The primary objective is to evaluate the ORR of trastuzumab deruxtecan in HER2-overexpressing and/or -HER2 mutated advanced NSCLC subjects.The secondary objectives are:- To evaluate DoR, DCR, PFS, and OS.- To further evaluate the safety of…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Endpoint:
The primary efficacy endpoint (primary outcome measure) is ORR assessed by
independent central review (ICR) based on RECIST version 1.1 for each cohort.
Secondary outcome
Secondary Efficacy Endpoints:
- DoR based on investigator assessment and ICR
- DCR based on investigator assessment and ICR
- PFS based on investigator assessment and ICR
- OS
- ORR based on investigator assessment
Secondary outcome measures include: ORR, DoR, and PFS, and OS.
Safety Endpoints:
The safety endpoints will include:
- Serious adverse events (SAEs)
- Treatment-emergent adverse events (TEAEs)
- - Physical examination findings (including ECOG PS)
- Vital sign measurements
- Standard clinical laboratory parameters (troponin)
- ECG parameters
- Echocardiogram (ECHO) or multigated acquisition (MUGA) scan findings
- Ophthalmologic findings
- Anti-drug antibody (ADA)
Pharmacokinetic (PK) Endpoints:
The PK endpoints (trastuzumab deruxtecan, total anti- HER2 antibody and
MAAA-1181a) will include:
- PK parameters: maximum plasma concentration (Cmax), time to Cmax (Tmax), area
under the concentration time-curve to the (AUClast) and
from time 0 to 21 d (AUC0-21d)
- Serum concentrations
Exploratory and Biomarker Endpoints:
The exploratory efficacy endpoints are:
- TTR
- Best percent change from baseline in the sum of the diameters for all target
lesions
- Analysis of biopsied materials for mechanisms of resistance to trastuzumab
deruxtecan
- To evaluate exposure-response relationships for efficacy and safety endpoints
Biomarker endpoints are:
- Analysis of tissue and/or blood for mechanisms of response/resistance to
trastuzumab deruxtecan
- To evaluate potential biomarkers of response
- Biomarker analysis using cell-free deoxyribonucleic acid (cfDNA)
Background summary
Non-small cell lung cancer (NSCLC) is one of the leading causes of
cancer-related mortality worldwide; accounting for approximately 18% of all
cancer deaths.1 For years, platinum-based chemotherapy has been the cornerstone
of treatment for NSCLC in the first-line. However, the 5-year survival with
conventional chemotherapy regimens is around only 5%. In recent years, several
targeted therapies have been approved and recommended for use in patients with
advanced/metastatic NSCLC including those with non-squamous disease. In
particular, the advent of targeted therapies for specific driver mutations such
as epidermal growth factor receptor (EGFR) as well immune checkpoint inhibitors
have
significantly changed the outlook for this disease. Despite these recent
advances, however, a significant number of patients are either not eligible for
the new therapies or eventually progress on these treatments. Hence, a
significant unmet need exists for patients with advanced/metastatic NSCLC.
Human epidermal growth factor receptor 2 (HER2) overexpression has been
reported in approximately 10% to15% of NSCLC, with a reported incidence as high
as 30% in adenocarcinoma. This overexpression is also associated with poor
disease prognosis and shortened overall survival (OS). HER2 activating mutation
is also reported in approximately 2% to 3% of all NSCLC adenocarcinoma,
particularly in patients who are
Asian, women, and nonsmokers. HER2 mutations and other driver oncogene
abnormalities are reported to be mutually exclusive.7
Results from clinical studies suggest a potential role of HER2-targeting
antibody-drug conjugate (ADC) in NSCLC. A recent study of T-DM1 in NSCLC based
on HER2 IHC expression showed an objective response rate (ORR) of 0% for IHC 2+
tumors, but did demonstrate efficacy with ORR 20% in IHC 3+ tumors. A separate
T-DM1 study reported an ORR of 44% in patients with HER2-mutant NSCLC. While
there is no direct HER2-targeted therapies approved for NSCLC, further
investigation of HER2-targeting strategies are warranted in this patient
population
Study objective
The primary objective is to evaluate the ORR of trastuzumab deruxtecan in
HER2-overexpressing and/or -HER2 mutated advanced NSCLC subjects.
The secondary objectives are:
- To evaluate DoR, DCR, PFS, and OS.
- To further evaluate the safety of trastuzumab deruxtecan
- To determine the PK of trastuzumab deruxtecan
Exploratory Objectives
The exploratory objectives are:
- To evaluate TTR and best percent change in the sum of the diameters for all
target lesions
- To evaluate potential biomarkers
- To evaluate exposure-response relationships for efficacy and safety endpoints
Study design
This is a multicenter, open-label, 2-cohort, Phase 2 study to investigate the
safety and efficacy of trastuzumab deruxtecan in HER2-over-expressing or
-mutated NSCLC subjects.
Cohort 1 will enroll approximately 40 subjects with HER2- over-expressing
(immunohistochemistry IHC 3+ or IHC2+), unresectable and/or metastatic NSCLC.
