THE PATIENT MUST FULFIL THE ELIGIBILITY CRITERIA WITHIN THE DETERMINE MASTER PROTOCOL
(NCT05722886) AND WITHIN THE TREATMENT ARM 06 (CAPMATINIB) OUTLINED BELOW*
*When capmatinib-specific inclusion/exclusion criteria or precautions below differ from
those specified in the Master Protocol, the capmatinib-specific criteria will take
precedence.
Inclusion criteria:
A. Confirmed diagnosis of a MET-positive malignancy using an analytically validated
next-generation sequencing method (METex14 skipping, MET amplification, MET fusion, or
MET activating mutation).
B. Adult patients ≥18 years old.
C. Women of childbearing potential are eligible, provided that they meet the following
criteria:
- - Have a negative serum or urine pregnancy test before enrolment, and.
- - Agree to use one form of highly effective birth control method (a method that can
achieve a failure rate of <1% when used consistently and correctly), such as:
I.
combined (oestrogen and progestogen containing) hormonal contraception associated with
inhibition of ovulation [oral, intravaginal or transdermal])
- II. progestogen-only
hormonal contraception associated with inhibition of ovulation (oral, injectable, or
implantable) III.
intrauterine device (IUD)
- IV. Intrauterine hormone-releasing system
(IUS) V.
bilateral tubal occlusion
- VI. vasectomised partner VII.
sexual abstinence
Effective from the first administration of capmatinib, throughout the trial and for seven
days after the last administration of capmatinib.
D. Male patients with partners who are women of childbearing potential are eligible
provided that they agree to the following, from first administration of capmatinib,
throughout the trial and for seven days after the last administration of capmatinib:
- - Agree to take measures not to father children by using a barrier method of
contraception (e.g. condom) or sexual abstinence.
- - Non-vasectomised male patients with partners who are women of childbearing potential
must also be willing to ensure that their partner uses a highly effective method of
contraception, as in criterion C above.
- - Male patients with pregnant or lactating partners must be advised to use barrier
method contraception (for example, condom) to prevent drug exposure of the foetus or
neonate.
All male patients must refrain from donating sperm for the same period.
E. Patients must be able and willing to undergo a fresh biopsy at baseline and blood
samples for translational research. Note that for patients with haematological
malignancies or neuroblastomas, blood, bone marrow aspiration and/or trephine or lymph
node biopsy samples may be taken.
F. Adequate organ function as per haematological and biochemical indices within the
ranges shown below. These measurements should be performed to confirm the patient's
eligibility.
Haemoglobin (Hb): ≥90 g/L (transfusion allowed)
Absolute neutrophil count (ANC): ≥1.5 × 10^9/L (no granulocyte colony-stimulating factor
[GCSF] support in preceding 72 hours)
Platelet count: ≥100 × 10^9/L (unsupported for 72 hours)
Total bilirubin: <1.5 × upper limit of normal (ULN) or ≤2.5 × ULN if raised due to
metastases (patients with Gilbert's syndrome may be included if total bilirubin is ≤3.0 ×
ULN and direct bilirubin is ≤1.5 × ULN).
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): ≤3 × ULN or ≤5 × ULN
if raised due to metastases.Coagulation
- - prothrombin (PT) (or international normalized ratio [INR]) and activated
partial thromboplastin clotting time (aPTT): ≤1.5 × ULN or ≤1.5 × below lower limit of
normal (LLN) (unless patient is on anticoagulants e.g. warfarin [INR should be stable and
within indicated therapeutic range], or direct oral anticoagulants [DOAC])
Estimated glomerular filtration rate (eGFR): eGFR: ≥30 mL/min (uncorrected value)
Asymptomatic amylase: ≤5 × ULN and no signs and/or symptoms suggesting pancreatitis or
pancreatic injury (e.g. elevated amylase, abnormal imaging findings of pancreas, etc.)
Asymptomatic lipase: ≤5 × ULN and no signs and/or symptoms suggesting pancreatitis or
pancreatic injury (e.g. elevated lipase, abnormal imaging findings of pancreas, etc.)
Exclusion criteria:
A.
Diagnosis of NSCLC with METex14 skipping mutation or MET amplification.
B. Prior treatment with a selective MET inhibitor or HGF-targeting therapy unless genetic
profile demonstrates a mechanism of resistance known to be potentially sensitive to
capmatinib.
C. Carcinomatous meningitis.
D. Presence or history of additional malignant disease that has been diagnosed and/or
required therapy within the past three years. Exceptions to this exclusion include:
completely resected basal cell and squamous cell skin cancers, and completely resected
carcinoma in situ of any type.
