A Phase 1b Dose Escalation and Dose Expansion Study Evaluating the Safety, Pharmacokinetics, and Antitumor Activity of Furmonertinib in Patients with Advanced or Metastatic Non-Small Cell Lung Cancer with Activating EGFR or HER2 Mutations

Patients must meet the following criteria for study entry:
General Inclusion Criteria
1. Signed Informed Consent Form
2. Age >= 18 years at time of signing Informed Consent Form
3. Ability to comply with the study protocol, in the investigator*s judgment
4. Measurable disease per RECIST v1.1
Note: Measurable target lesions (TLs) can neither be subject to local therapy
such as radiotherapy nor used for biopsy in the screening period; if there is
only one measurable TL, this TL will be permitted to be biopsied. However, the
baseline radiologic examination should be performed for this lesion at least 14
days after biopsy.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
6. Life expectancy of >= 12 weeks
7. Adequate hematologic and organ function within 14 days prior to initiation
of study treatment, defined by the following:
• Absolute neutrophil count >= 1500/µL
• Hemoglobin >= 9 g/dL
• Platelet count >= 100,000/µL
• Total bilirubin <= 1.5 × upper limit of normal (ULN) or <= 3 × ULN in the
presence of documented Gilbert*s Syndrome
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 2.5 ×
ULN with the following exception:
- Patients with documented liver metastases may have AST and/or ALT <= 5.0 × ULN
• Creatinine clearance >= 30 mL/min based on the Cockcroft-Gault estimation:
(140 * age) × (weight in kg) × (0.85 if female)
72 × (serum creatinine in mg/dL)
• International normalized ratio (INR) <= 1.5 × ULN and activated partial
thromboplastin time (aPTT) <= 1.5 × ULN
Note: This applies only to patients who are not receiving therapeutic
anticoagulation. Patients receiving therapeutic anticoagulation should be on a
stable dose for at least 1 week prior to Cycle 1, Day 1.
8. For women of childbearing potential (WOCBPs): Agreement to remain abstinent
(refrain from heterosexual intercourse) or use contraception, and agreement to
refrain from donating eggs, as defined below:
• A woman is considered to be of childbearing potential if she is
postmenarchal, has not reached a postmenopausal state >= 12 continuous months of
amenorrhea with no identified cause other than menopause), and is not
permanently infertile due to surgery (i.e., removal of ovaries, fallopian
tubes, and/or uterus) or another cause as determined by the investigator (e.g.,
Müllerian agenesis). The definition of childbearing potential may be adapted
for alignment with local guidelines or regulations.
• WOCBPs must remain abstinent or use a barrier method such as a condom plus an
additional contraceptive method that together result in a failure rate of < 1%
per year during the treatment period and at least 60 days after the final dose
of furmonertinib. WOCBPs must refrain from donating eggs during the treatment
period and 6 months after the final dose of furmonertinib.
• Examples of contraceptive methods with a failure rate of < 1% per year
include bilateral tubal ligation, male sterilization, hormonal oral
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices,
and copper intrauterine devices.
Note: The reliability of sexual abstinence should be evaluated in relation to
the duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not adequate methods of
contraception. If required per local guidelines or regulations, locally
recognized adequate methods of contraception and information about the
reliability of abstinence will be described in the local Informed Consent Form.
9. For men who are not surgically sterile: Agreement to remain abstinent
(refrain from heterosexual intercourse) or use contraception, and agreement to
refrain from donating sperm, as defined below:
• With a female partner of childbearing potential who is not pregnant, men must
remain abstinent or use a condom plus an additional contraceptive method that
together result in a failure rate of < 1% per year during the treatment period
and for at least 60 days after the final dose of furmonertinib.
• Must refrain from donating sperm during the treatment period and for at least
60 days after the final dose of furmonertinib.
• With pregnant female partners, men must remain abstinent or use a condom to
avoid exposing the embryo during the treatment period and for at least 60 days
after the final dose of furmonertinib.
Note: The reliability of sexual abstinence should be evaluated in relation to
the duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not adequate methods of
contraception. If required per local guidelines or regulations, locally
recognized adequate methods of contraception and information about the
reliability of abstinence will be described in the local Informed Consent Form.