At least 10 IHC 3+ and at least 10 IHC 2+ subjects will be enrolled.
Cohort 2 will enroll approximately 40 subjects with HER2- mutated, unresectable
and/or metastatic NSCLC.
There will be follow-up visits after permanent discontinuation of study drug to
obtain information about subsequent treatment(s) and survival status.
Intervention
There will be subjects allocated to two different cohorts according to the
centrally confirmed HER2 IHC status and documented HER2 mutation status. All
subjects will receive trastuzumab deruxtecan treatment of the 6.4 mg/kg Q3W.
Study burden and risks
The research consists of a tissue screening period, screening period, a
treatment period, and a follow-up period.
The screening period lasts a maximum of 28 days, the treatment period lasts
about 8 cycles, depending on how the patient responds to the treatment. After
the last treatment the patient will come back for a follow-up visit.
Then there is a long-term follow-up period in which the patient has a telephone
conversation every 3 months (or hospitalvisit if deemed necessary).
In total the patient comes to the hospital about 22 times.
The following tests and procedures will take place during the various visits
1x medical history check, 11x physical examination,, 11x Eye examination, 10x
ECG (more often as needed), 11x ECOG performance status, 10x disease assessment
(CT or MRI scans), 15x blood collection,
10x pregnancy test (if applicable), 1x tumor biopsy, 22x assessing side effects
and use of medication, 8x administration of study
medication.
Mount Airy Road 211
Basking Ridge NJ 07920
US
Mount Airy Road 211
Basking Ridge NJ 07920
US
Listed location countries
Age
Inclusion criteria
1. Must have provided informed consent for study participation (see Section
15.3) before performance of any study-specific procedure or test.
2. Age >=20 y old in Japan, >=18 y old in other countries.
3. Pathologically documented unresectable and/or metastatic nonsquamous NSCLC.
4. Has relapsed from or is refractory to standard treatment or for which no
standard treatment is available.
5. For Cohort 1 and Cohort 1a only: HER2-overexpression (IHC 2+ or 3+) status
must be assessed and confirmed by Clinical Laboratory Improvement Amendments
(CLIA)-certified laboratory or equivalent, from an archival tumor tissue sample.
For Cohort 2 only: Documented any known activating HER2 mutation from an
archival tumor tissue sample analyzed by CLIA laboratory or equivalent,
specifically exon 20 insYVMA (Y772_A775dup), insGSP (G778_P780dup), insTGT
(G776delinsVC), single base pair substitutions
L755S, V777L, or S310F or another HER2 mutation listed in the appendix (see
Section 17.7). Note: HER2 mutation documented only from a liquid biopsy sample
cannot be used for enrollment.
6. Presence of at least 1 measurable lesion assessed by the investigator based
on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
7. Is willing and able to provide an adequate archival tumor tissue sample.
Fine needle aspirates are not acceptable
8. Is willing to undergo a tissue biopsy, after the completion of the most
recent treatment regimen.
9. Has Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to
1.
Exclusion criteria
1. Previously treated with HER2-targeted therapies, except for pan-HER class
tyrosine kinase inhibitors. 2. For Cohort 1 and Cohort 1a only: Has known HER2
mutation. 3. Uncontrolled or significant cardiovascular disease, including any
of the following: a. Medical history of myocardial infarction within 6 months
prior to enrollment b. Symptomatic congestive heart failure (CHF) (New York
Heart Association Class II to IV) 28 d prior to enrollment c. Troponin levels
consistent with myocardial infarction (as defined by the manufacturer) 28 d
prior to enrollment d. History of unstable angina, or serious cardiac
arrhythmia requiring treatment e. Left ventricular ejection fraction (LVEF) <
50% within 28 d prior to enrollment f. Has a corrected QT interval (QTcF)
prolongation to > 470 ms (females) or >450 ms (males) based on average of the
screening triplicate12-lead electrocardiogram (ECG). 4. Has a history of
(non-infectious) interstitial lung disease (ILD)/pneumonitis that required
steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis
cannot be ruled out by imaging at screening. 5. Has clinically significant
corneal disease in the opinion of the Investigator. 6. Has spinal cord
compression or clinically active central nervous system metastases, defined as
untreated and symptomatic, or requiring therapy with corticosteroids or
anticonvulsants to control associated symptoms. Subjects with clinically
inactive brain metastases may be included in the study. Subjects with treated
brain metastases that are no longer symptomatic and who require no treatment
with corticosteroids or anticonvulsants may be included in the study if they
have recovered from the acute toxic effect of radiotherapy. A minimum of 2 wk
must have elapsed between the end of whole brain radiotherapy and study
enrollment. 7. Has multiple primary malignancies within 3 y, except adequately
resected non-melanoma skin cancer, curatively treated in-situ disease, or other
solid tumors curatively treated.
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 | EUCTR2017-004781-94-NL |
| CCMO | NL65483.031.18 |