- - GENERAL INCLUSION CRITERIA (Patients will be included in the study only if they meet
all the following inclusion criteria):
1.
Patient must be capable to understand the purpose of the study and have signed
written informed consent form (ICF) prior to beginning specific protocol
procedures.
2. Age ≥ 18 years at the time of signing ICF.
3. Life expectancy ≥ 6 weeks.
4. Karnofsky Performance Status (KPS) ≥70%, Eastern Cooperative Oncology Group
(ECOG) performance status (PS) ≤ 2.
5. Patient must be able to tolerate therapy.
6. Availability and willingness to provide the most recently available tumor tissue
sample (formalin-fixed paraffin-embedded [FFPE], no cytology/cell block, no
bone/decalcified bone sample) of primary tumor or any metastatic site from biopsy
collected after last round of prior treatment and ≤ 6 months prior to HER3-DXd,
if possible, for retrospective exploratory biomarker testing. If archival tissue
is not available, a newly obtained baseline biopsy of an accessible tumor lesion
is required prior to start of study treatment (unless not possible because of
inaccessible tumor location or safety concerns). Collection and/or shipment of
pre-treatment tumor tissue biopsy for retrospective biomarker testing should be
at least initiated treatment at the time of inclusion.
7. No indication for immediate local therapy.
8. Patient has adequate bone marrow, liver, and renal function:
1. Hematological (without platelet, red blood cell transfusion, and/or
granulocyte colony-stimulating factor support within 7 days before first
study treatment dose): White blood cell (WBC) count > 3.0 x 109/L, absolute
neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and
hemoglobin ≥ 10.0 g/dL (≥ 6.2 mmol/L).
2. Hepatic: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times upper limit
of normal (ULN) (≤ 3 in patients with liver metastases or know history of
Gilbert's disease); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate
transaminase (AST); alanine transaminase (ALT) ≤ 3 times ULN (≤ 5 in
patients with liver metastases); international normalized ratio (INR) < 1.5.
3. Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min/1.73
m2 based on Cockcroft-Gault glomerular filtration rate estimation for
patients with creatinine levels above institutional normal.
9. Patients must have received at least 1 prior line of systemic treatment* in the
advanced setting.
- - Prior systemic treatments for eligible patients with BC are defined as
follows:
- Patients with triple-negative breast cancer (TNBC) must have received
at least one line of prior systemic therapy for advanced disease.
- - Patients with luminal BC must have received at least one line of ET and
one line of CT in the advanced setting.
- - Patients with HER2-positive BC must have progressed to at least two
previous treatments with HER2-targeted therapies in the advanced
setting.
- - Prior systemic treatments for eligible patients with aNSCLC are defined as
follows:
- Patients without activating driver alterations must have received at
least one prior line of standard of care systemic therapy for locally
advanced or metastatic disease.
- - Patients with activating driver alterations must have received at least
one prior line of an approved genotype-directed therapy.
- - Patients with EGFR T790M mutation who received first-line treatment
with erlotinib, gefitinib, afatinib, or dacomitinib must have received
second-line treatment with osimertinib and have documentation of
radiological disease progression.
10. Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1
as determined by the US National Cancer Institute (NCI)-Common Terminology
Criteria for Adverse Events (CTCAE) version 5.0 (v.5.0).
Note: Except for alopecia or other toxicities not considered a safety risk for
the patient at investigator's discretion.
11. For women of childbearing potential: agreement to remain abstinent (must refrain
from heterosexual intercourse) or use highly effective contraceptive methods, or
two effective contraceptive methods, as defined in the protocol, during the
treatment period and for at least 7 months after the last dose of study
treatment, whichever is longer. Women of childbearing potential must have a
negative serum pregnancy test within 14 days before study treatment initiation
and must agree to refrain from donating eggs during the entire study treatment
period and for 7 months after the last administration of the study drug.
12. For male subjects: being surgically sterile or having agreed to true abstinence
(must refrain from heterosexual intercourse) or having female partners willing to
agree with true abstinence or use barrier contraceptive measures mentioned above
during the entire study treatment period and for 4 months after the last
administration of the study drug. Male patients must agree to refrain from
donating sperm during the entire study treatment period and for 4 months after
the last administration of the study drug.
13. Patient must be accessible for treatment and follow-up.
- - SPECIFIC INCLUSION CRITERION FOR COHORT 1 AND COHORT 2 (Cohort 1 and cohort 2 patients
will be included in the study only if they meet all the following inclusion criteria):
1.
Histologically documented BC (cohort 1) or NSCLC of squamous or non-squamous
histologic types (cohort 2).
2. Radiologically documented metastatic disease.
3. Newly diagnosed BM or BM progressing after local treatment.
4. Measurable disease according to Response Assessment in Neuro-Oncology Brain
Metastases (RANO-BM) criteria, with at least one measurable brain lesion of ≥10
mm on T1-weighted, gadolinium-enhanced MRI.
- - SPECIFIC INCLUSION CRITERION FOR COHORT 1 AND COHORT 2 (Cohort 1 and cohort 2 patients
will be included in the study only if they meet all the following inclusion criteria):
1.
Histologically documented BC (cohort 1) or NSCLC of squamous or non-squamous
histologic types (cohort 2).
