Volitinib in Treating Participants With MET Amplified Metastatic or Unresectable Colorectal Cancer

PRIMARY OBJECTIVES:

I. To determine the objective response rate (ORR) of volitinib (savolitinib) in patients with
MET amplified metastatic colorectal cancer (CRC).

SECONDARY OBJECTIVES:

I. To describe the clinical activity (duration of response, progression free survival [PFS])
of savolitinib in patients with MET amplified metastatic CRC.

II. To describe the toxicities of savolitinib in patients with MET amplified metastatic CRC.

III. To explore the effect of RAS mutation status on response to savolitinib. IV. To explore
any correlation between tissue and blood based biomarkers and clinical outcomes.

OUTLINE:

Participants receive volitinib orally (PO) once daily (QD) on days 1-28. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 30 days, and then every
12 weeks thereafter.

Inclusion Criteria:

- Histologically or cytologically confirmed adenocarcinoma of the colon or rectum that
is metastatic and/or unresectable

- Documented wild-type in KRAS and NRAS (codons 12, 13, 59, 61, 117, and 146) and in
BRAF codon 600, based on tumor tissue taken from primary or metastatic site

- At least one site of disease that is measurable by Response Evaluation Criteria in
Solid Tumors (RECIST) criteria

- MET amplification detected by the Guardant360 circulating free deoxyribonucleic acid
(cfDNA) screening assay

- Clinical or radiographic progression on treatments containing a fluoropyrimidine
(e.g., 5- fluorouracil or capecitabine), oxaliplatin, irinotecan, and an anti-VEGF
monoclonal antibody (bevacizumab, ziv-aflibercept) or anti-VEGFR monoclonal antibody
(ramucirumab), or the treatments were not tolerated or contraindicated

- Clinical or radiographic progression on prior anti-EGFR antibody therapy (either
panitumumab or cetuximab)

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky >= 80%)

- Absolute neutrophil count (ANC) >= 1,500/mcL

- Hemoglobin (Hgb) >= 9 g/dL (no transfusion in the past 2 weeks)

- Platelets >= 100,000/mcL (no transfusion in the past 10 days)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x the
institutional upper limit of normal (ULN) with total bilirubin (TBL) =< 1 x ULN OR

- Total bilirubin (TBL) > ULN =<1.5 × ULN with ALT and AST =< 1x ULN

- Creatinine < 2 x the institutional ULN OR glomerular filtration rate (GFR) >= 30
mL/min, as assessed using the standard methodology at the investigating center (e.g.
Cockcroft-Gault, Modification of Diet in Renal Disease [MDRD] or Chronic Kidney
Disease Epidemiology Collaboration [CKD-EPI] formula, ethylenediamine tetraacetic acid
[EDTA] clearance or 24-hour urine collection)

- International normalization ratio (INR) < 1.5 x ULN and activated partial
thromboplastin time (aPTT) < 1.5 x ULN unless patients are receiving therapeutic
anticoagulation which affects these parameters

- Females of childbearing potential should be willing to use adequate contraceptive
measures, should not be breast feeding, and must have a negative pregnancy test if of
childbearing potential or must have evidence of non-childbearing potential by
fulfilling one of the following criteria at screening:

- Post-menopausal is defined as aged more than 50 years and amenorrheic for at
least 12 months following cessation of all exogenous hormonal treatments; women
under the age of 50 years would be considered postmenopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and with luteinizing hormone (LH) and follicle stimulating hormone
(FSH) levels in the post-menopausal range for the institution; or women with
documentation of irreversible surgical sterilization by hysterectomy, bilateral
oophorectomy or bilateral salpingectomy but not tubal ligation

- Male patients with female partner of childbearing potential should be willing to use
barrier contraception during the study and for 6 months following discontinuation of
study drug

- Ability to swallow and retain oral medications

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

Exclusion Criteria:

- Cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic
agents (e.g. cytokines or antibodies) within 3 weeks of first dose of study treatment

- Not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =<
grade 1 from adverse events due to all prior anti-cancer therapies except alopecia,
oxaliplatin-related neuropathy, and other non-clinically significant adverse events

- Any other investigational agents within 21 days before the first dose of study
treatment

- Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89)
administered =< 28 days or limited field radiation for palliation =< 7 days prior to
starting study drug or has not recovered from side effects of such therapy

