| Eligibility |
Inclusion Criteria:
1. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this
protocol.
2. Provision of signed and dated written ICF prior to any mandatory study specific
procedures, sampling, and analyses.
3. Male and female patients must be at least 18 years of age.
4. Patients must have documented (only allowed for EGFRm+ [exon 19 deletions or L858R] in
pre-treated patients) and/or confirmed central/local test result showing eligible EGFR
mutation status as specified below:
- EGFR TKI pre-treated patients: EGFRm+ (exon 19 deletions or L858R), along with valid
T790M mutation status
5. All patients will be required to have NSCLC associated with at least 1 site of LM as
identified by the Investigator that can be assessed by MRI scan and that is suitable
for repeat assessments. Measurable INC or EXC disease by RECIST 1.1 is not required.
Concomitant brain metastases and brain metastases previously treated with radiation
therapy are allowed. In addition, asymptomatic untreated BM is also allowed.
6. EGFR TKI pre-treated patients must have had at least 1 prior EGFR TKI (eg, gefitinib,
erlotinib, icotinib, dacomitinib or afatinib) and may have had other lines of therapy
7. If the patients is T790M negative, EXC must be stable following previous EGFR TKI
treatment. EXC progression is allowed if patients are T790M positive patients
8. ECOG/WHO performance status 0 to 2 with no deterioration over the previous 2 weeks and
a minimum life expectancy of 12 weeks.
9. Females must be using highly effective contraceptive measures and must have a negative
pregnancy test prior to start of dosing if of childbearing potential, or must have
evidence of non-childbearing potential by fulfilling one of the following criteria at
screening:
- Post-menopausal, defined as aged more than 50 years and amenorrheic for at least
12 months following cessation of all exogenous hormonal treatments
- Women under 50 years old would be considered postmenopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and with luteinizing hormone and follicle-stimulating hormone levels
in the post-menopausal range for the institution
- Documentation of irreversible surgical sterilization by hysterectomy, bilateral
oophorectomy, or bilateral salpingectomy but not tubal ligation Further
information is in Appendix I (Definition of women of childbearing potential and
acceptable contraceptive methods).
10. Male patients must be willing to use barrier contraception
11. For inclusion in the optional genetics research study, patients must provide informed
consent for genetic research.
12. If a patient declines to participate in any voluntary exploratory research of the
study, there will be no penalty or loss of benefit to the patient and he/she will not
be excluded from other aspects of the study.
Exclusion Criteria:
1. EGFR TKI pre-treated patients whose T790M mutation status cannot be determined.
2. EGFR TKI pre-treated patients with progressing EXC disease who are T790M
mutation-negative. Progressing EXC disease is defined as RECIST 1.1 PD no more than 3
months prior to enrollment, per Investigator assessment.
3. Past medical history of ILD, drug-induced ILD, radiation pneumonitis that required
steroid treatment, or any evidence of clinically active ILD.
4. Significant medical or psychiatric illness that would interfere with compliance and
ability to tolerate treatment as outlined in the protocol.
5. Any of the following cardiac criteria:
- Mean resting corrected QTc >470 msec, obtained from ECGs, using the screening
clinic ECG machine-derived QTc value
- Any clinically important abnormalities in rhythm, conduction, or morphology of
resting ECG (eg, complete left bundle branch block, third degree heart block, and
second degree heart block)
- Patients with any factors that increase the risk of QTc prolongation or risk of
arrhythmic events such as the following electrolyte abnormalities, heart failure,
congenital long QT syndrome, family history of long QT syndrome, or unexplained
sudden death under 40 years of age in first-degree relatives or any concomitant
medication known to prolong the QT interval and cause Torsades de Pointes (TdP):
- Hypokalemia (serum potassium <3.5 mmol/L)
- Hypomagnesemia (serum magnesium <0.7 mmol/L)
- Hypocalcemia (corrected serum calcium <2.1 mmol/L)
6. Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values:
- Absolute neutrophil count <1.5×109/L
- Platelet count <100×109/L
- Hemoglobin <90 g/L
- Alanine aminotransferase (ALT) >2.5× the upper limit of normal (ULN) if no
demonstrable liver metastases or >5× ULN in the presence of liver metastases
- Aspartate aminotransferase (AST) >2.5× ULN if no demonstrable liver metastases or
>5× ULN in the presence of liver metastases
- Total bilirubin (TBL) >1.5× ULN if no liver metastases or >3× ULN in the presence
of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver
metastases
- Creatinine >1.5× ULN concurrent with creatinine clearance <50 mL/min (measured or
calculated by Cockcroft and Gault equation); confirmation of creatinine clearance
