Merestinib In Non-Small Cell Lung Cancer And Solid Tumors

This is an open-label, phase II study of merestinib in patients with advanced NSCLC with a
MET exon 14 mutation or patients with advanced cancer harboring an NTRK1, 2, or 3
rearrangement. Twenty patients with a MET mutation will be evaluated in a single-arm design.
A small separate cohort of 5 NTRK patients will be evaluated for exploratory purposes.

Merestinib (LY2801653) is a small molecule that has been shown in vitro to be a reversible
type II ATP-competitive inhibitor of MET. Pre-clinical testing also has shown merestinib to
inhibit several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK,
ROS1, NTRK1/2/3, and DDR1/2 and the serine/threonine kinases MKNK1/2.

Inclusion Criteria:

- Baseline evaluations are to be conducted within 14 days prior to start of protocol
therapy, with the exception of the informed consent and baseline tumor imaging which
may be obtained up to 28 days prior to the start of protocol therapy.

- For enrollment into the MET cohort: Participants must have a histologically or
cytologically confirmed advanced NSCLC and must have received at least one prior line
of therapy in the metastatic setting.

- For enrollment into the NTRK cohort: Participants must have a histologically or
cytologically confirmed advanced solid tumor and must have received at least one prior
line of therapy in the metastatic setting.

- Participants enrolling into the MET cohort must have a MET exon 14 mutation as
confirmed by targeted NextGen Sequencing using the DFCI/BWH OncoPanel or another
CLIA-certified method. Participants whose NSCLC specimens contain actionable genetic
mutations/alterations (e.g. ALK/EGFR) should receive appropriate targeted therapies
prior to enrollment in the trial.

- Participants enrolling into the NTRK cohort must have an NTRK1, 2, or 3 rearrangement
as confirmed by targeted NextGen Sequencing using the DFCI/BWH OncoPanel or another
CLIA-certified method.

- Participants must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventional
techniques or as ≥ 10 mm with spiral CT scan, MRI, or calipers by clinical exam.

- Participants enrolling to the MET cohort who have received treatment with a prior MET
inhibitor must be able and willing to undergo a baseline tumor biopsy.

- Participants enrolling to the NTRK cohort who have received treatment with a prior
NTRK inhibitor must be able and willing to undergo a baseline tumor biopsy.

- Age ≥ 18 years. As no dosing or adverse event data are currently available in
participants < 18 years of age, children are excluded from this study but will be
eligible for future pediatric trials.

- ECOG performance status ≤ 1 (see Appendix A).

- Participants must have normal organ and marrow function as defined below:

- Absolute neutrophil count ≥ 1.5 K/uL

- Platelets ≥ 100 K/uL

- Hemoglobin ≥ 9 g/dL (with or without transfusion support)

- Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)

- AST(SGOT)/ALT(SGPT)≤ 2.5 × institutional ULN, unless liver metastases are present
and then ≤ 5 × institutional ULN is acceptable

- Serum creatinine ≤ 1.5 × institutional ULN

- The effects of merestinib on the developing human fetus are unknown. For this reason
and because MET inhibitor agents are known to be teratogenic, women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier method
of birth control; abstinence) prior to study entry and for the duration of study
participation. Should a woman become pregnant or suspect she is pregnant while she or
her partner is participating in this study, she should inform her treating physician
immediately. Men treated or enrolled on this protocol must also agree to use adequate
contraception prior to the study, for the duration of study participation, and 4
months after completion of merestinib administration.

- Ability to understand and the willingness to sign a written informed consent document.

- Participants must be able to swallow and retain oral medication or have an enteral
feeding tube in place for study drug administration.

- Participants who have received prior oral tyrosine kinase inhibitors (TKIs) will be
allowed on study if at least 5 half-lives have elapsed since the date of their last
dose of TKI.

Exclusion Criteria:

- Participants who have had chemotherapy, immune therapy, other investigational therapy,
major surgery, or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin
C) prior to entering the study.

- Participants who have not recovered to eligibility levels from adverse events due to
agents administered more than 3 weeks earlier.

- Participants who are receiving any other investigational agents.

- Participants with untreated brain metastases should be excluded from this clinical
trial because of their poor prognosis and because they often develop progressive
neurologic dysfunction that would confound the evaluation of neurologic and other
adverse events. Participants with a history of brain metastases that have been
treated, are no longer taking corticosteroids, and have been stable on imaging for ≥ 4
weeks following the last date of treatment are permitted. Note: a brain MRI is
required during the screening period.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to merestinib.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because merestinib is an agent with the
potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with merestinib, breastfeeding should be discontinued if the mother is treated
with merestinib.

- Known HIV-positive participants are ineligible because these participants are at
increased risk of lethal infections when treated with marrow-suppressive therapy.
Appropriate studies will be undertaken in participants receiving combination
antiretroviral therapy when indicated.

- Participants enrolling to the MET cohort who have received a prior MET inhibitor may
not be on anticoagulant therapy unless the investigator has deemed it safe to
temporarily hold to facilitate the baseline tumor biopsy.

- Participants enrolling to the NTRK cohort who have received a prior NTRK inhibitor may
not be on anticoagulant therapy unless the investigator has deemed it safe to
temporarily hold to facilitate the baseline tumor biopsy.

- Participants with uncontrolled high blood pressure, defined as a blood pressure during
screening of ≥ 160/100 despite medical management.

- Participants must not have any clinically significant gastrointestinal abnormalities
that in the opinion of the treating investigator may alter absorption of oral
medications, such as malabsorption syndrome or major resection of the stomach or
bowels.

- Participants with a history of a second primary malignancy. Exceptions include:
patients with a history of malignancies that were treated curatively and have not
recurred within 3 years prior to study entry; resected basal and squamous cell
carcinomas of the skin, and completely resected carcinoma in situ of any type.