| Eligibility |
Inclusion Criteria:
1. Provision of informed consent prior to any study specific procedures.
2. Have a histologically or cytologically confirmed diagnosis of (locally) advanced stage
EGFR mutation positive NSCLC, not amenable for curative intent treatment.
3. Have measurable disease according to RECIST 1.1.
4. At least two lesions with a long axis diameter =2 cm.
5. Have received at least one line of EGFR TKI treatment for (locally) advanced stage
NSCLC.
6. In case the tumor is positive for T790M mutation, prior treatment with a third
generation EGFR TKI is mandatory.
7. Patients must be =18 years of age.
8. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1 at the time of
Screening.
9. Has adequate bone marrow reserve and organ function, based on local laboratory data
within 14 days prior to Cycle 1, Day 1, defined as:
- Platelet count =100 000/mm3 or =100 × 109/L (platelet transfusions are not
allowed up to 14 days prior to Cycle 1 Day 1 to meet eligibility)
- Hemoglobin (Hgb) =9.0 g/dL or 5.6 mmol/L (transfusion and/or growth factor
support is allowed)
- Absolute neutrophil count (ANC) =1500/mm3 or =1.5 × 109/L
- Creatinine clearance (CrCl) =30 mL/min as calculated using the Cockcroft-Gault
equation or measured CrCl
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =3 × ULN (if
liver metastases are present, =5 ×ULN)
- Total bilirubin (TBL) =1.5 × ULN if no liver metastases (<3 × ULN in the presence
of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver
metastases)
- Serum albumin =2.5 g/dL or 25 g/L
- Prothrombin time (PT) or Prothrombin time- international normalized ratio
(PT-INR) and activated partial thromboplastin time (aPTT)/partial thromboplastin
time (PTT) =1.5 × (ULN), except for subjects on coumarin-derivative
anticoagulants or other similar anticoagulant therapy, who must have PT-INR
within therapeutic range as deemed appropriate by the Investigator
10. Be willing to provide a qualifying tumor tissue specimen. A pretreatment tumor biopsy
(if medically feasible) or otherwise archival tumor tissue is required. Samples must
be of sufficient quantity and of adequate tumor tissue content (as defined in the
Laboratory Manual).
1. A Baseline pretreatment tumor biopsy must be of the primary (if intact) and/or
metastatic lesion(s) not previously irradiated and amenable to core biopsy. Any
serious adverse event (SAE) directly related to the new biopsy should be reported
as outlined in Section 8.
2. If not medically feasible to collect the pretreatment tumor biopsy, archival
tumor tissue not previously irradiated must be collected from a biopsy on or
after treatment with the most recent EGFR TKI cancer therapy regimen.
11. If the subject is a female of childbearing potential, she must have a negative serum
pregnancy test at screening and must be willing to use a highly effective birth
control upon enrollment, during the Treatment Period, and for 7 months, following the
last dose of study drug. A female is considered of childbearing potential following
menarche and until becoming postmenopausal (no menstrual period for a minimum of 12
months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy
or bilateral oophorectomy) with surgery at least 1 month before the first dose or
confirmed by follicle stimulating hormone (FSH) test.
12. Female subjects must not donate, or retrieve for their own use, ova from the time of
screening and throughout the study treatment period, and for at least 7 months after
the final study drug administration.
13. If male, the subject must be surgically sterile or willing to use a highly effective
birth control upon enrollment, during the treatment period, and for at least 4 months
following the last dose of study drug.
14. Male subjects must not freeze or donate sperm starting at screening and throughout the
study period, and for at least 4 months after the final study drug administration.
Exclusion Criteria:
1. Any history of interstitial lung disease (ILD) (including pulmonary fibrosis or
radiation pneumonitis), has current ILD, or is suspected to have such disease by
imaging during screening.
2. Clinically severe pulmonary compromise (based on investigator's assessment) resulting
from intercurrent pulmonary illnesses including, but not limited to:
1. any underlying pulmonary disorder (eg, pulmonary emboli, severe asthma, severe
chronic obstructive lung disease (COPD), restrictive lung disease, pleural
effusion);
2. any autoimmune, connective tissue or inflammatory disorder with pulmonary
involvement (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis); OR prior
pneumonectomy.
3. Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent
or any form of immunosuppressive therapy prior to Cycle 1 Day 1. Subjects who require
use of bronchodilators, inhaled steroids, or local steroid injections may be included
in the study.