E. Presence or history of interstitial lung disease (ILD) and/or interstitial
pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting
activities of daily living or requiring therapeutic intervention) and evidence of active
pneumonitis on screening chest computed tomography (CT) scan. Prior localised
radiotherapy related pneumonitis is permitted if resolved and off steroids and
asymptomatic for at least six months.
F. Clinically significant, uncontrolled heart disease such as:
- - Unstable angina within three months prior to screening.
- - Myocardial infarction within three months prior to screening.
- - History of documented congestive heart failure (New York Heart Association
functional classification III-IV)
- Uncontrolled hypertension defined by a systolic blood pressure ≥160 mm Hg and/or
diastolic blood pressure ≥100 mm Hg, with or without antihypertensive medication.
Initiation or adjustment of antihypertensive medication(s) is allowed prior to
screening.
Patients with a cerebrovascular event (including stroke or transient ischaemic attack
[TIA]) within three months before screening.
• Patients with primary CNS tumours may be considered unless intra-tumoural bleeding has
occurred within two weeks of the first dose of capmatinib, and patients with punctate CNS
haemorrhages <3 mm may be considered.
G. History or current diagnosis of electrocardiogram (ECG) abnormalities indicating
significant risk of safety for patients participating in the trial such as:
- - Concomitant clinically significant cardiac arrhythmias (atrial and ventricular),
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 QTcF (Corrected QT interval by Fridericia formula) ≥450 msec (male) or ≥460
msec (female) at screening ECG (as a mean of triplicate ECG)
H.
Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within four
weeks prior to starting trial treatment (two weeks for resection of brain lesions) or
patients who have not recovered from side effects of such procedure. Video-assisted
thoracic surgery (VATS) and mediastinoscopy will not be counted as major surgery and
patients can be enrolled in the trial at least one week after the procedure.
- I. Patients receiving treatment with strong inducers of cytochrome P450 (CYP) 3A that
cannot be discontinued at least one week prior to the start of treatment with capmatinib
and for the duration of the trial.
J. Any clinically significant concomitant disease or condition (or its treatment) that
could interfere with the conduct of the trial (including absorption of oral medications)
that would, in the opinion of the Investigator, pose an unacceptable risk to the patient
in this trial.
K. Any impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the administration or absorption of capmatinib (e.g., Crohn's disease, ulcerative
diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome or short gut
syndrome). Unable to swallow capmatinib intact, without chewing or crushing the tablets
(as per the dosing schedule).
L. Active infections including, but not limited to, hepatitis B virus (HBV), hepatitis C
virus (HCV) and human immunodeficiency virus (HIV). Screening for known chronic
conditions is not required. Patients with known serological evidence of chronic HBV or
HCV infection whose disease is controlled under antiviral therapy according to local
regulation are eligible. Patients with history of testing positive for human
immunodeficiency virus (HIV) infection are eligible provided the each of the following
conditions are met:
- - CD4 count ≥350/μL;
- undetectable viral load;
- receiving antiretroviral therapy (ART) that does not interact with IMP (patients
should be on established ART for at least four weeks); and.
- - no HIV/ acquired immune deficiency syndrome-associated opportunistic infection in
the last 12 months.
M. Known hypersensitivity to any of the excipients of capmatinib.
N. Patients with symptomatic central nervous system (CNS) metastases who are
neurologically unstable or have required increasing doses of steroids within the two
weeks prior to trial entry to manage CNS symptoms. Primary brain or CNS malignancies are
allowed providing the patient is clinically stable (if corticosteroids are required, they
must be at a stable or decreasing dose for at least 14 days prior to Cycle 1 Day 1). If
patients are on corticosteroids for endocrine deficiencies or tumour-associated symptoms
other than CNS related, the dose must have been stabilised (or decreasing) for at least
five days before Cycle 1 Day 1.
O. Patients receiving treatment with any enzyme-inducing anticonvulsant that cannot be
discontinued at least one week before first dose of capmatinib, and for the duration of
the trial. Patients on non-enzyme-inducing anticonvulsants are eligible.
P. Female patients who are pregnant, breastfeeding or planning to become pregnant during
the trial or for seven days following their last dose of capmatinib.
Q. Patients who were administered a live, attenuated vaccine within 28 days prior to
enrolment, or anticipation of need for such a vaccine during capmatinib treatment or
within six months after the final dose of capmatinib.
