PrimaryTo evaluate confirmed ORR of Trastuzumab deruxtecan in human epidermal growth factor receptor 2- (HER2-) mutated NSCLC subjects treated at 5.4 and 6.4 mg/kg doses.Secundary- To evaluate the clinical efficacy of Trastuzumab deruxtecan at 5.4…
ID
Source
Brief title
Condition
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is confirmed ORR, defined as the proportion of
subjects with CR or PR, assessed by the blinded independent
central review (BICR) based on RECIST version 1.1
Secondary outcome
- Confirmed ORR as indicated above assessed by investigator assessment based on
RECIST v.1.1.
- DoR, defined as time from the initial response (CR or PR) by BICR and
investigator assessment until documented tumor progression or death
from any cause.
- DCR, defined as the proportion of subjects who achieve CR, PR, or stable
disease (SD) during study treatment. DCR based on BICR and
DCR based on investigator assessments will both be determined.
- PFS, defined as the time from date of randomization until first objective
radiographic tumor progression or death from any cause, based on BICR and
investigator assessment
- OS, defined as the time from date of randomization until death from any cause.
- Adverse Events (AEs) including TEAEs, serious adverse events (SAEs) and
adverse events of special interest (AESIs) that will be graded according to the
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
- Physical examination findings that may include Eastern Cooperative Oncology
Group (ECOG) Performance Status (PS), vital sign measurements,
ophthalmologic findings, standard clinical laboratory parameters,
electrocardiogram (ECG) parameters, echocardiogram (ECHO)/multi-gated
acquisition (MUGA) findings, and radiologic findings.
- The PK endpoints include serum concentrations of Trastuzumab deruxtecan,
total anti-HER2 antibody, and MAAA 1181a.
- The immunogenicity endpoint includes incidence of ADA.
The (patient-reported outcomes) PROs include:
- Change from baseline in European Organization for Research and Treatment of
Cancer (EORTC) core quality of life questionnaire (QLQC30) and EORTC quality of
life questionnaire for lung cancer trials (QLQLC13) scale scores
- Time to definitive deterioration in EORTC QLQ-C30 scores
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. In particular, the advent
of targeted therapies for specific driver mutations such as epidermal growth
factor receptor (EGFR) as well as immune checkpoint inhibitors have
significantly changed the outlook for this disease. Despite recent advances,
however, a significant number of advanced/metastatic NSCLC patients eventually
progress on these treatments, and hence an unmet medical need exists for these
patients.
Human epidermal growth factor receptor 2 (HER2) activating mutations have been
reported in approximately 2% to 3% of all NSCLC adenocarcinoma patients. Whilst
in an afatinib Phase 3 trial, 4.9% (12 of 245) of the squamous NSCLC patients
also had the HER2 mutation.
Results from clinical studies suggest a potential role of an HER2-targeting
antibody-drug conjugate (ADC) in NSCLC. A trastuzumab emtansine (T-DM1) study
reported an objective response rate (ORR) of 44% in patients with HER2-mutated
NSCLC.HER2 mutation is also considered a distinct molecular target, however, no
HER2-targeted therapies are approved in NSCLC.
Study objective
Primary
To evaluate confirmed ORR of Trastuzumab deruxtecan in human epidermal growth
factor receptor 2- (HER2-) mutated NSCLC subjects treated at 5.4 and 6.4 mg/kg
doses.
Secundary
- To evaluate the clinical efficacy of Trastuzumab deruxtecan at 5.4 and 6.4
mg/kg doses by confirmed ORR by investigator assessment
- To evaluate the clinical efficacy of Trastuzumab deruxtecan at 5.4 and 6.4
mg/kg doses by duration of response (DoR).
- To evaluate further the clinical efficacy of Trastuzumab deruxtecan at 5.4
and 6.4 mg/kg doses by disease control rate (DCR), progression-free survival
(PFS) and Overall survival (OS)
- To evaluate safety of Trastuzumab deruxtecan at 5.4 and 6.4 mg/kg doses.
- To evaluate pharmacokinetics (PK) and immunogenicity of Trastuzumab
deruxtecan at 5.4 and 6.4 mg/kg doses.
- To assess symptoms, functioning and Health-related Quality of life (HRQoL) in
subjects treated with Trastuzumab deruxtecan at 5.4 and 6.4 mg/kg doses.
Study design
This is a randomized, 2 arm, Phase 2, multicenter study to evaluate the safety
and efficacy of Trastuzumab deruxtecan at 5.4 or 6.4 mg/kg in HER2-mutated
NSCLC subjects who had disease recurrence or progression during/after at least
one regimen of prior anticancer therapy (second-line or later, 2L+) that must
have contained a platinum-based chemotherapy drug. The study is designed to
randomize approximately 150 subjects to one of the following two arms in a 2:1
ratio to receive Trastuzumab deruxtecan at a dose of 5.4 mg/kg every 3 weeks
(Q3W) or 6.4 mg/kg Q3W, respectively. Randomization will be stratified by
subjects who (i) received prior anti-programmed cell death receptor-1 (PD-1)
and/or anti-programmed cell death ligand 1 (PD-L1) treatment and (ii) those who
received neither.