10. For Stage 1 dose escalation and backfill cohorts and Stage 2 Cohorts 1, 2,
and 4: Patients with CNS metastases (including leptomeningeal disease) are
eligible, provided they meet the following criteria:
• Measurable disease outside the CNS
• No requirement for immediate local therapy or ongoing requirement for
corticosteroids as therapy for CNS metastases, with corticosteroids
discontinued for >= 2 weeks prior to enrollment
• No ongoing symptoms attributed to CNS metastases
• No CNS metastases or spinal cord compression requiring anticonvulsants or
corticosteroids for symptomatic control
• For patients with previously treated brain metastases
- No evidence of interim CNS disease progression between the completion of CNS
directed therapy and the screening radiographic study
- Patients treated with CNS local therapy for newly identified lesions found on
contrast brain magnetic resonance imaging (MRI) performed during screening may
be eligible to enroll if all of the following criteria are met:
o Time since whole-brain radiation therapy (WBRT) is >= 21 days prior to first
dose of study treatment, time since stereotactic radiosurgery (SRS) is >= 7 days
prior to first dose of study treatment, or time since surgical resection is >=
28 days
o Do not require immediate local therapy
o Patients who undergo local treatment for lesions identified by screening
contrast brain MRI may still be eligible for the study based on criteria
described above.
11. Histologically or cytologically documented, locally advanced or metastatic
NSCLC not amenable to curative surgery or radiotherapy
12. Consent to provide archival tumor tissue specimen (formalin-fixed,
paraffin-embedded [FFPE] tissue block [preferred] or at least 15 unstained
serially cut sections on slides from FFPE tumor specimen). The specimens must
be provided during the screening or no later than within 30 days of Cycle 1,
Day 1 and must be accompanied by a pathology report.
• It is preferred that the specimen be prepared from the most recently
collected and available tumor tissue, and, whenever possible, from a metastatic
site of disease. See the laboratory manual for instructions.
13. For patients with EGFR mutations sensitive to osimertinib, the patient must
have received osimertinib prior to study enrollment in regions where
osimertinib is approved, including the United States (US).
14. No known acquired resistance to osimertinib (e.g., C797S or cMet amp).
Other alterations should be discussed with the Medical Monitor.
Stage 1 Dose Escalation and Backfill Cohorts and Stage 2, Cohorts 1, 2, and 3
Inclusion Criteria
15. Disease that has progressed after at least 1 available standard therapy, or
for which standard therapy has proven to be ineffective, intolerable, or
considered inappropriate, or for which a clinical trial of an investigational
agent is a reco

General Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study
entry:
1. Inability or unwillingness to swallow pills
1. Inability to comply with study and follow-up procedures
2. Malabsorption syndrome or other condition that would interfere with enteral
absorption
3. Pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures biweekly or more frequently
• Indwelling pleural or abdominal catheters may be allowed, provided the
patient has adequately recovered from the procedure, is hemodynamically stable
and symptomatically improved, and after discussion with the Sponsor.
4. Severe acute or chronic infections, including:
• Uncontrolled acute infection, active infection that necessitates systemic
treatment or systemic antibiotic treatment within 2 weeks prior to the first
dose of furmonertinib.
• Known history of human immunodeficiency virus (HIV) infection and/or acquired
immune deficiency syndrome. Patients with unknown HIV infection status who
don*t agree to take HIV test are not eligible.
• Patients with active chronic hepatitis B or with active hepatitis C
infection, which includes patients who are hepatitis B surface antigen (HbsAg)
positive or hepatitis C virus (HCV) antibody positive at screening, are not
eligible until further definite quantitative testing of hepatitis B virus (HBV)
DNA (e.g., <= 2500 copies/mL or 500 IU/mL) and HCV RNA tests (e.g., <= lower
limit of detection) can conclusively rule out presence of active hepatitis B or
C infection that requires treatment.
Note: Patients who are carriers of HBV, with stable HBV infection (e.g., HBV
DNA quantitative test showed DNA <= 2500 copies/mL or 500 IU/mL) after medical
treatment or with cured hepatitis C are permitted to enroll. If the lower limit
of detection of HBV DNA assay in the site is higher than 2500 cps/mL or 500
IU/mL, patients with HBV DNA quantitative test result lower than the lower
limit of detection in the site are considered eligible.
5. In the setting of a pandemic or epidemic, screening for active infections
should be considered according to local or institutional guidelines or those of
applicable professional societies (e.g., American Society of Clinical Oncology
[ASCO] or European Society for Medical Oncology [ESMO]).
6. Previous interstitial lung disease (ILD), drug induced ILD, radiation
pneumonitis; or active ILD.
