2) Overall Survival (OS)
Secondary outcome
1) Occurrence of treatment-emergent adverse events (TEAEs) and
treatment-related adverse events (AE)s
2) OR according to RECIST 1.1 assessed by Independent Review Committee (IRC)
3) Duration of Response (DOR) assessed from complete response (CR) or partial
response (PR) according to RECIST 1.1 assessed by IRC until progressive
disease (PD), death, or last tumor assessment
4) Pharmacokinetic (PK) profile of M7824 in terms of Ceoi (concentration at end
of infusion)
5) PK profile of M7824 in terms of Ctrough (concentration at end of the dosing
interval)
6) Immunogenicity as measured by anti-drug antibodies (ADA) assays at Baseline
and Ontreatment
Background summary
Lung cancer is the leading cause of cancer death in the USA and results in more
cancer deaths than breast cancer, prostate cancer, and colorectal cancer
combined. Non-small cell lung cancer accounts for approximately 80% of all
cases of lung cancer. It is estimated in 2018 there would
be 234,030 new cases of lung and bronchus cancer and 154,050 people would die
from their lung cancers in the USA alone. In the EU, 275,700 deaths due to lung
cancer were predicted in 2017. Worldwide, an estimated 1.8 million new cases of
lung cancer were diagnosed in 2012, approximately 13% of the total of all new
cancers diagnosed.
M7824 is a first-in-class bifunctional fusion protein that combines a
programmed death-ligand 1 (PD-L1) antibody and transforming growth factor *
(TGF*) receptor II as a TGF* neutralizing *trap* into a single molecule. It
thereby targets 2 major mechanisms of immunosuppression in the tumor
microenvironment (blocking both the cell intrinsic PD-L1/PD-1 interaction and
the immunosuppressive TGF*). Immune checkpoint inhibitors have shown improved
treatment outcomes in patients with NSCLC; however, there is room to further
improve benefits. A novel agent such as M7824 is hypothesized to be more
effective than agents that target only a single pathway.
Study objective
To demontrate improvement of progression-free survival (PFS) and/or overall
survival (OS) with M7824 compared with pembrolizumab in first-line participants
with advanced NSCLC with high PD-L1 tumor expression.
Study design
This is an adaptive phase 3, multicenter, international, randomized,
open-label, controlled study to examine the efficacy and safety of intravenous
(iv) M7824 monotherapy versus pembrolizumab as first-line treatment for
participants with advanced NSCLC with high PD-L1 tumor expression.
Intervention
Participants who meet the study criteria will be randomly assigned in a 1:1
ratio to receive either:
- M7824 at a dose of 1200 mg per i.v. infusion once every 2 weeks (q2w), or
- Pembrolizumab at a dose of 200 mg per i.v. infusion once every 3 weeks (q3w).
Study burden and risks
Preclinical data suggest that M7824 strongly enhances antitumor activity and
prolongs survival in mouse tumor models above the effect of either the
anti-PD-L1 antibody avelumab or the TGF* Trap control alone. M7824 is currently
being investigated in Phase I trials (EMR200647-001, MS200647-0008) in patients
with advanced solid tumors including NSCLC in which it has demonstrated an
acceptable safety profile to date. In study EMR200647-001, the response rates
for M7824 in second-line NSCLC participants are substantially better than
historical controls, and are further improved with higher PD-L1 tumor
expression. The benefit/risk ratio of the proposed trial is therefore
considered to be positive.
Frankfurter Strasse 250
Darmstadt 64293
DE
Frankfurter Strasse 250
Darmstadt 64293
DE
Listed location countries
Age
Inclusion criteria
1. * 18 years of age inclusive, at the time of signing the informed consent
2. histologically confirmed diagnosis of advanced NSCLC and:
a. Have not received prior systemic therapy treatment for their advanced/Stage
IV
NSCLC. Completion of treatment with cytotoxic chemotherapy, biological therapy,
and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as
therapy
was completed at least 6 months prior to the diagnosis of metastatic disease.
Confirmation of resolution of toxic effects of previous neoadjuvant/adjuvant
chemotherapy therapy to Grade * 1. For radiation toxicity or prior major
surgeries, participants should have recovered from side effects and/or
complications.
b. Have measurable disease based on RECIST 1.1
c. Have a life expectancy of at least 3 months
d. Availability of tumor tissue (< 6 months old, excluding bone biopsies)
before the first dose is mandatory to determine PD-L1 expression level prior to
enrollment
e. PD-L1 high status by central testing is required
(other protocol defined criteria could apply)
Exclusion criteria
1. Participants with nonsquamous NSCLC histologies whose tumor harbors any of
the following molecular alterations and targeted therapy is locally approved:
a. EGFR sensitizing (activating) mutation
b. ALK translocation(s) associated with responsiveness to ALK tyrosine kinase
inhibitors
c. ROS1 rearrangement(s) associated with responsiveness to ROS1 tyrosine kinase
inhibitors
d. BRAF V600E mutation
2. Has received major surgery within 4 weeks prior to the first dose of study
intervention;
received thoracic RT of > 30 Gy within 6 months prior to the first dose of study
7. Known severe hypersensitivity reactions (Grade * 3 National Cancer Institute
[NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0) to
investigational product (M7824 or pembrolizumab) or any components in their
formulations, or uncontrolled asthma (ie, 3 or more features of partially
controlled asthma)
8. Receipt of any organ transplantation
9. Has interstitial lung disease (ILD) OR has had a history of pneumonitis that
has required oral or IV steroids
10. Significant acute or chronic infections
11. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with
participation for the full duration of the study, or is not in the best
interest of the participant, in the opinion of the treating Investigator.
Participants with history of bleeding diathesis or recent major bleeding events
considered by the Investigator as high risk for investigational drug treatment,
such as patients with clinically relevant bleeding events of hemoptysis * Grade
2 within the last month, are also excluded
12. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2,
anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)
antibody (including ipilimumab or any other antibody or drug specifically
targeting T-cell costimulation or checkpoint pathways) intervention.
13. Previous malignant disease
14. Has active CNS metastases causing clinical symptoms or metastases that
require therapeutic intervention and/or carcinomatosis meningitis
15. Active autoimmune disease that has required systemic treatment in past 1
year OR is
receiving systemic steroid therapy < 3 days prior to the first dose of study
intervention or
receiving any other form of immunosuppressive medication.
16. Is expected to require any other form of systemic or localized
antineoplastic therapy
while on study (including maintenance therapy with another agent for NSCLC, RT,
and/or surgical resection) , (other protocol defined criteria could apply)
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 | EUCTR2018-001517-32-NL |
| ClinicalTrials.gov | NCT03631706 |
| CCMO | NL66163.031.18 |