| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Type of lung cancer with certain genetic alterations (mutations) of a gene called MET, but without mutations in their EGFR or ALK genes, and in which the cancer has spread to the brain |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To establish the intracranial anti-tumor activity of capmatinib, as measured by overall intracranial response rate (OIRR) by BIRC in Cohort 1 (MET exon 14 mutated advanced NSCLC with asymptomatic brain metastases and no prior brain therapy) |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the intracranial anti-tumor activity, as measured by OIRR by investigator in Cohort 1
To evaluate intracranial tumor-response related endpoints as assessed by investigators and BIRC in Cohort 1 and Cohort 2, separately
To evaluate the intracranial anti-tumor activity, as measured by OIRR by BIRC in Cohort 2
To evaluate extracranial tumor-response related endpoints as assessed by investigators and by BIRC in Cohort 1 and Cohort 2, separately
To evaluate whole body tumor-response related endpoints as assessed by investigators and by BIRC in Cohort 1 and Cohort 2
To evaluate the overall survival (OS) in this patient population in Cohort 1 and Cohort 2, separately
To assess safety and tolerability of capmatinib
To assess the effect of capmatinib on patient-reported disease-related symptoms, functioning and healthrelated quality of life (HRQoL)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult ≥ 18 years old at the time of informed consent
2. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
3. Written informed consent must be obtained prior to participation in the study
4. Histologically confirmed stage IV (according to Version 8 of the American Joint
Committee on Cancer (AJCC)) NSCLC that is:
• EGFR wt. This should have been assessed as part of the patient’s standard of
care by a validated test for EGFR mutations as per local guidelines. The EGFR wt
status (for EGFR mutations that predict sensitivity to EGFR therapy, including, but
not limited to exon 19 deletions and exon 21 L858R substitution mutations) must be
documented in the patient source documents before the patient can be consented for
pre-screening for MET mutation status. Patients with NSCLC of pure squamous cell
histology can enter prescreening without EGFR mutation testing or result, however,
patients with pure squamous cell histology who are known to have EGFR activating
mutations will be excluded.
• AND ALK rearrangement negative. This should have been assessed as part of the
patient’s standard of care by a validated test. The ALK rearrangement negative status
must be documented in the patient source documents before the patient can be
consented for pre-screening for MET mutation status; if local ALK testing is not
available at the time of molecular prescreening, patient status will be determined
centrally by Novartis. Patients with NSCLC of pure squamous cell histology can enter
pre-screening without ALK testing or result, however patients with pure squamous
cell histology that are known to have ALK rearrangement will be excluded.
• AND has METΔex14 mutation per central Novartis laboratory or (US only) per local
F1CDx.
5. Treatment naïve or up to two prior lines of systemic therapy for stage IIIb-IV NSCLC
6. Measurable intracranial lesions:
• Cohort 1 and Cohort 2 (without leptomeningeal carcinoma): At least 1 measurable
intracranial lesion per RANO-BM criteria, documented by a
radiologist/neuroradiologist (treated or untreated). A previously irradiated site lesion
may only be counted as a target lesion if there is clear sign of progression since the
irradiation
• Cohort 2 (with leptomeningeal carcinoma): participants with leptomeningeal
carcinoma may not have measurable lesions. In this circumstance, the participant’s
disease will be considered to have non-target lesions only at baseline and
their response based on descriptive clinical criteria by physician assessment.
7. Capable of undergoing magnetic resonance imaging (MRI)
8. Participants must have recovered from all toxicities related to prior anticancer therapies to
grade ≤ 1 ([Common Terminology Criteria Adverse Event]CTCAE v5.0). Patients with
any grade of alopecia are allowed to enter the study
9. Participants must have 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 ≥ 75 x 109/L
• Hemoglobin (Hgb) ≥ 9 g/dL
• Calculated creatinine clearance (using Cockcroft-Gault formula) ≥ 45 mL/min
• Total bilirubin (TBL) ≤ 1.5 x ULN (upper limit of normal)
• Aspartate transaminase (AST) ≤ 3 x ULN, except for patients with liver metastasis,
who may only be included if AST ≤ 5 x ULN
• Alanine transaminase (ALT) ≤ 3 x ULN, except for patients with liver metastasis,
who may only be included if ALT ≤ 5 x ULN
• Alkaline phosphatase (ALP) ≤ 5.0 x ULN
Clinical Trial Protocol (Version No. 00) Protocol No. CINC280A2203
• Asymptomatic serum amylase ≤ Grade 2. Patients with Grade 1 or Grade 2 serum
amylase at the beginning of the study must be confirmed to have no signs and/or
symptoms suggesting pancreatitis or pancreatic injury (e.g. elevated P-amylase,
abnormal imaging findings of pancreas, etc.)
