A Study of Capmatinib (INC280) in NSCLC Patients With MET Exon 14 Alterations Who Have Received Prior MET Inhibitor

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational intervention to learn whether the intervention works
in treating a specific disease. "Investigational" means that the intervention is being
studied.

The FDA (the U.S. Food and Drug Administration) has not approved Capmatinib as a treatment
for any disease.

In this research study, the investigators are using the study drug called Capmatinib.
Capmatinib is a specific blocker of the cMET protein. This protein acts as a trigger to start
a series of events in your cells in what is known as the C-Met pathway. Patients with MET
exon 14 skipping have activation of the MET pathway. By blocking MET, Capmatinib may slow or
stop the growth and/or survival of cancer cells. Capmatinib is not yet FDA approved for the
treatment of people with this type of cancer. It is not known if capmatinib will be effective
in people who have previously had other drugs that block the cMET pathway. This study will
help us understand how capmatinib works in the body and what capmatinib does to cancer. Any
potential harmful effects of capmatinib will also be studied.

Inclusion Criteria:

- Written informed consent must be obtained prior to any screening procedures.

- Age ≥ 18 years

- Histologically or cytologically confirmed non-small cell lung cancer, advanced,
recurrent, or metastatic

- MET exon 14 skipping alteration by molecular testing (local testing is accepted for
eligibility; all patients will have confirmation by NGS-rearrangement assay at MGH but
this result is not necessary for eligibility; local molecular pathology result will
suffice). This testing can be from any archival or fresh sample.

- Must have received prior platinum containing chemotherapy for advanced/metastatic
non-small cell lung cancer, or have refused or be ineligible for such therapy. Prior
neoadjuvant/adjuvant platinum containing chemotherapy will count has having received
prior platinum, provided that disease recurred within 6 months of completion of
neoadjuvant/adjuvant therapy.

- EGFR and ALK status must be known in all patients with adenocarcinoma histology.
Patients with activating EGFR mutations or ALK translocations are excluded from this
study, unless disease has progressed on all available, approved therapies targeting
these alterations.

- At least one measurable lesion as defined by RECIST 1.1. A previously irradiated site
lesion may only be counted as a target lesion if there is clear sign of progression
since the irradiation.

- Must have received prior MET inhibitor as their immediately preceding therapy. There
are no limits to the number of lines of prior therapy as long as prior MET inhibitor
is the most recent therapy.

- Patients must have recovered from all toxicities related to prior anticancer therapies
to grade ≤ 1 (CTCAE v 4.03). Patients with any grade of alopecia are allowed to enter
the study.

- Patients 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 ≤ 1.5 x ULN, except for patients with Gilbert's syndrome, who may
only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN

- Aspartate transaminase (AST) ≤ 3 x ULN, except for patients with liver
metastasis, who are included if AST ≤ 5 x ULN

- Alanine transaminase (ALT) ≤ 3 x ULN, except for patients with liver metastasis,
who are only included if ALT ≤ 5 x ULN

- Alkaline phosphatase (ALP) ≤ 5.0 x ULN

- 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

- Patients must have the following laboratory values within the laboratory normal
limits or corrected to within normal limits with supplements during screening:

- Potassium

- Magnesium

- Phosphorus

- Total calcium (corrected for serum albumin)

- ECOG performance status (PS) of 0 or 1

- Willing and able to comply with scheduled visits, treatment plan and laboratory tests.

Exclusion Criteria:

- Patients with known hypersensitivity to any of the excipients of INC280 (crospovidone,
mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate, magnesium
stearate, colloidal silicon dioxide, and various coating premixes).

- Patients with symptomatic central nervous system (CNS) metastases who are
neurologically unstable or have required increasing doses of steroids within the 2
weeks prior to study entry to manage CNS symptoms

- Presence or history of carcinomatous meningitis

- Presence or history of a malignant disease other than disease to be treated in current
protocol that has been diagnosed and/or required therapy within the past 3 years.
Exceptions to this exclusion include the following: completely resected basal cell and
squamous cell skin cancers, indolent malignancies that currently do not require
treatment, and completely resected carcinoma in situ of any type

- 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 > 480 msec

- Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting INC280 or patients
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 INC280 or patients who have not recovered from radiotherapy-related
toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting
INC280 is allowed

- Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks
prior (2 weeks for resection of brain metastases) to starting INC280 or 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 study ≥ 1 week after the procedure

- Patients receiving treatment with medications that meet one of the following criteria
and that cannot be discontinued at least 1 week prior to the start of treatment with
INC280 and for the duration of the study:

- Strong and moderate inhibitors of CYP3A4

- Strong inducers of CYP3A4

- Proton pump inhibitors (PPI)

- Impairment of GI function or GI disease that may significantly alter the absorption of
INC280 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or
malabsorption syndrome)

- Unable or unwilling to swallow tablets as per dosing schedule

- Patients receiving unstable or increasing doses of corticosteroids. If patients are on
corticosteroids for endocrine deficiencies or tumor-associated symptoms other than CNS
related, dose must have been stabilized (or decreasing) for at least 5 days before
first dose of INC280

- Patients receiving treatment with any enzyme-inducing anticonvulsant that cannot be
discontinued at least 1 week before first dose of INC280, and for the duration of the
study. Patients on non-enzyme-inducing anticonvulsants are eligible

- Previous anti-cancer and investigational agents within 4 weeks or ≤ 5 x half-life of
the agent (whichever is longer) before first dose of INC280. If previous treatment is
a monoclonal antibody, then the treatment must be discontinued at least 4 weeks before
first dose of INC280

- Other severe, acute, or chronic medical or psychiatric 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

- Any other condition that would, in the Investigator's judgment, contraindicate
patient's participation in the clinical study due to safety concerns or compliance
with clinical study procedures, e.g., infection/inflammation, intestinal obstruction,
unable to swallow medication, social/ psychological issues, etc.

- Pregnant or nursing 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

- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 7 days after stopping treatment. Highly effective contraception
methods include:

- Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception

- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
case of oophorectomy alone, only when the reproductive status of the woman has been
confirmed by follow up hormone level assessment

- Male sterilization (at least 6 months prior to screening). For female subjects on the
study the vasectomized male partner should be the sole partner for that subject

- Combination of any two of the following (a+b or a+c, or b+c):

- Use of oral, injected or implanted hormonal methods of contraception or other
forms of hormonal contraception that have comparable efficacy (failure rate ≤
1%), for example hormone vaginal ring or transdermal hormone contraception

- Placement of an intrauterine device (IUD) or intrauterine system (IUS)

- Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

- In case of use of oral contraception women should have been stable on the same
pill for a minimum of 3 months before taking study treatment.

- Women are considered post-menopausal and not of child bearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago.
In the case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment is she considered not of child
bearing potential

- Sexually active males unless they use a condom during intercourse while taking drug
and for 7 days after stopping treatment and 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 drug via seminal fluid