The treatment assignment will remain blinded to study subjects, Investigators,
study site personnel (except the unblinded pharmacist and other unblinded staff
members as deemed necessary for site operations to maintain the blind), central
imaging readers and Interstitial Lung Disease (ILD) Adjudication Committee. The
Sponsor and the Contract Research Organization (CRO) are not blinded to the
treatment assignment of subjects. The
study start date is the date when the first subject has signed informed consent
form (ICF). A subject is randomized when the Investigator or designee has
obtained written consent, has confirmed all eligibility criteria have been met
and all screening procedures have been completed.
Participation of a subject in the study will be divided into three periods:
Screening, Treatment, and Follow-up (which includes the 40-day Follow-up [40-D
FUP] and the Long-Term Survival Follow-Up [LTSFU]). The Screening Period will
be a maximum of 28 days (d) after the ICF is signed. Subjects will be
randomized once considered eligible and will then enter the Treatment Period. A
maximum of 7 days are allowed between randomization and first dose of the
treatment in the study. Subjects will undergo radiographic assessment of the
disease status every 6 weeks (Q6W) ± 1 week from the first dose of study
treatment until disease progression. The Follow-up Period begins upon
discontinuation from study drug, regardless of reason. After completion of the
40-D FUP visit, subsequent LTSFU visits will occur at the following frequencies
to assess survival and collect information on anticancer treatments.
Please refer to figure 1.1 of the study protocol for the study flow diagram.
Intervention
Subjects will be Randomly assigned to one of the following treatment groups:
- Group 1, approximately 100 subjects will receive 5.4 mg/kg of the study drug
- Group 2, approximately 50 subjects will receive 6.4 mg/kg of the study drug.
The study drug will be given once every 3 weeks via an intravenous infusion.
Study burden and risks
The subject's participation in this study will last about 16 months. The total
duration of the subjects participation will also depend on how their cancer
responds to the study drug and the ability to be safely treated without
significant side effects.
This study is divided into 4 periods: a pre-screening phase, screening phase,
treatment phase and a follow-up phase (which alsoincludes a long term survival
fullow-up). In total the subject will visit the hospital approximately 22times
during this study. Each visit will take about 2 to 4 hours to complete.
Please refer to paragraph 1.3 of the protocol (schedule of events) for more
information.
The following tests and procedures will take place during these visits:
- Questions are asked about the medical history, demographics and eligibility
questions..
- Measurement of vital signs / physical examination (e.g. blood pressure, heart
rate, temperature, and respiratory rate), height, weight, check of oxygen
levels)
- Eye test
- Blood and urine samples are taken for different tests
- Pregnancy test for woman of childbearing potential.
- ECG
- ECHO/MUGA
- CT/MRI
- Tumor biopsy
If required, as per study doctor's discretion:
- Bone scan
- PET scan
- Pulmonary Function Test (PFT)
Possible side effects that are already known are described in the
Investigator's Brochure and the subject informed consent form.
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
10.1.2 of the protocol) before performance of any study-specific procedure or
test.
2. Men or women >=18 years old. (Please follow local regulatory requirements if
the legal age of
consent for study participation is >18 years old).
3. Pathologically documented metastatic NSCLC with a known activating HER2
mutation
(please refer to the list of HER2 mutations, see Table 10.2 of the protocol).
The HER2 mutation must be documented from an archival or fresh tumor tissue
sample analyzed by Clinical Laboratory
Improvement Amendments (CLIA) certified laboratory or equivalent laboratory
performing
testing to Good Laboratory Practice (GLP) standard.
Note: HER2 mutation documented only from a liquid biopsy sample cannot be used
for
enrollment.
4. Subjects who had previous treatment including platinum therapy in the
metastatic/locally advanced setting and not amenable to curative surgery or
radiation. The subject must have progressed during or after the last treatment
regimen or discontinued because of unacceptable toxicity.
5. Presence of at least 1 measurable lesion confirmed by BICR based on RECIST
version 1.1.
6. Is willing and able to provide an adequate archival tumor tissue sample. A
fresh biopsy is
required if an archival tumor tissue sample cannot be supplied. Resection and
core needle biopsy are acceptable. Other tissue samples, eg, fine needle
aspirates or cell block are not
acceptable. For detailed instruction on tissue submission, please refer to the
laboratory manual.
7. Has ECOG PS of 0 to 1.
8. Has left ventricular ejection fraction (LVEF) >= 50% within 28 days before
randomization.
9. Has adequate organ function within 14 days before randomization (please
refer to additional information in the protocol, paragraph 5.1).