• Serum lipase ≤ ULN
10. Willing and able to comply with scheduled visits, treatment plan and laboratory tests
|
|
| E.4 | Principal exclusion criteria |
1. Only for Cohort 1: any neurological symptoms related to brain metastases
2. For participants in Cohort 2 with prior brain therapy: Treatment with stereotactic
radiosurgery within 14 days prior to the start of study treatment or treatment with WBRT
within 14 days prior to the start of study treatment
3. Prior treatment with any MET targeting therapy or HGF inhibitor
4. Presence or history of a malignant disease other than NSCLC that has been diagnosed
and/or required therapy within the past 3 years. Exceptions to this exclusion include:
completely resected basal cell and squamous cell skin cancers, and completely resected
carcinoma in situ of any type
5. Participants with other known druggable molecular alterations (such as ROS1
translocation or BRAF mutation) who might be candidates to alternative targeted therapies
as applicable per local regulations and treatment guidelines
6. Presence or history of ILD or interstitial pneumonitis, including clinically significant
radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic
intervention)
7. Clinically significant, uncontrolled heart diseases
• Unstable angina within 6 months prior to screening
• Myocardial infarction within 6 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 (SBP) ≥ 160 mm Hg
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without
antihypertensive medication. Initiation or adjustment of antihypertensive
medication(s) is allowed prior to screening
• Ventricular arrhythmias
• Supraventricular and nodal arrhythmias not controlled with medication
• Other cardiac arrhythmia not controlled with medication
• QTcF ≥ 470 ms on the screening ECG (as mean of triplicate ECG)
• History of familial long QT syndrome, sudden death or congenital long QT syndrome
8. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting capmatinib 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 capmatinib or participants who have not recovered from radiotherapy-related
toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting capmatinib is
allowed
9. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior to
starting study treatment (2 weeks for resection of brain metastases) or participants who
have not recovered from the side effects of such a procedure.
Video-assisted thoracic surgery (VATS) and mediastinoscopy will not be counted as
major surgery and participants can be enrolled in the study ≥1 week after the procedure
10. Participants receiving treatment with strong inducers of CYP3A and could not be
discontinued at least 1 week prior to the start of treatment with capmatinib and for the
duration of the study
11. Previous anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, targeted
therapy, vaccine therapy) and investigational agents within 4 weeks or ≤ 5 x half-life of
the agent (whichever is longer) before first dose of study treatment. If previous treatment
is a monoclonal antibody or an anti PD-(L)1 checkpoint inhibitor, then the treatment must
be discontinued at least 4 weeks before first dose of study treatment. If previous treatment
is an oral targeted agent, then the treatment must be discontinued at least 5 x half-life of
the agent
12. Impairment of GI function or GI disease that may significantly alter the absorption of
capmatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or
malabsorption syndrome)
13. Unable or unwilling to swallow tablets as per dosing schedule
14. Current or expected use of a prohibited medication as described in Section 16.3. of the study protocol.
15. Other severe, acute, or chronic medical or psychotic conditions or laboratory
abnormalities that in the opinion of the investigator may increase the risk associated with
study participation, or that may interfere with the interpretation of study results
Detailed information on the 21 study exclusion criteria is available from the study protocol.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall Intracranial Response Rate (OIRR) in Cohort 1, defined as the proportion of participants with a confirmed best intracranial overall response of Complete Response (CR) or Partial Response (PR) per RANO-BM criteria as assessed by BIRC review |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Intracranial disease will be assessed and response to treatment will be evaluated using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria every 8 weeks. Extracranial and whole body disease will be assessed and response to treatment will be evaluated using RECIST 1.1 every 8 weeks. |
|
| E.5.2 | Secondary end point(s) |
Overall Intracranial Response Rate (OIRR) per RANO-BM criteria by investigator review in Cohort 1
Intracranial Disease Control Rate (IDCR), Time to intracranial tumor Response (TTIR), and Duration of Intracranial Response (DOIR) per RANO-BM criteria by investigator review and by BIRC review
Overall Intracranial Response Rate (OIRR) per RANO-BM criteria by investigator review and by BIRC review in Cohort 2
Overall Extracranial Response Rate (OERR), Extracranial Disease Control Rate (EDCR), Time to Extracranial Response (TTER), and Duration of Extracranial Response (DOER) per Response Evaluation Criteria In Solid Tumors (RECIST 1.1) by investigator review and by BIRC review
Overall Response Rate (ORR), Disease Control Rate (DCR), Time to response (TTR), Duration of response (DOR), Progression free survival (PFS) in the whole body per RECIST 1.1 by investigator review and by BIRC review
OS
Safety
HRQoL in both cohorts with the EORTC QLQC30, QLQ-LC13 and EQ-5D-5L
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Intracranial disease will be assessed and response to treatment will be evaluated using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria every 8 weeks. Extracranial and whole body disease will be assessed and response to treatment will be evaluated using RECIST 1.1 every 8 weeks. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Germany |
| Hungary |
| Italy |
| Japan |
| Norway |
| Romania |
| Spain |
| Taiwan |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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