2. Radiologically documented metastatic disease. 3. Newly diagnosed BM or BM
progressing after local treatment. 4. Measurable disease according to Response
Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, with at least
one measurable brain lesion of ≥10 mm on T1-weighted, gadolinium-enhanced MRI.
- - SPECIFIC INCLUSION CRITERION FOR COHORT 1 (Cohort 1 patients will be included in the
study only if they meet the following inclusion criterion):
1.
Locally determined HER2 status.
- - SPECIFIC INCLUSION CRITERIA FOR COHORT 3 (Cohort 3 patients will be included in the
study only if they meet all the following inclusion criteria):
1.
Histologically documented solid tumor of any type.
2. Type I LMD, defined by positive CSF cytology or leptomeningeal biopsy, or type II
LMD, defined by clinical findings and neuroimaging only, according to European
Society for Molecular Oncology (ESMO) Standard Operating Procedures (SOPs) for
Clinical Practice Guideline (CPG) 2017.
3. Newly diagnosed LMD or LMD progressing after radiotherapy.
- - EXCLUSION CRITERIA (Patients will be excluded from the study if they meet any of the
following criteria):
1.
Current participation in another therapeutic clinical trial.
2. Treatment with approved or investigational cancer therapy within 14 days prior to
initiation of study drug.
3. Patients have a concurrent malignancy or malignancy within five years of study
enrollment with the exception of carcinoma in situ of the cervix, non-melanoma
skin carcinoma, or stage I uterine cancer. For other cancers considered to have a
low risk of recurrence, discussion with the Medical Monitor is required.
4. Previous systemic therapy with any anti-HER3 directed drug.
5. Known allergy or hypersensitivity to HER3-DXd or any of the drug components.
6. Radiotherapy or limited-field palliative radiotherapy within seven days prior to
study enrolment, or patients who have not recovered from radiotherapy-related
toxicities to baseline or grade ≤ 1 and/or from whom ≥ 25% of the bone marrow has
been previously irradiated.
7. Patients with an active cardiac disease or a history of cardiac dysfunction or
conduction abnormalities including any of the following:
1. Unstable angina pectoris or documented myocardial infarction within 6 months
prior to study entry.
2. Symptomatic pericarditis.
3. Documented congestive heart failure (CHF) (New York Heart Association [NYHA]
Class III-IV).
4. Left ventricular ejection fraction (LVEF) < 50% as determined by multigated
acquisition (MUGA) scan or echocardiogram (ECHO).
5. Ventricular arrhythmias except for benign premature ventricular
contractions.
6. Other cardiac arrhythmias requiring a pacemaker or not controlled with
medication.
7. Long QT syndrome (QTcF interval > 450 ms).
8. Clinically severe pulmonary compromise resulting from intercurrent pulmonary
illnesses including, but not limited to, any underlying pulmonary disorder (i.e.,
pulmonary emboli within three months of the study enrolment, severe asthma,
severe chronic obstructive pulmonary disease [COPD], restrictive lung disease,
pleural effusion etc.), and any autoimmune, connective tissue or inflammatory
disorders with pulmonary involvement (i.e., rheumatoid arthritis, Sjogren's
syndrome, sarcoidosis etc.), or prior pneumonectomy.
9. History of non-infectious interstitial lung disease (ILD)/pneumonitis that
required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis
that cannot be ruled out by imaging at screening.
10. Pregnant or lactating women.
11. Any serious medical condition or abnormality in clinical laboratory tests that,
in the investigator's judgment, precludes the patient's safe participation in and
completion of the study.
12. Current known infection with hepatitis B virus (HBV), or hepatitis C virus (HCV).
Patients with past HBV infection or resolved HBV infection (defined as having a
negative hepatitis B surface antibody [HBsAg] test and a positive hepatitis B
core antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible.
Patients positive for HCV antibody are eligible only if polymerase chain reaction
(PCR) is negative for HCV RNA.
13. Known human immunodeficiency virus (HIV) infection that is not well controlled.
All of the following criteria are required to define an HIV infection that is
well controlled: undetectable viral RNA, CD4-positive cells' count ≥ 350, no
history of AIDS-defining opportunistic infection within the past 12 months, and
stable for at least 4 weeks on the same anti-HIV medications (meaning there are
no expected further changes in that time to the number or type of antiretroviral
drugs in the regimen). If an HIV infection meets the above criteria, monitoring
of viral RNA load and CD4-positive cells' count is recommended.
14. History of a major surgical procedure (defined as requiring general anesthesia)
or significant traumatic injury within 21 days prior to randomization, or
patients who have not recovered from the side effects of any major surgery.
15. History of uncontrolled seizures, CNS disorders or serious and/or unstable
pre-existing psychiatric disability judged by the investigator to be clinically
significant and adversely affecting compliance to study drugs or interfering with
subject safety.
16. Patients requiring concomitant use of chronic systemic (intravenously [IV] or
oral) corticosteroids at doses higher than 8 mg dexamethasone per day or other
immunosuppressive medications except for managing adverse events (AEs), including
immune-related adverse events (irAEs) for patients that received immunotherapy in
a previous line; (inhaled steroids or intra articular steroid injections are
permitted in this study).
Note: The use of stable corticosteroid therapy in patients with brain metastases
can be discussed with the Medical Monitor.
17. Patients with known 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.
18. Participants who are unable or unwilling to comply with the requirements of the
protocol in the opinion of the investigator.