10. Has adequate treatment washout period before randomization (please refer to
additional information in the protocol, paragraph 5.1)
11. Male and female subjects of reproductive/childbearing potential must agree
to use a highly
effective form of contraception or avoid intercourse during and upon completion
of the study
and for at least 7 months for females and 4 months for males, after the last
dose of study drug.
Methods considered as highly effective methods of contraception are described
in Section 5.1 of the protocol.
12. Male subjects must not freeze or donate sperm starting at randomization and
throughout the study period, and at least 4 months after the final study drug
administration. Preservation of sperm
should be considered prior to randomization in this study.
13. Female subjects must not donate, or retrieve for their own use, ova from
the time of randomization and throughout the study treatment period, and for at
least 7 months after the final study drug administration. Female subjects must
refrain from breastfeeding throughout this time. Preservation of ova may be
considered prior to randomization in this study.
14. Life expectancy of 3 months or more.
Please refer to protocol for complete list of inclusion criteria.
Exclusion criteria
Has a known driver mutation in the epidermal growth factor receptor (EGFR),
BRAF or MET exon 14 gene or a known anaplastic lymphoma kinase (ALK), ROS1, RET
or NTRK fusion.
2. Medical history of myocardial infarction within 6 months before
randomization, symptomatic
congestive heart failure (CHF) (New York Heart Association Class II to IV.
Subjects with
troponin levels above ULN at screening (as defined by the manufacturer), and
without any MI
related symptoms should have a cardiologic consultation before randomization to
rule out MI.
3. Has a corrected QT interval (QTcF) prolongation > 470 msec (females) or >450
msec (males)
based on average of triplicate12-lead ECG at screening.
4. Has a history of (non-infectious) ILD/pneumonitis that required steroids,
has current
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by
imaging at
screening.
5. 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
weeks must have elapsed between the end of brain radiotherapy and study
randomization.
6. Has multiple primary malignancies within 3 years, except adequately resected
non-melanoma
skin cancer, curatively treated in-situ disease, or other solid tumors
curatively treated.
7. Has a history of severe hypersensitivity reactions to either the drug
substances or inactive
ingredients in the drug product.
8. Has a history of severe hypersensitivity reactions to other monoclonal
antibodies.
9. Has an uncontrolled infection requiring intravenous (IV) antibiotics,
antivirals, or antifungals.
10. Has substance abuse or any other medical conditions such as clinically
significant cardiac or
psychological conditions, that may, in the opinion of the investigator,
interfere with the
subject*s participation in the clinical study or evaluation of the clinical
study results.
11. Known human immunodeficiency virus (HIV) infection. Subjects should be
tested for HIV
prior to randomization if required by local regulations or institutional review
board (IRB)/
independent ethics committee (IEC).
12. Known active clinically relevant liver disease (eg, active hepatitis B, or
active hepatitis C), such as those with serologic evidence of viral infection
within 28 days of Cycle 1, Day 1. Subjects with past or resolved hepatitis B
virus (HBV) infection are eligible, if negative for hepatitis B surface antigen
(HBsAg[-]) and positive for hepatitis B core antibody (anti-HBc[+]). Subjects
positive for hepatitis C (HCV) antibody are eligible only if the polymerase
chain reaction is negative for HCV RNA.
13. Unresolved toxicities from previous anticancer therapy, defined as
toxicities (other than
alopecia) not yet resolved to Grade <= 1 or baseline. Note: Subjects may be
enrolled with
chronic Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3
months prior to
randomization and managed with standard of care treatment) which the
investigator deems
related to previous anticancer therapy, such as:
Chemotherapy-induced neuropathy
b. Fatigue
c. Residual toxicities from prior IO treatment: Grade 1 or Grade 2
endocrinopathies which may
include:
• Hypothyroidism/ hyperthyroidism
• Type I diabetes
• Hyperglycemia
• Adrenal insufficiency
• Adrenalitis
• Skin hypopigmentation (vitiligo)
14. Is pregnant, breastfeeding, or planning to become pregnant.
15. Otherwise considered inappropriate for the study by the investigator.
16. Lung-specific intercurrent clinically significant illnesses including, but
not limited to, any
underlying pulmonary disorder (eg. pulmonary emboli within three months of the
study
randomization, severe asthma, severe COPD, restrictive lung disease, pleural
effusion etc.).
17. Any autoimmune, connective tissue or inflammatory disorders (e.g.,
Rheumatoid arthritis,
Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of
pulmonary
involvement at the time of screening. Full details of the disorder should be
recorded in the
eCRF for subjects who are included in the study.
18. Prior complete pneumonectomy
19. Had prior treatment with any agent, including an antibody drug conjugate
(ADC), containing a chemotherapeutic agent targeting topoisomerase I.
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 | EUCTR2020-003427-42-NL |
| ClinicalTrials.gov | NCT04644237 |
| CCMO | NL76070.031.21 |