4. Evidence of any leptomeningeal disease.
5. Has clinically significant corneal disease.
6. Any evidence of severe or uncontrolled systemic diseases (including active bleeding
diatheses, active infection, psychiatric illness/social situations, geographical
factors, substance abuse, or other factors which in the Investigator's opinion makes
it undesirable for the subject to participate in the study or which would jeopardize
compliance with the protocol. Screening for chronic conditions is not required.
7. Evidence of clinically active spinal cord compression or brain metastases, defined as
untreated and symptomatic, or requiring therapy with corticosteroids or
anticonvulsants to control associated symptoms. Subjects with clinically inactive or
treated brain metastases who are asymptomatic (ie, without neurologic signs or
symptoms and do not require treatment with corticosteroids or anticonvulsants) may be
included in the study. Subjects must have a stable neurologic status for at least 2
weeks prior to Cycle 1 Day 1.
8. Inadequate washout period prior to Cycle 1 Day 1, defined as:
1. Whole brain radiation therapy <14 days or stereotactic brain radiation therapy <7
days.
2. Any cytotoxic chemotherapy, investigational agents or other anticancer drug(s)
from a previous cancer treatment regimen or clinical study (other than Epidermal
growth factor receptor tyrosine kinase inhibitor (EGFR TKI)), <14 days or 5
half-lives, whichever is longer.
3. Monoclonal antibodies other than immune checkpoint inhibitors, such as
bevacizumab (anti-VEGF) and cetuximab (anti-EGFR) <28 days.
4. Immune checkpoint inhibitor therapy < 21 days.
5. Major surgery (excluding placement of vascular access) < 28 days.
6. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field
of radiation < 28 days or palliative radiation therapy < 14 days.
7. Chloroquine or hydroxychloroquine = 14 days.
9. Prior treatment with an HER3 antibody and/or antibody drug conjugate (ADC) that
consists of an exatecan derivative that is a topoisomerase I inhibitor (eg,
trastuzumab deruxtecan).
10. Has unresolved toxicities from previous anticancer therapy, defined as toxicities
(other than alopecia) not yet resolved to National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI-CTCAE) version 5.0, grade =1 or baseline. Subjects
with chronic Grade 2 toxicities may be enrolled at the discretion of the Investigator
after consultation with the Sponsor Medical Monitor or designee.
11. Has known hypersensitivity to either the drug substances or inactive ingredients in
the drug product.
12. Has any primary malignancy other than locally advanced or metastatic NSCLC within 3
years prior to Cycle 1 Day 1, except adequately resected non-melanoma skin cancer,
curatively treated in-situ disease, or other solid tumors curatively treated.
13. Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1, including:
1. QT interval corrected by Fridericia's formula (QTcF) prolongation interval of
>470 ms for females and >450 ms for males.
2. Left ventricular ejection fraction (LVEF) <50% by either echocardiogram (ECHO) or
multi-gated acquisition (MUGA) scan.
3. Resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg.
4. Myocardial infarction within 6 months.
5. New York Heart Association (NYHA) Classes 2 to 4 within 28 days.
6. Uncontrolled angina pectoris within 6 months.
7. Cardiac arrhythmia requiring antiarrhythmic treatment.
14. Active Hepatitis B and/or Hepatitis C infection, such as those with serologic evidence
of viral infection within 28 days of Cycle 1, Day 1.
a. Subjects with past or resolved Hepatitis B virus (HBV) infection are eligible if:
i. Hepatitis surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc)
positive; OR ii. HBsAg positive and HBV DNA viral load is documented to be = 2000
IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to
the viral load evaluation with normal transaminases (in the absence of liver
metastasis); OR iii. HBsAg positive and HBV DNA viral load is documented to be = 2000
IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to
the viral load evaluation with liver metastasis and abnormal transaminases AST/ALT < 3
ULN.
b. Subjects with a history of Hepatitis C infection will be eligible for enrollment
only if the viral load according to local standards of detection, is documented to be
below the level of detection in the absence of anti-viral therapy during the previous
12 weeks (ie, sustained viral response according to the local product label but no
less than 12 weeks, whichever is longer).
15. Female subject who is pregnant or breastfeeding or intends to become pregnant during
the study.
16. Subjects with known human immunodeficiency virus (HIV) infection.
17. Prior or ongoing clinically relevant illness, medical condition, surgical history,
physical finding, or laboratory abnormality that, in the Investigator's judgment,
could affect the safety of the subject; alter the absorption, distribution, metabolism
or excretion of the study drug; or confound the assessment of study results.
18. Live virus vaccination 28 days prior to Cycle 1 Day 1.
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