7. History of or active clinically significant cardiovascular dysfunction,
including the following:
• History of stroke or transient ischemic attack within 6 months prior to first
dose of furmonertinib
• History of myocardial infarction within 6 months prior to first dose of
furmonertinib
• New York Heart Association Class III or IV cardiac disease or congestive
heart failure requiring medication
• Uncontrolled arrhythmias, history of or active ventricular arrhythmia
requiring medication
• Coronary heart disease that is symptomatic or unstable angina
8. Mean resting QT interval corrected through use of Fridericia*s formula
(QTcF) > 470 ms, obtained from triplicate electrocardiograms (ECGs), using the
screening clinic ECG machine-derived QTcF value.
9. Clinically significant prolonged QT interval or other arrhythmia or clinical
status considered by investigators that may increase the risk of prolonged QT
interval (e.g., complete left bundle branch block, degree III atrioventricular
block, second-degree heart block, PR interval > 250 ms, congenital long QT
syndrome, family history of long QT syndrome, or unexplained sudden death under
40 years of age in first-degree relatives, serious hypokalemia, heart failure)
or current use of the drugs that may lead to prolonged QT interval.
10. Symptomatic hypercalcemia requiring continued use of bisphosphonate therapy
or denosumab.
11. Significant traumatic injury or major surgical procedure within 4 weeks
prior to Day 1 of Cycle 1.
12. Patients with chronic diarrhea, short bowel syndrome or significant upper
gastrointestinal (GI) surgery including gastric resection, a history of
inflammatory bowel disease (e.g., Crohn*s disease or ulcerative colitis) or any
active bowel inflammation (including diverticulitis).
13. Any other diseases, such as pulmonary dysfunction, metabolic dysfunction,
physical examination finding, or clinical laboratory finding giving reasonable
suspicion of a disease or condition that contraindicates the use of
furmonertinib, that may affect the interpretation of the results, or renders
the patients at high risk from treatment complications (e.g., uncontrolled
hypertension, active bleeding).
14. Treatment with chemotherapy, targeted therapy, biologic therapy, or an
investigational agent as anticancer therapy within 3 weeks or 5 elimination
half-lives prior to initiation of furmonertinib, whichever is shorter
15. Radiation therapy (other than palliative radiation to bone metastases and
radiation to CNS metastases as described above) as cancer therapy within 4
weeks prior to initiation of furmonertinib.
16. Palliative radiation to bone metastases within 2 weeks prior to initiation
of furmonertinib.
17. AEs from prior anticancer therapy that have not resolved to Grade <= 1
except for alopecia or Grade <= 2 peripheral neuropathy.
18. History of other malignancy within 3 years prior to screening, with the
exception of patients with a negligible risk of metastasis or death and/or
treated with expected curative outcome (such as appropriately treated carcinoma
in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer,
ductal carcinoma in situ, or Stage I uterine cancer).
19. Pregnant, breastfeeding, or intending to become pregnant during the study
or within 60 days after the final dose of furmonertinib.
• WOCBPs (including those who have had a tubal ligation) must have a negative
serum pregnancy test result within 14 days prior to initiation of study drug.
20. Known or suspected allergy to furmonertinib or other components of its
preparation.
21. Use of a strong CYP3A4 inhibitor within 7 days prior to the first dose of
investigational product or a strong CYP3A4 inducer within 21 days prior to the
first dose of investigational product.
22. Use of an herbal medicine (e.g., Chinese medicine or traditional Chinese
medicine preparation indicated for cancer, or a traditional Chinese medicine or
traditional Chinese medicine preparation with adjuvant anticancer effects)
within 2 weeks prior to the first dose of furmonertinib, or if herbal medicine
is expected to be used during the study.
Stage 2, Cohort 3 (Previously Treated, Locally Advanced or Metastatic NSCLC
Patients with EGFR Activating Mutations and Excluding Exon 20 Insertion
Mutations and PACC Mutations) Exclusion Criteria.
23. NSCLC patients with a documented EGFR exon 20 insertion mutation by a local
test (tumor tissue or blood)
24. NSCLC patients with a documented EGFR PACC mutation by a local test (tumor
tissue or blood)
Stage 2, Cohort 4 (Untreated or Previously Treated EGFR-TKI-Naïve, Locally
Advanced or Metastatic NSCLC Patients with EGFR PACC Mutations) Exclusion
Criteria
25. Prior treatment with any EGFR-TKIs
26. Progression during neoadjuvant or adjuvant therapy (e.g., chemotherapy,
radiotherapy, immunotherapy or investigational agents) or within 12 months of
completion of above therapies