- Known brain metastases. (Radiated or resected lesions are permitted, provided the
lesions are fully treated and inactive, patient is asymptomatic, and no steroids have
been administered for at least 30 days)

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

- Prior treatment with a small molecule inhibitor of c-MET or monoclonal antibody
against c-MET or HGF

- Any of the following concurrent medication use:

- Herbal preparations/medications are not allowed throughout the study. These
herbal medications include, but are not limited to: St. John's wort, kava,
ephedra (ma huang), gingko biloba, dehydroepiandrosterone (dhea), yohimbe, saw
palmetto, and ginseng. Patients should stop using these herbal medications 7 days
prior to first dose of study drug (three weeks for St. John's wort)

- Patients receiving or requiring strong inducers or strong inhibitors of CYP3A4,
strong inhibitors of CYP1A2, or CYP3A4 substrates which have a narrow therapeutic
range within 2 weeks of the first dose of study treatment (3 weeks for st john's
wort) will be excluded

- Concomitant use of drugs that are known to be strong inhibitors of CYP3A4 or
CYP1A2 is not permitted during the trial or must be stopped at least 2 weeks
prior to receiving the first dose of savolitinib

- Any of the following cardiac disease currently or within the last 6 months:

- Unstable angina pectoris

- Congestive heart failure (New York Heart Association [NYHA]) >= grade II

- Acute myocardial infarction

- Stroke or transient ischemic attack

- Known hypersensitivity to the active or inactive excipients of AZD6094

- Uncontrolled hypertension (blood pressure [BP] >= 150/95 mmHg despite medical therapy)

- Active gastrointestinal disease or other condition that will interfere significantly
with the absorption, distribution, metabolism, or excretion of oral therapy (e.g.
ulcerative disease, uncontrolled nausea, vomiting, diarrhea grade >= 2, and
malabsorption syndrome)

- Mean resting correct QT interval (QTc) > 470 msec on screening obtained from 3
electrocardiograms (ECGs) or factors that may increase the risk of QTc prolongation
such as chronic hypokalemia not correctable with supplements, congenital or familial
long QT syndrome, or family history of unexplained sudden death under 40 years of age

- Any clinically important abnormalities in rhythm, conduction or morphology of resting
electrocardiograms (ECGs), e.g. complete left bundle branch block, third degree heart
block, second degree heart block, PR interval > 250 msec

- Major surgical procedures =< 28 days of beginning study drug or minor surgical
procedures =< 7 days. No waiting is required following port-a-cath placement

- Serious underlying medical condition at the time of treatment that would impair the
ability of the patient to receive protocol treatment

- Active hepatitis B (positive hepatitis b virus [HBV] surface antigen [HBsAg] result)
or hepatitis C (hepatitis C virus [HCV]) infection. Patients with positive HCV
antibody are eligible only if the polymerase chain reaction is negative for HCV
ribonucleic acid (RNA). Patients with a past or resolved HBV infection are eligible
if:

- Negative for HBsAg and positive for hepatitis B core antibody [anti-HBc] OR

- Positive for HBsAg, but for > 6 months have had normal transaminases and HBV DNA
levels between 0 - 2000 IU/ml (inactive carrier state) and willing to start and
maintain antiviral treatment for at least the duration of the study OR

- HBV DNA levels > 2000 IU/ml but on prophylactic antiviral treatment for the past
3 months and will maintain the antiviral treatment during the study

- Known serious active infection including, but not limited to, tuberculosis, or human
immunodeficiency virus (positive HIV 1/2 antibodies). Human immunodeficiency virus
(HIV)-positive patients are excluded because of concerns of treatment safety given
potential drug-drug interaction with concurrent highly active antiretroviral therapy
(HARRT) therapy as well as patients' immune-compromised status

- Presence of other active cancers, or history of treatment for invasive cancer, within
the last 5 years. Patients with stage I cancer who have received definitive local
treatment at least 3 years previously, and are considered unlikely (less than 5%
probability) to recur are eligible. All patients with previously treated in situ
carcinoma (i.e., non-invasive) are eligible, as are patients with history of
non-melanoma skin cancer

- Psychiatric illness/social situations that would limit compliance with study
requirements

- Judgment by the investigator that the patients should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and requirements