is only required when creatinine is >1.5× ULN
7. Known INC hemorrhage that is unrelated to tumor.
8. Patients with the clinical manifestation of nervous system failure including severe
encephalopathy or with severe nervous system injury related with treatment, such as
chemical meningitis.
9. Non-malignant neurological disease that would interfere with evaluation of symptoms or
signs of LM.
10. CNS complications that require urgent neurosurgical intervention (eg, resection or
shunt placement) up to 2 weeks before to start of IP or patients who have not
recovered from side effects of such intervention.
11. Treatment with any of the following:
- Any cytotoxic chemotherapy, investigational agents, or anticancer drugs (other
than EGFR TKI) for the treatment of advanced NSCLC from a previous treatment
regimen or clinical study up to 14 days before the first dose of IP.
- Treatment with an EGFR TKI (eg, afatinib, erlotinib, icotinib, dacomitinib or
gefitinib) up to 8 days or approximately 5× half-life, whichever is the longer,
before the first dose of IP (if sufficient wash-out time has not occurred due to
schedule or PK properties, an alternative appropriate wash-out time based on
known duration and time to reversibility of drug-related AEs could be agreed upon
by principal investigator).
- Patients currently receiving (or unable to stop use prior to receiving the first
dose of study treatment) medications or herbal supplements known to be strong
inducers of cytochrome P450 (CYP) 3A4 (at least 3 weeks prior) (see Appendix H).
All patients must try to avoid concomitant use of any medications, herbal
supplements, and/or ingestion of foods with known inducer effects on CYP3A4.
- Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the
time of starting study treatment with the exception of alopecia and Grade 2 prior
platinum-therapy related neuropathy.
- Any evidence of severe or uncontrolled systemic diseases, including uncontrolled
hypertension and active bleeding diatheses, which in the Investigator's opinion
makes it undesirable for the patient to participate in the study or which would
jeopardize compliance with the protocol, or active infection including hepatitis
B, hepatitis C, and human immunodeficiency virus. Screening for chronic
conditions is not required.
- Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated product, or previous significant bowel resection that
would preclude adequate absorption of osimertinib.
- Major surgery (excluding placement of vascular access) up to 4 weeks before the
first dose of IP.
- Radiotherapy, as specified, during the following windows:
- Radiotherapy with a wide field of radiation (including whole brain
radiotherapy) up to 2 weeks before the first dose of IP
- Radiotherapy with a limited field of radiation for palliation up to 1 week
before the first dose of IP except for patients receiving radiation to more
than 30% of the bone marrow, which must be completed up to 2 weeks before
the first dose of IP.
- Patients receiving intrathecal chemotherapy up to 2 weeks before the first dose
of IP.
- Previously treated with osimertinib.
- Any requirement for concurrent therapy including radiotherapy for LM other than
the specified treatment in this study.
- Use of corticosteroid to control increased intracranial pressure is allowed
12. History of hypersensitivity to active or inactive excipients of osimertinib or drugs
with a similar chemical structure or class to osimertinib.
13. Patient with involvement in the planning and/or conduct of the study (applies to both
principal investigator and/or staff at the study site).
14. Judgment by the Investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions, and
requirements.
15. Patient has previously participated in the present study, except for rescreened
patients with T790M mutation-negative disease who were previously screened but were
excluded due to progressing EXC disease that has subsequently been stabilized.
16. For female patients only - Women who are breastfeeding or currently pregnant
(confirmed with positive pregnancy test).
17. Contraindication to MRI, including, but not limited to, claustrophobia, pacemakers,
metal implants, INC surgical clips, and metal foreign bodies.
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