| Eligibility |
Inclusion Criteria:
In order to be eligible to participate in this study, a subject must meet all of the
following criteria:
1. Signed informed consent must be obtained prior to participation in the study.
2. Participant is an adult = 18 years of age at the time of informed consent.
3. ECOG performance status =2.
4. Estimated life expectancy of 12 weeks or more
5. Metastatic (stage IV) NSCLC with the presence of a KRAS G12C mutation (local test,
tissue as well as liquid biopsy allowed) and untreated or progressing asymptomatic BM
(cohort A) or treated and stable BM (cohort B).
6. BM not in eloquent area (all patients have at least to be discussed with a
neurologist, and preferably they are discussed in a neuro-oncology MDT). If treated
with radiotherapy and stable, these patients are eligible for cohort B.
7. Max BM size 2 cm in longest diameter (for each BM) for cohort A
8. For cohort A: at least one untreated brain metastasis = 5mm:
1. Patients with largest measurable intracranial lesion =5 mm but <10 mm may be
allowed to enroll upon agreement with the principal investigator (for patients
with target lesions of = 5mm but <10 mm, 1.5 mm slice thickness brain MRI is
required).
2. Prior local treatment is permissible if completed at least 14 days prior to study
enrollment and provided unequivocal progression in the lesion has since occurred
or if new lesions have occurred.
3. For at least 7 days prior to first dose of JDQ443 in this study: Patient must be
asymptomatic from CNS metastases and on a stable dose of corticosteroids, with a
maximum of 4 mg dexamethasone/day. Anti-epileptic dose should also be stable for
7 days.
9. Participant must have recovered from all toxicities related to prior treatments to
grade = 1 (CTCAE v 5.0). Exception to this criterion are alopecia and vitiligo of any
grades.
10. Adequate organ function including the following laboratory values at the screening
visit:
- Absolute neutrophil count (ANC) = 1.5 x 109/L (without growth factor support),
- Platelets = 100 x 109/L (without growth factor support),
- Hemoglobin (Hgb) = 6 mmol/l (= 9 g/dl) (7 days without transfusions or growth
factor support),
- Aspartate transaminase (AST) = 3 x ULN,
- Alanine transaminase (ALT) = 3 x ULN,
- Total bilirubin = 1.5 ULN,
- Serum lipase = 1.5 x ULN,
- Creatinine clearance = 60 mL/min by calculation using Cockcroft-Gault formula or
based on 24-hour urine sample assessment.
11. Participant is capable of swallowing study medication and following instructions
regarding study treatment administration.
12. Participant must be able to communicate with the Investigator and comply with the
requirements of the study procedures.
Exclusion Criteria:
A potential subject who meets any of the following criteria will be excluded from
participation in this study:
1. Leptomeningeal metastasis (based on MRI or CSF cytology, if strong suspicion despite
negative MRI, CSF analysis should be done)
2. Previous treatment with KRAS G12C inhibitor except if = 1 year has elapsed since last
dose
3. Tumors harbouring other oncogenic drivers for which targeted therapy is available
(note: patients with KRAS G12C mutation as a resistance mechanism on for example EGFR
or ALK inhibitors are not eligible).
4. History of severe hypersensitivity reaction to JDQ443 or its excipients.
5. History of allogeneic bone marrow or solid organ transplant
6. Participant has had major surgery (e.g., intra-thoracic, intra-abdominal or
intra-pelvic) within 4 weeks prior to starting study treatment or has not recovered
from side effects of such procedure.
7. Thoracic radiotherapy to lung fields = 4 weeks prior to starting the study treatment
or participants who have not recovered from radiotherapy-related toxicities. For all
other anatomic sites (including radiotherapy to thoracic vertebrae and ribs)
radiotherapy = 2 weeks prior to starting the study treatment or has not recovered from
radiotherapy-related toxicities. Palliative radiotherapy for bone lesions = 2 weeks
prior to starting study treatment is allowed.
8. Clinically significant, uncontrolled cardiac disease and/or recent cardiac events
(within 6 months), such as:
- Unstable angina or myocardial infarction within 6 months prior to screening.
- Symptomatic congestive heart failure (defined as New York Heart Association Grade
II or greater).
- Documented cardiomyopathy.
- Clinically significant cardiac arrhythmias (e.g. sustained ventricular
tachycardia, and clinically significant second or third degree AV block without a
pacemaker)
- Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) = 160 mm Hg
and/or Diastolic Blood Pressure (DBP) = 100 mm Hg, unless controlled prior to
first dose of study treatment.
- History or current diagnosis of ECG abnormalities indicating significant risk of
safety for study participation such as: concomitant clinically significant
cardiac arrhythmias, e.g. sustained ventricular tachycardia, and clinically
significant second or third degree AV block without a pacemaker.
- History of familial long QT syndrome or known family history of Torsades de
Pointes.
- Resting QT interval corrected with Fridericia's formula (QTcF) > 480 msec on
screening ECG or congenital long QT syndrome.
- Concomitant medication(s) with a "Known Risk of Torsades de Pointe" per
www.qtdrugs.org that cannot be discontinued or replaced by safe alternative
9. A medical condition that results in increased photosensitivity (i.e. solar urticaria,
lupus erythematosus, etc.).
10. History of interstitial lung disease or pneumonitis grade = 2.
11. Current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (i.e.
uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or
hypercoagulability syndromes etc.).
12. Malignant disease, other than that is being treated in this study. Exceptions to this
criterion include the following: malignancies that were treated curatively and have
not recurred within two years prior to study treatment; completely resected basal cell
and squamous cell skin cancers; any malignancy considered to be indolent and that has
never required therapy; and completely resected carcinoma in situ of any type.
13. Any other concurrent severe and/or uncontrolled medical condition that would, in the
Investigator's judgment cause unacceptable safety risks, contra-indicate participation
in the clinical study or compromise compliance with the protocol (e.g. chronic
pancreatitis, uncontrolled diabetes, hepatic disorders including cirrhosis).
14. Any other medical condition (such as active infection including known hepatitis or
HIV, treated or untreated), which in the opinion of the Investigator represents an
unacceptable risk for participation in the study.
15. Any medical condition or prior surgical resection that may affect the absorption of
the investigational drug. Examples of medical conditions that may affect
investigational drug absorption include (but are not limited to) inflammatory bowel
disease (i.e. ulcerative colitis, Crohn's disease) and gastrointestinal disease such
as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, and malabsorption
syndrome.
16. Participants who are taking a prohibited medication (strong CYP3A inducers) that
cannot be discontinued at least seven days prior to the first dose of study treatment
and for the duration of the study.
17. Use of any live vaccines against infectious diseases within four weeks of initiation
of study treatment.
18. Participant is concurrently using other anti-cancer therapy.
19. Participation in any additional, parallel, investigational drug or device studies.
Participation in non-interventional observational studies which will not influence the
endpoints of the current studies is allowed (e.g. liquid biopsies, eNOSE, surveys).
20. Pregnant or breast-feeding women or women who plan to become pregnant or breast-feed
during the study. Pregnant women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test.
21. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
while taking study treatment and for 7 days after the last dose of JDQ443.
22. Sexually active males unless they use a condom during intercourse while taking study
treatment and for 7 days after the last dose of JDQ443. Male participants should not
father a child in this period. A condom is required to be used also by vasectomized
men in order to prevent delivery of the study treatment via seminal fluid. In
addition, male participants must not donate sperm and women participants must not
donate oocytes for the time period specified above.
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